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Sample records for preclinical efficacy studies

  1. Protective efficacy of Modified Vaccinia virus Ankara in preclinical studies.

    PubMed

    Volz, Asisa; Sutter, Gerd

    2013-09-01

    Modified Vaccinia virus Ankara (MVA) is a tissue culture-derived, highly attenuated strain of vaccinia virus (VACV) exhibiting characteristic defective replication in cells from mammalian hosts. In the 1960s MVA was originally generated as a candidate virus for safer vaccination against smallpox. Now, MVA is widely used in experimental vaccine development targeting important infectious diseases and cancer. Versatile technologies for genetic engineering, large-scale production, and quality control facilitate R&D of recombinant and non-recombinant MVA vaccines matching today's requirements for new biomedical products. Such vaccines are attractive candidates for delivering antigens from pathogens against which no, or no effective vaccine is available, including emerging infections caused by highly pathogenic influenza viruses, chikungunya virus, West Nile virus or zoonotic orthopoxviruses. Other directions are seeking valuable vaccines against highly complex diseases such as AIDS, malaria, and tuberculosis. Here, we highlight examples of MVA candidate vaccines against infectious diseases, and review the efforts made to assess both the efficacy of vaccination and immune correlates of protection in preclinical studies.

  2. Nonindustry-sponsored preclinical studies on statins yield greater efficacy estimates than industry-sponsored studies: a meta-analysis.

    PubMed

    Krauth, David; Anglemyer, Andrew; Philipps, Rose; Bero, Lisa

    2014-01-01

    Industry-sponsored clinical drug studies are associated with publication of outcomes that favor the sponsor, even when controlling for potential bias in the methods used. However, the influence of sponsorship bias has not been examined in preclinical animal studies. We performed a meta-analysis of preclinical statin studies to determine whether industry sponsorship is associated with either increased effect sizes of efficacy outcomes and/or risks of bias in a cohort of published preclinical statin studies. We searched Medline (January 1966-April 2012) and identified 63 studies evaluating the effects of statins on atherosclerosis outcomes in animals. Two coders independently extracted study design criteria aimed at reducing bias, results for all relevant outcomes, sponsorship source, and investigator financial ties. The I(2) statistic was used to examine heterogeneity. We calculated the standardized mean difference (SMD) for each outcome and pooled data across studies to estimate the pooled average SMD using random effects models. In a priori subgroup analyses, we assessed statin efficacy by outcome measured, sponsorship source, presence or absence of financial conflict information, use of an optimal time window for outcome assessment, accounting for all animals, inclusion criteria, blinding, and randomization. The effect of statins was significantly larger for studies sponsored by nonindustry sources (-1.99; 95% CI -2.68, -1.31) versus studies sponsored by industry (-0.73; 95% CI -1.00, -0.47) (p value<0.001). Statin efficacy did not differ by disclosure of financial conflict information, use of an optimal time window for outcome assessment, accounting for all animals, inclusion criteria, blinding, and randomization. Possible reasons for the differences between nonindustry- and industry-sponsored studies, such as selective reporting of outcomes, require further study.

  3. Nonindustry-sponsored preclinical studies on statins yield greater efficacy estimates than industry-sponsored studies: a meta-analysis.

    PubMed

    Krauth, David; Anglemyer, Andrew; Philipps, Rose; Bero, Lisa

    2014-01-01

    Industry-sponsored clinical drug studies are associated with publication of outcomes that favor the sponsor, even when controlling for potential bias in the methods used. However, the influence of sponsorship bias has not been examined in preclinical animal studies. We performed a meta-analysis of preclinical statin studies to determine whether industry sponsorship is associated with either increased effect sizes of efficacy outcomes and/or risks of bias in a cohort of published preclinical statin studies. We searched Medline (January 1966-April 2012) and identified 63 studies evaluating the effects of statins on atherosclerosis outcomes in animals. Two coders independently extracted study design criteria aimed at reducing bias, results for all relevant outcomes, sponsorship source, and investigator financial ties. The I(2) statistic was used to examine heterogeneity. We calculated the standardized mean difference (SMD) for each outcome and pooled data across studies to estimate the pooled average SMD using random effects models. In a priori subgroup analyses, we assessed statin efficacy by outcome measured, sponsorship source, presence or absence of financial conflict information, use of an optimal time window for outcome assessment, accounting for all animals, inclusion criteria, blinding, and randomization. The effect of statins was significantly larger for studies sponsored by nonindustry sources (-1.99; 95% CI -2.68, -1.31) versus studies sponsored by industry (-0.73; 95% CI -1.00, -0.47) (p value<0.001). Statin efficacy did not differ by disclosure of financial conflict information, use of an optimal time window for outcome assessment, accounting for all animals, inclusion criteria, blinding, and randomization. Possible reasons for the differences between nonindustry- and industry-sponsored studies, such as selective reporting of outcomes, require further study. PMID:24465178

  4. Nonindustry-Sponsored Preclinical Studies on Statins Yield Greater Efficacy Estimates Than Industry-Sponsored Studies: A Meta-Analysis

    PubMed Central

    Krauth, David; Anglemyer, Andrew; Philipps, Rose; Bero, Lisa

    2014-01-01

    Industry-sponsored clinical drug studies are associated with publication of outcomes that favor the sponsor, even when controlling for potential bias in the methods used. However, the influence of sponsorship bias has not been examined in preclinical animal studies. We performed a meta-analysis of preclinical statin studies to determine whether industry sponsorship is associated with either increased effect sizes of efficacy outcomes and/or risks of bias in a cohort of published preclinical statin studies. We searched Medline (January 1966–April 2012) and identified 63 studies evaluating the effects of statins on atherosclerosis outcomes in animals. Two coders independently extracted study design criteria aimed at reducing bias, results for all relevant outcomes, sponsorship source, and investigator financial ties. The I2 statistic was used to examine heterogeneity. We calculated the standardized mean difference (SMD) for each outcome and pooled data across studies to estimate the pooled average SMD using random effects models. In a priori subgroup analyses, we assessed statin efficacy by outcome measured, sponsorship source, presence or absence of financial conflict information, use of an optimal time window for outcome assessment, accounting for all animals, inclusion criteria, blinding, and randomization. The effect of statins was significantly larger for studies sponsored by nonindustry sources (−1.99; 95% CI −2.68, −1.31) versus studies sponsored by industry (−0.73; 95% CI −1.00, −0.47) (p value<0.001). Statin efficacy did not differ by disclosure of financial conflict information, use of an optimal time window for outcome assessment, accounting for all animals, inclusion criteria, blinding, and randomization. Possible reasons for the differences between nonindustry- and industry-sponsored studies, such as selective reporting of outcomes, require further study. PMID:24465178

  5. Design and Reporting of Targeted Anticancer Preclinical Studies: A Meta-Analysis of Animal Studies Investigating Sorafenib Antitumor Efficacy.

    PubMed

    Mattina, James; MacKinnon, Nathalie; Henderson, Valerie C; Fergusson, Dean; Kimmelman, Jonathan

    2016-08-15

    The validity of preclinical studies of candidate therapeutic agents has been questioned given their limited ability to predict their fate in clinical development, including due to design flaws and reporting bias. In this study, we examined this issue in depth by conducting a meta-analysis of animal studies investigating the efficacy of the clinically approved kinase inhibitor, sorafenib. MEDLINE, Embase, and BIOSIS databases were searched for all animal experiments testing tumor volume response to sorafenib monotherapy in any cancer published until April 20, 2012. We estimated effect sizes from experiments assessing changes in tumor volume and conducted subgroup analyses based on prespecified experimental design elements associated with internal, construct, and external validity. The meta-analysis included 97 experiments involving 1,761 animals. We excluded 94 experiments due to inadequate reporting of data. Design elements aimed at reducing internal validity threats were implemented only sporadically, with 66% reporting animal attrition and none reporting blinded outcome assessment or concealed allocation. Anticancer activity against various malignancies was typically tested in only a small number of model systems. Effect sizes were significantly smaller when sorafenib was tested against either a different active agent or combination arm. Trim and fill suggested a 37% overestimation of effect sizes across all malignancies due to publication bias. We detected a moderate dose-response in one clinically approved indication, hepatocellular carcinoma, but not in another approved malignancy, renal cell carcinoma, or when data were pooled across all malignancies tested. In support of other reports, we found that few preclinical cancer studies addressed important internal, construct, and external validity threats, limiting their clinical generalizability. Our findings reinforce the need to improve guidelines for the design and reporting of preclinical cancer studies

  6. Chronic Electrical Stimulation with a Suprachoroidal Retinal Prosthesis: A Preclinical Safety and Efficacy Study

    PubMed Central

    Nayagam, David A. X.; Williams, Richard A.; Allen, Penelope J.; Shivdasani, Mohit N.; Luu, Chi D.; Salinas-LaRosa, Cesar M.; Finch, Sue; Ayton, Lauren N.; Saunders, Alexia L.; McPhedran, Michelle; McGowan, Ceara; Villalobos, Joel; Fallon, James B.; Wise, Andrew K.; Yeoh, Jonathan; Xu, Jin; Feng, Helen; Millard, Rodney; McWade, Melanie; Thien, Patrick C.; Williams, Chris E.; Shepherd, Robert K.

    2014-01-01

    electrode impedance remained stable for stimulation durations of up to 15 weeks. This study has demonstrated the safety and efficacy of suprachoroidal stimulation with charge balanced stimulus currents. PMID:24853376

  7. Preclinical Studies Evaluating Subacute Toxicity and Therapeutic Efficacy of LQB-118 in Experimental Visceral Leishmaniasis.

    PubMed

    Cunha-Júnior, Edézio Ferreira; Martins, Thiago Martino; Canto-Cavalheiro, Marilene Marcuzzo; Marques, Paulo Roberto; Portari, Elyzabeth Avvad; Coelho, Marsen Garcia Pinto; Netto, Chaquip Daher; Costa, Paulo Roberto Ribeiro; Sabino, Katia Costa de Carvalho; Torres-Santos, Eduardo Caio

    2016-06-01

    Visceral leishmaniasis (VL) is the most severe form of leishmaniasis and is the second major cause of death by parasites, after malaria. The arsenal of drugs against leishmaniasis is small, and each has a disadvantage in terms of toxicity, efficacy, price, or treatment regimen. Our group has focused on studying new drug candidates as alternatives to current treatments. The pterocarpanquinone LQB-118 was designed and synthesized based on molecular hybridization, and it exhibited antiprotozoal and anti-leukemic cell line activities. Our previous work demonstrated that LQB-118 was an effective treatment for experimental cutaneous leishmaniasis. In this study, we observed that treatment with 10 mg/kg of body weight/day LQB-118 orally inhibited the development of hepatosplenomegaly with a 99% reduction in parasite load. An in vivo toxicological analysis showed no change in the clinical, biochemical, or hematological parameters. Histologically, all of the analyzed organs were normal, with the exception of the liver, where focal points of necrosis with leukocytic infiltration were observed at treatment doses 5 times higher than the therapeutic dose; however, these changes were not accompanied by an increase in transaminases. Our findings indicate that LQB-118 is effective at treating different clinical forms of leishmaniasis and presents no relevant signs of toxicity at therapeutic doses; thus, this framework is demonstrated suitable for developing promising drug candidates for the oral treatment of leishmaniasis. PMID:27067332

  8. 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.

  9. Allopregnanolone Preclinical Acute Pharmacokinetic and Pharmacodynamic Studies to Predict Tolerability and Efficacy for Alzheimer’s Disease

    PubMed Central

    Irwin, Ronald W.; Solinsky, Christine M.; Loya, Carlos M.; Salituro, Francesco G.; Rodgers, Kathleen E.; Bauer, Gerhard; Rogawski, Michael A.; Brinton, Roberta Diaz

    2015-01-01

    predicted MTD in human female is 0.37mg/kg. In male rats the NOAEL and MTD were less than those determined for female. Outcomes of these PK/PD studies predict a safe and efficacious dose range for initial clinical trials of allopregnanolone for Alzheimer’s disease. These findings have translational relevance to multiple neurodegenerative conditions. PMID:26039057

  10. Preclinical studies of low back pain

    PubMed Central

    2013-01-01

    Chronic low back pain is a major cause of disability and health care costs. Current treatments are inadequate for many patients. A number of preclinical models have been developed that attempt to mimic aspects of clinical conditions that contribute to low back pain. These involve application of nucleus pulposus material near the lumbar dorsal root ganglia (DRG), chronic compression of the DRG, or localized inflammation of the DRG. These models, which are primarily implemented in rats, have many common features including behavioral hypersensitivity of the hindpaw, enhanced excitability and spontaneous activity of sensory neurons, and locally elevated levels of inflammatory mediators including cytokines. Clinically, epidural injection of steroids (glucocorticoids) is commonly used when more conservative treatments fail, but clinical trials evaluating these treatments have yielded mixed results. There are relatively few preclinical studies of steroid effects in low back pain models. One preclinical study suggests that the mineralocorticoid receptor, also present in the DRG, may have pro-inflammatory effects that oppose the activation of the glucocorticoid receptor. Although the glucocorticoid receptor is the target of anti-inflammatory steroids, many clinically used steroids activate both receptors. This could be one explanation for the limited effects of epidural steroids in some patients. Additional preclinical research is needed to address other possible reasons for limited efficacy of steroids, such as central sensitization or presence of an ongoing inflammatory stimulus in some forms of low back pain. PMID:23537369

  11. Inhibition of DNA-repair genes Ercc1 and Mgmt enhances temozolomide efficacy in gliomas treatment: a pre-clinical study.

    PubMed

    Boccard, Sandra G; Marand, Sandie V; Geraci, Sandra; Pycroft, Laurie; Berger, François R; Pelletier, Laurent A

    2015-10-01

    Gliomas are the most common primary brain tumors. To date, therapies do not allow curing patients, and glioblastomas (GBMs) are associated with remarkably poor prognosis. This situation is at least partly due to intrinsic or acquired resistance to treatment, especially to chemotherapy. In 2005, temozolomide (TMZ) has become the first chemotherapeutic drug validated for GBM. Nevertheless TMZ efficacy depends on Mgmt status. While the methylation of Mgmt promoter was considered so far as a prognostic marker, its targeting is becoming an effective therapeutic opportunity. Thus, arrival of both TMZ and Mgmt illustrated that considerable progress can still be realized by optimizing adjuvant chemotherapy. A part of this progress could be accomplished in the future by overcoming residual resistance. The aim of the present study was to investigate the involvement of a set of other DNA-repair genes in glioma resistance to temozolomide. We focused on DNA-repair genes located in the commonly deleted chromosomal region in oligodendroglioma (1p/19q) highly correlated with patient response to chemotherapy. We measured effects of inhibition of ten DNA-repair genes expression using siRNAs on astrocytoma cell response to cisplatin (CDDP) and TMZ. SiRNAs targeting ercc1, ercc2, mutyh, and pnkp significantly sensitized cells to chemotherapy, increasing cell death by up to 25%. In vivo we observed a decrease of subcutaneous glioma tumor growth after injection of siRNA in conjunction with absorption of TMZ. We demonstrated in this pre-clinical study that targeting of DNA-repair genes such as Ercc1 could be used as an adjuvant chemosensitization treatment, similarly to Mgmt inhibition. PMID:26336131

  12. Inhibition of DNA-repair genes Ercc1 and Mgmt enhances temozolomide efficacy in gliomas treatment: a pre-clinical study

    PubMed Central

    Boccard, Sandra G.; Marand, Sandie V.; Geraci, Sandra; Pycroft, Laurie; Berger, François R.; Pelletier, Laurent A.

    2015-01-01

    Gliomas are the most common primary brain tumors. To date, therapies do not allow curing patients, and glioblastomas (GBMs) are associated with remarkably poor prognosis. This situation is at least partly due to intrinsic or acquired resistance to treatment, especially to chemotherapy. In 2005, temozolomide (TMZ) has become the first chemotherapeutic drug validated for GBM. Nevertheless TMZ efficacy depends on Mgmt status. While the methylation of Mgmt promoter was considered so far as a prognostic marker, its targeting is becoming an effective therapeutic opportunity. Thus, arrival of both TMZ and Mgmt illustrated that considerable progress can still be realized by optimizing adjuvant chemotherapy. A part of this progress could be accomplished in the future by overcoming residual resistance. The aim of the present study was to investigate the involvement of a set of other DNA-repair genes in glioma resistance to temozolomide. We focused on DNA-repair genes located in the commonly deleted chromosomal region in oligodendroglioma (1p/19q) highly correlated with patient response to chemotherapy. We measured effects of inhibition of ten DNA-repair genes expression using siRNAs on astrocytoma cell response to cisplatin (CDDP) and TMZ. SiRNAs targeting ercc1, ercc2, mutyh, and pnkp significantly sensitized cells to chemotherapy, increasing cell death by up to 25%. In vivo we observed a decrease of subcutaneous glioma tumor growth after injection of siRNA in conjunction with absorption of TMZ. We demonstrated in this pre-clinical study that targeting of DNA-repair genes such as Ercc1 could be used as an adjuvant chemosensitization treatment, similarly to Mgmt inhibition. PMID:26336131

  13. A Preclinical Study of the Safety and Efficacy of Occlusin Trade-Mark-Sign 500 Artificial Embolization Device in Sheep

    SciTech Connect

    Owen, Richard J.; Nation, Patrick N.; Polakowski, Robert; Biliske, Jennifer A.; Tiege, Paul B.

    2012-06-15

    Introduction: This study evaluated the safety, effectiveness, and biodegradation of a new embolic agent, Occlusin Trade-Mark-Sign 503 Artificial Embolization Device (OCL 503). The agent consists of biodegradable poly-lactic-co-glycolic acid microspheres (150-212 {mu}m) coated with type I bovine collagen and was compared with Embosphere{sup Registered-Sign} Microspheres (300-500 {mu}m) in this controlled study of uterine artery embolization (UAE) in sheep. Methods: Unilateral UAE was performed in 32 adult ewes randomly assigned. Vessels were embolized to effective stasis. The cohort was divided into four groups, which were sacrificed at 1, 3, 6, and 12 months. Results: Both agents were 100% effective in achieving stasis. At 6 months, all OCL 503-treated arteries were occluded, the microspheres degraded with time, and at 12 months all four animals examined demonstrated recanalization. OCL 503 was found in the untreated uterine artery in one animal with no other evidence of non target embolization. In the Embosphere-treated group, all vessels remained occluded and microspheres were detected in the contralateral uterine artery in 6 of 15 examined vessels and in 10 vaginal, 2 ovarian, and 1 vesical artery. No procedural-related complications were seen in either group. Conclusions: OCL 503 is as effective an embolic agent as Embosphere{sup Registered-Sign} Microspheres when embolizing ovine uterine arteries and resorbs with time, allowing recanalization of the treated arteries. No device-related issues or adverse events were observed.

  14. In-Vivo Efficacy of Compliant 3D Nano-Composite in Critical-Size Bone Defect Repair: a Six Month Preclinical Study in Rabbit

    PubMed Central

    Sagar, Nitin; Pandey, Alok K.; Gurbani, Deepak; Khan, Kainat; Singh, Dhirendra; Chaudhari, Bhushan P.; Soni, Vivek P.; Chattopadhyay, Naibedya; Dhawan, Alok; Bellare, Jayesh R.

    2013-01-01

    Bone defects above critical size do not heal completely by itself and thus represent major clinical challenge to reconstructive surgery. Numerous bone substitutes have already been used to promote bone regeneration, however their use, particularly for critical-sized bone defects along with their long term in vivo safety and efficacy remains a concern. The present study was designed to obtain a complete healing of critical-size defect made in the proximal tibia of New Zealand White rabbit, using nano-hydroxyapatite/gelatin and chemically carboxymethylated chitin (n-HA/gel/CMC) scaffold construct. The bone-implant interfaces and defect site healing was evaluated for a period up to 25 weeks using radiography, micro-computed tomography, fluorescence labeling, and histology and compared with respective SHAM (empty contra lateral control). The viscoelastic porous scaffold construct allows easy surgical insertion and post-operatively facilitate oxygenation and angiogenesis. Radiography of defect treated with scaffold construct suggested expedited healing at defect edges and within the defect site, unlike confined healing at edges of the SHAM sites. The architecture indices analyzed by micro-computed tomography showed a significant increase in percentage of bone volume fraction, resulted in reconciled cortico-trabecular bone formation at n-HA/gel/CMC constructs treated site (15.2% to 52.7%) when compared with respective SHAM (10.2% to 31.8%). Histological examination and fluorescence labeling revealed that the uniformly interconnected porous surface of scaffold construct enhanced osteoblasts’ activity and mineralization. These preclinical data suggest that, n-HA/gel/CMC construct exhibit stimulation of bone's innate regenerative capacity, thus underscoring their use in guided bone regeneration. PMID:24204879

  15. [Preclinical study of noopept toxicity].

    PubMed

    Kovalenko, L P; Smol'nikova, N M; Alekseeva, S V; Nemova, E P; Sorokina, A V; Miramedova, M G; Kurapova, S P; Sidorina, E I; Kulakova, A V; Daugel'-Dauge, N O

    2002-01-01

    Within the framework of a preclinical investigation, the new nootrope drug noopept (N-phenyl-acetyl-L-propyl-glycine ethylate) was tested for chronic toxicity upon peroral administration in a dose of 10 or 100 mg/kg over 6 months in both male and female rabbits. The results of observations showed that noopept administered in this dose range induced no irreversible pathologic changes in the organs and systems studied and exhibited no allergenic, immunotoxic, and mutagen activity. The drug affected neither the generative function nor the antenatal or postnatal progeny development. Noopept produced a dose-dependent suppression of inflammation reaction to concanavalin A and stimulated the cellular and humoral immune response in mice. PMID:12025790

  16. Recommendations for Benchmarking Preclinical Studies of Nanomedicines.

    PubMed

    Dawidczyk, Charlene M; Russell, Luisa M; Searson, Peter C

    2015-10-01

    Nanoparticle-based delivery systems provide new opportunities to overcome the limitations associated with traditional small-molecule drug therapy for cancer and to achieve both therapeutic and diagnostic functions in the same platform. Preclinical trials are generally designed to assess therapeutic potential and not to optimize the design of the delivery platform. Consequently, progress in developing design rules for cancer nanomedicines has been slow, hindering progress in the field. Despite the large number of preclinical trials, several factors restrict comparison and benchmarking of different platforms, including variability in experimental design, reporting of results, and the lack of quantitative data. To solve this problem, we review the variables involved in the design of preclinical trials and propose a protocol for benchmarking that we recommend be included in in vivo preclinical studies of drug-delivery platforms for cancer therapy. This strategy will contribute to building the scientific knowledge base that enables development of design rules and accelerates the translation of new technologies.

  17. Pre-clinical studies of toxin-specific nanobodies: evidence of in vivo efficacy to prevent fatal disturbances provoked by scorpion envenoming.

    PubMed

    Hmila, Issam; Cosyns, Bernard; Tounsi, Hayfa; Roosens, Bram; Caveliers, Vicky; Abderrazek, Rahma Ben; Boubaker, Samir; Muyldermans, Serge; El Ayeb, Mohamed; Bouhaouala-Zahar, Balkiss; Lahoutte, Tony

    2012-10-15

    Scorpions represent a significant threat to humans and animals in various countries throughout the world. Recently, we introduced Nanobodies (Nbs) to combat more efficiently scorpion envenoming and demonstrated the performance of NbAahIF12 and NbAahII10 to neutralize scorpion toxins of Androctonus australis hector venom. A bispecific Nb construct (NbF12-10) comprising these two Nbs is far more protective than the classic Fab'(2) based therapy and is the most efficient antivenom therapy against scorpion sting in preclinical studies. Now we investigate the biodistribution and pharmacokinetics of (99m)Tc labeled Nbs by in vivo imaging in rodents and compared these data with those of the Fab'(2) product (PAS). The pharmacodynamics of the Nbs was investigated in rats by in vivo echocardiography and it is shown that NbF12-10 prevents effectively the hemodynamic disturbances induced by a lethal dose of venom. Moreover, even a late injection of NbF12-10 restores the heart rate and brings the blood pressure to baseline values. Histology confirms that NbF12-10 prevents lung and heart lesions of treated mice after envenoming. In conjunction, in this preclinical study, we provide proof of concept that NbF12-10 prevents effectively the fatal disturbances induced by Androctonus venom, and that the Nanobody based therapeutic has a potential to substitute the classic Fab'(2) based product as immunotherapeutic in scorpion envenoming. Further clinical study using larger cohorts of animals should be considered to confirm the full protecting potential of our NbF12-10.

  18. Pre-clinical studies of toxin-specific Nanobodies: Evidence of in vivo efficacy to prevent fatal disturbances provoked by scorpion envenoming

    SciTech Connect

    Hmila, Issam; Cosyns, Bernard; Tounsi, Hayfa; Roosens, Bram; Caveliers, Vicky; Abderrazek, Rahma Ben; Boubaker, Samir; Muyldermans, Serge; El Ayeb, Mohamed; Bouhaouala-Zahar, Balkiss; Lahoutte, Tony

    2012-10-15

    Scorpions represent a significant threat to humans and animals in various countries throughout the world. Recently, we introduced Nanobodies (Nbs) to combat more efficiently scorpion envenoming and demonstrated the performance of NbAahIF12 and NbAahII10 to neutralize scorpion toxins of Androctonus australis hector venom. A bispecific Nb construct (NbF12-10) comprising these two Nbs is far more protective than the classic Fab′{sub 2} based therapy and is the most efficient antivenom therapy against scorpion sting in preclinical studies. Now we investigate the biodistribution and pharmacokinetics of {sup 99m}Tc labeled Nbs by in vivo imaging in rodents and compared these data with those of the Fab′{sub 2} product (PAS). The pharmacodynamics of the Nbs was investigated in rats by in vivo echocardiography and it is shown that NbF12-10 prevents effectively the hemodynamic disturbances induced by a lethal dose of venom. Moreover, even a late injection of NbF12-10 restores the heart rate and brings the blood pressure to baseline values. Histology confirms that NbF12-10 prevents lung and heart lesions of treated mice after envenoming. In conjunction, in this preclinical study, we provide proof of concept that NbF12-10 prevents effectively the fatal disturbances induced by Androctonus venom, and that the Nanobody based therapeutic has a potential to substitute the classic Fab′{sub 2} based product as immunotherapeutic in scorpion envenoming. Further clinical study using larger cohorts of animals should be considered to confirm the full protecting potential of our NbF12-10. -- Highlights: ► Nanobody therapy prevents the hemodynamic disturbances induced by a lethal dose. ► Late injection of Nanobody restores hemodynamic parameters to baseline values. ► Nanobody therapy prevents lung and heart lesions of treated mice after envenoming. ► Labeled Nanobody and Fab’2 pharmacokinetics curves reach plateau in favour of Nanobody.

  19. Preclinical studies of amixicile, a systemic therapeutic developed for treatment of Clostridium difficile infections that also shows efficacy against Helicobacter pylori.

    PubMed

    Hoffman, Paul S; Bruce, Alexandra M; Olekhnovich, Igor; Warren, Cirle A; Burgess, Stacey L; Hontecillas, Raquel; Viladomiu, Monica; Bassaganya-Riera, Josep; Guerrant, Richard L; Macdonald, Timothy L

    2014-08-01

    Amixicile shows efficacy in the treatment of Clostridium difficile infections (CDI) in a mouse model, with no recurrence of CDI. Since amixicile selectively inhibits the action of a B vitamin (thiamine pyrophosphate) cofactor of pyruvate:ferredoxin oxidoreductase (PFOR), it may both escape mutation-based drug resistance and spare beneficial probiotic gut bacteria that do not express this enzyme. Amixicile is a water-soluble derivative of nitazoxanide (NTZ), an antiparasitic therapeutic that also shows efficacy against CDI in humans. In comparative studies, amixicile showed no toxicity to hepatocytes at 200 μM (NTZ was toxic above 10 μM); was not metabolized by human, dog, or rat liver microsomes; showed equivalence or superiority to NTZ in cytochrome P450 assays; and did not activate efflux pumps (breast cancer resistance protein, P glycoprotein). A maximum dose (300 mg/kg) of amixicile given by the oral or intraperitoneal route was well tolerated by mice and rats. Plasma exposure (rats) based on the area under the plasma concentration-time curve was 79.3 h · μg/ml (30 mg/kg dose) to 328 h · μg/ml (100 mg/kg dose), the maximum concentration of the drug in serum was 20 μg/ml, the time to the maximum concentration of the drug in serum was 0.5 to 1 h, and the half-life was 5.6 h. Amixicile did not concentrate in mouse feces or adversely affect gut populations of Bacteroides species, Firmicutes, segmented filamentous bacteria, or Lactobacillus species. Systemic bioavailability was demonstrated through eradication of Helicobacter pylori in a mouse infection model. In summary, the efficacy of amixicile in treating CDI and other infections, together with low toxicity, an absence of mutation-based drug resistance, and excellent drug metabolism and pharmacokinetic metrics, suggests a potential for broad application in the treatment of infections caused by PFOR-expressing microbial pathogens in addition to CDI. PMID:24890599

  20. Preclinical Study of Single-Dose Moxidectin, a New Oral Treatment for Scabies: Efficacy, Safety, and Pharmacokinetics Compared to Two-Dose Ivermectin in a Porcine Model

    PubMed Central

    Bernigaud, Charlotte; Aho, Ludwig Serge; Dreau, Dominique; Kelly, Andrew; Sutra, Jean-François; Moreau, Francis; Lilin, Thomas; Botterel, Françoise; Guillot, Jacques; Chosidow, Olivier

    2016-01-01

    Background Scabies is one of the commonest dermatological conditions globally; however it is a largely underexplored and truly neglected infectious disease. Foremost, improvement in the management of this public health burden is imperative. Current treatments with topical agents and/or oral ivermectin (IVM) are insufficient and drug resistance is emerging. Moxidectin (MOX), with more advantageous pharmacological profiles may be a promising alternative. Methodology/Principal Findings Using a porcine scabies model, 12 pigs were randomly assigned to receive orally either MOX (0.3 mg/kg once), IVM (0.2 mg/kg twice) or no treatment. We evaluated treatment efficacies by assessing mite count, clinical lesions, pruritus and ELISA-determined anti-S. scabiei IgG antibodies reductions. Plasma and skin pharmacokinetic profiles were determined. At day 14 post-treatment, all four MOX-treated but only two IVM-treated pigs were mite-free. MOX efficacy was 100% and remained unchanged until study-end (D47), compared to 62% (range 26–100%) for IVM, with one IVM-treated pig remaining infected until D47. Clinical scabies lesions, pruritus and anti-S. scabiei IgG antibodies had completely disappeared in all MOX-treated but only 75% of IVM-treated pigs. MOX persisted ~9 times longer than IVM in plasma and skin, thereby covering the mite’s entire life cycle and enabling long-lasting efficacy. Conclusions/Significance Our data demonstrate that oral single-dose MOX was more effective than two consecutive IVM-doses, supporting MOX as potential therapeutic approach for scabies. PMID:27732588

  1. Preclinical Studies of Amixicile, a Systemic Therapeutic Developed for Treatment of Clostridium difficile Infections That Also Shows Efficacy against Helicobacter pylori

    PubMed Central

    Bruce, Alexandra M.; Olekhnovich, Igor; Warren, Cirle A.; Burgess, Stacey L.; Hontecillas, Raquel; Viladomiu, Monica; Bassaganya-Riera, Josep; Guerrant, Richard L.; Macdonald, Timothy L.

    2014-01-01

    Amixicile shows efficacy in the treatment of Clostridium difficile infections (CDI) in a mouse model, with no recurrence of CDI. Since amixicile selectively inhibits the action of a B vitamin (thiamine pyrophosphate) cofactor of pyruvate:ferredoxin oxidoreductase (PFOR), it may both escape mutation-based drug resistance and spare beneficial probiotic gut bacteria that do not express this enzyme. Amixicile is a water-soluble derivative of nitazoxanide (NTZ), an antiparasitic therapeutic that also shows efficacy against CDI in humans. In comparative studies, amixicile showed no toxicity to hepatocytes at 200 μM (NTZ was toxic above 10 μM); was not metabolized by human, dog, or rat liver microsomes; showed equivalence or superiority to NTZ in cytochrome P450 assays; and did not activate efflux pumps (breast cancer resistance protein, P glycoprotein). A maximum dose (300 mg/kg) of amixicile given by the oral or intraperitoneal route was well tolerated by mice and rats. Plasma exposure (rats) based on the area under the plasma concentration-time curve was 79.3 h · μg/ml (30 mg/kg dose) to 328 h · μg/ml (100 mg/kg dose), the maximum concentration of the drug in serum was 20 μg/ml, the time to the maximum concentration of the drug in serum was 0.5 to 1 h, and the half-life was 5.6 h. Amixicile did not concentrate in mouse feces or adversely affect gut populations of Bacteroides species, Firmicutes, segmented filamentous bacteria, or Lactobacillus species. Systemic bioavailability was demonstrated through eradication of Helicobacter pylori in a mouse infection model. In summary, the efficacy of amixicile in treating CDI and other infections, together with low toxicity, an absence of mutation-based drug resistance, and excellent drug metabolism and pharmacokinetic metrics, suggests a potential for broad application in the treatment of infections caused by PFOR-expressing microbial pathogens in addition to CDI. PMID:24890599

  2. Preclinical Childhood Sarcoma Models: Drug Efficacy Biomarker Identification and Validation

    PubMed Central

    Geier, Brian; Kurmashev, Dias; Kurmasheva, Raushan T.; Houghton, Peter J.

    2015-01-01

    Over the past 35 years, cure rates for pediatric cancers have increased dramatically. However, it is clear that further dose intensification using cytotoxic agents or radiation therapy is not possible without enhancing morbidity and long-term effects. Consequently, novel, less genotoxic, agents are being sought to complement existing treatments. Here, we discuss preclinical human tumor xenograft models of pediatric cancers that may be used practically to identify novel agents for soft tissue and bone sarcomas, and “omics” approaches to identifying biomarkers that may identify sensitive and resistant tumors to these agents. PMID:26380223

  3. [Present state of preclinical research on the efficacy and safety of para immunity inducers from poxviruses. A study of the literature].

    PubMed

    Mayr, B; Mayr, A

    1995-12-01

    The investigations on the "systemic level" after parenteral application of pox-inducers to man and animal have proved the preparations to be harmless and surprisingly effective with regard to certain indications. The clinical data correlate to laboratory parameters to serve as proof for the efficacy. The challenge models (VSV, Aujeszky) verify a dosis-efficacy relationship. The evaluation of the efficacy of the pox-inducers in isolated blood- and liver-cells respectively cell cultures (cellular "in vitro" level) provide a unified picture: increase of the phagocytosis, of the NK-cells and the thymidinkinase activity in liver cells. The investigations on the "cytokine release" illustrate that pox-inducers promote the release respectively the production of diverse cytokines important for the regulation of the immune system. This has been proved for interferon alpha and gamma, the interleukin 1, 2 and 12 as well as for CSF and TNF. To conclude, a regulative effect is ascribed to the poxvirus inducers in the network of paraspecific defence in regard to stimulating as well as inhibiting effects. The endogenous medication by way of pox-inducers (paramunization) is diametrically opposed to the exogenous application of cytokines.

  4. Combination therapy for hepatocellular carcinoma: Additive preclinical efficacy of the HDAC inhibitor panobinostat with sorafenib

    PubMed Central

    Lachenmayer, Anja; Toffanin, Sara; Cabellos, Laia; Alsinet, Clara; Hoshida, Yujin; Villanueva, Augusto; Minguez, Beatriz; Tsai, Hung-Wen; Ward, Stephen C.; Thung, Swan; Friedman, Scott L.; Llovet, Josep M.

    2012-01-01

    Background & Aims Hepatocellular carcinoma (HCC) is a heterogeneous cancer in which sorafenib is the only approved systemic therapy. Histone deacetylases (HDAC) are commonly dysregulated in cancer and therefore represent promising targets for therapies, however their role in HCC pathogenesis is still unknown. We analyzed the expression of 11 HDACs in human HCCs and assessed the efficacy of the pan-HDAC inhibitor panobinostat alone and in combination with sorafenib in preclinical models of liver cancer. Methods Gene expression and copy number changes were analyzed in a cohort of 334 human HCCs, while the effects of panobinostat and sorafenib were evaluated in 3 liver cancer cell lines and a murine xenograft model. Results Aberrant HDAC expression was identified and validated in 91 and 243 HCCs, respectively. Upregulation of HDAC3 and 5 mRNAs were significantly correlated with DNA copy number gains. Inhibiting HDACs with panobinostat led to strong anti-tumoral effects in vitro and vivo, enhanced by the addition of sorafenib. Cell viability and proliferation declined, while apoptosis and autophagy increased. Panobinostat increased Histone H3 and HSP90 acetylation, downregulated BIRC5 (survivin) and upregulated CDH1. Combination therapy with panobinostat and sorafenib significantly decreased vessel density, and most significantly decreased tumor volume and increased survival in HCC xenografts. Conclusions Aberrant expression of several HDACs and copy number gains of HDAC3 and HDAC5 occur in HCC. Treatment with panobinostat combined with sorafenib demonstrated the highest preclinical efficacy in HCC models, providing the rationale for clinical studies with this novel combination. PMID:22322234

  5. Oncolysis by paramyxoviruses: preclinical and clinical studies

    PubMed Central

    Matveeva, Olga V; Guo, Zong S; Senin, Vyacheslav M; Senina, Anna V; Shabalina, Svetlana A; Chumakov, Peter M

    2015-01-01

    Preclinical studies demonstrate that a broad spectrum of human malignant cells can be killed by oncolytic paramyxoviruses, which include cells of ecto-, endo-, and mesodermal origin. In clinical trials, significant reduction in size or even complete elimination of primary tumors and established metastases are reported. Different routes of viral administration (intratumoral, intravenous, intradermal, intraperitoneal, or intrapleural), and single- versus multiple-dose administration schemes have been explored. The reported side effects are grade 1 and 2, with the most common among them being mild fever. Some advantages in using paramyxoviruses as oncolytic agents versus representatives of other viral families exist. The cytoplasmic replication results in a lack of host genome integration and recombination, which makes paramyxoviruses safer and more attractive candidates for widely used therapeutic oncolysis in comparison with retroviruses or some DNA viruses. The list of oncolytic paramyxovirus representatives includes attenuated measles virus (MV), mumps virus (MuV), low pathogenic Newcastle disease (NDV), and Sendai (SeV) viruses. Metastatic cancer cells frequently overexpress on their surface some molecules that can serve as receptors for MV, MuV, NDV, and SeV. This promotes specific viral attachment to the malignant cell, which is frequently followed by specific viral replication. The paramyxoviruses are capable of inducing efficient syncytium-mediated lyses of cancer cells and elicit strong immunomodulatory effects that dramatically enforce anticancer immune surveillance. In general, preclinical studies and phase 1–3 clinical trials yield very encouraging results and warrant continued research of oncolytic paramyxoviruses as a particularly valuable addition to the existing panel of cancer-fighting approaches. PMID:26640815

  6. 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

  7. [Efficacy studies].

    PubMed

    Pedro-Botet, Juan; Flores-Le Roux, Juana A

    2014-07-01

    Pravafenix(®) is a fixed-dose combination of 40mg of pravastatin and 160 mg of fenofibrate. The rationale behind the use of Pravafenix(®) is based on the increased residual cardiovascular risk observed in high risk patients with hypertriglyceridemia and/or low HDL cholesterol levels despite treatment with statins in monotherapy. In this article, we review the available evidence on the clinical efficacy of Pravafenix(®), which shows complementary benefits in the overall lipid profile of high risk patients with mixed dyslipidemia not controlled with 40-mg pravastatin or 20-mg simvastatin. PMID:25043542

  8. [Efficacy studies].

    PubMed

    Pedro-Botet, Juan; Flores-Le Roux, Juana A

    2014-07-01

    Pravafenix(®) is a fixed-dose combination of 40mg of pravastatin and 160 mg of fenofibrate. The rationale behind the use of Pravafenix(®) is based on the increased residual cardiovascular risk observed in high risk patients with hypertriglyceridemia and/or low HDL cholesterol levels despite treatment with statins in monotherapy. In this article, we review the available evidence on the clinical efficacy of Pravafenix(®), which shows complementary benefits in the overall lipid profile of high risk patients with mixed dyslipidemia not controlled with 40-mg pravastatin or 20-mg simvastatin.

  9. Intravital microscopy as a tool to study drug delivery in preclinical studies

    PubMed Central

    Amornphimoltham, Panomwat; Masedunskas, Andrius; Weigert, Roberto

    2010-01-01

    The technical developments in the field of non-linear microscopy have made intravital microscopy one of the most successful techniques for studying physiological and pathological processes in live animals. Intravital microscopy has been utilized to address many biological questions in basic research and is now a fundamental tool for preclinical studies, with an enormous potential for clinical applications. The ability to dynamically image cellular and subcellular structures combined with the possibility to perform longitudinal studies have empowered investigators to use this discipline to study the mechanisms of action of therapeutic agents and assess the efficacy on their targets in vivo. The goal of this review is to provide a general overview of the recent advances in intravital microscopy and to discuss some of its applications in preclinical studies. PMID:20933026

  10. 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

  11. Efficacy of Mesenchymal Stromal Cell Therapy for Acute Lung Injury in Preclinical Animal Models: A Systematic Review

    PubMed Central

    McIntyre, Lauralyn A.; Moher, David; Fergusson, Dean A.; Sullivan, Katrina J.; Mei, Shirley H. J.; Lalu, Manoj; Marshall, John; Mcleod, Malcolm; Griffin, Gilly; Grimshaw, Jeremy; Turgeon, Alexis; Avey, Marc T.; Rudnicki, Michael A.; Jazi, Mazen; Fishman, Jason; Stewart, Duncan J.

    2016-01-01

    The Acute Respiratory Distress Syndrome (ARDS) is a devastating clinical condition that is associated with a 30–40% risk of death, and significant long term morbidity for those who survive. Mesenchymal stromal cells (MSC) have emerged as a potential novel treatment as in pre-clinical models they have been shown to modulate inflammation (a major pathophysiological hallmark of ARDS) while enhancing bacterial clearance and reducing organ injury and death. A systematic search of MEDLINE, EMBASE, BIOSIS and Web of Science was performed to identify pre-clinical studies that examined the efficacy MSCs as compared to diseased controls for the treatment of Acute Lung Injury (ALI) (the pre-clinical correlate of human ARDS) on mortality, a clinically relevant outcome. We assessed study quality and pooled results using random effect meta-analysis. A total of 54 publications met our inclusion criteria of which 17 (21 experiments) reported mortality and were included in the meta-analysis. Treatment with MSCs, as compared to controls, significantly decreased the overall odds of death in animals with ALI (Odds Ratio 0.24, 95% Confidence Interval 0.18–0.34, I2 8%). Efficacy was maintained across different types of animal models and means of ALI induction; MSC origin, source, route of administration and preparation; and the clinical relevance of the model (timing of MSC administration, administration of fluids and or antibiotics). Reporting of standard MSC characterization for experiments that used human MSCs and risks of bias was generally poor, and although not statistically significant, a funnel plot analysis for overall mortality suggested the presence of publication bias. The results from our meta-analysis support that MSCs substantially reduce the odds of death in animal models of ALI but important reporting elements were sub optimal and limit the strength of our conclusions. PMID:26821255

  12. Validation of a preclinical model for assessment of drug efficacy in melanoma

    PubMed Central

    Delyon, Julie; Varna, Mariana; Feugeas, Jean-Paul; Sadoux, Aurélie; Yahiaoui, Saliha; Podgorniak, Marie-Pierre; Leclert, Geoffroy; Dorval, Sarra Mazouz; Dumaz, Nicolas; Janin, Anne

    2016-01-01

    The aim of personalized medicine is to improve our understanding of the disease at molecular level and to optimize therapeutic management. In this context, we have developed in vivo and ex vivo preclinical strategies evaluating the efficacy of innovative drugs in melanomas. Human melanomas (n = 17) of different genotypes (mutated BRAF, NRAS, amplified cKIT and wild type) were successfully engrafted in mice then amplified by successive transplantations. The exhaustive characterization of patient-derived xenografts (PDX) at genomic level (transcriptomic and CGH arrays) revealed a similar distribution pattern of genetic abnormalities throughout the successive transplantations compared to the initial patient tumor, enabling their use for mutation-specific therapy strategies. The reproducibility of their spontaneous metastatic potential in mice was assessed in 8 models. These PDXs were used for the development of histoculture drug response assays (ex vivo) for the evaluation of innovative drug efficacy (BRAF and MEK inhibitors). The pharmacological effects of BRAF and MEK inhibitors were similar between PDX-derived histocultures and their corresponding PDX, on 2 models of BRAF and NRAS-mutated melanomas. These models constitute a validated, effective tool for preclinical investigation of new therapeutic agents, and improve therapeutic strategies in the treatment of metastatic melanoma. PMID:26909610

  13. Preclinical Data on Efficacy of 10 Drug-Radiation Combinations: Evaluations, Concerns, and Recommendations1

    PubMed Central

    Stone, Helen B.; Bernhard, Eric J.; Coleman, C. Norman; Deye, James; Capala, Jacek; Mitchell, James B.; Brown, J. Martin

    2016-01-01

    BACKGROUND: Clinical testing of new therapeutic interventions requires comprehensive, high-quality preclinical data. Concerns regarding quality of preclinical data have been raised in recent reports. This report examines the data on the interaction of 10 drugs with radiation and provides recommendations for improving the quality, reproducibility, and utility of future studies. The drugs were AZD6244, bortezomib, 17-DMAG, erlotinib, gefitinib, lapatinib, oxaliplatin/Lipoxal, sunitinib (Pfizer, Corporate headquarters, New York, NY), thalidomide, and vorinostat. METHODS: In vitro and in vivo data were tabulated from 125 published papers, including methods, radiation and drug doses, schedules of administration, assays, measures of interaction, presentation and interpretation of data, dosimetry, and conclusions. RESULTS: In many instances, the studies contained inadequate or unclear information that would hamper efforts to replicate or intercompare the studies, and that weakened the evidence for designing and conducting clinical trials. The published reports on these drugs showed mixed results on enhancement of radiation response, except for sunitinib, which was ineffective. CONCLUSIONS: There is a need for improved experimental design, execution, and reporting of preclinical testing of agents that are candidates for clinical use in combination with radiation. A checklist is provided for authors and reviewers to ensure that preclinical studies of drug-radiation combinations meet standards of design, execution, and interpretation, and report necessary information to ensure high quality and reproducibility of studies. Improved design, execution, common measures of enhancement, and consistent interpretation of preclinical studies of drug-radiation interactions will provide rational guidance for prioritizing drugs for clinical radiotherapy trials and for the design of such trials. PMID:26947881

  14. Preclinical development of a dengue tetravalent recombinant subunit vaccine: Immunogenicity and protective efficacy in nonhuman primates.

    PubMed

    Govindarajan, Dhanasekaran; Meschino, Steven; Guan, Liming; Clements, David E; ter Meulen, Jan H; Casimiro, Danilo R; Coller, Beth-Ann G; Bett, Andrew J

    2015-08-01

    We describe here the preclinical development of a dengue vaccine composed of recombinant subunit carboxy-truncated envelope (E) proteins (DEN-80E) for each of the four dengue serotypes. Immunogenicity and protective efficacy studies in Rhesus monkeys were conducted to evaluate monovalent and tetravalent DEN-80E vaccines formulated with ISCOMATRIX™ adjuvant. Three different doses and two dosing regimens (0, 1, 2 months and 0, 1, 2, and 6 months) were evaluated in these studies. We first evaluated monomeric (DEN4-80E) and dimeric (DEN4-80EZip) versions of DEN4-80E, the latter generated in an attempt to improve immunogenicity. The two antigens, evaluated at 6, 20 and 100 μg/dose formulated with ISCOMATRIX™ adjuvant, were equally immunogenic. A group immunized with 20 μg DEN4-80E and Alhydrogel™ induced much weaker responses. When challenged with wild-type dengue type 4 virus, all animals in the 6 and 20 μg groups and all but one in the DEN4-80EZip 100 μg group were protected from viremia. Two out of three monkeys in the Alhydrogel™ group had breakthrough viremia. A similar study was conducted to evaluate tetravalent formulations at low (3, 3, 3, 6 μg of DEN1-80E, DEN2-80E, DEN3-80E and DEN4-80E respectively), medium (10, 10, 10, 20 μg) and high (50, 50, 50, 100 μg) doses. All doses were comparably immunogenic and induced high titer, balanced neutralizing antibodies against all four DENV. Upon challenge with the four wild-type DENV, all animals in the low and medium dose groups were protected against viremia while two animals in the high-dose group exhibited breakthrough viremia. Our studies also indicated that a 0, 1, 2 and 6 month vaccination schedule is superior to the 0, 1, and 2 month schedule in terms of durability. Overall, the subunit vaccine was demonstrated to induce strong neutralization titers resulting in protection against viremia following challenge even 8-12 months after the last vaccine dose. PMID:26144900

  15. Preclinical Assessment of the Efficacy of Anti-Angiogenic Therapies in Hepatocellular Carcinoma.

    PubMed

    Barral, Matthias; Raballand, Annemilaï; Dohan, Anthony; Soyer, Philippe; Pocard, Marc; Bonnin, Philippe

    2016-02-01

    Diffuse hepatocellular carcinoma (HCC) is a complex affliction in which comorbidities can bias global outcome of cancer therapy. Better methods are thus warranted to directly assess effects of therapy on tumor angiogenesis and growth. As tumor angiogenesis is invariably associated with changes in local blood flow, we assessed the utility of ultrasound imaging in evaluation of the efficacy of anti-angiogenic therapy in a spontaneous transgenic mouse model of HCC. Blood flow velocities were measured monthly in the celiac trunk before and after administration of sorafenib or bevacizumab at doses corresponding to those currently used in clinical practice. Concordant with clinical experience, sorafenib, but not bevacizumab, reduced microvascular density and suppressed tumor growth relative to controls. Evolution of blood flow velocities correlated with microvascular density and with the evolution of tumor size. Ultrasound imaging thus provides a useful non-invasive tool for preclinical evaluation of new anti-angiogenic therapies for HCC. PMID:26626491

  16. Discovery and Optimization of Selective Nav1.8 Modulator Series That Demonstrate Efficacy in Preclinical Models of Pain.

    PubMed

    Bagal, Sharan K; Bungay, Peter J; Denton, Stephen M; Gibson, Karl R; Glossop, Melanie S; Hay, Tanya L; Kemp, Mark I; Lane, Charlotte A L; Lewis, Mark L; Maw, Graham N; Million, William A; Payne, C Elizabeth; Poinsard, Cedric; Rawson, David J; Stammen, Blanda L; Stevens, Edward B; Thompson, Lisa R

    2015-06-11

    Voltage-gated sodium channels, in particular Nav1.8, can be targeted for the treatment of neuropathic and inflammatory pain. Herein, we described the optimization of Nav1.8 modulator series to deliver subtype selective, state, and use-dependent chemical matter that is efficacious in preclinical models of neuropathic and inflammatory pain. PMID:26101568

  17. Discovery and Optimization of Selective Nav1.8 Modulator Series That Demonstrate Efficacy in Preclinical Models of Pain

    PubMed Central

    2015-01-01

    Voltage-gated sodium channels, in particular Nav1.8, can be targeted for the treatment of neuropathic and inflammatory pain. Herein, we described the optimization of Nav1.8 modulator series to deliver subtype selective, state, and use-dependent chemical matter that is efficacious in preclinical models of neuropathic and inflammatory pain. PMID:26101568

  18. PTEN status mediates 2ME2 anti-tumor efficacy in preclinical glioblastoma models: role of HIF1α suppression

    PubMed Central

    Muh, Carrie R.; Joshi, Shweta; Singh, Alok R.; Kesari, Santosh; Durden, Donald L.; Makale, Milan T.

    2013-01-01

    Glioblastoma (GBM) is the most common brain cancer and is highly lethal in both adults and children. 2-methoxyestradiol (2ME2) is a microtubule inhibitor that potently inhibits HIF1α, GBM angiogenesis and tumor growth in preclinical models. In patients, 2ME2 exhibits low toxicity and promising but inconsistent efficacy. Given its preclinical potency and its tolerability in patients, we sought to determine whether 2ME2 therapy could be enhanced by addressing resistance via combination therapy, and with biomarkers to identify responsive glioma subgroups. We demonstrate that the PTEN-PI3K axis regulates HIF1α in glioma models. We utilized isogenic-pairs of glioma cell lines, deficient in PTEN or stably reconstituted with PTEN, to determine the role of PTEN in 2ME2 sensitivity in vitro and in vivo. Chou-Talalay synergy studies reveal significant synergy when a pan-PI3K inhibitor is combined with 2ME2. This synergistic activity was correlated with a synergistic suppression of HIF1α accumulation under hypoxic conditions in glioma models. In vivo, 2ME2 markedly inhibited tumor-induced angiogenesis and significantly reduced tumor growth only in a PTEN reconstituted GBM models in both subcutaneous and orthotopic intracranial mouse models. Collectively, these results: (1) suggest that PTEN status predicts sensitivity to 2ME2 and (2) justify exploration of 2ME2 combined with panPI3K inhibitors for the treatment of this intractable brain cancer. PMID:24162827

  19. Analgesia in Amphibians: Preclinical Studies and Clinical Applications

    PubMed Central

    Stevens, Craig W.

    2010-01-01

    SYNOPSIS Preclinical studies of analgesia in amphibians or recommendations for clinical use of analgesics in amphibian species are extremely limited. This article briefly reviews the issues surrounding the use of analgesics in amphibians starting with common definitions of pain and analgesia when applied to non-human animals. Nociceptive and endogenous opioid systems in amphibians are reviewed and results of preclinical research on opioid and non-opioid analgesics summarized. Recommended opioid and non-opioid analgesics are summarized and practical recommendations made for their clinical use. PMID:21074701

  20. Evaluating the Suitability of Using Rat Models for Preclinical Efficacy and Side Effects with Inhaled Corticosteroids Nanosuspension Formulations

    NASA Astrophysics Data System (ADS)

    Chiang, Po-Chang; Hu, Yiding; Blom, Jason D.; Thompson, David C.

    2010-06-01

    Inhaled corticosteroids (ICS) are often prescribed as first-line therapy for patients with asthma Despite their efficacy and improved safety profile compared with oral corticosteroids, the potential for systemic side effects continues to cause concern. In order to reduce the potential for systemic side effects, the pharmaceutical industry has begun efforts to generate new drugs with pulmonary-targeted topical efficacy. One of the major challenges of this approach is to differentiate both efficacy and side effects (pulmonary vs. systemic) in a preclinical animal model. In this study, fluticasone and ciclesonide were used as tool compounds to explore the possibility of demonstrating both efficacy and side effects in a rat model using pulmonary delivery via intratracheal (IT) instillation with nanosuspension formulations. The inhibition of neutrophil infiltration into bronchoalveolar lavage fluid (BALF) and cytokine (TNFα) production were utilized to assess pulmonary efficacy, while adrenal and thymus involution as well as plasma corticosterone suppression was measured to assess systemic side effects. Based on neutrophil infiltration and cytokine production data, the ED50s for ciclesonide and fluticasone were calculated to be 0.1 and 0.03 mg, respectively. At the ED50, the average adrenal involution was 7.6 ± 5.3% for ciclesonide versus 16.6 ± 5.1% for fluticasone, while the average thymus involution was 41.0 ± 4.3% for ciclesonide versus 59.5 ± 5.8% for fluticasone. However, the differentiation became less significant when the dose was pushed to the EDmax (0.3 mg for ciclesonide, 0.1 mg for fluticasone). Overall, the efficacy and side effect profiles of the two compounds exhibited differentiation at low to mid doses (0.03-0.1 mg ciclesonide, 0.01-0.03 mg fluticasone), while this differentiation diminished at the maximum efficacious dose (0.3 mg ciclesonide, 0.1 mg fluticasone), likely due to overdosing in this model. We conclude that the rat LPS model using IT

  1. Preclinical studies of 5-fluoro-2'-deoxycytidine and tetrahydrouridine in pediatric brain tumors.

    PubMed

    Morfouace, Marie; Nimmervoll, Birgit; Boulos, Nidal; Patel, Yogesh T; Shelat, Anang; Freeman, Burgess B; Robinson, Giles W; Wright, Karen; Gajjar, Amar; Stewart, Clinton F; Gilbertson, Richard J; Roussel, Martine F

    2016-01-01

    Chemotherapies active in preclinical studies frequently fail in the clinic due to lack of efficacy, which limits progress for rare cancers since only small numbers of patients are available for clinical trials. Thus, a preclinical drug development pipeline was developed to prioritize potentially active regimens for pediatric brain tumors spanning from in vitro drug screening, through intracranial and intra-tumoral pharmacokinetics to in vivo efficacy studies. Here, as an example of the pipeline, data are presented for the combination of 5-fluoro-2'-deoxycytidine and tetrahydrouridine in three pediatric brain tumor models. The in vitro activity of nine novel therapies was tested against tumor spheres derived from faithful mouse models of Group 3 medulloblastoma, ependymoma, and choroid plexus carcinoma. Agents with the greatest in vitro potency were then subjected to a comprehensive series of in vivo pharmacokinetic (PK) and pharmacodynamic (PD) studies culminating in preclinical efficacy trials in mice harboring brain tumors. The nucleoside analog 5-fluoro-2'-deoxycytidine (FdCyd) markedly reduced the proliferation in vitro of all three brain tumor cell types at nanomolar concentrations. Detailed intracranial PK studies confirmed that systemically administered FdCyd exceeded concentrations in brain tumors necessary to inhibit tumor cell proliferation, but no tumor displayed a significant in vivo therapeutic response. Despite promising in vitro activity and in vivo PK properties, FdCyd is unlikely to be an effective treatment of pediatric brain tumors, and therefore was deprioritized for the clinic. Our comprehensive and integrated preclinical drug development pipeline should reduce the attrition of drugs in clinical trials. PMID:26518542

  2. Bridging Translation by Improving Preclinical Study Design in AKI.

    PubMed

    de Caestecker, Mark; Humphreys, Ben D; Liu, Kathleen D; Fissell, William H; Cerda, Jorge; Nolin, Thomas D; Askenazi, David; Mour, Girish; Harrell, Frank E; Pullen, Nick; Okusa, Mark D; Faubel, Sarah

    2015-12-01

    Despite extensive research, no therapeutic interventions have been shown to prevent AKI, accelerate recovery of AKI, or reduce progression of AKI to CKD in patients. This failure in translation has led investigators to speculate that the animal models being used do not predict therapeutic responses in humans. Although this issue continues to be debated, an important concern that has not been addressed is whether improvements in preclinical study design can be identified that might also increase the likelihood of translating basic AKI research into clinical practice using the current models. In this review, we have taken an evidence-based approach to identify common weaknesses in study design and reporting in preclinical AKI research that may contribute to the poor translatability of the findings. We focused on use of N-acetylcysteine or sodium bicarbonate for the prevention of contrast-induced AKI and use of erythropoietin for the prevention of AKI, two therapeutic approaches that have been extensively studied in clinical trials. On the basis of our findings, we identified five areas for improvement in preclinical study design and reporting. These suggested and preliminary guidelines may help improve the quality of preclinical research for AKI drug development. PMID:26538634

  3. Bridging Translation by Improving Preclinical Study Design in AKI.

    PubMed

    de Caestecker, Mark; Humphreys, Ben D; Liu, Kathleen D; Fissell, William H; Cerda, Jorge; Nolin, Thomas D; Askenazi, David; Mour, Girish; Harrell, Frank E; Pullen, Nick; Okusa, Mark D; Faubel, Sarah

    2015-12-01

    Despite extensive research, no therapeutic interventions have been shown to prevent AKI, accelerate recovery of AKI, or reduce progression of AKI to CKD in patients. This failure in translation has led investigators to speculate that the animal models being used do not predict therapeutic responses in humans. Although this issue continues to be debated, an important concern that has not been addressed is whether improvements in preclinical study design can be identified that might also increase the likelihood of translating basic AKI research into clinical practice using the current models. In this review, we have taken an evidence-based approach to identify common weaknesses in study design and reporting in preclinical AKI research that may contribute to the poor translatability of the findings. We focused on use of N-acetylcysteine or sodium bicarbonate for the prevention of contrast-induced AKI and use of erythropoietin for the prevention of AKI, two therapeutic approaches that have been extensively studied in clinical trials. On the basis of our findings, we identified five areas for improvement in preclinical study design and reporting. These suggested and preliminary guidelines may help improve the quality of preclinical research for AKI drug development.

  4. Genetically engineered humanized mouse models for preclinical antibody studies.

    PubMed

    Proetzel, Gabriele; Wiles, Michael V; Roopenian, Derry C

    2014-04-01

    The use of genetic engineering has vastly improved our capabilities to create animal models relevant in preclinical research. With the recent advances in gene-editing technologies, it is now possible to very rapidly create highly tunable mouse models as needs arise. Here, we provide an overview of genetic engineering methods, as well as the development of humanized neonatal Fc receptor (FcRn) models and their use for monoclonal antibody in vivo studies.

  5. [Latrepirdine: a systematic review of the preclinical studies].

    PubMed

    Cano-Cuenca, Nieves; Solís-García del Pozo, Julián; Jordán, Joaquín

    2015-01-01

    We conduct a systematic review of the preclinical studies published to date involving the use of latrepirdine (Dimebon ®). Latrepirdine is capable of modulating different targets, such as those related with mitochondria, acetylcholinesterase activity or intraneuronal calcium levels, perhaps thanks to its action upon the N-methyl-D-aspartate-type receptor, which belongs to the glutamate family. The findings published on the possible effect of latrepirdine in protein aggregation processes in disorders such as Alzheimer's disease and Parkinson's disease are quite controversial. Likewise, the possible neuroprotective effect of latrepirdine has been evaluated in animal models of neurodegenerative diseases, again with heterogeneous results. Consequently, it can be concluded that no preclinical scientific evidence has been found to justify carrying out clinical trials.

  6. Preclinical efficacy and mechanisms of mesenchymal stem cells in animal models of autoimmune diseases.

    PubMed

    Lee, Hong Kyung; Lim, Sang Hee; Chung, In Sung; Park, Yunsoo; Park, Mi Jeong; Kim, Ju Young; Kim, Yong Guk; Hong, Jin Tae; Kim, Youngsoo; Han, Sang-Bae

    2014-04-01

    Mesenchymal stem cells (MSCs) are present in diverse tissues and organs, including bone marrow, umbilical cord, adipose tissue, and placenta. MSCs can expand easily in vitro and have regenerative stem cell properties and potent immunoregulatory activity. They inhibit the functions of dendritic cells, B cells, and T cells, but enhance those of regulatory T cells by producing immunoregulatory molecules such as transforming growth factor-β, hepatic growth factors, prostaglandin E2, interleukin-10, indolamine 2,3-dioxygenase, nitric oxide, heme oxygenase-1, and human leukocyte antigen-G. These properties make MSCs promising therapeutic candidates for the treatment of autoimmune diseases. Here, we review the preclinical studies of MSCs in animal models for systemic lupus erythematosus, rheumatoid arthritis, Crohn's disease, and experimental autoimmune encephalomyelitis, and summarize the underlying immunoregulatory mechanisms. PMID:24851097

  7. Extended Preclinical Safety, Efficacy and Stability Testing of a Live-attenuated Chikungunya Vaccine Candidate.

    PubMed

    Plante, Kenneth S; Rossi, Shannan L; Bergren, Nicholas A; Seymour, Robert L; Weaver, Scott C

    2015-01-01

    We recently described a new, live-attenuated vaccine candidate for chikungunya (CHIK) fever, CHIKV/IRES. This vaccine was shown to be well attenuated, immunogenic and efficacious in protecting against CHIK virus (CHIKV) challenge of mice and nonhuman primates. To further evaluate its preclinical safety, we compared CHIKV/IRES distribution and viral loads in interferon-α/β receptor-incompetent A129 mice to another CHIK vaccine candidate, 181/clone25, which proved highly immunogenic but mildly reactive in human Phase I/II clinical trials. Compared to wild-type CHIK virus, (wt-CHIKV), both vaccines generated lower viral loads in a wide variety of tissues and organs, including the brain and leg muscle, but CHIKV/IRES exhibited marked restrictions in dissemination and viral loads compared to 181/clone25, and was never found outside the blood, spleen and muscle. Unlike wt-CHIKV, which caused disrupted splenic architecture and hepatic lesions, histopathological lesions were not observed in animals infected with either vaccine strain. To examine the stability of attenuation, both vaccines were passaged 5 times intracranially in infant A129 mice, then assessed for changes in virulence by comparing parental and passaged viruses for footpad swelling, weight stability and survival after subcutaneous infection. Whereas strain 181/clone25 p5 underwent a significant increase in virulence as measured by weight loss (from <10% to >30%) and mortality (from 0 to 100%), CHIKV/IRES underwent no detectible change in any measure of virulence (no significant weight loss and no mortality). These data indicate greater nonclinical safety of the CHIKV/IRES vaccine candidate compared to 181/clone25, further supporting its eligibility for human testing.

  8. Extended Preclinical Safety, Efficacy and Stability Testing of a Live-attenuated Chikungunya Vaccine Candidate.

    PubMed

    Plante, Kenneth S; Rossi, Shannan L; Bergren, Nicholas A; Seymour, Robert L; Weaver, Scott C

    2015-01-01

    We recently described a new, live-attenuated vaccine candidate for chikungunya (CHIK) fever, CHIKV/IRES. This vaccine was shown to be well attenuated, immunogenic and efficacious in protecting against CHIK virus (CHIKV) challenge of mice and nonhuman primates. To further evaluate its preclinical safety, we compared CHIKV/IRES distribution and viral loads in interferon-α/β receptor-incompetent A129 mice to another CHIK vaccine candidate, 181/clone25, which proved highly immunogenic but mildly reactive in human Phase I/II clinical trials. Compared to wild-type CHIK virus, (wt-CHIKV), both vaccines generated lower viral loads in a wide variety of tissues and organs, including the brain and leg muscle, but CHIKV/IRES exhibited marked restrictions in dissemination and viral loads compared to 181/clone25, and was never found outside the blood, spleen and muscle. Unlike wt-CHIKV, which caused disrupted splenic architecture and hepatic lesions, histopathological lesions were not observed in animals infected with either vaccine strain. To examine the stability of attenuation, both vaccines were passaged 5 times intracranially in infant A129 mice, then assessed for changes in virulence by comparing parental and passaged viruses for footpad swelling, weight stability and survival after subcutaneous infection. Whereas strain 181/clone25 p5 underwent a significant increase in virulence as measured by weight loss (from <10% to >30%) and mortality (from 0 to 100%), CHIKV/IRES underwent no detectible change in any measure of virulence (no significant weight loss and no mortality). These data indicate greater nonclinical safety of the CHIKV/IRES vaccine candidate compared to 181/clone25, further supporting its eligibility for human testing. PMID:26340754

  9. Extended Preclinical Safety, Efficacy and Stability Testing of a Live-attenuated Chikungunya Vaccine Candidate

    PubMed Central

    Plante, Kenneth S; Rossi, Shannan L.; Bergren, Nicholas A.; Seymour, Robert L.; Weaver, Scott C.

    2015-01-01

    We recently described a new, live-attenuated vaccine candidate for chikungunya (CHIK) fever, CHIKV/IRES. This vaccine was shown to be well attenuated, immunogenic and efficacious in protecting against CHIK virus (CHIKV) challenge of mice and nonhuman primates. To further evaluate its preclinical safety, we compared CHIKV/IRES distribution and viral loads in interferon-α/β receptor-incompetent A129 mice to another CHIK vaccine candidate, 181/clone25, which proved highly immunogenic but mildly reactive in human Phase I/II clinical trials. Compared to wild-type CHIK virus, (wt-CHIKV), both vaccines generated lower viral loads in a wide variety of tissues and organs, including the brain and leg muscle, but CHIKV/IRES exhibited marked restrictions in dissemination and viral loads compared to 181/clone25, and was never found outside the blood, spleen and muscle. Unlike wt-CHIKV, which caused disrupted splenic architecture and hepatic lesions, histopathological lesions were not observed in animals infected with either vaccine strain. To examine the stability of attenuation, both vaccines were passaged 5 times intracranially in infant A129 mice, then assessed for changes in virulence by comparing parental and passaged viruses for footpad swelling, weight stability and survival after subcutaneous infection. Whereas strain 181/clone25 p5 underwent a significant increase in virulence as measured by weight loss (from <10% to >30%) and mortality (from 0 to 100%), CHIKV/IRES underwent no detectible change in any measure of virulence (no significant weight loss and no mortality). These data indicate greater nonclinical safety of the CHIKV/IRES vaccine candidate compared to 181/clone25, further supporting its eligibility for human testing. PMID:26340754

  10. Preclinical profile of a potent gamma-secretase inhibitor targeting notch signaling with in vivo efficacy and pharmacodynamic properties.

    PubMed

    Luistro, Leopoldo; He, Wei; Smith, Melissa; Packman, Kathryn; Vilenchik, Maria; Carvajal, Daisy; Roberts, John; Cai, James; Berkofsky-Fessler, Windy; Hilton, Holly; Linn, Michael; Flohr, Alexander; Jakob-Røtne, Roland; Jacobsen, Helmut; Glenn, Kelli; Heimbrook, David; Boylan, John F

    2009-10-01

    Notch signaling is an area of great interest in oncology. RO4929097 is a potent and selective inhibitor of gamma-secretase, producing inhibitory activity of Notch signaling in tumor cells. The RO4929097 IC50 in cell-free and cellular assays is in the low nanomolar range with >100-fold selectivity with respect to 75 other proteins of various types (receptors, ion channels, and enzymes). RO4929097 inhibits Notch processing in tumor cells as measured by the reduction of intracellular Notch expression by Western blot. This leads to reduced expression of the Notch transcriptional target gene Hes1. RO4929097 does not block tumor cell proliferation or induce apoptosis but instead produces a less transformed, flattened, slower-growing phenotype. RO4929097 is active following oral dosing. Antitumor activity was shown in 7 of 8 xenografts tested on an intermittent or daily schedule in the absence of body weight loss or Notch-related toxicities. Importantly, efficacy is maintained after dosing is terminated. Angiogenesis reverse transcription-PCR array data show reduced expression of several key angiogenic genes. In addition, comparative microarray analysis suggests tumor cell differentiation as an additional mode of action. These preclinical results support evaluation of RO4929097 in clinical studies using an intermittent dosing schedule. A multicenter phase I dose escalation study in oncology is under way. PMID:19773430

  11. Preclinical profile of a potent gamma-secretase inhibitor targeting notch signaling with in vivo efficacy and pharmacodynamic properties.

    PubMed

    Luistro, Leopoldo; He, Wei; Smith, Melissa; Packman, Kathryn; Vilenchik, Maria; Carvajal, Daisy; Roberts, John; Cai, James; Berkofsky-Fessler, Windy; Hilton, Holly; Linn, Michael; Flohr, Alexander; Jakob-Røtne, Roland; Jacobsen, Helmut; Glenn, Kelli; Heimbrook, David; Boylan, John F

    2009-10-01

    Notch signaling is an area of great interest in oncology. RO4929097 is a potent and selective inhibitor of gamma-secretase, producing inhibitory activity of Notch signaling in tumor cells. The RO4929097 IC50 in cell-free and cellular assays is in the low nanomolar range with >100-fold selectivity with respect to 75 other proteins of various types (receptors, ion channels, and enzymes). RO4929097 inhibits Notch processing in tumor cells as measured by the reduction of intracellular Notch expression by Western blot. This leads to reduced expression of the Notch transcriptional target gene Hes1. RO4929097 does not block tumor cell proliferation or induce apoptosis but instead produces a less transformed, flattened, slower-growing phenotype. RO4929097 is active following oral dosing. Antitumor activity was shown in 7 of 8 xenografts tested on an intermittent or daily schedule in the absence of body weight loss or Notch-related toxicities. Importantly, efficacy is maintained after dosing is terminated. Angiogenesis reverse transcription-PCR array data show reduced expression of several key angiogenic genes. In addition, comparative microarray analysis suggests tumor cell differentiation as an additional mode of action. These preclinical results support evaluation of RO4929097 in clinical studies using an intermittent dosing schedule. A multicenter phase I dose escalation study in oncology is under way.

  12. Preclinical safety and efficacy models for pulmonary drug delivery of antimicrobials with focus on in vitro models.

    PubMed

    Hittinger, Marius; Juntke, Jenny; Kletting, Stephanie; Schneider-Daum, Nicole; de Souza Carvalho, Cristiane; Lehr, Claus-Michael

    2015-05-01

    New pharmaceutical formulations must be proven as safe and effective before entering clinical trials. Also in the context of pulmonary drug delivery, preclinical models allow testing of novel antimicrobials, reducing risks and costs during their development. Such models allow reducing the complexity of the human lung, but still need to reflect relevant (patho-) physiological features. This review focuses on preclinical pulmonary models, mainly in vitro models, to assess drug safety and efficacy of antimicrobials. Furthermore, approaches to investigate common infectious diseases of the respiratory tract, are emphasized. Pneumonia, tuberculosis and infections occurring due to cystic fibrosis are in focus of this review. We conclude that especially in vitro models offer the chance of an efficient and detailed analysis of new antimicrobials, but also draw attention to the advantages and limitations of such currently available models and critically discuss the necessary steps for their future development.

  13. Optimized design and analysis of preclinical intervention studies in vivo

    PubMed Central

    Laajala, Teemu D.; Jumppanen, Mikael; Huhtaniemi, Riikka; Fey, Vidal; Kaur, Amanpreet; Knuuttila, Matias; Aho, Eija; Oksala, Riikka; Westermarck, Jukka; Mäkelä, Sari; Poutanen, Matti; Aittokallio, Tero

    2016-01-01

    Recent reports have called into question the reproducibility, validity and translatability of the preclinical animal studies due to limitations in their experimental design and statistical analysis. To this end, we implemented a matching-based modelling approach for optimal intervention group allocation, randomization and power calculations, which takes full account of the complex animal characteristics at baseline prior to interventions. In prostate cancer xenograft studies, the method effectively normalized the confounding baseline variability, and resulted in animal allocations which were supported by RNA-seq profiling of the individual tumours. The matching information increased the statistical power to detect true treatment effects at smaller sample sizes in two castration-resistant prostate cancer models, thereby leading to saving of both animal lives and research costs. The novel modelling approach and its open-source and web-based software implementations enable the researchers to conduct adequately-powered and fully-blinded preclinical intervention studies, with the aim to accelerate the discovery of new therapeutic interventions. PMID:27480578

  14. Optimized design and analysis of preclinical intervention studies in vivo.

    PubMed

    Laajala, Teemu D; Jumppanen, Mikael; Huhtaniemi, Riikka; Fey, Vidal; Kaur, Amanpreet; Knuuttila, Matias; Aho, Eija; Oksala, Riikka; Westermarck, Jukka; Mäkelä, Sari; Poutanen, Matti; Aittokallio, Tero

    2016-01-01

    Recent reports have called into question the reproducibility, validity and translatability of the preclinical animal studies due to limitations in their experimental design and statistical analysis. To this end, we implemented a matching-based modelling approach for optimal intervention group allocation, randomization and power calculations, which takes full account of the complex animal characteristics at baseline prior to interventions. In prostate cancer xenograft studies, the method effectively normalized the confounding baseline variability, and resulted in animal allocations which were supported by RNA-seq profiling of the individual tumours. The matching information increased the statistical power to detect true treatment effects at smaller sample sizes in two castration-resistant prostate cancer models, thereby leading to saving of both animal lives and research costs. The novel modelling approach and its open-source and web-based software implementations enable the researchers to conduct adequately-powered and fully-blinded preclinical intervention studies, with the aim to accelerate the discovery of new therapeutic interventions. PMID:27480578

  15. Preclinical screening methods in cancer

    PubMed Central

    Kumar, Sachin; Bajaj, Sakshi; Bodla, Ramesh Babu

    2016-01-01

    Cancer, a group of diseases of unregulated cell proliferation, is a leading cause of death worldwide. More than 80% of compounds which have shown promising effects in preclinical studies could not get through Phase II of clinical trials. Such high attrition rate is due to improper or selective use of preclinical modalities in anticancer drug screening. The various preclinical screening methods available such as in vitro human cancer cell lines, in vivo tumor xenograft model, or genetically engineered mouse model have their respective pros and cons. Scrupulous use of these preclinical screening methods vis-à-vis efficacy of potential anticancer compound with diverse mechanism of action can help in bringing down the rate of failure of anticancer compound at clinical phase. This article provides an insight into the various preclinical methods used in anticancer studies along with their advantages and disadvantages. PMID:27721530

  16. Resveratrol: A review of preclinical studies for human cancer prevention

    SciTech Connect

    Athar, Mohammad; Back, Jung Ho; Tang Xiuwei; Kim, Kwang Ho; Kopelovich, Levy; Bickers, David R.; Kim, Arianna L.

    2007-11-01

    The search for novel and effective cancer chemopreventive agents has led to the identification of various naturally occurring compounds one of which is resveratrol (trans-3,4',5-trihydroxystilbene), a phytoalexin derived from the skin of grapes and other fruits. Resveratrol is known to have potent anti-inflammatory and antioxidant effects and to inhibit platelet aggregation and the growth of a variety of cancer cells. Its potential chemopreventive and chemotherapeutic activities have been demonstrated in all three stages of carcinogenesis (initiation, promotion, and progression), in both chemically and UVB-induced skin carcinogenesis in mice, as well as in various murine models of human cancers. Evidence from numerous in vitro and in vivo studies has confirmed its ability to modulate various targets and signaling pathways. This review discusses the current preclinical and mechanistic data available and assesses resveratrol's anticancer effects to support its potential as an anticancer agent in human populations.

  17. Novel Epigenetic Target Therapy for Prostate Cancer: A Preclinical Study

    PubMed Central

    Gherardini, Lisa; Pelosi, Gualtiero; Viglione, Federica; Grimaldi, Settimio; Pani, Luca; Cinti, Caterina

    2014-01-01

    Epigenetic events are critical contributors to the pathogenesis of cancer, and targeting epigenetic mechanisms represents a novel strategy in anticancer therapy. Classic demethylating agents, such as 5-Aza-2′-deoxycytidine (Decitabine), hold the potential for reprograming somatic cancer cells demonstrating high therapeutic efficacy in haematological malignancies. On the other hand, epigenetic treatment of solid tumours often gives rise to undesired cytotoxic side effects. Appropriate delivery systems able to enrich Decitabine at the site of action and improve its bioavailability would reduce the incidence of toxicity on healthy tissues. In this work we provide preclinical evidences of a safe, versatile and efficient targeted epigenetic therapy to treat hormone sensitive (LNCap) and hormone refractory (DU145) prostate cancers. A novel Decitabine formulation, based on the use of engineered erythrocyte (Erythro-Magneto-Hemagglutinin Virosomes, EMHVs) drug delivery system (DDS) carrying this drug, has been refined. Inside the EMHVs, the drug was shielded from the environment and phosphorylated in its active form. The novel magnetic EMHV DDS, endowed with fusogenic protein, improved the stability of the carried drug and exhibited a high efficiency in confining its delivery at the site of action in vivo by applying an external static magnetic field. Here we show that Decitabine loaded into EMHVs induces a significant tumour mass reduction in prostate cancer xenograft models at a concentration, which is seven hundred times lower than the therapeutic dose, suggesting an improved pharmacokinetics/pharmacodynamics of drug. These results are relevant for and discussed in light of developing personalised autologous therapies and innovative clinical approach for the treatment of solid tumours. PMID:24851905

  18. Novel epigenetic target therapy for prostate cancer: a preclinical study.

    PubMed

    Naldi, Ilaria; Taranta, Monia; Gherardini, Lisa; Pelosi, Gualtiero; Viglione, Federica; Grimaldi, Settimio; Pani, Luca; Cinti, Caterina

    2014-01-01

    Epigenetic events are critical contributors to the pathogenesis of cancer, and targeting epigenetic mechanisms represents a novel strategy in anticancer therapy. Classic demethylating agents, such as 5-Aza-2'-deoxycytidine (Decitabine), hold the potential for reprograming somatic cancer cells demonstrating high therapeutic efficacy in haematological malignancies. On the other hand, epigenetic treatment of solid tumours often gives rise to undesired cytotoxic side effects. Appropriate delivery systems able to enrich Decitabine at the site of action and improve its bioavailability would reduce the incidence of toxicity on healthy tissues. In this work we provide preclinical evidences of a safe, versatile and efficient targeted epigenetic therapy to treat hormone sensitive (LNCap) and hormone refractory (DU145) prostate cancers. A novel Decitabine formulation, based on the use of engineered erythrocyte (Erythro-Magneto-Hemagglutinin Virosomes, EMHVs) drug delivery system (DDS) carrying this drug, has been refined. Inside the EMHVs, the drug was shielded from the environment and phosphorylated in its active form. The novel magnetic EMHV DDS, endowed with fusogenic protein, improved the stability of the carried drug and exhibited a high efficiency in confining its delivery at the site of action in vivo by applying an external static magnetic field. Here we show that Decitabine loaded into EMHVs induces a significant tumour mass reduction in prostate cancer xenograft models at a concentration, which is seven hundred times lower than the therapeutic dose, suggesting an improved pharmacokinetics/pharmacodynamics of drug. These results are relevant for and discussed in light of developing personalised autologous therapies and innovative clinical approach for the treatment of solid tumours.

  19. Efficacy of the Novel Antibiotic POL7001 in Preclinical Models of Pseudomonas aeruginosa Pneumonia.

    PubMed

    Cigana, Cristina; Bernardini, Francesca; Facchini, Marcella; Alcalá-Franco, Beatriz; Riva, Camilla; De Fino, Ida; Rossi, Alice; Ranucci, Serena; Misson, Pauline; Chevalier, Eric; Brodmann, Maj; Schmitt, Michel; Wach, Achim; Dale, Glenn E; Obrecht, Daniel; Bragonzi, Alessandra

    2016-08-01

    The clinical development of antibiotics with a new mode of action combined with efficient pulmonary drug delivery is a priority against untreatable Pseudomonas aeruginosa lung infections. POL7001 is a macrocycle antibiotic belonging to the novel class of protein epitope mimetic (PEM) molecules with selective and potent activity against P. aeruginosa We investigated ventilator-associated pneumonia (VAP) and cystic fibrosis (CF) as indications of the clinical potential of POL7001 to treat P. aeruginosa pulmonary infections. MICs of POL7001 and comparators were measured for reference and clinical P. aeruginosa strains. The therapeutic efficacy of POL7001 given by pulmonary administration was evaluated in murine models of P. aeruginosa acute and chronic pneumonia. POL7001 showed potent in vitro activity against a large panel of P. aeruginosa isolates from CF patients, including multidrug-resistant (MDR) isolates with adaptive phenotypes such as mucoid or hypermutable phenotypes. The efficacy of POL7001 was demonstrated in both wild-type and CF mice. In addition to a reduced bacterial burden in the lung, POL7001-treated mice showed progressive body weight recovery and reduced levels of inflammatory markers, indicating an improvement in general condition. Pharmacokinetic studies indicated that POL7001 reached significant concentrations in the lung after pulmonary administration, with low systemic exposure. These results support the further evaluation of POL7001 as a novel therapeutic agent for the treatment of P. aeruginosa pulmonary infections.

  20. Endothelin receptor antagonists in clinical research--lessons learned from preclinical and clinical kidney studies.

    PubMed

    Reichetzeder, Christoph; Tsuprykov, Oleg; Hocher, Berthold

    2014-11-24

    Endothelin receptor antagonists (ETRAs) are approved for the treatment of pulmonary hypertension and scleroderma-related digital ulcers. The efforts to approve this class of drugs for renal indications, however, failed so far. Preclinical studies were promising. Transgenic overexpression of ET-1 or ET-2 in rodents causes chronic renal failure. Blocking the ET system was effective in the treatment of renal failure in rodent models. However, various animal studies indicate that blocking the renal tubular ETAR and ETBR causes water and salt retention partially mediated via the epithelial sodium transporter in tubular cells. ETRAs were successfully tested clinically in renal indications in phase 2 trials for the treatment of diabetic nephropathy. They showed efficacy in terms of reducing albumin excretion on top of guideline based background therapy (RAS blockade). However, these promising results could not be translated to successful phase III trials so far. The spectrum of serious adverse events was similar to other phase III trials using ETRAs. Potential underlying reasons for these failures and options to solve these issues are discussed. In addition preclinical and clinical studies suggest caution when addressing renal patient populations such as patients with hepatorenal syndrome, patients with any type of cystic kidney disease and patients at risk of contrast media induced nephropathy. The lessons learned in renal indications are also important for other potential promising indications of ETRAs like cancer and heart failure.

  1. Electrochemotherapy in pancreatic adenocarcinoma treatment: pre-clinical and clinical studies

    PubMed Central

    Leongito, Maddalena; Granata, Vincenza; Barbieri, Antonio; del Vecchio, Vitale; Falco, Michela; Nasto, Aurelio; Albino, Vittorio; Piccirillo, Mauro; Palaia, Raffaele; Amore, Alfonso; Giacomo, Raimondo di; Lastoria, Secondo; Setola, Sergio Venanzio; Fusco, Roberta; Petrillo, Antonella; Izzo, Francesco

    2016-01-01

    Background Pancreatic adenocarcinoma is currently one of the deadliest cancers with high mortality rate. This disease leads to an aggressive local invasion and early metastases, and is poorly responsive to treatment with chemotherapy or chemo-radiotherapy. Radical resection is still the only curative treatment for pancreatic cancer, but it is generally accepted that a multimodality strategy is necessary for its management. Therefore, new alternative therapies have been considered for local treatment. Conclusions Chemotherapeutic resistance in pancreatic cancer is associated to a low penetration of drugs into tumour cells due to the presence of fibrotic stroma surrounding cells. In order to increase the uptake of chemotherapeutic drugs into tumour cells, electrochemotherapy can be used for treatment of pancreatic adenocarcinoma leading to an increased tumour response rate. This review will summarize the published papers reported in literature on the efficacy and safety of electrochemotherapy in pre-clinical and clinical studies on pancreatic cancer. PMID:27069445

  2. Novel technology to prepare oral formulations for preclinical safety studies.

    PubMed

    Niwa, Toshiyuki; Hashimoto, Naofumi

    2008-02-28

    A novel method to prepare oral formulations, normally suspended dosage form, for preclinical safety studies in animals has been developed using a rotation/revolution mixer. Small hard balls made of zirconia were added to the mixing process to evaluate effectiveness in making a high quality suspension. The driving with balls loaded in the cylindrical container (vessel) of the mixer was quite efficient in dispersing and milling the particles of the active pharmaceutical ingredient (API) in an aqueous medium. The API powder and a small amount of oral aqueous medium (vehicle) were successfully mixed by the spinning motion of the balls in the vessel as though the paste-like suspension was kneaded with a mortar and pestle. It was found that the milled suspension with the mean size of 10-20microm could be prepared, in addition finer milling of less than 10microm could be achieved by selecting the material of vessel. Optimum driving conditions including mixing time, size and quantity of balls, and the standard operational procedure was established using compounds varying in physicochemical properties. The particle size and quantitative analysis by HPLC showed that the resultant suspension was well-milled and highly homogeneous with the nearly intended concentration of API. The proposed method established by this experiment could be applied to the actual safety studies in the real preparation scale of oral suspension. PMID:17942253

  3. Preclinical studies on new proteins as carrier for glycoconjugate vaccines.

    PubMed

    Tontini, M; Romano, M R; Proietti, D; Balducci, E; Micoli, F; Balocchi, C; Santini, L; Masignani, V; Berti, F; Costantino, P

    2016-07-29

    Glycoconjugate vaccines are made of carbohydrate antigens covalently bound to a carrier protein to enhance their immunogenicity. Among the different carrier proteins tested in preclinical and clinical studies, five have been used so far for licensed vaccines: Diphtheria and Tetanus toxoids, the non-toxic mutant of diphtheria toxin CRM197, the outer membrane protein complex of Neisseria meningitidis serogroup B and the Protein D derived from non-typeable Haemophilus influenzae. Availability of novel carriers might help to overcome immune interference in multi-valent vaccines containing several polysaccharide-conjugate antigens, and also to develop vaccines which target both protein as well saccharide epitopes of the same pathogen. Accordingly we have conducted a study to identify new potential carrier proteins. Twenty-eight proteins, derived from different bacteria, were conjugated to the model polysaccharide Laminarin and tested in mice for their ability in inducing antibodies against the carbohydrate antigen and eight of them were subsequently tested as carrier for serogroup meningococcal C oligosaccharides. Four out of these eight were able to elicit in mice satisfactory anti meningococcal serogroup C titers. Based on immunological evaluation, the Streptococcus pneumoniae protein spr96/2021 was successfully evaluated as carrier for serogroups A, C, W, Y and X meningococcal capsular saccharides. PMID:27317455

  4. A formulation-enabled preclinical efficacy assessment of a farnesoid X receptor agonist, GW4064, in hamsters and cynomolgus monkeys.

    PubMed

    Chiang, Po-Chang; Thompson, David C; Ghosh, Sarbani; Heitmeier, Monique R

    2011-11-01

    The farnesoid X receptor (FXR) belongs to one of the human nuclear receptor superfamilies that regulate gene transcription. FXR is widely expressed in liver, gall bladder, intestine, kidney, and adrenal glands. It serves as a key controller of bile acid homeostasis through its regulation of bile acid synthesis, conjugation, secretion, and absorption. FXR is also known to play a role in lipid regulation, triglyceride synthesis, and lipoprotein metabolism and clearance. We used a commercially available FXR agonist, GW4064, as a model compound to assess preclinical efficacy in two species (hamster and cynomolgus monkey). The crystalline GW4064, however, was found to have limited solubility, which resulted in poor oral bioavailability. This made it difficult to assess in vivo efficacy at the exposure levels desired. The physiochemical properties of GW4064 were assessed and both salt and self-emulsifying drug delivery system (SEDDS) formulation were developed and tested. The SEDDS formulation was found to greatly improve the oral bioavailability of GW4064, and permitted the evaluation of FXR agonist target efficacy.

  5. Decellularized myocardial matrix hydrogels: In basic research and preclinical studies.

    PubMed

    Wang, Raymond M; Christman, Karen L

    2016-01-15

    A variety of decellularized materials have been developed that have demonstrated potential for treating cardiovascular diseases and improving our understanding of cardiac development. Of these biomaterials, decellularized myocardial matrix hydrogels have shown great promise for creating cellular microenvironments representative of the native cardiac tissue and treating the heart after a myocardial infarction. Decellularized myocardial matrix hydrogels derived from porcine cardiac tissue form a nanofibrous hydrogel once thermally induced at physiological temperatures. Use of isolated cardiac extracellular matrix in 2D and 3D in vitro platforms has demonstrated the capability to provide tissue specific cues for cardiac cell growth and differentiation. Testing of the myocardial matrix hydrogel as a therapy after myocardial infarction in both small and large animal models has demonstrated improved left ventricular function, increased cardiac muscle, and cellular recruitment into the treated infarct. Based on these results, steps are currently being taken to translate these hydrogels into a clinically used injectable biomaterial therapy. In this review, we will focus on the basic science and preclinical studies that have accelerated the development of decellularized myocardial matrix hydrogels into an emerging novel therapy for treating the heart after a myocardial infarction.

  6. Tailored Pig Models for Preclinical Efficacy and Safety Testing of Targeted Therapies.

    PubMed

    Klymiuk, Nikolai; Seeliger, Frank; Bohlooly-Y, Mohammad; Blutke, Andreas; Rudmann, Daniel G; Wolf, Eckhard

    2016-04-01

    Despite enormous advances in translational biomedical research, there remains a growing demand for improved animal models of human disease. This is particularly true for diseases where rodent models do not reflect the human disease phenotype. Compared to rodents, pig anatomy and physiology are more similar to humans in cardiovascular, immune, respiratory, skeletal muscle, and metabolic systems. Importantly, efficient and precise techniques for genetic engineering of pigs are now available, facilitating the creation of tailored large animal models that mimic human disease mechanisms at the molecular level. In this article, the benefits of genetically engineered pigs for basic and translational research are exemplified by a novel pig model of Duchenne muscular dystrophy and by porcine models of cystic fibrosis. Particular emphasis is given to potential advantages of using these models for efficacy and safety testing of targeted therapies, such as exon skipping and gene editing, for example, using the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated system. In general, genetically tailored pig models have the potential to bridge the gap between proof-of-concept studies in rodents and clinical trials in patients, thus supporting translational medicine.

  7. Preclinical Development and In Vivo Efficacy of Ceftiofur-PLGA Microparticles.

    PubMed

    Vilos, Cristian; Velasquez, Luis A; Rodas, Paula I; Zepeda, Katherine; Bong, Soung-Jae; Herrera, Natalia; Cantin, Mario; Simon, Felipe; Constandil, Luis

    2015-01-01

    Drug delivery systems based on polymeric microparticles represent an interesting field of development for the treatment of several infectious diseases for humans and animals. In this work, we developed PLGA microparticles loaded with ceftiofur (PLGA-cef), a third- generation cephalosporin that is used exclusively used in animals. PLGA-cef was prepared by the double emulsion w/o/w method, and exhibited a diameter in the range of 1.5-2.2 μm, and a negative ζ potential in the range of -35 to -55 mV. The loading yield of PLGA-cef was ~7% and encapsulation efficiency was approximately 40%. The pharmacokinetic study demonstrated a sustained release profile of ceftiofur for 20 days. PLGA-cef administrated in a single dose was more effective than ceftiofur non-encapsulated in rats challenged with S. Typhimurium. The in vivo toxicological evaluation showed that PLGA-cef did not affect the blood biochemical, hematological and hemostasis parameters. Overall, the PLGA-cef showed slow in vivo release profile, high antibacterial efficacy, and low toxicity. The results obtained supports the safe application of PLGA-cef as sustained release platform in the veterinary industry.

  8. Tailored Pig Models for Preclinical Efficacy and Safety Testing of Targeted Therapies.

    PubMed

    Klymiuk, Nikolai; Seeliger, Frank; Bohlooly-Y, Mohammad; Blutke, Andreas; Rudmann, Daniel G; Wolf, Eckhard

    2016-04-01

    Despite enormous advances in translational biomedical research, there remains a growing demand for improved animal models of human disease. This is particularly true for diseases where rodent models do not reflect the human disease phenotype. Compared to rodents, pig anatomy and physiology are more similar to humans in cardiovascular, immune, respiratory, skeletal muscle, and metabolic systems. Importantly, efficient and precise techniques for genetic engineering of pigs are now available, facilitating the creation of tailored large animal models that mimic human disease mechanisms at the molecular level. In this article, the benefits of genetically engineered pigs for basic and translational research are exemplified by a novel pig model of Duchenne muscular dystrophy and by porcine models of cystic fibrosis. Particular emphasis is given to potential advantages of using these models for efficacy and safety testing of targeted therapies, such as exon skipping and gene editing, for example, using the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated system. In general, genetically tailored pig models have the potential to bridge the gap between proof-of-concept studies in rodents and clinical trials in patients, thus supporting translational medicine. PMID:26511847

  9. Preclinical Development and In Vivo Efficacy of Ceftiofur-PLGA Microparticles

    PubMed Central

    Vilos, Cristian; Velasquez, Luis A.; Rodas, Paula I.; Zepeda, Katherine; Bong, Soung-Jae; Herrera, Natalia; Cantin, Mario; Simon, Felipe; Constandil, Luis

    2015-01-01

    Drug delivery systems based on polymeric microparticles represent an interesting field of development for the treatment of several infectious diseases for humans and animals. In this work, we developed PLGA microparticles loaded with ceftiofur (PLGA-cef), a third- generation cephalosporin that is used exclusively used in animals. PLGA-cef was prepared by the double emulsion w/o/w method, and exhibited a diameter in the range of 1.5–2.2 μm, and a negative ζ potential in the range of -35 to -55 mV. The loading yield of PLGA-cef was ~7% and encapsulation efficiency was approximately 40%. The pharmacokinetic study demonstrated a sustained release profile of ceftiofur for 20 days. PLGA-cef administrated in a single dose was more effective than ceftiofur non-encapsulated in rats challenged with S. Typhimurium. The in vivo toxicological evaluation showed that PLGA-cef did not affect the blood biochemical, hematological and hemostasis parameters. Overall, the PLGA-cef showed slow in vivo release profile, high antibacterial efficacy, and low toxicity. The results obtained supports the safe application of PLGA-cef as sustained release platform in the veterinary industry. PMID:25915043

  10. Preclinical safety studies on autologous cultured human skin fibroblast transplantation.

    PubMed

    Zeng, Wei; Zhang, Shuying; Liu, Dai; Chai, Mi; Wang, Jiaqi; Zhao, Yuming

    2014-01-01

    Recently, FDA approved the clinical use of autologous fibroblasts (LAVIV™) for the improvement of nasolabial fold wrinkles in adults. The use of autologous fibroblasts for the augmentation of dermal and subcutaneous defects represents a potentially exciting natural alternative to the use of other filler materials for its long-term corrective ability and absence of allergic adverse effects proved by clinical application. However, compared to the clinical evidence, preclinical studies are far from enough. In this study, human skin-derived fibroblasts were cultured and expanded for both in vitro and in vivo observations. In vitro, the subcultured fibroblasts were divided into two groups. One set of cells underwent cell cycle and karyotype analysis at passages 5 and 10. The second group of cells was cocultured in medium with different concentrations of human skin extract D for the measurement of collagen concentration and cell count. In vivo, the subcultured fibroblasts were injected into nude mice subcutaneously. Biopsies were taken for morphology observation and specific collagen staining at 1, 2, and 3 months after injection. The results in vitro showed no significant differences in cell cycle distribution between passages 5 and 10. Cell proliferation and secretion were inhibited as the concentration of extract D increased. In vivo, the fibroblasts were remarkably denser on the experimental side with no dysplastic cells. Mitotic cells were easily observed at the end of the first month but were rare at the end of the third month. Type III collagen was detected at the end of the first month, while collagen type I was positive at the end of the second month. The content of both collagens increased as time passed. The above results indicated that the use of the autologous fibroblasts was safe, providing a basic support for clinical use of fibroblasts.

  11. Preclinical examination of clofarabine in pediatric ependymoma: intratumoral concentrations insufficient to warrant further study.

    PubMed

    Patel, Yogesh T; Jacus, Megan O; Boulos, Nidal; Dapper, Jason D; Davis, Abigail D; Vuppala, Pradeep K; Freeman, Burgess B; Mohankumar, Kumarasamypet M; Throm, Stacy L; Gilbertson, Richard J; Stewart, Clinton F

    2015-05-01

    Clofarabine, a deoxyadenosine analog, was an active anticancer drug in our in vitro high-throughput screening against mouse ependymoma neurospheres. To characterize the clofarabine disposition in mice for further preclinical efficacy studies, we evaluated the plasma and central nervous system disposition in a mouse model of ependymoma. A plasma pharmacokinetic study of clofarabine (45 mg/kg, IP) was performed in CD1 nude mice bearing ependymoma to obtain initial plasma pharmacokinetic parameters. These estimates were used to derive D-optimal plasma sampling time points for cerebral microdialysis studies. A simulation of clofarabine pharmacokinetics in mice and pediatric patients suggested that a dosage of 30 mg/kg IP in mice would give exposures comparable to that in children at a dosage of 148 mg/m(2). Cerebral microdialysis was performed to study the tumor extracellular fluid (ECF) disposition of clofarabine (30 mg/kg, IP) in the ependymoma cortical allografts. Plasma and tumor ECF concentration-time data were analyzed using a nonlinear mixed effects modeling approach. The median unbound fraction of clofarabine in mouse plasma was 0.79. The unbound tumor to plasma partition coefficient (K pt,uu: ratio of tumor to plasma AUCu,0-inf) of clofarabine was 0.12 ± 0.05. The model-predicted mean tumor ECF clofarabine concentrations were below the in vitro 1-h IC50 (407 ng/mL) for ependymoma neurospheres. Thus, our results show the clofarabine exposure reached in the tumor ECF was below that associated with an antitumor effect in our in vitro washout study. Therefore, clofarabine was de-prioritized as an agent to treat ependymoma, and further preclinical studies were not pursued.

  12. Preclinical examination of clofarabine in pediatric ependymoma: intratumoral concentrations insufficient to warrant further study.

    PubMed

    Patel, Yogesh T; Jacus, Megan O; Boulos, Nidal; Dapper, Jason D; Davis, Abigail D; Vuppala, Pradeep K; Freeman, Burgess B; Mohankumar, Kumarasamypet M; Throm, Stacy L; Gilbertson, Richard J; Stewart, Clinton F

    2015-05-01

    Clofarabine, a deoxyadenosine analog, was an active anticancer drug in our in vitro high-throughput screening against mouse ependymoma neurospheres. To characterize the clofarabine disposition in mice for further preclinical efficacy studies, we evaluated the plasma and central nervous system disposition in a mouse model of ependymoma. A plasma pharmacokinetic study of clofarabine (45 mg/kg, IP) was performed in CD1 nude mice bearing ependymoma to obtain initial plasma pharmacokinetic parameters. These estimates were used to derive D-optimal plasma sampling time points for cerebral microdialysis studies. A simulation of clofarabine pharmacokinetics in mice and pediatric patients suggested that a dosage of 30 mg/kg IP in mice would give exposures comparable to that in children at a dosage of 148 mg/m(2). Cerebral microdialysis was performed to study the tumor extracellular fluid (ECF) disposition of clofarabine (30 mg/kg, IP) in the ependymoma cortical allografts. Plasma and tumor ECF concentration-time data were analyzed using a nonlinear mixed effects modeling approach. The median unbound fraction of clofarabine in mouse plasma was 0.79. The unbound tumor to plasma partition coefficient (K pt,uu: ratio of tumor to plasma AUCu,0-inf) of clofarabine was 0.12 ± 0.05. The model-predicted mean tumor ECF clofarabine concentrations were below the in vitro 1-h IC50 (407 ng/mL) for ependymoma neurospheres. Thus, our results show the clofarabine exposure reached in the tumor ECF was below that associated with an antitumor effect in our in vitro washout study. Therefore, clofarabine was de-prioritized as an agent to treat ependymoma, and further preclinical studies were not pursued. PMID:25724157

  13. Selective small molecule angiotensin II type 2 receptor antagonists for neuropathic pain: preclinical and clinical studies.

    PubMed

    Smith, Maree T; Anand, Praveen; Rice, Andrew S C

    2016-02-01

    Neuropathic pain affects up to 10% of the general population, but drug treatments recommended for the treatment of neuropathic pain are associated with modest efficacy and/or produce dose-limiting side effects. Hence, neuropathic pain is an unmet medical need. In the past 2 decades, research on the pathobiology of neuropathic pain has revealed many novel pain targets for use in analgesic drug discovery programs. However, these efforts have been largely unsuccessful as molecules that showed promising pain relief in rodent models of neuropathic pain generally failed to produce analgesia in early phase clinical trials in patients with neuropathic pain. One notable exception is the angiotensin II type 2 (AT2) receptor that has clinical validity on the basis of a successful double-blind, randomized, placebo-controlled, clinical trial of EMA401, a highly selective, orally active, peripherally restricted AT2 receptor antagonist in patients with postherpetic neuralgia. In this study, we review research to date on target validation, efficacy, and mode of action of small molecule AT2 receptor antagonists in rodent models of peripheral neuropathic pain and in cultured human sensory neurons, the preclinical pharmacokinetics of these compounds, and the outcome of the above clinical trial.

  14. 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.

  15. 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. PMID:27509594

  16. Preclinical studies identify novel targeted pharmacological strategies for treatment of human malignant pleural mesothelioma

    PubMed Central

    Favoni, Roberto E; Daga, Antonio; Malatesta, Paolo; Florio, Tullio

    2012-01-01

    The incidence of human malignant pleural mesothelioma (hMPM) is still increasing worldwide. hMPM prognosis is poor even if the median survival time has been slightly improved after the introduction of the up-to-date chemotherapy. Nevertheless, large phase II/III trials support the combination of platinum derivatives and pemetrexed or raltitrexed, as preferred first-line schedule. Better understanding of the molecular machinery of hMPM will lead to the design and synthesis of novel compounds targeted against pathways identified as crucial for hMPM cell proliferation and spreading. Among them, several receptors tyrosine kinase show altered activity in subsets of hMPM. This observation suggests that these kinases might represent novel therapeutic targets in this chemotherapy-resistant disease. Over these foundations, several promising studies are ongoing at preclinical level and novel molecules are currently under evaluation as well. Yet, established tumour cell lines, used for decades to investigate the efficacy of anticancer agents, although still the main source of drug efficacy studies, after long-term cultures tend to biologically diverge from the original tumour, limiting the predictive potential of in vivo efficacy. Cancer stem cells (CSCs), a subpopulation of malignant cells capable of self-renewal and multilineage differentiation, are believed to play an essential role in cancer initiation, growth, metastasization and relapse, being responsible of chemo- and radiotherapy refractoriness. According to the current carcinogenesis theory, CSCs represent the tumour-initiating cell (TIC) fraction, the only clonogenic subpopulation able to originate a tumour mass. Consequently, the recently described isolation of TICs from hMPM, the proposed main pharmacological target for novel antitumoural drugs, may contribute to better dissect the biology and multidrug resistance pathways controlling hMPM growth. PMID:22289125

  17. Preclinical efficacy of a gastro-sparing novel thiazolidin-4-one in alleviating secondary lesions of polyarthritis: A multi-parametric approach.

    PubMed

    Mudgal, Jayesh; Gowdra, Vasantharaju S; Mudgal, Piya P; Nayak, Pawan G; Kumar, Nitesh; Attari, Zenab; Rao, C Mallikarjuna; Nampurath, Gopalan K

    2016-08-25

    The promising role of thiazolidin-4-ones (TZOs) against inflammatory conditions has been reported. From our lab, one of the TZO derivatives, compound 4C, exerted anti-inflammatory potential via inhibition of locally released cytokines and prostaglandin. In continuance, a detailed study was undertaken for the preclinical profiling of this promising TZO derivative against polyarthritis in rats, along with assessment of risk associated with the treatment. Male Sprague-Dawley rats were used for the adjuvant-induced arthritis (AIA) model. Based on the development of secondary lesion, the animals were randomized into different treatment groups. To establish the efficacy of the test compound, parameters such as inflammation, pain, disease progression, cytokines and prostaglandin (PG)-E2 levels and complete blood cell profile were recorded along with radiological and histological examinations of joints. The study also focused on evaluating the side effect of test compound on gastric, liver, renal, blood and cardiovascular components. Compound 4C exerted promising therapeutic effect against secondary lesions in polyarthritis in rats. It limited the progression of chronic inflammation and associated pain in rats. Modulation of cytokine signalling and arachidonate metabolism by 4C was evident from inhibition of interleukin (IL)-6, tumor necrosis factor (TNF)-α and PGE2 generation in AIA rats. Comparatively, compound 4C was safer than diclofenac to cause gastric, liver, renal, blood and cardiovascular toxicities. These finding supports the efficacy and safety profile of 4C, a TZO derivative in limiting the progression of arthritis when administered orally. PMID:27283483

  18. 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

  19. Discovery and preclinical antitumor efficacy evaluations of LY32262 and LY33169.

    PubMed

    Corbett, Thomas H; White, Kathryn; Polin, Lisa; Kushner, Juiwanna; Paluch, Jennifer; Shih, Chuan; Grossman, Cora Sue

    2003-02-01

    The discoveries of a new antitumor agent (LY32262) (N-[2,4-dichlorobenzoyl]phenylsulfonamide) and a close analog (LY33169) are described. For this discovery, a disk-diffusion-soft-agar-colony-formation-assay was used to screen a portion of the Eli Lilly inventory, with the evaluation of each agent against normal cells, leukemic cells and several solid tumors, including a multidrug-resistant solid tumor (with marked selective cytotoxicity for Colon-38 and Human-Colon-15/MDR compared to normal fibroblasts and L1210 leukemic cells characterizing the discovery). In mice, LY32262 and/or LY33169 had curative activity against Colon Adenocarcinoma-38, Human Colon-116, Human Prostate LNCaP, and Human Breast WSU-Br-1. In addition, many other tumors were highly sensitive: Panc-03 = 2.4 log kill (LK); Panc-02 = 2.9-4.1 LK; Squamous Lung LC-12 = 2.1 LK; Colon-26 = 2.2 LK; AML1498 = 2.7 LK; Human Sm Cell Lung DMS-273 = 6.3 LK; Human Squamous Lung 165 = 3.7 LK; Human Ovarian BG-1 = 3.7 LK; Human Colon CX-1 (H29) = 1.6 LK; Human Colon-15/MDR (a p-glycoprotein positive multidrug resistant tumor) = 2.3 LK; Human CNS-gliosarcoma-SF295 = 3.8 LK. Several tumors were only marginally responsive or totally unresponsive: Mammary Adenocarcinoma-16/C = 0.6 LK; Mammary Adenocarcinoma-17 = no kill; Colon Adenocarcinoma-11 = no kill; L1210 leukemia = 1.3 LK; Human Prostate PC-3 = 0.5 LK; Human Adenosquamous Lung H125 = no kill; and Human Breast Adenocarcinoma MX-1 = 0.9 LK. There was no absolute tissue of origin correlation with antitumor efficacy, although colon tumors were most responsive and mammary tumors least responsive. The cause of the "hit and miss" efficacy has not been determined. PMID:12795528

  20. Tracking the extramedullary PML-RARα-positive cell reservoirs in a preclinical model: biomarker of long-term drug efficacy.

    PubMed

    Pokorna, Katerina; Le Pogam, Carole; Chopin, Martine; Balitrand, Nicole; Reboul, Murielle; Cassinat, Bruno; Chomienne, Christine; Padua, Rose Ann; Pla, Marika

    2013-02-01

    Using an acute promyelocytic leukemia (APL) preclinical model, we show that oncogene-specific PCR (Polymerase Chain Reaction)-based assays allow to evaluate the efficacy of immunotherapy combining all-trans retinoic acid (ATRA) and a DNA-based vaccine targeting the promyelocytic leukemia-retinoic acid receptor alpha (PML-RARα) oncogene. Kaplan-Meier survival analysis according to the peripheral blood PML-RARα normalized copy number (NCN) clearly shows that ATRA + DNA-treated mice with an NCN lower than 10 (43%) formed the group with a highly significant (p < 0.0001) survival advantage. Furthermore, a PCR assay was used to assess various tissues and organs for the presence of PML-RARα-positive cells in long-term survivors (n = 15). As expected, the majority of mice (n = 10) had no measurable tissue level of PML-RARα. However, five mice showed a weak positive signal in both the brain and spleen (n = 2), in the brain only (n = 2) and in the spleen only (n = 1). Thus tracking the oncogene-positive cells in long-term survivors reveals for the first time that extramedullary PML-RARα-positive cell reservoirs such as the brain may persist and be involved in relapses.

  1. Fluorescence detection of tumors: studies on the early diagnosis of microscopic lesions in preclinical and clinical studies

    NASA Astrophysics Data System (ADS)

    Mang, Thomas S.; McGinnis, Carolyn; Crean, David H.; Khan, S.; Liebow, Charles

    1991-06-01

    The growth of microscopic tumor lesions at or beyond treatment field lesions poses major problems in the diagnosis and curative treatment of numerous cancers. Early detection techniques which clearly define the extent of condemned or field spread of disease may improve the primary treatment of the disease. In vivo fluorescence photometry is a non-imaging technique which digitally displays relative fluorescence values in volts. The sensitivity of the instrument has allowed the detection of micrometastases in both pre-clinical and clinical studies using drug doses that are 80-90 lower than those used therapeutically. This technique is now being applied in preliminary experiments to the hamster cheek pouch models to (1) discern varying grades of dysplasia; (2) levels of uptake of the drug in normal growing and quiescent tumors. Results will be shown in two models in which this technique has shown to be efficacious preclinically in the Pollard rat adenocarcinoma model in which micrometastases in the lymph node have been detected, and preliminary studies involving the hamster cheek pouch model in which the pouch is painted with 9, 10 dimethyl-1, 2-benzanthracene (DMBA) for initiation and promotion of tumors. Clinically results will be shown in which fluorescence detection, confirmed by biopsy and histopathological examination, was capable of detecting the existence of micrometastatic involvement of less than 100 cells.

  2. Cognitive and emotional behavioural changes associated with methylphenidate treatment: a review of preclinical studies.

    PubMed

    Britton, Gabrielle B

    2012-02-01

    There is evidence from animal studies that repeated exposure to methylphenidate (MPH), a widely used psychostimulant for the treatment of attention deficit hyperactivity disorder (ADHD), produces behavioural, structural and neurochemical changes that persist long after drug administration has ended. However, the translational utility of much of this work is compromised by the use of drug doses and routes of administration that produce plasma and brain MPH levels that fall outside the clinical range, i.e. experimental parameters more relevant to drug abuse than ADHD. We used PubMed to identify pre-clinical studies that employed repeated MPH administration at low doses in young rodents and examined long-term effects on cognition, emotion, and brain structure and function. A review of this work suggests that repeated MPH treatment during early development can modify a number of cognitive, behavioural and brain processes, but these are reduced when low therapeutic doses are employed. Moreover, MPH sites of action extend beyond those implicated in ADHD. Studies that combined neurobiological and behavioural approaches provide important insights into the mechanisms underlying MPH-produced effects on cognitive and behavioural processes, which may be relevant to MPH therapeutic efficacy. There is an emerging consensus that pharmacological treatment of childhood psychiatric disorders produces persistent neuroadaptations, highlighting the need for studies that assess long-term effects of early developmental pharmacotherapy. In this regard, studies that mimic clinical therapy with rodents are useful experimental approaches for defining the behavioural and neural plasticity associated with stimulant therapy in paediatric populations.

  3. A Polymer-Based Antibody-Vinca Drug Conjugate Platform: Characterization and Preclinical Efficacy.

    PubMed

    Yurkovetskiy, Alexander V; Yin, Mao; Bodyak, Natalya; Stevenson, Cheri A; Thomas, Joshua D; Hammond, Charles E; Qin, LiuLiang; Zhu, Bangmin; Gumerov, Dmitry R; Ter-Ovanesyan, Elena; Uttard, Alex; Lowinger, Timothy B

    2015-08-15

    Antibody-drug conjugates (ADC) are an emerging drug class that uses antibodies to improve cytotoxic drug targeting for cancer treatment. ADCs in current clinical trials achieve a compromise between potency and physicochemical/pharmacokinetic properties by conjugating potent cytotoxins directly to an antibody at a 4:1 or less stoichiometric ratio. Herein, we report a novel, polyacetal polymer-based platform for creating ADC that use poly-1-hydroxymethylethylene hydroxymethyl-formal (PHF), also known as Fleximer. The high hydrophilicity and polyvalency properties of the Fleximer polymer can be used to produce ADC with high drug loading without compromising physicochemical and pharmacokinetic properties. Using trastuzumab and a vinca drug derivative to demonstrate the utility of this platform, a novel Fleximer-based ADC was prepared and characterized in vivo. The ADC prepared had a vinca-antibody ratio of 20:1. It exhibited a high antigen-binding affinity, an excellent pharmacokinetic profile and antigen-dependent efficacy, and tumor accumulation in multiple tumor xenograft models. Our findings illustrate the robust utility of the Fleximer platform as a highly differentiated alternative to the conjugation platforms used to create ADC currently in clinical development. PMID:26113086

  4. Assessing Immune-Related Adverse Events of Efficacious Combination Immunotherapies in Preclinical Models of Cancer.

    PubMed

    Liu, Jing; Blake, Stephen J; Harjunpää, Heidi; Fairfax, Kirsten A; Yong, Michelle C R; Allen, Stacey; Kohrt, Holbrook E; Takeda, Kazuyoshi; Smyth, Mark J; Teng, Michele W L

    2016-09-15

    New combination immunotherapies are displaying both efficacy and immune-related adverse events (irAE) in humans. However, grade 3/4 irAEs occur in a high proportion, which can lead to discontinuation of treatment and can result in fatalities if not promptly treated. Prolonged T regulatory cell (Treg) depletion in tumor-bearing Foxp3-DTR mice using diphtheria toxin (DT) mirrored the spectrum of antitumor responses and severity of irAEs that can occur in ipilimumab/nivolumab-treated patients. In contrast, transient Treg depletion or anti-CTLA-4/PD-1 therapy had equivalent effects in mice, lowering the immune tolerance threshold and allowing irAEs to be more easily induced following treatment with additional immunomodulatory antibodies. Transient Treg depletion of DT in combination with anti-PD-1 or anti-TIM-3 monoclonal antibodies had a high therapeutic window compared with DT plus anti-CD137. In contrast, DT plus anti-CD137-treated mice developed severe irAEs similar to grade 3/4 clinical symptoms. These irAEs appeared because of an infiltration of activated proliferating effector T cells in the tissues producing IFNγ and TNF; however, TNF blockade decreased irAEs severity without impacting on tumor growth. Cancer Res; 76(18); 5288-301. ©2016 AACR. PMID:27503925

  5. Standardization of the Filovirus Plaque Assay for Use in Preclinical Studies

    PubMed Central

    Shurtleff, Amy C.; Biggins, Julia E.; Keeney, Ashley E.; Zumbrun, Elizabeth E.; Bloomfield, Holly A.; Kuehne, Ana; Audet, Jennifer L.; Alfson, Kendra J.; Griffiths, Anthony; Olinger, Gene G.; Bavari, Sina

    2012-01-01

    The filovirus plaque assay serves as the assay of choice to measure infectious virus in a cell culture, blood, or homogenized tissue sample. It has been in use for more than 30 years and is the generally accepted assay used to titrate virus in samples from animals treated with a potential antiviral therapeutic or vaccine. As these animal studies are required for the development of vaccines and therapeutics under the FDA Animal Rule, it is essential to have a standardized assay to compare their efficacies against the various filoviruses. Here, we present an evaluation of the conditions under which the filovirus plaque assay performs best for the Ebola virus Kikwit variant and the Angola variant of Marburg virus. The indicator cell type and source, inoculum volumes, length of incubation and general features of filovirus biology as visualized in the assay are addressed in terms of the impact on the sample viral titer calculations. These optimization studies have resulted in a plaque assay protocol which can be used for preclinical studies, and as a standardized protocol for use across institutions, to aid in data comparison. This protocol will be validated for use in GLP studies supporting advanced development of filovirus therapeutics and vaccines. PMID:23223188

  6. Noninferiority of Shanghai Cingular biotech’s bovine pericardial valve preclinical study in juvenile ovine model

    PubMed Central

    Chen, Jin-Miao; Ding, Yu; Lu, Shu-Yang; Pan, Sun; Abudupataer, Mieradilijiang

    2016-01-01

    Background This study introduces a newly Chinese domestic-designed/manufactured bovine pericardial valve, the SCBC valve (Shanghai Cingular Biotech Corporation, Shanghai, China), and evaluates its hemodynamic performance and calcification potential compared with the Carpentier-Edwards (CE) PerimountTM valve (Edwards Lifesciences, Irvine, CA, USA) in juvenile sheep for preclinical study. Methods Five SCBC valves in study group and three CE PerimountTM valves (6900P with TFX) in control group were implanted in the mitral position of juvenile sheep and followed up for five months. Transthoracic echocardiography (TTE) for hemodynamic measurement was performed ten days, three months and five months postoperatively. Valve calcification was assessed by X-ray after euthanasia. Other collected data included macroscopic examination, blood analysis, microorganism culture and histological assessment. Results All sheep in two groups lived to sacrifice without evidence of valvular dysfunction. The SCBC valve had similar hemodynamic performance and susceptibility of calcification compared with the CE PerimountTM valve in juvenile ovine model. In all other parameters, the SCBC valve also exhibited no significant difference compared with the CE PerimountTM valve. Conclusions Our study demonstrated that the SCBC valve can exhibit similar mid-term satisfactory safety and efficacy compared with the CE PerimountTM valve in the mitral position of juvenile sheep model. PMID:27293835

  7. The effect of learning styles and study behavior on success of preclinical students in pharmacology

    PubMed Central

    Asci, Halil; Kulac, Esin; Sezik, Mekin; Cankara, F. Nihan; Cicek, Ekrem

    2016-01-01

    Objectives: To evaluate the effect of learning styles and study behaviors on preclinical medical students’ pharmacology exam scores in a non-Western setting. Materials and Methods: Grasha–Reichmann Student Learning Study Scale and a modified Study Behavior Inventory were used to assess learning styles and study behaviors of preclinical medical students (n = 87). Logistic regression models were used to evaluate the independent effect of gender, age, learning style, and study behavior on pharmacology success. Results: Collaborative (40%) and competitive (27%) dominant learning styles were frequent in the cohort. The most common study behavior subcategories were study reading (40%) and general study habits (38%). Adequate listening and note-taking skills were associated with pharmacology success, whereas students with adequate writing skills had lower exam scores. These effects were independent of gender. Conclusions: Preclinical medical students’ study behaviors are independent predictive factors for short-term pharmacology success. PMID:26997716

  8. Miltefosine Lipid Nanocapsules for Single Dose Oral Treatment of Schistosomiasis Mansoni: A Preclinical Study

    PubMed Central

    Eissa, Maha M.; El-Moslemany, Riham M.; Ramadan, Alyaa A.; Amer, Eglal I.; El-Azzouni, Mervat Z.; El-Khordagui, Labiba K.

    2015-01-01

    Miltefosine (MFS) is an alkylphosphocholine used for the local treatment of cutaneous metastases of breast cancer and oral therapy of visceral leishmaniasis. Recently, the drug was reported in in vitro and preclinical studies to exert significant activity against different developmental stages of schistosomiasis mansoni, a widespread chronic neglected tropical disease (NTD). This justified MFS repurposing as a potential antischistosomal drug. However, five consecutive daily 20 mg/kg doses were needed for the treatment of schistosomiasis mansoni in mice. The present study aims at enhancing MFS efficacy to allow for a single 20mg/kg oral dose therapy using a nanotechnological approach based on lipid nanocapsules (LNCs) as oral nanovectors. MFS was incorporated in LNCs both as membrane-active structural alkylphospholipid component and active antischistosomal agent. MFS-LNC formulations showed high entrapment efficiency (EE%), good colloidal properties, sustained release pattern and physical stability. Further, LNCs generally decreased MFS-induced erythrocyte hemolytic activity used as surrogate indicator of membrane activity. While MFS-free LNCs exerted no antischistosomal effect, statistically significant enhancement was observed with all MFS-LNC formulations. A maximum effect was achieved with MFS-LNCs incorporating CTAB as positive charge imparting agent or oleic acid as membrane permeabilizer. Reduction of worm load, ameliorated liver pathology and extensive damage of the worm tegument provided evidence for formulation-related efficacy enhancement. Non-compartmental analysis of pharmacokinetic data obtained in rats indicated independence of antischistosomal activity on systemic drug exposure, suggesting possible gut uptake of the stable LNCs and targeting of the fluke tegument which was verified by SEM. The study findings put forward MFS-LNCs as unique oral nanovectors combining the bioactivity of MFS and biopharmaceutical advantages of LNCs, allowing targeting

  9. Copper-64 Dichloride as Theranostic Agent for Glioblastoma Multiforme: A Preclinical Study.

    PubMed

    Ferrari, Cristina; Asabella, Artor Niccoli; Villano, Carlo; Giacobbi, Beatrice; Coccetti, Daniela; Panichelli, Paola; Rubini, Giuseppe

    2015-01-01

    Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults with a median survival time less than one year. To date, there are only a limited number of effective agents available for GBM therapy and this does not seem to add much survival advantage over the conventional approach based on surgery and radiotherapy. Therefore, the development of novel therapeutic approaches to GBM is essential and those based on radionuclide therapy could be of significant clinical impact. Experimental evidence has clearly demonstrated that cancer cells have a particularly high fractional content of copper inside the nucleus compared to normal cells. This behavior can be conveniently exploited both for diagnosis and for delivering therapeutic payloads (theranostic) of the radionuclide copper-64 into the nucleus of cancerous cells by intravenous administration of its simplest chemical form as dichloride salt [(64)Cu]CuCl2. To evaluate the potential theranostic role of [(64)Cu]CuCl2 in GBM, the present work reports results from a preclinical study carried out in a xenografted GBM tumor mouse model. Biodistribution data of this new agent were collected using a small-animal PET tomograph. Subsequently, groups of tumor implanted nude mice were treated with [(64)Cu]CuCl2 to simulate single- and multiple-dose therapy protocols, and results were analyzed to estimate therapeutic efficacy.

  10. Stem cell therapy for ischaemic stroke: translation from preclinical studies to clinical treatment.

    PubMed

    Balami, Joyce S; Fricker, Rosemary A; Chen, Ruoli

    2013-03-01

    No pharmacological intervention has been shown convincingly to improve neurological outcome in stroke patients after the brain tissue is infarcted. While conventional therapeutic strategies focus on preventing brain damage, stem cell treatment has the potential to repair the injured brain tissue. Stem cells not only produce a source of trophic molecules to minimize brain damage caused by ischaemia/reperfusion and promote recovery, but also potentially turn to new cells to replace those lost in ischaemic core. Although preclinical studies have shown promise, stem cell therapy for stroke treatment in human is still at an early stage and it is difficult to draw conclusions from current clinical trials about the efficacy of the different treatments used in humans. This article reviews the potential of various types of stem cells, from embryonic to adult to induced pluripotent stem cells, in stroke therapy, highlights new evidence from the ongoing clinical trials and discusses some of the problems associated with translating stem cell technology to a clinical therapy for stroke. PMID:23394533

  11. Enhanced preclinical efficacy of tamoxifen developed as alginate-cysteine/disulfide bond reduced albumin nanoparticles.

    PubMed

    Martínez, A; Muñiz, E; Iglesias, I; Teijón, J M; Blanco, M D

    2012-10-15

    Tamoxifen (TMX) is the most common clinical choice for the treatment of advanced or metastatic estrogen-dependent breast cancer. However, research on new challenging therapies is necessary due to its undesirable side effects and the limitation of the treatment only to the oral route. In this study, the antitumor activity of TMX-loaded nanoparticles based on different mixtures of alginate-cysteine and disulfide bond reduced bovine serum albumin was tested in vivo in MCF-7 nude mice xenograft model. These systems showed an enhancement of the TMX antitumor activity, since lower tumor evolutions and lower tumor growth rates were observed in mice treated with them. Moreover, histological and immunohistochemical studies revealed that treatments with TMX-loaded nanoparticles showed the most regressive and less proliferative tumor tissues. TMX biodistribution studies determined that TMX-loaded nanoparticles caused more accumulation of the drug into the tumor site with undetectable levels of TMX in plasma, reducing the possibility of delivering TMX to other not-targeted organs and, consequently, developing possible side effects. Thus, these TMX nanoparticulate systems are expected to provide a novel approach to the treatment of breast cancer in the future. PMID:22850290

  12. Potent efficacy of metronomic topotecan and pazopanib combination therapy in preclinical models of primary or late stage metastatic triple-negative breast cancer

    PubMed Central

    Man, Shan; Bocci, Guido; Kerbel, Robert S.

    2015-01-01

    Metronomic chemotherapy has shown promising activity in numerous preclinical studies and also some phase II clinical studies involving various tumor types, and is currently undergoing phase III trial evaluation. Triple-negative breast cancer (TNBC) is an aggressive histological subtype with limited treatment options and very poor prognosis following progression after standard chemotherapeutic regimens. Herein, we evaluated the potential therapeutic impact and molecular mechanisms of topotecan administered in a continuous low-dose metronomic (LDM) manner, alone or in concurrent combination with pazopanib, an antiangiogenic tyrosine kinase inhibitor (TKI), in a triple-negative, primary and metastatic breast cancer orthotopic model; potential molecular mechanisms of efficacy were also studied, especially the impact of hypoxic conditions. The combination of metronomic topotecan and pazopanib significantly enhanced antitumor activity compared to monotherapy with either drug and prolonged survival, even in the advanced metastatic survival setting, with a marked decrease in tumor vascularity, proliferative index, and the induction of apoptosis. Significant changes in tumor angiogenesis, cancer cell proliferation, apoptosis, HIF1α levels, HIF-1 target genes and ABCG2 were found both in vitro and in tumor tissue. Notably, the pazopanib and metronomic topotecan combination treatment inhibited expression of HIF1α and ABCG2 genes in cells grown under hypoxic conditions, and this was associated with an increased intracellular concentration of the active form of topotecan. Our results suggest a potential novel therapeutic option for the treatment of metastatic triple-negative breast cancer patients. PMID:26623560

  13. Magnetic Fluid Hyperthermia for Bladder Cancer: A Preclinical Dosimetry Study

    PubMed Central

    Oliveira, Tiago R.; Stauffer, Paul R.; Lee, Chen-Ting; Landon, Chelsea D.; Etienne, Wiguins; Ashcraft, Kathleen A.; McNerny, Katie L.; Mashal, Alireza; Nouls, John; Maccarini, Paolo F.; Beyer, Wayne F.; Inman, Brant; Dewhirst, Mark W.

    2014-01-01

    Purpose This paper describes a preclinical investigation of the feasibility of thermotherapy treatment of bladder cancer with Magnetic Fluid Hyperthermia (MFH), performed by analyzing the thermal dosimetry of nanoparticle heating in a rat bladder model. Materials and Methods The bladders of twenty-five female rats were instilled with magnetite-based nanoparticles, and hyperthermia was induced using a novel small animal magnetic field applicator (Actium Biosystems, Boulder, CO). We aimed to increase the bladder lumen temperature to 42°C in <10 min and maintain that temperature for 60 min. Temperatures were measured within the bladder lumen and throughout the rat with seven fiberoptic probes (OpSens Technologies, Quebec, Canada). An MRI analysis was used to confirm the effectiveness of the catheterization method to deliver and maintain various nanoparticle volumes within the bladder. Thermal dosimetry measurements recorded the temperature rise of rat tissues for a variety of nanoparticle exposure conditions. Results Thermal dosimetry data demonstrated our ability to raise and control the temperature of rat bladder lumen ≥1°C/min to a steady-state of 42°C with minimal heating of surrounding normal tissues. MRI scans confirmed the homogenous nanoparticle distribution throughout the bladder. Conclusion These data demonstrate that our MFH system with magnetite-based nanoparticles provide well-localized heating of rat bladder lumen with effective control of temperature in the bladder and minimal heating of surrounding tissues. PMID:24050253

  14. Efficacy, safety, and use of ginkgo biloba in clinical and preclinical applications.

    PubMed

    McKenna, D J; Jones, K; Hughes, K

    2001-01-01

    Ginkgo biloba is a dioecious tree with a history of use in traditional Chinese medicine. Although the seeds are most commonly employed in traditional Chinese medicine, in recent years standardized extracts of the leaves have been widely sold as a phytomedicine in Europe and as a dietary supplement in the United States. The primary active constituents of the leaves include flavonoid glycosides and unique diterpenes known as ginkgolides; the latter are potent inhibitors of platelet activating factor. Clinical studies have shown that ginkgo extracts exhibit therapeutic activity in a variety of disorders including Alzheimer's disease, failing memory, age-related dementias, poor cerebral and ocular blood flow, congestive symptoms of premenstrual syndrome, and the prevention of altitude sickness. Due in part to its potent antioxidant properties and ability to enhance peripheral and cerebral circulation, ginkgo's primary application lies in the treatment of cerebrovascular dysfunctions and peripheral vascular disorders.

  15. What level of accuracy is achievable for preclinical dose painting studies on a clinical irradiation platform?

    PubMed

    Trani, Daniela; Reniers, Brigitte; Persoon, Lucas; Podesta, Mark; Nalbantov, Georgi; Leijenaar, Ralph T H; Granzier, Marlies; Yaromina, Ala; Dubois, Ludwig; Verhaegen, Frank; Lambin, Philippe

    2015-05-01

    Advancements made over the past decades in both molecular imaging and radiotherapy planning and delivery have enabled studies that explore the efficacy of heterogeneous radiation treatment ("dose painting") of solid cancers based on biological information provided by different imaging modalities. In addition to clinical trials, preclinical studies may help contribute to identifying promising dose painting strategies. The goal of this current study was twofold: to develop a reproducible positioning and set-up verification protocol for a rat tumor model to be imaged and treated on a clinical platform, and to assess the dosimetric accuracy of dose planning and delivery for both uniform and positron emission tomography-computed tomography (PET-CT) based heterogeneous dose distributions. We employed a syngeneic rat rhabdomyosarcoma model, which was irradiated by volumetric modulated arc therapy (VMAT) with uniform or heterogeneous 6 MV photon dose distributions. Mean dose to the gross tumor volume (GTV) as a whole was kept at 12 Gy for all treatment arms. For the nonuniform plans, the dose was redistributed to treat the 30% of the GTV representing the biological target volume (BTV) with a dose 40% higher than the rest of the GTV (GTV - BTV) (~15 Gy was delivered to the BTV vs. ~10.7 Gy was delivered to the GTV - BTV). Cone beam computed tomography (CBCT) images acquired for each rat prior to irradiation were used to correctly reposition the tumor and calculate the delivered 3D dose. Film quality assurance was performed using a water-equivalent rat phantom. A comparison between CT or CBCT doses and film measurements resulted in passing rates >98% with a gamma criterion of 3%/2 mm using 2D dose images. Moreover, between the CT and CBCT calculated doses for both uniform and heterogeneous plans, we observed maximum differences of <2% for mean dose to the tumor and mean dose to the biological target volumes. In conclusion, we have developed a robust method for dose painting

  16. Nanomedicine-nanoemulsion formulation improves safety and efficacy of the anti-cancer drug paclitaxel according to preclinical assessment.

    PubMed

    Lee, King C; Maturo, Claudia; Rodriguez, Robert; Nguyen, Hoang-Lan; Shorr, Robert

    2011-08-01

    Paclitaxel is an important anticancer drug and is currently used to treat a variety of cancers, including ovarian carcinomas, breast cancer, non-small cell lung cancer, and AIDS-related Kaposi's sarcoma. The objectives of the studies were to assess and compare the safety and efficacy of EmPAC (a newly developed nanoemulsion formulation of paclitaxel) versus Taxol (the injectable formulation of paclitaxel involving the use of polyethylated or polyoxyl castor oil currently used in the clinic). The objectives were also to investigate the mechanism for the improved safety and efficacy of EmPAC over Taxol. These results showed that EmPAC had better anti-tumor efficacy than Taxol, according to in vitro cell culture studies and studies in animal tumor models. EmPAC had improved anti-tumor efficacy even in tumor cell lines that are known to be multi-drug resistant. Part of the mechanism of action for the improved efficacy may be related to EmPAC inducing greater cellular uptake of paclitaxel into tumor cells than Taxol did, according to the in vitro cell culture radioactive-labeled studies and in vitro cell culture antibody studies. It may also partly be because EmPAC delivered more paclitaxel to the tumor mass than Taxol, while the delivery of paclitaxel to other tissues (e.g., blood, muscle, liver, spleen, kidney and lung) were similar between the two formulations of paclitaxel, according to studies in animals with tumor xenograft. EmPAC also had better safety than Taxol according to toxicology studies in rabbits. This may be because EmPAC does not contain the toxic ingredients used in formulating Taxol (such as polyethylated or polyoxyl castor oil). These results support the clinical development of the nanoemulsion formulation of paclitaxel.

  17. Ethical challenges in preclinical Alzheimer's disease observational studies and trials: Results of the Barcelona summit.

    PubMed

    Molinuevo, José L; Cami, Jordi; Carné, Xavier; Carrillo, Maria C; Georges, Jean; Isaac, Maria B; Khachaturian, Zaven; Kim, Scott Y H; Morris, John C; Pasquier, Florence; Ritchie, Craig; Sperling, Reisa; Karlawish, Jason

    2016-05-01

    Alzheimer's disease (AD) is among the most significant health care burdens. Disappointing results from clinical trials in late-stage AD persons combined with hopeful results from trials in persons with early-stage suggest that research in the preclinical stage of AD is necessary to define an optimal therapeutic success window. We review the justification for conducting trials in the preclinical stage and highlight novel ethical challenges that arise and are related to determining appropriate risk-benefit ratios and disclosing individuals' biomarker status. We propose that to conduct clinical trials with these participants, we need to improve public understanding of AD using unified vocabulary, resolve the acceptable risk-benefit ratio in asymptomatic participants, and disclose or not biomarker status with attention to study type (observational studies vs clinical trials). Overcoming these challenges will justify clinical trials in preclinical AD at the societal level and aid to the development of societal and legal support for trial participants.

  18. Ethical challenges in preclinical Alzheimer's disease observational studies and trials: Results of the Barcelona summit.

    PubMed

    Molinuevo, José L; Cami, Jordi; Carné, Xavier; Carrillo, Maria C; Georges, Jean; Isaac, Maria B; Khachaturian, Zaven; Kim, Scott Y H; Morris, John C; Pasquier, Florence; Ritchie, Craig; Sperling, Reisa; Karlawish, Jason

    2016-05-01

    Alzheimer's disease (AD) is among the most significant health care burdens. Disappointing results from clinical trials in late-stage AD persons combined with hopeful results from trials in persons with early-stage suggest that research in the preclinical stage of AD is necessary to define an optimal therapeutic success window. We review the justification for conducting trials in the preclinical stage and highlight novel ethical challenges that arise and are related to determining appropriate risk-benefit ratios and disclosing individuals' biomarker status. We propose that to conduct clinical trials with these participants, we need to improve public understanding of AD using unified vocabulary, resolve the acceptable risk-benefit ratio in asymptomatic participants, and disclose or not biomarker status with attention to study type (observational studies vs clinical trials). Overcoming these challenges will justify clinical trials in preclinical AD at the societal level and aid to the development of societal and legal support for trial participants. PMID:26988427

  19. Drugs under preclinical and clinical study for treatment of acute and chronic lymphoblastic leukemia

    PubMed Central

    Jacob, Joe Antony; Salmani, Jumah Masoud Mohammad; Chen, Baoan

    2016-01-01

    Targeted therapy has modernized the treatment of both chronic and acute lymphoblastic leukemia. The introduction of monoclonal antibodies and combinational drugs has increased the survival rate of patients. Preclinical studies with various agents have resulted in positive outputs with Phase III trial drugs and monoclonal antibodies entering clinical trials. Most of the monoclonal antibodies target the CD20 and CD22 receptors. This has led to the approval of a few of these drugs by the US Food and Drug Administration. This review focuses on the drugs under preclinical and clinical study in the ongoing efforts for treatment of acute and chronic lymphoblastic leukemia. PMID:27382259

  20. Pre-clinical immunotoxicity studies of nanotechnology-formulated drugs: Challenges, considerations and strategy.

    PubMed

    Dobrovolskaia, Marina A

    2015-12-28

    Assorted challenges in physicochemical characterization, sterilization, depyrogenation, and in the assessment of pharmacology, safety, and efficacy profiles accompany pre-clinical development of nanotechnology-formulated drugs. Some of these challenges are not unique to nanotechnology and are common in the development of other pharmaceutical products. However, nanoparticle-formulated drugs are biochemically sophisticated, which causes their translation into the clinic to be particularly complex. An understanding of both the immune compatibility of nanoformulations and their effects on hematological parameters is now recognized as an important step in the (pre)clinical development of nanomedicines. An evaluation of nanoparticle immunotoxicity is usually performed as a part of a traditional toxicological assessment; however, it often requires additional in vitro and in vivo specialized immuno- and hematotoxicity tests. Herein, I review literature examples and share the experience with the NCI Nanotechnology Characterization Laboratory assay cascade used in the early (discovery-level) phase of pre-clinical development to summarize common challenges in the immunotoxicological assessment of nanomaterials, highlight considerations and discuss solutions to overcome problems that commonly slow or halt the translation of nanoparticle-formulated drugs toward clinical trials. Special attention will be paid to the grand-challenge related to detection, quantification and removal of endotoxin from nanoformulations, and practical considerations related to this challenge.

  1. Magnetic Drug Targeting: Preclinical in Vivo Studies, Mathematical Modeling, and Extrapolation to Humans.

    PubMed

    Al-Jamal, Khuloud T; Bai, Jie; Wang, Julie Tzu-Wen; Protti, Andrea; Southern, Paul; Bogart, Lara; Heidari, Hamed; Li, Xinjia; Cakebread, Andrew; Asker, Dan; Al-Jamal, Wafa T; Shah, Ajay; Bals, Sara; Sosabowski, Jane; Pankhurst, Quentin A

    2016-09-14

    A sound theoretical rationale for the design of a magnetic nanocarrier capable of magnetic capture in vivo after intravenous administration could help elucidate the parameters necessary for in vivo magnetic tumor targeting. In this work, we utilized our long-circulating polymeric magnetic nanocarriers, encapsulating increasing amounts of superparamagnetic iron oxide nanoparticles (SPIONs) in a biocompatible oil carrier, to study the effects of SPION loading and of applied magnetic field strength on magnetic tumor targeting in CT26 tumor-bearing mice. Under controlled conditions, the in vivo magnetic targeting was quantified and found to be directly proportional to SPION loading and magnetic field strength. Highest SPION loading, however, resulted in a reduced blood circulation time and a plateauing of the magnetic targeting. Mathematical modeling was undertaken to compute the in vivo magnetic, viscoelastic, convective, and diffusive forces acting on the nanocapsules (NCs) in accordance with the Nacev-Shapiro construct, and this was then used to extrapolate to the expected behavior in humans. The model predicted that in the latter case, the NCs and magnetic forces applied here would have been sufficient to achieve successful targeting in humans. Lastly, an in vivo murine tumor growth delay study was performed using docetaxel (DTX)-encapsulated NCs. Magnetic targeting was found to offer enhanced therapeutic efficacy and improve mice survival compared to passive targeting at drug doses of ca. 5-8 mg of DTX/kg. This is, to our knowledge, the first study that truly bridges the gap between preclinical experiments and clinical translation in the field of magnetic drug targeting. PMID:27541372

  2. Combined targeting of EGFR-dependent and VEGF-dependent pathways: rationale, preclinical studies and clinical applications.

    PubMed

    Tortora, Giampaolo; Ciardiello, Fortunato; Gasparini, Giampietro

    2008-09-01

    Cellular heterogeneity, redundancy of molecular pathways and effects of the microenvironment contribute to the survival, motility and metastasis of cells in solid tumors. It is unlikely that tumors are entirely dependent on only one abnormally activated signaling pathway; consequently, treatment with an agent that interferes with a single target may be insufficient. Combined blockade of functionally linked and relevant multiple targets has become an attractive therapeutic strategy. The EGFR and ERBB2 (HER2) pathways and VEGF-dependent angiogenesis have a pivotal role in cancer pathogenesis and progression. Robust experimental evidence has shown that these pathways are functionally linked and has demonstrated a suggested role for VEGF in the acquired resistance to anti-ERBB drugs when these receptors are pharmacologically blocked. Combined inhibition of ERBB and VEGF signaling interferes with a molecular feedback loop responsible for acquired resistance to anti-ERBB agents and promotes apoptosis while ablating tumor-induced angiogenesis. To this aim, either two agents highly selective against VEGF and ERBB respectively, or, alternatively, a single multitargeted agent, can be used. Preclinical studies have proven the efficacy of both these approaches and early clinical studies have provided encouraging results. This Review discusses the experimental rationale for, preclinical studies of and clinical trials on combined blockade of ERBB and VEGF signaling.

  3. Exploratory Study of Factors Related to Educational Scores of First Preclinical Year Medical Students

    ERIC Educational Resources Information Center

    Sitticharoon, Chantacha; Srisuma, Sorachai; Kanavitoon, Sawita; Summachiwakij, Sarawut

    2014-01-01

    The relationships among the scores of major subjects taught in the first preclinical year of a Thai medical school, previous academic achievements, and daily life activities are rarely explored. We therefore performed an exploratory study identifying various factors possibly related to the educational scores of these medical students.…

  4. Preclinical toxicity evaluation of AAV for pain: evidence from human AAV studies and from the pharmacology of analgesic drugs

    PubMed Central

    2014-01-01

    Gene therapy with adeno-associated virus (AAV) has advanced in the last few years from promising results in animal models to >100 clinical trials (reported or under way). While vector availability was a substantial hurdle a decade ago, innovative new production methods now routinely match the scale of AAV doses required for clinical testing. These advances may become relevant to translational research in the chronic pain field. AAV for pain targeting the peripheral nervous system was proven to be efficacious in rodent models several years ago, but has not yet been tested in humans. The present review addresses the steps needed for translation of AAV for pain from the bench to the bedside focusing on pre-clinical toxicology. We break the potential toxicities into three conceptual categories of risk: First, risks related to the delivery procedure used to administer the vector. Second, risks related to AAV biology, i.e., effects of the vector itself that may occur independently of the transgene. Third, risks related to the effects of the therapeutic transgene. To identify potential toxicities, we consulted the existing evidence from AAV gene therapy for other nervous system disorders (animal toxicology and human studies) and from the clinical pharmacology of conventional analgesic drugs. Thereby, we identified required preclinical studies and charted a hypothetical path towards a future phase I/II clinical trial in the oncology-palliative care setting. PMID:25183392

  5. 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…

  6. Effect of Currently Approved Carriers and Adjuvants on the Pre-Clinical Efficacy of a Conjugate Vaccine against Oxycodone in Mice and Rats

    PubMed Central

    Pravetoni, Marco; Vervacke, Jeffrey S.; Distefano, Mark D.; Tucker, Ashli M.; Laudenbach, Megan; Pentel, Paul R.

    2014-01-01

    Vaccination against the highly abused prescription opioid oxycodone has shown pre-clinical efficacy for blocking oxycodone effects. The current study further evaluated a candidate vaccine composed of oxycodone derivatized at the C6 position (6OXY) conjugated to the native keyhole limpet hemocyanin (nKLH) carrier protein. To provide an oxycodone vaccine formulation suitable for human studies, we studied the effect of alternative carriers and adjuvants on the generation of oxycodone-specific serum antibody and B cell responses, and the effect of immunization on oxycodone distribution and oxycodone-induced antinociception in mice and rats. 6OXY conjugated to tetanus toxoid (TT) or a GMP grade KLH dimer (dKLH) was as effective as 6OXY conjugated to the nKLH decamer in mice and rats, while the 6OXY hapten conjugated to a TT-derived peptide was not effective in preventing oxycodone-induced antinociception in mice. Immunization with 6OXY-TT s.c. absorbed on alum adjuvant provided similar protection to 6OXY-TT administered i.p. with Freund’s adjuvant in rats. The toll-like receptor 4 (TLR4) agonist monophosphoryl lipid A (MPLA) adjuvant, alone or in combination with alum, offered no advantage over alum alone for generating oxycodone-specific serum antibodies or 6OXY-specific antibody secreting B cells in mice vaccinated with 6OXY-nKLH or 6OXY-TT. The immunogenicity of oxycodone vaccines may be modulated by TLR4 signaling since responses to 6OXY-nKLH in alum were decreased in TLR4-deficient mice. These data suggest that TT, nKLH and dKLH carriers provide consistent 6OXY conjugate vaccine immunogenicity across species, strains and via different routes of administration, while adjuvant formulations may need to be tailored to individual immunogens or patient populations. PMID:24797666

  7. A phase III, randomized, double-blind, matched-pairs, active-controlled clinical trial and preclinical animal study to compare the durability, efficacy and safety between polynucleotide filler and hyaluronic acid filler in the correction of crow's feet: a new concept of regenerative filler.

    PubMed

    Pak, Chang Sik; Lee, Jongho; Lee, Hobin; Jeong, Jaehoon; Kim, Eun-Hee; Jeong, Jinwook; Choi, Hyeyeon; Kim, Byunghwi; Oh, Sujin; Kim, Iksoo; Heo, Chan Yeong

    2014-11-01

    The Rejuran® is a new filler product made from purified polynucleotides. Here we present data from an animal study and a clinical trial to examine the durability, efficacy and safety of the Rejuran® on crow's feet. For the animal study, 25 mice were divided into three groups: Group 1 received phosphate buffered saline (PBS); Group 2 were treated with Yvoire®; and Group 3 were treated with Rejuran®. The durability and efficacy of each treatment were assessed by microscopy and staining. In the clinical trial, 72 patients were randomized to receive Rejuran® treatment for crow's feet on one side and Yvoire-Hydro® on the contralateral side, at a ratio of 1:1. Repeated treatments were performed every two weeks for a total of three times, over a total of 12 weeks' observation. All injections and observations of efficacy and safety were performed by the same two investigators. In the animal study, the Rejuran® group showed similar durability and inflammatory response to the Yvoire® group. Upon efficacy assessment, the Rejuran® group showed the greatest elasticity and collagen composition, and a significant difference in skin surface roughness and wrinkle depth. In the clinical trial, the primary and secondary objective efficacy outcome measure showed no statistical significance between the two groups, and in safety outcomes there were no unexpected adverse effects. Our data suggest that the Rejuran®, as a new regenerative filler, can be useful to reduce wrinkles, by showing evidence for its efficacy and safety.

  8. Plant-based medicines for anxiety disorders, part 2: a review of clinical studies with supporting preclinical evidence.

    PubMed

    Sarris, Jerome; McIntyre, Erica; Camfield, David A

    2013-04-01

    Research in the area of herbal psychopharmacology has revealed a variety of promising medicines that may provide benefit in the treatment of general anxiety and specific anxiety disorders. However, a comprehensive review of plant-based anxiolytics has been absent to date. Thus, our aim was to provide a comprehensive narrative review of plant-based medicines that have clinical and/or preclinical evidence of anxiolytic activity. We present the article in two parts. In part one, we reviewed herbal medicines for which only preclinical investigations for anxiolytic activity have been performed. In this current article (part two), we review herbal medicines for which there have been both preclinical and clinical investigations of anxiolytic activity. A search of MEDLINE (PubMed), CINAHL, Scopus and the Cochrane Library databases was conducted (up to 28 October 2012) for English language papers using the search terms 'anxiety' OR 'anxiety disorder' OR 'generalized anxiety disorder' OR 'social phobia' OR 'post-traumatic stress disorder' OR 'panic disorder' OR 'agoraphobia' OR 'obsessive compulsive disorder' in combination with the search terms 'Herb*' OR 'Medicinal Plants' OR 'Botanical Medicine' OR 'Chinese herb*', in addition to individual herbal medicines. This search of the literature revealed 1,525 papers, of which 53 plants were included in the review (having at least one study using the whole plant extract). Of these plants, 21 had human clinical trial evidence (reviewed here in part two), with the other 32 having solely preclinical evidence (reviewed in part one). Support for efficacy was found for chronic use (i.e. greater than one day) of the following herbs in treating a range of anxiety disorders in human clinical trials: Piper methysticum, Matricaria recutita, Ginkgo biloba, Scutellaria lateriflora, Silybum marianum, Passiflora incarnata, Withania somniferum, Galphimia glauca, Centella asiatica, Rhodiola rosea, Echinacea spp., Melissa officinalis and Echium

  9. Plant-based medicines for anxiety disorders, part 2: a review of clinical studies with supporting preclinical evidence.

    PubMed

    Sarris, Jerome; McIntyre, Erica; Camfield, David A

    2013-04-01

    Research in the area of herbal psychopharmacology has revealed a variety of promising medicines that may provide benefit in the treatment of general anxiety and specific anxiety disorders. However, a comprehensive review of plant-based anxiolytics has been absent to date. Thus, our aim was to provide a comprehensive narrative review of plant-based medicines that have clinical and/or preclinical evidence of anxiolytic activity. We present the article in two parts. In part one, we reviewed herbal medicines for which only preclinical investigations for anxiolytic activity have been performed. In this current article (part two), we review herbal medicines for which there have been both preclinical and clinical investigations of anxiolytic activity. A search of MEDLINE (PubMed), CINAHL, Scopus and the Cochrane Library databases was conducted (up to 28 October 2012) for English language papers using the search terms 'anxiety' OR 'anxiety disorder' OR 'generalized anxiety disorder' OR 'social phobia' OR 'post-traumatic stress disorder' OR 'panic disorder' OR 'agoraphobia' OR 'obsessive compulsive disorder' in combination with the search terms 'Herb*' OR 'Medicinal Plants' OR 'Botanical Medicine' OR 'Chinese herb*', in addition to individual herbal medicines. This search of the literature revealed 1,525 papers, of which 53 plants were included in the review (having at least one study using the whole plant extract). Of these plants, 21 had human clinical trial evidence (reviewed here in part two), with the other 32 having solely preclinical evidence (reviewed in part one). Support for efficacy was found for chronic use (i.e. greater than one day) of the following herbs in treating a range of anxiety disorders in human clinical trials: Piper methysticum, Matricaria recutita, Ginkgo biloba, Scutellaria lateriflora, Silybum marianum, Passiflora incarnata, Withania somniferum, Galphimia glauca, Centella asiatica, Rhodiola rosea, Echinacea spp., Melissa officinalis and Echium

  10. MEK plus PI3K/mTORC1/2 therapeutic efficacy is impacted by TP53 mutation in preclinical models of colorectal cancer

    PubMed Central

    Ibrahim, Yasir H.; Calvo, María Teresa; Gris-Oliver, Albert; Rodríguez, Olga; Grueso, Judit; Antón, Pilar; Guzmán, Marta; Aura, Claudia; Nuciforo, Paolo; Jessen, Katti; Argilés, Guillem; Dienstmann, Rodrigo; Bertotti, Andrea; Trusolino, Livio; Matito, Judit; Vivancos, Ana; Chicote, Irene; Palmer, Héctor G.; Tabernero, Josep; Scaltriti, Maurizio; Baselga, José; Serra, Violeta

    2016-01-01

    Purpose PI3K-pathway activation occurs in concomitance with RAS/BRAF mutations in colorectal cancer (CRC) limiting the sensitivity to targeted therapies. Several clinical studies are being conducted to test the tolerability and clinical activity of dual MEK and PI3K-pathway blockade in solid tumors. Experimental design In the present study we explored the efficacy of dual pathway blockade in CRC preclinical models harboring concomitant activation of the ERK- and PI3K-pathways. Moreover, we investigated if TP53 mutation impacts the response to this therapy. Results Dual MEK and mTORC1/2 blockade resulted in synergistic antiproliferative effects in cell lines bearing alterations in KRAS/BRAF and PIK3CA/PTEN. Although the on-treatment cell cycle effects were not impacted by the TP53 status, a marked proapoptotic response to therapy was observed exclusively in wild-type TP53 CRC models. We further interrogated two independent panels of KRAS/BRAF- and PIK3CA/PTEN-altered cell line- and patient-derived tumor xenografts for the antitumor response towards this combination of agents. A combination-response that resulted in substantial antitumor activity was exclusively observed among the wild-type TP53-models (two out of five, 40%), while there was no such response across the eight mutant TP53 models (0%). Interestingly, within a cohort of fourteen CRC patients treated with these agents for their metastatic disease, two patients with long-lasting responses (32 weeks) had TP53 wild-type tumors. Conclusions Our data supports that in wild-type TP53-CRC cells with ERK- and PI3K-pathway alterations MEK-blockade results in potent p21-induction preventing apoptosis to occur. In turn, mTORC1/2 inhibition blocks MEK-inhibitor-mediated p21-induction, unleashing apoptosis. PMID:26272063

  11. Spinal Cord Tolerance in the Age of Spinal Radiosurgery: Lessons From Preclinical Studies

    SciTech Connect

    Medin, Paul M.; Boike, Thomas P.

    2011-04-01

    Clinical implementation of spinal radiosurgery has increased rapidly in recent years, but little is known regarding human spinal cord tolerance to single-fraction irradiation. In contrast, preclinical studies in single-fraction spinal cord tolerance have been ongoing since the 1970s. The influences of field length, dose rate, inhomogeneous dose distributions, and reirradiation have all been investigated. This review summarizes literature regarding single-fraction spinal cord tolerance in preclinical models with an emphasis on practical clinical significance. The outcomes of studies that incorporate uniform irradiation are surprisingly consistent among multiple small- and large-animal models. Extensive investigation of inhomogeneous dose distributions in the rat has demonstrated a significant dose-volume effect while preliminary results from one pig study are contradictory. Preclinical spinal cord dose-volume studies indicate that dose distribution is more critical than the volume irradiated suggesting that neither dose-volume histogram analysis nor absolute volume constraints are effective in predicting complications. Reirradiation data are sparse, but results from guinea pig, rat, and pig studies are consistent with the hypothesis that the spinal cord possesses a large capacity for repair. The mechanisms behind the phenomena observed in spinal cord studies are not readily explained and the ability of dose response models to predict outcomes is variable underscoring the need for further investigation. Animal studies provide insight into the phenomena and mechanisms of radiosensitivity but the true significance of animal studies can only be discovered through clinical trials.

  12. Therapeutic Applications of Incretin Mimetics for Metabolic Diseases: Preclinical Studies

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Exenatide (exendin-4) is an incretin mimetic peptide that shares several glucoregulatory actions with the endogenous incretin GLP-1. In addition to its actions on glucose control, exenatide produces effects to reduce food intake and body weight in all species studied. GLP-1 and exenatide have also b...

  13. A magnetic resonance (MR) compatible selective brain temperature manipulation system for preclinical study

    PubMed Central

    Liu, Qingwei; Cai, Yu; Lin, Weili; Turner, Gregory H; An, Hongyu

    2012-01-01

    There is overwhelming evidence that hypothermia can improve the outcome of an ischemic stroke. However, the most widely used systemic cooling method could lead to multiple side effects, while the incompatibility with magnetic resonance imaging of the present selective cooling methods highly limit their application in preclinical studies. In this study, we developed a magnetic resonance compatible selective brain temperature manipulation system for small animals, which can regulate brain temperature quickly and accurately for a desired period of time, while maintaining the normal body physiological conditions. This device was utilized to examine the relationship between T1 relaxation, cerebral blood flow, and temperature in brain tissue during magnetic resonance imaging of ischemic stroke. The results showed that this device can be an efficient brain temperature manipulation tool for preclinical studies needing local hypothermic or hyperthermic conditions. PMID:23166453

  14. From Bench to Bedside: Lessons Learned in Translating Preclinical Studies in Cancer Drug Development

    PubMed Central

    2013-01-01

    The development of targeted agents in oncology has rapidly expanded over the past 2 decades and has led to clinically significant improvements in the treatment of numerous cancers. Unfortunately, not all success at the bench in preclinical experiments has translated to success at the bedside. As preclinical studies shift toward defining proof of mechanism, patient selection, and rational drug combinations, it is critical to understand the lessons learned from prior translational studies to gain an understanding of prior drug development successes and failures. By learning from prior drug development, future translational studies will provide more clinically relevant data, and the underlying hope is that the clinical success rate will improve and the treatment of patients with ineffective targeted therapy will be limited. PMID:24052618

  15. Feasibility of a porcine oral mucosa equivalent: a preclinical study.

    PubMed

    Kinikoglu, Beste; Hemar, Julie; Hasirci, Vasif; Breton, Pierre; Damour, Odile

    2012-08-01

    Oral tissue engineering aims to treat and fill tissue deficits caused by congenital defects, facial trauma, or malignant lesion surgery, as well as to study the biology of oral mucosa. The Food and Drug Administration (FDA) and the European Medicines Agency (EMA) require a large animal model to evaluate cell-based devices, including tissue-engineered oral mucosa, prior to initiating human clinical studies. Porcine oral mucosa is non-keratinized and resembles that of humans more closely than any other animal in terms of structure and composition; however, there have not been any reports on the reconstruction of a porcine oral mucosa equivalent, probably due to the difficulty to culture porcine fibroblasts. In this study, we demonstrate the feasibility of a 3D porcine oral mucosa equivalent based on a collagen-GAG-chitosan scaffold, as well as reconstructed porcine epithelium by using an amniotic membrane as support, or without any support in form of epithelial cell sheets by using thermoresponsive culture plates. Explants technique was used for the isolation of the porcine fibroblasts and a modified fibroblast medium containing 20% fetal calf serum was used for their culture. The histological and transmission electron microscopic analyses of the resulting porcine oral mucosa models showed the presence of non-keratinized epithelia expressing keratin 13, the major differentiation marker of non-keratinized oral mucosa, in all models, and the presence of newly synthesized collagen fibers in the lamina propria equivalent of the full-thickness model, indicating the functionality of porcine fibroblasts. PMID:22309108

  16. Preclinical studies of indapamide, a new 2-methylindoline antihypertensive diuretic

    SciTech Connect

    Pruss, T.; Wolf, P.S.

    1983-07-01

    Indapamide is a new indoline antihypertensive diuretic agent whose chemical structure differs substantially from those of the thiazides. The hydrophobic indoline moiety of indapamide confers a lipid solubility to the molecule that is 5 to 80 times greater than that of the thiazide diuretics. Thus indapamide accumulates in vascular smooth muscle at a concentration 10 times higher than that of protein-free perfusate. The affinity of indapamide for vascular smooth muscle manifests itself in vitro and in vivo as a decrease in reactivity following various pharmacologic interventions. Moreover, in vitro studies have demonstrated that indapamide decreases the inward calcium current and the transmembrane influx of calcium. The diuretic effect of indapamide is predominantly due to inhibition of sodium reabsorption at the cortical diluting segment of the distal convoluted tubule. In animal studies, intravenous indapamide has no effect on glomerular filtration rate or renal blood flow. Indapamide is well absorbed and extensively metabolized in animals and humans, with biliary excretion being the predominant route of elimination in animals. Most important, repeat administration of indapamide to dogs with both kidneys removed produces no accumulation of intact indapamide or its metabolites. Extensive drug safety studies in animals indicate that indapamide produces no overt toxicity and exhibits a good margin of safety.

  17. Preclinical safety, pharmacokinetics, pharmacodynamics, and biodistribution studies with Ad35K++ protein: a novel rituximab cotherapeutic

    PubMed Central

    Richter, Maximilian; Yumul, Roma; Saydaminova, Kamola; Wang, Hongjie; Gough, Michael; Baldessari, Audrey; Cattaneo, Roberto; Lee, Frank; Wang, Chung-Huei Katherine; Jang, Haishan; Astier, Anne; Gopal, Ajay; Carter, Darrick; Lieber, André

    2016-01-01

    Rituximab is a mouse/human chimeric monoclonal antibody targeted toward CD20. It is efficient as first-line therapy of CD20-positive B-cell malignancies. However, a large fraction of treated patients relapse with rituximab-resistant disease. So far, only modest progress has been made in treatment options for rituximab refractory patients. One of the mechanisms for rituximab resistance involves the upregulation of CD46, which is a key cell surface protein that blocks the activation of complement. We have recently developed a technology that depletes CD46 from the cell surface and thereby sensitizes tumor cells to complement-dependent cytotoxicity. This technology is based on a small recombinant protein, Ad35K++ that binds with high affinity to CD46. In preliminary studies using a 6 × histidinyl tagged protein, we had demonstrated that intravenous Ad35K++ injection in combination with rituximab was safe and increased rituximab-mediated killing of CD20-positive target cells in mice and nonhuman primates (NHPs). The presence of the tag, while allowing for easy purification by Ni-NTA chromatography, has the potential to increase the immunogenicity of the recombinant protein. For clinical application, we therefore developed an Ad35K++ protein without His-tag. In the present study, we performed preclinical studies in two animal species (mice and NHPs) with this protein demonstrating its safety and efficacy. These studies estimated the Ad35K++ dose range and treatment regimen to be used in patients. Furthermore, we showed that intravenous Ad35K++ injection triggers the shedding of the CD46 extracellular domain in xenograft mouse tumor models and in macaques. Shed serum CD46 can be measured in the serum and can potentially be used as a pharmacodynamic marker for monitoring Ad35K++ activity in patient undergoing treatment with this agent. These studies create the basis for an investigational new drug application for the use of Ad35K++ in combination with rituximab in the

  18. Relation between preclinical atherosclerosis and venous thromboembolism in patients with thrombophilias - longitudinal study.

    PubMed

    Auzký, O; Dembovská, R; Mrázková, J; Nováková, Š; Pagáčová, L; Piťha, J

    2014-01-01

    Preclinical atherosclerosis may represent a risk factor for venous thromboembolism (VTE). In longitudinal study we followed longitudinally 96 patients (32 men) with thrombophilias with (n=51) and without (n=45) history of VTE. In both groups we studied the changes of preclinical atherosclerosis at peripherally located arteries detected by ultrasound. In addition, we assessed changes in selected risk factors of atherosclerosis. During the mean follow-up of 56.0+/-7.62 months we did not find significant change in preclinical atherosclerosis defined as Belcaro score in either group (-3 % in the VTE group vs 0 % in non VTE group). Significant increase in body mass index (1.03+/-1.98 kg*m(-2), resp. 1.21+/-1.67 kg*m(-2), p<0.01) and non-significant increase in systolic blood pressure were detected in both groups. Waist circumference increased significantly only in patients without VTE (4.11+/-7.84 cm, p<0.05). No differences in changes of risk factors under study between both groups were detected. In summary, patients with thrombophilia and history of VTE showed no evidence of greater progression of atherosclerosis or increase in traditional risk factors of atherosclerosis than patients with thrombophilia without history of VTE. Unfavorable changes of body mass index, waist circumference and systolic blood pressure were detected in both groups during study period.

  19. Pediatric Autoimmune Disorders Associated with Streptococcal Infections and Tourette's Syndrome in Preclinical Studies

    PubMed Central

    Spinello, Chiara; Laviola, Giovanni; Macrì, Simone

    2016-01-01

    Accumulating evidence suggests that Tourette's Syndrome (TS) – a multifactorial pediatric disorder characterized by the recurrent exhibition of motor tics and/or vocal utterances – can partly depend on immune dysregulation provoked by early repeated streptococcal infections. The natural and adaptive antibody-mediated reaction to streptococcus has been proposed to potentially turn into a pathological autoimmune response in vulnerable individuals. Specifically, in conditions of increased permeability of the blood brain barrier (BBB), streptococcus-induced antibodies have been proposed to: (i) reach neuronal targets located in brain areas responsible for motion control; and (ii) contribute to the exhibition of symptoms. This theoretical framework is supported by indirect evidence indicating that a subset of TS patients exhibit elevated streptococcal antibody titers upon tic relapses. A systematic evaluation of this hypothesis entails preclinical studies providing a proof of concept of the aforementioned pathological sequelae. These studies shall rest upon individuals characterized by a vulnerable immune system, repeatedly exposed to streptococcus, and carefully screened for phenotypes isomorphic to the pathological signs of TS observed in patients. Preclinical animal models may thus constitute an informative, useful tool upon which conducting targeted, hypothesis-driven experiments. In the present review we discuss the available evidence in preclinical models in support of the link between TS and pediatric autoimmune neuropsychiatric disorders associated with streptococcus infections (PANDAS), and the existing gaps that future research shall bridge. Specifically, we report recent preclinical evidence indicating that the immune responses to repeated streptococcal immunizations relate to the occurrence of behavioral and neurological phenotypes reminiscent of TS. By the same token, we discuss the limitations of these studies: limited evidence of behavioral phenotypes

  20. Pediatric Autoimmune Disorders Associated with Streptococcal Infections and Tourette's Syndrome in Preclinical Studies.

    PubMed

    Spinello, Chiara; Laviola, Giovanni; Macrì, Simone

    2016-01-01

    Accumulating evidence suggests that Tourette's Syndrome (TS) - a multifactorial pediatric disorder characterized by the recurrent exhibition of motor tics and/or vocal utterances - can partly depend on immune dysregulation provoked by early repeated streptococcal infections. The natural and adaptive antibody-mediated reaction to streptococcus has been proposed to potentially turn into a pathological autoimmune response in vulnerable individuals. Specifically, in conditions of increased permeability of the blood brain barrier (BBB), streptococcus-induced antibodies have been proposed to: (i) reach neuronal targets located in brain areas responsible for motion control; and (ii) contribute to the exhibition of symptoms. This theoretical framework is supported by indirect evidence indicating that a subset of TS patients exhibit elevated streptococcal antibody titers upon tic relapses. A systematic evaluation of this hypothesis entails preclinical studies providing a proof of concept of the aforementioned pathological sequelae. These studies shall rest upon individuals characterized by a vulnerable immune system, repeatedly exposed to streptococcus, and carefully screened for phenotypes isomorphic to the pathological signs of TS observed in patients. Preclinical animal models may thus constitute an informative, useful tool upon which conducting targeted, hypothesis-driven experiments. In the present review we discuss the available evidence in preclinical models in support of the link between TS and pediatric autoimmune neuropsychiatric disorders associated with streptococcus infections (PANDAS), and the existing gaps that future research shall bridge. Specifically, we report recent preclinical evidence indicating that the immune responses to repeated streptococcal immunizations relate to the occurrence of behavioral and neurological phenotypes reminiscent of TS. By the same token, we discuss the limitations of these studies: limited evidence of behavioral phenotypes

  1. Pediatric Autoimmune Disorders Associated with Streptococcal Infections and Tourette's Syndrome in Preclinical Studies.

    PubMed

    Spinello, Chiara; Laviola, Giovanni; Macrì, Simone

    2016-01-01

    Accumulating evidence suggests that Tourette's Syndrome (TS) - a multifactorial pediatric disorder characterized by the recurrent exhibition of motor tics and/or vocal utterances - can partly depend on immune dysregulation provoked by early repeated streptococcal infections. The natural and adaptive antibody-mediated reaction to streptococcus has been proposed to potentially turn into a pathological autoimmune response in vulnerable individuals. Specifically, in conditions of increased permeability of the blood brain barrier (BBB), streptococcus-induced antibodies have been proposed to: (i) reach neuronal targets located in brain areas responsible for motion control; and (ii) contribute to the exhibition of symptoms. This theoretical framework is supported by indirect evidence indicating that a subset of TS patients exhibit elevated streptococcal antibody titers upon tic relapses. A systematic evaluation of this hypothesis entails preclinical studies providing a proof of concept of the aforementioned pathological sequelae. These studies shall rest upon individuals characterized by a vulnerable immune system, repeatedly exposed to streptococcus, and carefully screened for phenotypes isomorphic to the pathological signs of TS observed in patients. Preclinical animal models may thus constitute an informative, useful tool upon which conducting targeted, hypothesis-driven experiments. In the present review we discuss the available evidence in preclinical models in support of the link between TS and pediatric autoimmune neuropsychiatric disorders associated with streptococcus infections (PANDAS), and the existing gaps that future research shall bridge. Specifically, we report recent preclinical evidence indicating that the immune responses to repeated streptococcal immunizations relate to the occurrence of behavioral and neurological phenotypes reminiscent of TS. By the same token, we discuss the limitations of these studies: limited evidence of behavioral phenotypes

  2. Curcumin nanoformulations: a review of pharmaceutical properties and preclinical studies and clinical data related to cancer treatment.

    PubMed

    Naksuriya, Ornchuma; Okonogi, Siriporn; Schiffelers, Raymond M; Hennink, Wim E

    2014-03-01

    Curcumin, a natural yellow phenolic compound, is present in many kinds of herbs, particularly in Curcuma longa Linn. (turmeric). It is a natural antioxidant and has shown many pharmacological activities such as anti-inflammatory, anti-microbial, anti-cancer, and anti-Alzheimer in both preclinical and clinical studies. Moreover, curcumin has hepatoprotective, nephroprotective, cardioprotective, neuroprotective, hypoglycemic, antirheumatic, and antidiabetic activities and it also suppresses thrombosis and protects against myocardial infarction. Particularly, curcumin has demonstrated efficacy as an anticancer agent, but a limiting factor is its extremely low aqueous solubility which hampers its use as therapeutic agent. Therefore, many technologies have been developed and applied to overcome this limitation. In this review, we summarize the recent works on the design and development of nano-sized delivery systems for curcumin, including liposomes, polymeric nanoparticles and micelles, conjugates, peptide carriers, cyclodextrins, solid dispersions, lipid nanoparticles and emulsions. Efficacy studies of curcumin nanoformulations using cancer cell lines and in vivo models as well as up-to-date human clinical trials are also discussed. PMID:24439402

  3. Use of standardized SCID-hu Thy/Liv mouse model for preclinical efficacy testing of anti-human immunodeficiency virus type 1 compounds.

    PubMed Central

    Rabin, L; Hincenbergs, M; Moreno, M B; Warren, S; Linquist, V; Datema, R; Charpiot, B; Seifert, J; Kaneshima, H; McCune, J M

    1996-01-01

    We have developed standardized procedures and practices for infection of SCID-hu Thy/Liv mice with human immunodeficiency virus type 1 for the prophylactic administration of antiviral compounds and for evaluation of the antiviral effect in vivo. Endpoint analyses included quantitation of viral load by intracellular p24 enzyme-linked immunosorbent assay, DNA PCR for the presence of proviral genomes, flow cytometry to measure the representation of CD4+ and CD8+ cells, and cocultivation for the isolation of virus. Efficacy tests in this model are demonstrated with the nucleoside analogs zidovudine and dideoxyinosine and with the nonnucleoside reverse transcriptase inhibitor nevirapine. This small-animal model should be particularly useful in the preclinical prioritization of lead compounds within a common chemical class, in the evaluation of alternative in vivo dosing regimens, and in the determination of appropriate combination therapy in vivo. PMID:8851606

  4. Toxicity of Bothrops sp snake venoms from Ecuador and preclinical assessment of the neutralizing efficacy of a polyspecific antivenom from Costa Rica.

    PubMed

    Laines, Johana; Segura, Álvaro; Villalta, Mauren; Herrera, María; Vargas, Mariángela; Alvarez, Gladys; Gutiérrez, José María; León, Guillermo

    2014-09-01

    The toxicological profile of the venoms of the snakes Bothrops asper and Bothrops atrox from Ecuador was investigated, together with the venom of a population of B. asper formerly classified as 'Bothrops xanthogrammus'. The three venoms exerted lethal, hemorrhagic, myotoxic, coagulant and defibrinogenating effects, in agreement with the characteristic toxicological profile of Bothrops sp venoms. A polyspecific antivenom (bothropic-crotalic-lachesic) manufactured in Costa Rica was assessed for its preclinical efficacy against the toxic activities of these Ecuadorian venoms. Antivenom was effective in the neutralization of the five activities tested in the three venoms. These observations are in agreement with previous reports on the extensive cross-reactivity and paraspecific neutralization of antivenoms manufactured in Latin America against the venoms of Bothrops sp snakes. PMID:24950051

  5. Use of standardized SCID-hu Thy/Liv mouse model for preclinical efficacy testing of anti-human immunodeficiency virus type 1 compounds.

    PubMed

    Rabin, L; Hincenbergs, M; Moreno, M B; Warren, S; Linquist, V; Datema, R; Charpiot, B; Seifert, J; Kaneshima, H; McCune, J M

    1996-03-01

    We have developed standardized procedures and practices for infection of SCID-hu Thy/Liv mice with human immunodeficiency virus type 1 for the prophylactic administration of antiviral compounds and for evaluation of the antiviral effect in vivo. Endpoint analyses included quantitation of viral load by intracellular p24 enzyme-linked immunosorbent assay, DNA PCR for the presence of proviral genomes, flow cytometry to measure the representation of CD4+ and CD8+ cells, and cocultivation for the isolation of virus. Efficacy tests in this model are demonstrated with the nucleoside analogs zidovudine and dideoxyinosine and with the nonnucleoside reverse transcriptase inhibitor nevirapine. This small-animal model should be particularly useful in the preclinical prioritization of lead compounds within a common chemical class, in the evaluation of alternative in vivo dosing regimens, and in the determination of appropriate combination therapy in vivo.

  6. Translation of Pre-Clinical Studies into Successful Clinical Trials for Alzheimer's Disease: What are the Roadblocks and How Can They Be Overcome?

    PubMed

    Banik, Avijit; Brown, Richard E; Bamburg, James; Lahiri, Debomoy K; Khurana, Dheeraj; Friedland, Robert P; Chen, Wei; Ding, Ying; Mudher, Amritpal; Padjen, Ante L; Mukaetova-Ladinska, Elizabeta; Ihara, Masafumi; Srivastava, Sudhir; Padma Srivastava, M V; Masters, Colin L; Kalaria, Raj N; Anand, Akshay

    2015-01-01

    Preclinical studies are essential for translation to disease treatments and effective use in clinical practice. An undue emphasis on single approaches to Alzheimer's disease (AD) appears to have retarded the pace of translation in the field, and there is much frustration in the public about the lack of an effective treatment. We critically reviewed past literature (1990-2014), analyzed numerous data, and discussed key issues at a consensus conference on Brain Ageing and Dementia to identify and overcome roadblocks in studies intended for translation. We highlight various factors that influence the translation of preclinical research and highlight specific preclinical strategies that have failed to demonstrate efficacy in clinical trials. The field has been hindered by the domination of the amyloid hypothesis in AD pathogenesis while the causative pathways in disease pathology are widely considered to be multifactorial. Understanding the causative events and mechanisms in the pathogenesis are equally important for translation. Greater efforts are necessary to fill in the gaps and overcome a variety of confounds in the generation, study design, testing, and evaluation of animal models and the application to future novel anti-dementia drug trials. A greater variety of potential disease mechanisms must be entertained to enhance progress.

  7. Development and preclinical efficacy of novel transforming growth factor-β1 short interfering RNAs for pulmonary fibrosis.

    PubMed

    D'Alessandro-Gabazza, Corina N; Kobayashi, Tetsu; Boveda-Ruiz, Daniel; Takagi, Takehiro; Toda, Masaaki; Gil-Bernabe, Paloma; Miyake, Yasushi; Yasukawa, Atsushi; Matsuda, Yoshikazu; Suzuki, Noboru; Saito, Hiromitsu; Yano, Yutaka; Fukuda, Ayako; Hasegawa, Tetsuya; Toyobuku, Hidekazu; Rennard, Stephen I; Wagner, Peter D; Morser, John; Takei, Yoshiyuki; Taguchi, Osamu; Gabazza, Esteban C

    2012-03-01

    Idiopathic pulmonary fibrosis is a chronic devastating disease of unknown etiology. No therapy is currently available. A growing body of evidence supports the role of transforming growth factor (TGF)-β1 as the major player in the pathogenesis of the disease. However, attempts to control its expression and to improve the outcome of pulmonary fibrosis have been disappointing. We tested the hypothesis that TGF-β1 is the dominant factor in the acute and chronic phases of pulmonary fibrosis and developed short interfering (si)RNAs directed toward molecules implicated in the disease. This study developed novel sequences of siRNAs targeting the TGF-β1 gene and evaluated their therapeutic efficacy in two models of pulmonary fibrosis: a model induced by bleomycin and a novel model of the disease developed spontaneously in mice overexpressing the full length of human TGF-β1 in the lungs. Intrapulmonary delivery of aerosolized siRNAs of TGF-β1 with sequences common to humans and rodents significantly inhibited bleomycin-induced pulmonary fibrosis in the acute and chronic phases of the disease and in a dose-dependent manner. Aerosolized human-specific siRNA also efficiently inhibited pulmonary fibrosis, improved lung function, and prolonged survival in human TGF-β1 transgenic mice. Mice showed no off-target effects after intratracheal administration of siRNA. These results suggest the applicability of these novel siRNAs as tools for treating pulmonary fibrosis in humans. PMID:22033267

  8. Attempted and successful compensation in preclinical and early manifest neurodegeneration - a review of task FMRI studies.

    PubMed

    Scheller, Elisa; Minkova, Lora; Leitner, Mathias; Klöppel, Stefan

    2014-01-01

    Several models of neural compensation in healthy aging have been suggested to explain brain activity that aids to sustain cognitive function. Applying recently suggested criteria of "attempted" and "successful" compensation, we reviewed existing literature on compensatory mechanisms in preclinical Huntington's disease (HD) and amnestic mild cognitive impairment (aMCI). Both disorders constitute early stages of neurodegeneration ideal for examining compensatory mechanisms and developing targeted interventions. We strived to clarify whether compensation criteria derived from healthy aging populations can be applied to early neurodegeneration. To concentrate on the close coupling of cognitive performance and brain activity, we exclusively addressed task fMRI studies. First, we found evidence for parallels in compensatory mechanisms between healthy aging and neurodegenerative disease. Several studies fulfilled criteria of attempted compensation, while reports of successful compensation were largely absent, which made it difficult to conclude on. Second, comparing working memory studies in preclinical HD and aMCI, we identified similar compensatory patterns across neurodegenerative disorders in lateral and medial prefrontal cortex. Such patterns included an inverted U-shaped relationship of neurodegeneration and compensatory activity spanning from preclinical to manifest disease. Due to the lack of studies systematically targeting all criteria of compensation, we propose an exemplary study design, including the manipulation of compensating brain areas by brain stimulation. Furthermore, we delineate the benefits of targeted interventions by non-invasive brain stimulation, as well as of unspecific interventions such as physical activity or cognitive training. Unambiguously detecting compensation in early neurodegenerative disease will help tailor interventions aiming at sustained overall functioning and delayed clinical disease onset. PMID:25324786

  9. Osteogenic Potential of Dental Mesenchymal Stem Cells in Preclinical Studies: A Systematic Review Using Modified ARRIVE and CONSORT Guidelines

    PubMed Central

    Ramamoorthi, Murali; Bakkar, Mohammed; Jordan, Jack; Tran, Simon D.

    2015-01-01

    Background and Objective. Dental stem cell-based tissue engineered constructs are emerging as a promising alternative to autologous bone transfer for treating bone defects. The purpose of this review is to systematically assess the preclinical in vivo and in vitro studies which have evaluated the efficacy of dental stem cells on bone regeneration. Methods. A literature search was conducted in Ovid Medline, Embase, PubMed, and Web of Science up to October 2014. Implantation of dental stem cells in animal models for evaluating bone regeneration and/or in vitro studies demonstrating osteogenic potential of dental stem cells were included. The preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines were used to ensure the quality of the search. Modified ARRIVE (Animal research: reporting in invivo experiments) and CONSORT (Consolidated reporting of trials) were used to critically analyze the selected studies. Results. From 1914 citations, 207 full-text articles were screened and 137 studies were included in this review. Because of the heterogeneity observed in the studies selected, meta-analysis was not possible. Conclusion. Both in vivo and in vitro studies indicate the potential use of dental stem cells in bone regeneration. However well-designed randomized animal trials are needed before moving into clinical trials. PMID:26106427

  10. Exploratory study of factors related to educational scores of first preclinical year medical students.

    PubMed

    Sitticharoon, Chantacha; Srisuma, Sorachai; Kanavitoon, Sawita; Summachiwakij, Sarayut

    2014-03-01

    The relationships among the scores of major subjects taught in the first preclinical year of a Thai medical school, previous academic achievements, and daily life activities are rarely explored. We therefore performed an exploratory study identifying various factors possibly related to the educational scores of these medical students. Questionnaires were sent out to all first preclinical year medical students, with 79.8% being returned (245/307 questionnaires). Positive correlations were revealed between the premedical year grade point average (pre-MD GPA) and anatomy, physiology, and biochemistry scores (R = 0.664, 0.521, and 0.653, respectively, P < 0.001 for all) by Pearson's method. Using multiple linear regression analysis, anatomy scores could be predicted by pre-MD GPA, student satisfaction with anatomy, the percentage of expected reading, monthly earnings, reading after class and near exam time, and duration of sleeping periods near exam time (R = 0.773, R(2) = 0.598, P < 0.001). Physiology scores could be estimated by pre-MD GPA, the percentage of expected reading, monthly earnings, and percentage of those who fell asleep during class and near exam time (R = 0.722, R(2) = 0.521, P < 0.001). Biochemistry scores could be calculated by pre-MD GPA, the percentage of expected reading, motivation to study medicine, student satisfaction with biochemistry, and exam performance expectations (R = 0.794, R(2) = 0.630, P < 0.001). In conclusion, pre-MD GPA and the percentage of expected reading are factors involved in producing good academic results in the first preclinical year. Anatomy and biochemistry, but not physiology, scores are influenced by satisfaction.

  11. Plant-based medicines for anxiety disorders, Part 1: a review of preclinical studies.

    PubMed

    Sarris, Jerome; McIntyre, Erica; Camfield, David A

    2013-03-01

    Research in the area of herbal psychopharmacology has revealed a variety of promising medicines that may provide benefit in the treatment of general anxiety and specific anxiety disorders. However, a comprehensive review of plant-based anxiolytics has been absent to date. This article (part 1) reviews herbal medicines for which only preclinical investigations for anxiolytic activity have been performed. In part 2, we review herbal medicines for which there have been clinical investigations for anxiolytic activity. An open-ended, language-restricted (English) search of MEDLINE (PubMed), CINAHL, Scopus and the Cochrane Library databases was conducted (up to 28 October 2012) using specific search criteria to identify herbal medicines that have been investigated for anxiolytic activity. This search of the literature revealed 1,525 papers, from which 53 herbal medicines were included in the full review (having at least one study using the whole plant extract). Of these plants, 21 had human clinical trial evidence (reviewed in part 2), with another 32 having solely preclinical studies (reviewed here in part 1). Preclinical evidence of anxiolytic activity (without human clinical trials) was found for Albizia julibrissin, Sonchus oleraceus, Uncaria rhynchophylla, Stachys lavandulifolia, Cecropia glazioui, Magnolia spp., Eschscholzia californica, Erythrina spp., Annona spp., Rubus brasiliensis, Apocynum venetum, Nauclea latifolia, Equisetum arvense, Tilia spp., Securidaca longepedunculata, Achillea millefolium, Leea indica, Juncus effusus, Coriandrum sativum, Eurycoma longifolia, Turnera diffusa, Euphorbia hirta, Justicia spp., Crocus sativus, Aloysia polystachya, Albies pindrow, Casimiroa edulis, Davilla rugosa, Gastrodia elata, Sphaerathus indicus, Zizyphus jujuba and Panax ginseng. Common mechanisms of action for the majority of botanicals reviewed primarily involve GABA, either via direct receptor binding or ionic channel or cell membrane modulation; GABA transaminase

  12. Plant-based medicines for anxiety disorders, Part 1: a review of preclinical studies.

    PubMed

    Sarris, Jerome; McIntyre, Erica; Camfield, David A

    2013-03-01

    Research in the area of herbal psychopharmacology has revealed a variety of promising medicines that may provide benefit in the treatment of general anxiety and specific anxiety disorders. However, a comprehensive review of plant-based anxiolytics has been absent to date. This article (part 1) reviews herbal medicines for which only preclinical investigations for anxiolytic activity have been performed. In part 2, we review herbal medicines for which there have been clinical investigations for anxiolytic activity. An open-ended, language-restricted (English) search of MEDLINE (PubMed), CINAHL, Scopus and the Cochrane Library databases was conducted (up to 28 October 2012) using specific search criteria to identify herbal medicines that have been investigated for anxiolytic activity. This search of the literature revealed 1,525 papers, from which 53 herbal medicines were included in the full review (having at least one study using the whole plant extract). Of these plants, 21 had human clinical trial evidence (reviewed in part 2), with another 32 having solely preclinical studies (reviewed here in part 1). Preclinical evidence of anxiolytic activity (without human clinical trials) was found for Albizia julibrissin, Sonchus oleraceus, Uncaria rhynchophylla, Stachys lavandulifolia, Cecropia glazioui, Magnolia spp., Eschscholzia californica, Erythrina spp., Annona spp., Rubus brasiliensis, Apocynum venetum, Nauclea latifolia, Equisetum arvense, Tilia spp., Securidaca longepedunculata, Achillea millefolium, Leea indica, Juncus effusus, Coriandrum sativum, Eurycoma longifolia, Turnera diffusa, Euphorbia hirta, Justicia spp., Crocus sativus, Aloysia polystachya, Albies pindrow, Casimiroa edulis, Davilla rugosa, Gastrodia elata, Sphaerathus indicus, Zizyphus jujuba and Panax ginseng. Common mechanisms of action for the majority of botanicals reviewed primarily involve GABA, either via direct receptor binding or ionic channel or cell membrane modulation; GABA transaminase

  13. Preclinical development and first-in-human study of ATX-MS-1467 for immunotherapy of MS

    PubMed Central

    Streeter, Heather B.; Rigden, Rachel; Martin, Keith F.; Scolding, Neil J.

    2015-01-01

    Objective: The study was designed to test the efficacy of ATX-MS-1467 in a relevant preclinical model and to assess its safety for the treatment of patients with secondary progressive multiple sclerosis (SPMS). Methods: ATX-MS-1467 was tested for its ability to suppress experimental autoimmune encephalomyelitis (EAE) in the (Ob x DR2)F1 mouse both before and after disease onset. Safety was assessed by clinical assessment, MRI analysis, and the measurement of immune responses to self- and nonself-antigens in patients with SPMS. Results: ATX-MS-1467 displayed a dose-dependent inhibition of EAE and was more effective than glatiramer acetate in the treatment of ongoing disease in humanized mice. A phase 1 open-label dose-escalating study demonstrated that ATX-MS-1467 was safe and well-tolerated in a group of 6 patients with SPMS, up to a dose of 800 µg. Conclusions: The results of this study support further development of ATX-MS-1467 in a clinical trial powered to investigate the immunologic and clinical benefits of treatment in relapsing-remitting MS. Classification of evidence: This study provides Class IV evidence that ATX-MS-1467 is safe and tolerated in a group of 6 patients with SPMS. PMID:25798453

  14. Food for Thought Look Back in Anger – What Clinical Studies Tell Us About Preclinical Work

    PubMed Central

    Hartung, Thomas

    2013-01-01

    Summary Misled by animal studies and basic research? Whenever we take a closer look at the outcome of clinical trials in a field such as, most recently, stroke or septic shock, we see how limited the value of our preclinical models was. For all indications, 95% of drugs that enter clinical trials do not make it to the market, despite all promise of the (animal) models used to develop them. Drug development has started already to decrease its reliance on animal models: In Europe, for example, despite increasing R&D expenditure, animal use by pharmaceutical companies dropped by more than 25% from 2005 to 2008. In vitro studies are likewise limited: questionable cell authenticity, over-passaging, mycoplasma infections, and lack of differentiation as well as non-homeostatic and non-physiologic culture conditions endanger the relevance of these models. The standards of statistics and reporting often are poor, further impairing reliability. Alarming studies from industry show miserable reproducibility of landmark studies. This paper discusses factors contributing to the lack of reproducibility and relevance of pre-clinical research. The conclusion: Publish less but of better quality and do not rely on the face value of animal studies. PMID:23861075

  15. Comparative Plasma Exposure and Lung Distribution of Two Human Use Commercial Azithromycin Formulations Assessed in Murine Model: A Preclinical Study

    PubMed Central

    Rivulgo, Virginia; Sparo, Mónica; Ceci, Mónica; Fumuso, Elida; Confalonieri, Alejandra; Sánchez Bruni, Sergio F.

    2013-01-01

    Azithromycin (AZM) therapeutic failure and relapses of patients treated with generic formulations have been observed in clinical practice. The main goal of this research was to compare in a preclinical study the serum exposure and lung tissue concentration of two commercial formulations AZM-based in murine model. The current study involved 264 healthy Balb-C. Mice were divided into two groups (n = 44): animals of Group A (reference formulation -R-) were orally treated with AZM suspension at 10 mg/kg of b.w. Experimental animals of Group B (generic formulation -G-) received identical treatment than Group A with a generic formulation AZM-based. The study was repeated twice as Phase II and III. Serum and lung tissue samples were taken 24 h post treatment. Validated microbiological assay was used to determine the serum pharmacokinetic and lung distribution of AZM. After the pharmacokinetic analysis was observed, a similar serum exposure for both formulations of AZM assayed. In contrast, statistical differences (P < 0.001) were obtained after comparing the concentrations of both formulations in lung tissue, being the values obtained for AUC and Cmax (AZM-R-) +1586 and 122%, respectively, than those obtained for AZM-G- in lung. These differences may indicate large differences on the distribution process of both formulations, which may explain the lack of efficacy/therapeutic failure observed on clinical practice. PMID:24073402

  16. Preclinical studies in the mdx mouse model of duchenne muscular dystrophy with the histone deacetylase inhibitor givinostat.

    PubMed

    Consalvi, Silvia; Mozzetta, Chiara; Bettica, Paolo; Germani, Massimiliano; Fiorentini, Francesco; Del Bene, Francesca; Rocchetti, Maurizio; Leoni, Flavio; Monzani, Valmen; Mascagni, Paolo; Puri, Pier Lorenzo; Saccone, Valentina

    2013-01-01

    Previous work has established the existence of dystrophin-nitric oxide (NO) signaling to histone deacetylases (HDACs) that is deregulated in dystrophic muscles. As such, pharmacological interventions that target HDACs (that is, HDAC inhibitors) are of potential therapeutic interest for the treatment of muscular dystrophies. In this study, we explored the effectiveness of long-term treatment with different doses of the HDAC inhibitor givinostat in mdx mice--the mouse model of Duchenne muscular dystrophy (DMD). This study identified an efficacy for recovering functional and histological parameters within a window between 5 and 10 mg/kg/d of givinostat, with evident reduction of the beneficial effects with 1 mg/kg/d dosage. The long-term (3.5 months) exposure of 1.5-month-old mdx mice to optimal concentrations of givinostat promoted the formation of muscles with increased cross-sectional area and reduced fibrotic scars and fatty infiltration, leading to an overall improvement of endurance performance in treadmill tests and increased membrane stability. Interestingly, a reduced inflammatory infiltrate was observed in muscles of mdx mice exposed to 5 and 10 mg/kg/d of givinostat. A parallel pharmacokinetic/pharmacodynamic analysis confirmed the relationship between the effective doses of givinostat and the drug distribution in muscles and blood of treated mice. These findings provide the preclinical basis for an immediate translation of givinostat into clinical studies with DMD patients. PMID:23552722

  17. Preclinical Studies in the mdx Mouse Model of Duchenne Muscular Dystrophy with the Histone Deacetylase Inhibitor Givinostat

    PubMed Central

    Consalvi, Silvia; Mozzetta, Chiara; Bettica, Paolo; Germani, Massimiliano; Fiorentini, Francesco; Del Bene, Francesca; Rocchetti, Maurizio; Leoni, Flavio; Monzani, Valmen; Mascagni, Paolo; Puri, Pier Lorenzo; Saccone, Valentina

    2013-01-01

    Previous work has established the existence of dystrophin–nitric oxide (NO) signaling to histone deacetylases (HDACs) that is deregulated in dystrophic muscles. As such, pharmacological interventions that target HDACs (that is, HDAC inhibitors) are of potential therapeutic interest for the treatment of muscular dystrophies. In this study, we explored the effectiveness of long-term treatment with different doses of the HDAC inhibitor givinostat in mdx mice—the mouse model of Duchenne muscular dystrophy (DMD). This study identified an efficacy for recovering functional and histological parameters within a window between 5 and 10 mg/kg/d of givinostat, with evident reduction of the beneficial effects with 1 mg/kg/d dosage. The long-term (3.5 months) exposure of 1.5-month-old mdx mice to optimal concentrations of givinostat promoted the formation of muscles with increased cross-sectional area and reduced fibrotic scars and fatty infiltration, leading to an overall improvement of endurance performance in treadmill tests and increased membrane stability. Interestingly, a reduced inflammatory infiltrate was observed in muscles of mdx mice exposed to 5 and 10 mg/kg/d of givinostat. A parallel pharmacokinetic/pharmacodynamic analysis confirmed the relationship between the effective doses of givinostat and the drug distribution in muscles and blood of treated mice. These findings provide the preclinical basis for an immediate translation of givinostat into clinical studies with DMD patients. PMID:23552722

  18. From mouse to man: predictions of human pharmacokinetics of orally administered docetaxel from preclinical studies.

    PubMed

    Koolen, S L W; van Waterschoot, R A B; van Tellingen, O; Schinkel, A H; Beijnen, J H; Schellens, J H M; Huitema, A D R

    2012-03-01

    Intravenously administered docetaxel is approved for the treatment of various types of cancer. An oral regimen, in combination with ritonavir, is being evaluated in clinical trials. The pharmacokinetics of docetaxel are determined by the activity of the metabolizing enzyme cytochrome P450 3A (CYP3A) and the drug efflux transporter P-glycoprotein (P-gp). The effects of these proteins on the pharmacokinetics of docetaxel were investigated in different mouse models that lack 1 or both detoxifying systems. Docetaxel was given to these mice orally or intravenously with or without a strong CYP3A inhibitor, ritonavir. The data of these 2 preclinical studies were pooled and analyzed using nonlinear mixed-effects modeling. The results of the preclinical studies could be integrated successfully, with only a small difference in residual error (33% and 26%, respectively). Subsequently, the model was used to predict human exposure using allometric scaling and this was compared with clinical trial data. This model led to adequate predictions of docetaxel exposure in humans.

  19. Neuropharmacological Aspects of Crocus sativus L.: A Review of Preclinical Studies and Ongoing Clinical Research.

    PubMed

    Singh, Damanpreet

    2015-01-01

    Crocus sativus L. (Iridaceae) is an important member of the genus Crocus having high medicinal value. Its dried stigmas, known as "saffron" are being widely used form past many centuries as a food additive, coloring agent, flavoring agent and a potential source of traditional medicine. The stigmas along with other botanical parts of Crocus sativus are being extensively used in ethnomedical treatment of varied central nervous system diseases. In line with its ethnomedical importance, several preclinical studies have been carried out to validate its traditional uses, identify active principle(s), understand pharmacological basis of therapeutic action and explore novel medicinal uses. The bioactive components of Crocus sativus have been found to modulate several synaptic processes via direct/indirect interplay with neurotransmitter receptor functions, interaction with neuronal death/survival pathways and alteration in neuronal proteins expression. Many clinical studies proving beneficial effect of Crocus sativus in depressive disorders, Alzheimer's disease and some other neurological abnormalities have also been carried out. Based on the vast literature reports available, an attempt has been made to comprehend the fragmented information on neuropharmacological aspects, chemistry and safety of Crocus sativus. Although the plant has been well explored, but still a large scope of future preclinical and clinical research exist to explore its potential in neurological diseases, that has been discussed in depth in the present review.

  20. Assessment of an Orofacial Operant Pain Assay as a Preclinical Tool for Evaluating Analgesic Efficacy in Rodents

    PubMed Central

    Ramirez, Harvey E; Queeney, Timothy J; Dunbar, Misha L; Eichner, Michael C; Del Castillo, Dania I; Battles, August H; Neubert, John K

    2015-01-01

    A model system capable of providing clinically relevant analgesic doses with minimal trauma has been elusive in laboratory animal medicine. Our laboratory has developed an orofacial operant pain system that effectively discriminates between nonnoxious and noxious thermal stimuli in rats and mice. Male and female rats (Crl:SD) and mice (Crl:SKR-HRhr) were trained to perform a task (placing their face through an opening and having their cheeks stay in contact with thermodes) to receive a reward (a solution of sweetened condensed milk). Currently accepted doses of buprenorphine were tested by using a crossover design. Pain was induced in both species by sensitizing the depilated skin over both cheeks with capsaicin cream or by creating a surgical incision (rats only) and then allowing the animals to contact a temperature-regulated thermode while obtaining a reward. Optimal antinociceptive doses included 0.05 and 0.1 mg/kg in male mice but only 0.05 mg/kg in female mice. In rats, optimal antinociceptive doses included 0.03 and 0.05 mg/kg for male rats but only 0.03 mg/kg for female rats. The 2 pain-induction models in rats (capsaicin cream and surgical incision) did not differ. Our orofacial operant pain assay can determine clinically relevant analgesic doses for rodents in a preclinical assay. The automated, investigator-independent nature of the assay, in conjunction with its high sensitivity, makes this method an improvement over traditional noninvasive methods, providing better data for developing optimal analgesic recommendations for rats and mice. PMID:26224444

  1. Assessment of an Orofacial Operant Pain Assay as a Preclinical Tool for Evaluating Analgesic Efficacy in Rodents.

    PubMed

    Ramirez, Harvey E; Queeney, Timothy J; Dunbar, Misha L; Eichner, Michael C; Del Castillo, Dania I; Battles, August H; Neubert, John K

    2015-07-01

    A model system capable of providing clinically relevant analgesic doses with minimal trauma has been elusive in laboratory animal medicine. Our laboratory has developed an orofacial operant pain system that effectively discriminates between non-noxious and noxious thermal stimuli in rats and mice. Male and female rats (Crl:SD) and mice (Crl:SKR-HR(hr)) were trained to perform a task (placing their face through an opening and having their cheeks stay in contact with thermodes) to receive a reward (a solution of sweetened condensed milk). Currently accepted doses of buprenorphine were tested by using a crossover design. Pain was induced in both species by sensitizing the depilated skin over both cheeks with capsaicin cream or by creating a surgical incision (rats only) and then allowing the animals to contact a temperature-regulated thermode while obtaining a reward. Optimal antinociceptive doses included 0.05 and 0.1 mg/kg in male mice but only 0.05 mg/kg in female mice. In rats, optimal antinociceptive doses included 0.03 and 0.05 mg/kg for male rats but only 0.03 mg/kg for female rats. The 2 pain-induction models in rats (capsaicin cream and surgical incision) did not differ. Our orofacial operant pain assay can determine clinically relevant analgesic doses for rodents in a preclinical assay. The automated, investigator-independent nature of the assay, in conjunction with its high sensitivity, makes this method an improvement over traditional noninvasive methods, providing better data for developing optimal analgesic recommendations for rats and mice.

  2. Critical questions for preclinical trials on safety and efficacy of vascular endothelial growth factor-based therapeutic angiogenesis for ischemic stroke.

    PubMed

    Manoonkitiwongsa, P S

    2011-03-01

    Therapeutic angiogenesis is a novel treatment for ischemic stroke, and vascular endothelial growth factor (VEGF) is a key angiogenic and neuroprotective pharmacological candidate for therapy. However, the greatest challenge of preclinical studies is demonstrating that VEGF-based therapeutic angiogenesis is safe and effective for ischemic stroke patients. This review presents the following crucial questions which must first be answered by preclinical studies before VEGF-based therapeutic angiogenesis advances to human stroke trials, (1) Does angiogenesis induced by VEGF monotherapy promote neuroprotection or further damage the nervous tissue? (2) Does angiogenesis by VEGF in combination with other agents (combination therapy) promote greater neuroprotection than monotherapy, and without additional side effects? (3) Which exogenous VEGF isoform best promotes angiogenesis and neuroprotection, with least adverse effects on other organs? (4) Does angiogenesis induced by exogenous VEGF produce similar results in different animal models of ischemic stroke, including variations in age, gender and coexisting chronic diseases? (5) Can angiogenesis be induced by exogenous VEGF without clinically-significant alterations of systemic hemodynamics? (6) Are gene therapy and stem cells more beneficial than recombinant protein for VEGF-based therapeutic angiogenesis? (7) What are the best routes, timing and duration for administering VEGF, and how do these parameters influence inflammation? (8) Does exogenous VEGF exacerbate inflammation when traumatic or other injuries are present with ischemia? (9) Are VEGF doses not causing tissue alterations at the light microscopy level associated with clinically-significant ultrastructural damages of the neurovascular unit? Both published and unpublished preclinical data from the author's laboratory are presented. PMID:20874695

  3. Preclinical assessment of carboplatin treatment efficacy in lung cancer by 18F-ICMT-11-positron emission tomography.

    PubMed

    Witney, Timothy H; Fortt, R; Fortt, Robin R; Aboagye, Eric O

    2014-01-01

    Tumour response to therapy is assessed primarily in the clinic by monitoring reductions in tumour size. However, this approach lacks sensitivity since in many cases several weeks may elapse before there is evidence of tumour shrinkage. There is therefore a need to develop non-invasive imaging techniques for monitoring tumour treatment response in the clinic. Here, we assessed the pre-clinical utility of (18)F-ICMT-11 positron emission tomography--a method for detecting caspase 3/7 activation--in non-small cell lung cancer (NSCLC). (18)F-ICMT-11 uptake was compared to molecular biochemical measures of cell death in PC9 and A549 NSCLC cells following treatment with carboplatin in vitro and in vivo. Carboplatin-induced apoptosis in the ERCC1 low/mutant EGFR PC9 cells was characterised by time and dose-related increased caspase-3/7 activation, poly-ADP-ribose polymerase cleavage and Annexin V staining. 18F-ICMT-11 uptake was consequently increased up to 14-fold at 200 µM carboplatin compared to vehicle treated cells (P<0.01). In contrast, necrosis was the predominant death mechanism in ERCC1 high/wt EGFR A549 cells and no change in (18)F-ICMT-11 uptake was detected. In vivo, histological analysis of PC9 tumour xenografts indicated high pre-therapy necrosis. A 4.6-fold increase in cleaved caspase-3/7 was measured in non-necrotic regions of PC9 tumours at 48 h post carboplatin therapy. Average PET-derived tumour (18)F-ICMT-11 uptake was insensitive to changes in apoptosis in the presence of substantial pre-existing necrosis. PET-based voxel intensity sorting however, identified intra-tumoural regions of high (18)F-ICMT-11 uptake, enabling accurate assessment of apoptosis and therefore therapy response. In A549 tumours that lacked high pre-therapy necrosis, carboplatin induced growth inhibition that was only minimally associated with apoptosis and thus not detectable by (18)F-ICMT-11 PET.

  4. FV-162 is a novel, orally bioavailable, irreversible proteasome inhibitor with improved pharmacokinetics displaying preclinical efficacy with continuous daily dosing.

    PubMed

    Wang, Z; Dove, P; Wang, X; Shamas-Din, A; Li, Z; Nachman, A; Oh, Y J; Hurren, R; Ruschak, A; Climie, S; Press, B; Griffin, C; Undzys, E; Aman, A; Al-awar, R; Kay, L E; O'Neill, D; Trudel, S; Slassi, M; Schimmer, A D

    2015-01-01

    Approved proteasome inhibitors have advanced the treatment of multiple myeloma but are associated with serious toxicities, poor pharmacokinetics, and most with the inconvenience of intravenous administration. We therefore sought to identify novel orally bioavailable proteasome inhibitors with a continuous daily dosing schedule and improved therapeutic window using a unique drug discovery platform. We employed a fluorine-based medicinal chemistry technology to synthesize 14 novel analogs of epoxyketone-based proteasome inhibitors and screened them for their stability, ability to inhibit the chymotrypsin-like proteasome, and antimyeloma activity in vitro. The tolerability, pharmacokinetics, pharmacodynamic activity, and antimyeloma efficacy of our lead candidate were examined in NOD/SCID mice. We identified a tripeptide epoxyketone, FV-162, as a metabolically stable, potent proteasome inhibitor cytotoxic to human myeloma cell lines and primary myeloma cells. FV-162 had limited toxicity and was well tolerated on a continuous daily dosing schedule. Compared with the benchmark oral irreversible proteasome inhibitor, ONX-0192, FV-162 had a lower peak plasma concentration and longer half-life, resulting in a larger area under the curve (AUC). Oral FV-162 treatment induced rapid, irreversible inhibition of chymotrypsin-like proteasome activity in murine red blood cells and inhibited tumor growth in a myeloma xenograft model. Our data suggest that oral FV-162 with continuous daily dosing schedule displays a favorable safety, efficacy, and pharmacokinetic profile in vivo, identifying it as a promising lead for clinical evaluation in myeloma therapy.

  5. Heparin in malignant glioma: review of preclinical studies and clinical results.

    PubMed

    Schnoor, Rosalie; Maas, Sybren L N; Broekman, Marike L D

    2015-09-01

    Glioblastoma multiforme (GBM) is the most common primary brain tumor that is invariably lethal. Novel treatments are desperately needed. In various cancers, heparin and its low molecular weight derivatives (LMWHs), commonly used for the prevention and treatment of thrombosis, have shown therapeutic potential. Here we systematically review preclinical and clinical studies of heparin and LMWHs as anti-tumor agents in GBM. Even though the number of studies is limited, there is suggestive evidence that heparin may have various effects on GBM. These effects include the inhibition of tumor growth and angiogenesis in vitro and in vivo, and the blocking of uptake of extracellular vesicles. However, heparin can also block the uptake of (potential) anti-tumor agents. Clinical studies suggest a non-significant trend of prolonged survival of LMWH treated GBM patients, with some evidence of increased major bleedings. Heparin mimetics lacking anticoagulant effect are therefore a potential alternative to heparin/LMWH and are discussed as well.

  6. Systematic reviews and meta-analysis of preclinical studies: why perform them and how to appraise them critically.

    PubMed

    Sena, Emily S; Currie, Gillian L; McCann, Sarah K; Macleod, Malcolm R; Howells, David W

    2014-05-01

    The use of systematic review and meta-analysis of preclinical studies has become more common, including those of studies describing the modeling of cerebrovascular diseases. Empirical evidence suggests that too many preclinical experiments lack methodological rigor, and this leads to inflated treatment effects. The aim of this review is to describe the concepts of systematic review and meta-analysis and consider how these tools may be used to provide empirical evidence to spur the field to improve the rigor of the conduct and reporting of preclinical research akin to their use in improving the conduct and reporting of randomized controlled trials in clinical research. As with other research domains, systematic reviews are subject to bias. Therefore, we have also suggested guidance for their conduct, reporting, and critical appraisal.

  7. Improving the Predictive Value of Preclinical Studies in Support of Radiotherapy Clinical Trials.

    PubMed

    Coleman, C Norman; Higgins, Geoff S; Brown, J Martin; Baumann, Michael; Kirsch, David G; Willers, Henning; Prasanna, Pataje G S; Dewhirst, Mark W; Bernhard, Eric J; Ahmed, Mansoor M

    2016-07-01

    There is an urgent need to improve reproducibility and translatability of preclinical data to fully exploit opportunities for molecular therapeutics involving radiation and radiochemotherapy. For in vitro research, the clonogenic assay remains the current state-of-the-art of preclinical assays, whereas newer moderate and high-throughput assays offer the potential for rapid initial screening. Studies of radiation response modification by molecularly targeted agents can be improved using more physiologic 3D culture models. Elucidating effects on the cancer stem cells (CSC, and CSC-like) and developing biomarkers for defining targets and measuring responses are also important. In vivo studies are necessary to confirm in vitro findings, further define mechanism of action, and address immunomodulation and treatment-induced modification of the microenvironment. Newer in vivo models include genetically engineered and patient-derived xenograft mouse models and spontaneously occurring cancers in domesticated animals. Selection of appropriate endpoints is important for in vivo studies; for example, regrowth delay measures bulk tumor killing, whereas local tumor control assesses effects on CSCs. The reliability of individual assays requires standardization of procedures and cross-laboratory validation. Radiation modifiers must be tested as part of clinical standard of care, which includes radiochemotherapy for most tumors. Radiation models are compatible with but also differ from those used for drug screening. Furthermore, the mechanism of a drug as a chemotherapeutic agent may be different from its interaction with radiation and/or radiochemotherapy. This provides an opportunity to expand the use of molecular-targeted agents. Clin Cancer Res; 22(13); 3138-47. ©2016 AACR. PMID:27154913

  8. Preclinical animal acute toxicity studies of new developed MRI contrast agent based on gadolinium

    NASA Astrophysics Data System (ADS)

    Nam, I. F.; Zhuk, V. V.

    2015-04-01

    Acute toxicity test of new developed MRI contrast agent based on disodium salt of gadopentetic acid complex were carried out on Mus musculus and Sprague Dawley rats according to guidelines of preclinical studies [1]. Groups of six animals each were selected for experiment. Death and clinical symptoms of animals were recorded during 14 days. As a result the maximum tolerated dose (MTD) for female mice is 2.8 mM/kg of body weight, male mice - 1.4 mM/kg, female rats - 2.8 mM/kg, male rats - 5.6 mM/kg of body weight. No Observed Adverse Effect Dose (NOAEL) for female mice is 1.4 mM/kg, male mice - 0.7 mM/kg, male and female rats - 0.7 mM/kg. According to experimental data new developed MRI contrast agent based on Gd-DTPA complex is low-toxic.

  9. [Preclinical study of the safety of the new Soviet tranquilizer gindarin].

    PubMed

    Arzamastsev, E V; Mironova, M I; Krepkova, L V; Bortnikova, V V; Kuznetsov, Iu V

    1983-01-01

    The Soviet plant tranquilizer gindarin (an isoquinoline series alkaloid I-tetrahydropalmatine) isolated from the tubers of Stephania glabra Miers was subjected to a preclinical study. As regards the toxicity measured during a single administration to the laboratory animals, gindarin may be classified with moderately toxic substances. Daily intragastric administration of gindarin to rats in doses of 20 and 60 mg/kg for 3 months is likely to give rise to the changes in functions of the CNS, liver and blood. In doses of 1--50 mg/kg gindarin does not exhibit any allergizing, mutagenic or teratogenic properties. Administration of the drug in doses of 1--50 mg/kg from the 1st to the 20th day of pregnancy has shown it to produce marked embryotoxic action. In view of this fact gindarin is contraindicated in pregnancy.

  10. Delivery of small molecules for bone regenerative engineering: preclinical studies and potential clinical applications

    PubMed Central

    Laurencin, Cato T.; Ashe, Keshia M.; Henry, Nicole; Kan, Ho Man; Lo, Kevin W-H.

    2014-01-01

    Stimulation of bone regeneration using growth factors is a promising approach for musculoskeletal regenerative engineering. Common limitations with protein growth factors are high manufacturing costs, protein instability, contamination issues, and unwanted immunogenic responses of the host. New strategies for bone regeneration that obviate these problems can have a significant impact on the treatment of skeletal injury and diseases. Over the past decade, a large number of small molecules with the potential of regenerating skeletal tissue have been reported in the literature. Here, we review this literature, paying specific attention to the prospects for small molecule-based bone-regenerative engineering. We also review the preclinical study of small molecules associated with bone regeneration. PMID:24508820

  11. A Small-Molecule Antagonist of HIF2α Is Efficacious in Preclinical Models of Renal Cell Carcinoma.

    PubMed

    Wallace, Eli M; Rizzi, James P; Han, Guangzhou; Wehn, Paul M; Cao, Zhaodan; Du, Xinlin; Cheng, Tzuling; Czerwinski, Robert M; Dixon, Darryl D; Goggin, Barry S; Grina, Jonas A; Halfmann, Megan M; Maddie, Melissa A; Olive, Sarah R; Schlachter, Stephen T; Tan, Huiling; Wang, Bin; Wang, Keshi; Xie, Shanhai; Xu, Rui; Yang, Hanbiao; Josey, John A

    2016-09-15

    More than 90% of clear cell renal cell carcinomas (ccRCC) exhibit inactivation of the von Hippel-Lindau (pVHL) tumor suppressor, establishing it as the major underlying cause of this malignancy. pVHL inactivation results in stabilization of the hypoxia-inducible transcription factors, HIF1α and HIF2α, leading to expression of a genetic program essential for the initiation and progression of ccRCC. Herein, we describe the potent, selective, and orally active small-molecule inhibitor PT2385 as a specific antagonist of HIF2α that allosterically blocks its dimerization with the HIF1α/2α transcriptional dimerization partner ARNT/HIF1β. PT2385 inhibited the expression of HIF2α-dependent genes, including VEGF-A, PAI-1, and cyclin D1 in ccRCC cell lines and tumor xenografts. Treatment of tumor-bearing mice with PT2385 caused dramatic tumor regressions, validating HIF2α as a pivotal oncogenic driver in ccRCC. Notably, unlike other anticancer agents that inhibit VEGF receptor signaling, PT2385 exhibited no adverse effect on cardiovascular performance. Thus, PT2385 represents a novel class of therapeutics for the treatment of RCC with potent preclincal efficacy as well as improved tolerability relative to current agents that target the VEGF pathway. Cancer Res; 76(18); 5491-500. ©2016 AACR. PMID:27635045

  12. Efficacy of a cathepsin K inhibitor in a preclinical model for prevention and treatment of breast cancer bone metastasis.

    PubMed

    Duong, Le T; Wesolowski, Gregg A; Leung, Patrick; Oballa, Renata; Pickarski, Maureen

    2014-12-01

    Cathepsin K (CatK) is essential for osteoclast-mediated bone resorption. CatK expression is also detected in breast cancer cells that metastasize to bone. Here, the CatK inhibitor L-235 dosed in prevention (10, 30, and 100 mg/kg, p.o., b.i.d.) or treatment regimen (30 mg/kg) was compared with the bisphosphonate zoledronic acid (ZOL, 7.5 μg/kg/wk, s.c.) in the intratibial injection model of MDA-MB-231 breast carcinoma in nude rats. Progression of osteolysis, skeletal tumor burden, and local metastasis was evaluated by radiography through 42 days and ex vivo μCT and histology. IHC and RT-PCR confirmed the increases in CatK protein and mRNA levels in human breast cancer primary and metastatic tumors. In the experimental model of breast cancer bone metastasis, L-235 dosed in preventive mode resulted in a dose-related reduction of osteolysis of 72%, 75%, and 87% respectively, compared with ZOL by 86% versus intact. Similarly, L-235 significantly reduced intratibial tumor volume by 29%, 40%, and 63%, respectively, compared with 56% by ZOL versus vehicle. Efficacy of L-235 and ZOL on reduction of osteolytic lesions and tumor burden was comparable in treatment versus preventive regimens. All L-235 doses inhibited cortical disruption and extraskeletal tumor growth to a level comparable with ZOL. Assessment of local metastasis demonstrated that treatment with the CatK inhibitor was more effective than ZOL in reducing breast cancer invasion. These data support the role of CatK in breast cancer skeletal growth and metastasis and CatK inhibitors may represent a novel oral therapy for treatment of metastatic breast cancer.

  13. Selective Allosteric Inhibition of MMP9 Is Efficacious in Preclinical Models of Ulcerative Colitis and Colorectal Cancer.

    PubMed

    Marshall, Derek C; Lyman, Susan K; McCauley, Scott; Kovalenko, Maria; Spangler, Rhyannon; Liu, Chian; Lee, Michael; O'Sullivan, Christopher; Barry-Hamilton, Vivian; Ghermazien, Haben; Mikels-Vigdal, Amanda; Garcia, Carlos A; Jorgensen, Brett; Velayo, Arleene C; Wang, Ruth; Adamkewicz, Joanne I; Smith, Victoria

    2015-01-01

    Expression of matrix metalloproteinase 9 (MMP9) is elevated in a variety of inflammatory and oncology indications, including ulcerative colitis and colorectal cancer. MMP9 is a downstream effector and an upstream mediator of pathways involved in growth and inflammation, and has long been viewed as a promising therapeutic target. However, previous efforts to target matrix metalloproteinases (MMPs), including MMP9, have utilized broad-spectrum or semi-selective inhibitors. While some of these drugs showed signs of efficacy in patients, all MMP-targeted inhibitors have been hampered by dose-limiting toxicity or insufficient clinical benefit, likely due to their lack of specificity. Here, we show that selective inhibition of MMP9 did not induce musculoskeletal syndrome (a characteristic toxicity of pan-MMP inhibitors) in a rat model, but did reduce disease severity in a dextran sodium sulfate-induced mouse model of ulcerative colitis. We also found that MMP9 inhibition decreased tumor growth and metastases incidence in a surgical orthotopic xenograft model of colorectal carcinoma, and that inhibition of either tumor- or stroma-derived MMP9 was sufficient to reduce primary tumor growth. Collectively, these data suggest that selective MMP9 inhibition is a promising therapeutic strategy for treatment of inflammatory and oncology indications in which MMP9 is upregulated and is associated with disease pathology, such as ulcerative colitis and colorectal cancer. In addition, we report the development of a potent and highly selective allosteric MMP9 inhibitor, the humanized monoclonal antibody GS-5745, which can be used to evaluate the therapeutic potential of MMP9 inhibition in patients. PMID:25961845

  14. The Metabotropic Glutamate Receptor 4-Positive Allosteric Modulator VU0364770 Produces Efficacy Alone and in Combination with l-DOPA or an Adenosine 2A Antagonist in Preclinical Rodent Models of Parkinson's Disease

    PubMed Central

    Jones, Carrie K.; Bubser, Michael; Thompson, Analisa D.; Dickerson, Jonathan W.; Turle-Lorenzo, Nathalie; Amalric, Marianne; Blobaum, Anna L.; Bridges, Thomas M.; Morrison, Ryan D.; Jadhav, Satyawan; Engers, Darren W.; Italiano, Kimberly; Bode, Jacob; Daniels, J. Scott; Lindsley, Craig W.; Hopkins, Corey R.; Conn, P. Jeffrey

    2012-01-01

    Parkinson's disease (PD) is a debilitating neurodegenerative disorder associated with severe motor impairments caused by the loss of dopaminergic innervation of the striatum. Previous studies have demonstrated that positive allosteric modulators (PAMs) of metabotropic glutamate receptor 4 (mGlu4), including N-phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxamide, can produce antiparkinsonian-like effects in preclinical models of PD. However, these early mGlu4 PAMs exhibited unsuitable physiochemical properties for systemic dosing, requiring intracerebroventricular administration and limiting their broader utility as in vivo tools to further understand the role of mGlu4 in the modulation of basal ganglia function relevant to PD. In the present study, we describe the pharmacologic characterization of a systemically active mGlu4 PAM, N-(3-chlorophenyl)picolinamide (VU0364770), in several rodent PD models. VU0364770 showed efficacy alone or when administered in combination with l-DOPA or an adenosine 2A (A2A) receptor antagonist currently in clinical development (preladenant). When administered alone, VU0364770 exhibited efficacy in reversing haloperidol-induced catalepsy, forelimb asymmetry-induced by unilateral 6-hydroxydopamine (6-OHDA) lesions of the median forebrain bundle, and attentional deficits induced by bilateral 6-OHDA nigrostriatal lesions in rats. In addition, VU0364770 enhanced the efficacy of preladenant to reverse haloperidol-induced catalepsy when given in combination. The effects of VU0364770 to reverse forelimb asymmetry were also potentiated when the compound was coadministered with an inactive dose of l-DOPA, suggesting that mGlu4 PAMs may provide l-DOPA-sparing activity. The present findings provide exciting support for the potential role of selective mGlu4 PAMs as a novel approach for the symptomatic treatment of PD and a possible augmentation strategy with either l-DOPA or A2A antagonists. PMID:22088953

  15. Simvastatin Hydroxy Acid Fails to Attain Sufficient Central Nervous System Tumor Exposure to Achieve a Cytotoxic Effect: Results of a Preclinical Cerebral Microdialysis Study.

    PubMed

    Patel, Yogesh T; Jacus, Megan O; Davis, Abigail D; Boulos, Nidal; Turner, David C; Vuppala, Pradeep K; Freeman, Burgess B; Gilbertson, Richard J; Stewart, Clinton F

    2016-04-01

    3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors were potent hits against a mouse ependymoma cell line, but their effectiveness against central nervous system tumors will depend on their ability to cross the blood-brain barrier and attain a sufficient exposure at the tumor. Among 3-hydroxy-3-methylglutaryl coenzyme A inhibitors that had activity in vitro, we prioritized simvastatin (SV) as the lead compound for preclinical pharmacokinetic studies based on its potential for central nervous system penetration as determined from in silico models. Furthermore, we performed systemic plasma disposition and cerebral microdialysis studies of SV (100 mg/kg, p.o.) in a murine model of ependymoma to characterize plasma and tumor extracellular fluid (tECF) pharmacokinetic properties. The murine dosage of SV (100 mg/kg, p.o.) was equivalent to the maximum tolerated dose in patients (7.5 mg/kg, p.o.) based on equivalent plasma exposure of simvastatin acid (SVA) between the two species. SV is rapidly metabolized in murine plasma with 15 times lower exposure compared with human plasma. SVA exposure in tECF was <33.8 ± 11.9 µg/l per hour, whereas the tumor to plasma partition coefficient of SVA was <0.084 ± 0.008. Compared with in vitro washout IC50 values, we did not achieve sufficient exposure of SVA in tECF to suggest tumor growth inhibition; therefore, SV was not carried forward in subsequent preclinical efficacy studies. PMID:26802130

  16. Using Bayesian analysis in repeated preclinical in vivo studies for a more effective use of animals.

    PubMed

    Walley, Rosalind; Sherington, John; Rastrick, Joe; Detrait, Eric; Hanon, Etienne; Watt, Gillian

    2016-05-01

    Whilst innovative Bayesian approaches are increasingly used in clinical studies, in the preclinical area Bayesian methods appear to be rarely used in the reporting of pharmacology data. This is particularly surprising in the context of regularly repeated in vivo studies where there is a considerable amount of data from historical control groups, which has potential value. This paper describes our experience with introducing Bayesian analysis for such studies using a Bayesian meta-analytic predictive approach. This leads naturally either to an informative prior for a control group as part of a full Bayesian analysis of the next study or using a predictive distribution to replace a control group entirely. We use quality control charts to illustrate study-to-study variation to the scientists and describe informative priors in terms of their approximate effective numbers of animals. We describe two case studies of animal models: the lipopolysaccharide-induced cytokine release model used in inflammation and the novel object recognition model used to screen cognitive enhancers, both of which show the advantage of a Bayesian approach over the standard frequentist analysis. We conclude that using Bayesian methods in stable repeated in vivo studies can result in a more effective use of animals, either by reducing the total number of animals used or by increasing the precision of key treatment differences. This will lead to clearer results and supports the "3Rs initiative" to Refine, Reduce and Replace animals in research. Copyright © 2016 John Wiley & Sons, Ltd.

  17. Mouse Model for the Preclinical Study of Metastatic Disease | NCI Technology Transfer Center | TTC

    Cancer.gov

    The Laboratory of Cancer Biology and Genetics, National Cancer Institute seeks partners for collaborative research to co-develop a mouse model that shows preclinical therapeutic response of residual metastatic disease.

  18. Exercise as a Potential Treatment for Drug Abuse: Evidence from Preclinical Studies

    PubMed Central

    Smith, Mark A.; Lynch, Wendy J.

    2012-01-01

    Epidemiological studies reveal that individuals who engage in regular aerobic exercise are less likely to use and abuse illicit drugs. Until recently, very few studies had examined the causal influences that mediate this relationship, and it was not clear whether exercise was effective at reducing substance use and abuse. In the past few years, several preclinical studies have revealed that exercise reduces drug self-administration in laboratory animals. These studies have revealed that exercise produces protective effects in procedures designed to model different transitional phases that occur during the development of, and recover from, a substance use disorder (e.g., acquisition, maintenance, escalation, and relapse/reinstatement of drug use). Moreover, recent studies have revealed several behavioral and neurobiological consequences of exercise that may be responsible for its protective effects in these assays. Collectively, these studies have provided convincing evidence to support the development of exercise-based interventions to reduce compulsive patterns of drug intake in clinical and at-risk populations. PMID:22347866

  19. CCD-camera-based diffuse optical tomography to study ischemic stroke in preclinical rat models

    NASA Astrophysics Data System (ADS)

    Lin, Zi-Jing; Niu, Haijing; Liu, Yueming; Su, Jianzhong; Liu, Hanli

    2011-02-01

    Stroke, due to ischemia or hemorrhage, is the neurological deficit of cerebrovasculature and is the third leading cause of death in the United States. More than 80 percent of stroke patients are ischemic stroke due to blockage of artery in the brain by thrombosis or arterial embolism. Hence, development of an imaging technique to image or monitor the cerebral ischemia and effect of anti-stoke therapy is more than necessary. Near infrared (NIR) optical tomographic technique has a great potential to be utilized as a non-invasive image tool (due to its low cost and portability) to image the embedded abnormal tissue, such as a dysfunctional area caused by ischemia. Moreover, NIR tomographic techniques have been successively demonstrated in the studies of cerebro-vascular hemodynamics and brain injury. As compared to a fiberbased diffuse optical tomographic system, a CCD-camera-based system is more suitable for pre-clinical animal studies due to its simpler setup and lower cost. In this study, we have utilized the CCD-camera-based technique to image the embedded inclusions based on tissue-phantom experimental data. Then, we are able to obtain good reconstructed images by two recently developed algorithms: (1) depth compensation algorithm (DCA) and (2) globally convergent method (GCM). In this study, we will demonstrate the volumetric tomographic reconstructed results taken from tissuephantom; the latter has a great potential to determine and monitor the effect of anti-stroke therapies.

  20. Review of Preclinical and Clinical Studies of Bone Marrow-Derived Cell Therapies for Intracerebral Hemorrhage

    PubMed Central

    de Carvalho, Felipe Gonçalves; de Freitas, Gabriel Rodriguez

    2016-01-01

    Stroke is the second leading cause of mortality worldwide, causing millions of deaths annually, and is also a major cause of disability-adjusted life years. Hemorrhagic stroke accounts for approximately 10 to 27% of all cases and has a fatality rate of about 50% in the first 30 days, with limited treatment possibilities. In the past two decades, the therapeutic potential of bone marrow-derived cells (particularly mesenchymal stem cells and mononuclear cells) has been intensively investigated in preclinical models of different neurological diseases, including models of intracerebral hemorrhage and subarachnoid hemorrhage. More recently, clinical studies, most of them small, unblinded, and nonrandomized, have suggested that the therapy with bone marrow-derived cells is safe and feasible in patients with ischemic or hemorrhagic stroke. This review discusses the available evidence on the use of bone marrow-derived cells to treat hemorrhagic strokes. Distinctive properties of animal studies are analyzed, including study design, cell dose, administration route, therapeutic time window, and possible mechanisms of action. Furthermore, clinical trials are also reviewed and discussed, with the objective of improving future studies in the field.

  1. Review of Preclinical and Clinical Studies of Bone Marrow-Derived Cell Therapies for Intracerebral Hemorrhage

    PubMed Central

    de Carvalho, Felipe Gonçalves; de Freitas, Gabriel Rodriguez

    2016-01-01

    Stroke is the second leading cause of mortality worldwide, causing millions of deaths annually, and is also a major cause of disability-adjusted life years. Hemorrhagic stroke accounts for approximately 10 to 27% of all cases and has a fatality rate of about 50% in the first 30 days, with limited treatment possibilities. In the past two decades, the therapeutic potential of bone marrow-derived cells (particularly mesenchymal stem cells and mononuclear cells) has been intensively investigated in preclinical models of different neurological diseases, including models of intracerebral hemorrhage and subarachnoid hemorrhage. More recently, clinical studies, most of them small, unblinded, and nonrandomized, have suggested that the therapy with bone marrow-derived cells is safe and feasible in patients with ischemic or hemorrhagic stroke. This review discusses the available evidence on the use of bone marrow-derived cells to treat hemorrhagic strokes. Distinctive properties of animal studies are analyzed, including study design, cell dose, administration route, therapeutic time window, and possible mechanisms of action. Furthermore, clinical trials are also reviewed and discussed, with the objective of improving future studies in the field. PMID:27698671

  2. [GOOD PLANNING PRACTICE IN PRECLINICAL AND CLINICAL STUDIES OF UNFRACTIONATED AND FRACTIONATED HEPARINS IN RUSSIA AS THE BASIS OF SAFE AND EFFECTIVE ANTICOAGULATION THERAPY].

    PubMed

    Gavrishina, E V; Dobrovolskii, A V; Niyazov, R R; Romodanovskii, D P; Vasil'ev, A N

    2015-01-01

    General principles of appropriate strategies for preclinical and clinical development of unfractionated and low-molecular-weight heparins and demonstration of their biosimilarity to corresponding reference medicinal products are provided. Demonstration of the biosimilarity of heparin-containing medicinal products constitutes the basis for their efficacy and safety during anticoagulation therapy. The main quality, safety, and efficacy characteristics of heparin products are described and the extent of non-clinical and clinical investigations necessary prior to drug marketing authorization are considered. PMID:27017700

  3. Small Molecular TRAIL Inducer ONC201 Induces Death in Lung Cancer Cells: A Preclinical Study.

    PubMed

    Feng, Yuan; Zhou, Jihong; Li, Zhanhua; Jiang, Ying; Zhou, Ying

    2016-01-01

    Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) selectively targets cancer cells. The present preclinical study investigated the anti-cancer efficiency of ONC201, a first-in-class small molecule TRAIL inducer, in lung cancer cells. We showed that ONC201 was cytotoxic and anti-proliferative in both established (A549 and H460 lines) and primary human lung cancer cells. It was yet non-cytotoxic to normal lung epithelial cells. Further, ONC201 induced exogenous apoptosis activation in lung cancer cells, which was evidenced by TRAIL/death receptor-5 (DR5) induction and caspase-8 activation. The caspase-8 inhibitor or TRAIL/DR5 siRNA knockdown alleviated ONC201's cytotoxicity against lung cancer cells. Molecularly, ONC201 in-activated Akt-S6K1 and Erk signalings in lung cancer cells, causing Foxo3a nuclear translocation. For the in vivo studies, intraperitoneal injection of ONC201 at well-tolerated doses significantly inhibited xenografted A549 tumor growth in severe combined immunodeficient (SCID) mice. Further, ONC201 administration induced TRAIL/DR5 expression, yet inactivated Akt-S6K1 and Erk in tumor tissues. These results of the study demonstrates the potent anti-lung cancer activity by ONC201. PMID:27626799

  4. Reference values of clinical pathology parameters in cynomolgus monkeys (Macaca fascicularis) used in preclinical studies.

    PubMed

    Park, Hyun-Kyu; Cho, Jae-Woo; Lee, Byoung-Seok; Park, Heejin; Han, Ji-Seok; Yang, Mi-Jin; Im, Wan-Jung; Park, Do-Yong; Kim, Woo-Jin; Han, Su-Cheol; Kim, Yong-Bum

    2016-06-01

    Nonhuman primates are increasingly used in biomedical research since they are highly homologous to humans compared to other rodent animals. However, there is limited reliable reference data of the clinical pathology parameters in cynomolgus monkeys, and in particular, only some coagulation and urinalysis parameters have been reported. Here, we reported the reference data of clinical chemical, hematological, blood coagulation, and urinalysis parameters in cynomolgus monkeys. The role of sex differences was analyzed and several parameters (including hematocrit, hemoglobin, red blood cell, blood urea nitrogen, total bilirubin, alkaline phosphatase, creatinine kinase, gamma-glutamyl tranferase, and lactate dehydrogenase) significantly differed between male and female subjects. In addition, compared to previous study results, lactate dehydrogenase, creatinine kinase, and aspartate aminotransferase showed significant variation. Interstudy differences could be affected by several factors, including age, sex, geographic origin, presence/absence of anesthetics, fasting state, and the analytical methods used. Therefore, it is important to deliberate with the overall reference indices. In conclusion, the current study provides a comprehensive and updated reference data of the clinical pathology parameters in cynomolgus monkeys and provides improved assessment criteria for evaluating preclinical studies or biomedical research. PMID:27382375

  5. Benznidazole Extended-Release Tablets for Improved Treatment of Chagas Disease: Preclinical Pharmacokinetic Study

    PubMed Central

    Campos, Michel Leandro; Rosa, Talita Atanazio; Padilha, Elias Carvalho; Alzate, Alejandro Henao; Rolim, Larissa Araújo; Rolim-Neto, Pedro José

    2016-01-01

    Benznidazole (BNZ) is the first-line drug for the treatment of Chagas disease. The drug is available in the form of immediate-release tablets for 100-mg (adult) and 12.5-mg (pediatric) doses. The drug is administered two or three times daily for 60 days. The high frequency of daily administrations and the long period of treatment are factors that significantly contribute to the abandonment of therapy, affecting therapeutic success. Accordingly, this study aimed to evaluate the preclinical pharmacokinetics of BNZ administered as extended-release tablets (200-mg dose) formulated with different types of polymers (hydroxypropyl methylcellulose K4M and K100M), compared to the tablets currently available. The studies were conducted with rabbits, and BNZ quantification was performed in plasma and urine by ultraperformance liquid chromatography methods previously validated. The bioavailability of BNZ was adequate in the administration of extended-release tablets; however, with the administration of the pediatric tablet, the bioavailability was lower than with other tablets, which showed that the clinical use of this formulation should be monitored. The pharmacokinetic parameters demonstrated that the extended-release tablets prolonged drug release from the pharmaceutical matrix and provided an increase in the maintenance of the drug concentration in vivo, which would allow the frequency of administration to be reduced. Thus, a relative bioavailability study in humans will be planned for implementation of a new product for the treatment of Chagas disease. PMID:26883698

  6. Small Molecular TRAIL Inducer ONC201 Induces Death in Lung Cancer Cells: A Preclinical Study

    PubMed Central

    Feng, Yuan; Zhou, Jihong; Li, Zhanhua; Jiang, Ying; Zhou, Ying

    2016-01-01

    Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) selectively targets cancer cells. The present preclinical study investigated the anti-cancer efficiency of ONC201, a first-in-class small molecule TRAIL inducer, in lung cancer cells. We showed that ONC201 was cytotoxic and anti-proliferative in both established (A549 and H460 lines) and primary human lung cancer cells. It was yet non-cytotoxic to normal lung epithelial cells. Further, ONC201 induced exogenous apoptosis activation in lung cancer cells, which was evidenced by TRAIL/death receptor-5 (DR5) induction and caspase-8 activation. The caspase-8 inhibitor or TRAIL/DR5 siRNA knockdown alleviated ONC201’s cytotoxicity against lung cancer cells. Molecularly, ONC201 in-activated Akt-S6K1 and Erk signalings in lung cancer cells, causing Foxo3a nuclear translocation. For the in vivo studies, intraperitoneal injection of ONC201 at well-tolerated doses significantly inhibited xenografted A549 tumor growth in severe combined immunodeficient (SCID) mice. Further, ONC201 administration induced TRAIL/DR5 expression, yet inactivated Akt-S6K1 and Erk in tumor tissues. These results of the study demonstrates the potent anti-lung cancer activity by ONC201. PMID:27626799

  7. Benznidazole Extended-Release Tablets for Improved Treatment of Chagas Disease: Preclinical Pharmacokinetic Study.

    PubMed

    Davanço, Marcelo Gomes; Campos, Michel Leandro; Rosa, Talita Atanazio; Padilha, Elias Carvalho; Alzate, Alejandro Henao; Rolim, Larissa Araújo; Rolim-Neto, Pedro José; Peccinini, Rosângela Gonçalves

    2016-04-01

    Benznidazole (BNZ) is the first-line drug for the treatment of Chagas disease. The drug is available in the form of immediate-release tablets for 100-mg (adult) and 12.5-mg (pediatric) doses. The drug is administered two or three times daily for 60 days. The high frequency of daily administrations and the long period of treatment are factors that significantly contribute to the abandonment of therapy, affecting therapeutic success. Accordingly, this study aimed to evaluate the preclinical pharmacokinetics of BNZ administered as extended-release tablets (200-mg dose) formulated with different types of polymers (hydroxypropyl methylcellulose K4M and K100M), compared to the tablets currently available. The studies were conducted with rabbits, and BNZ quantification was performed in plasma and urine by ultraperformance liquid chromatography methods previously validated. The bioavailability of BNZ was adequate in the administration of extended-release tablets; however, with the administration of the pediatric tablet, the bioavailability was lower than with other tablets, which showed that the clinical use of this formulation should be monitored. The pharmacokinetic parameters demonstrated that the extended-release tablets prolonged drug release from the pharmaceutical matrix and provided an increase in the maintenance of the drug concentrationin vivo, which would allow the frequency of administration to be reduced. Thus, a relative bioavailability study in humans will be planned for implementation of a new product for the treatment of Chagas disease. PMID:26883698

  8. High-density lipoprotein and atherosclerosis regression: evidence from preclinical and clinical studies.

    PubMed

    Feig, Jonathan E; Hewing, Bernd; Smith, Jonathan D; Hazen, Stanley L; Fisher, Edward A

    2014-01-01

    High-density lipoprotein (HDL) particles transport (among other molecules) cholesterol (HDL-C). In epidemiological studies, plasma HDL-C levels have an inverse relationship to the risk of atherosclerotic cardiovascular disease. It has been assumed that this reflects the protective functions of HDL, which include their ability to promote cholesterol efflux. Yet, several recent pharmacological and genetic studies have failed to demonstrate that increased plasma levels of HDL-C resulted in decreased cardiovascular disease risk, giving rise to a controversy regarding whether plasma levels of HDL-C reflect HDL function, or that HDL is even as protective as assumed. The evidence from preclinical and (limited) clinical studies shows that HDL can promote the regression of atherosclerosis when the levels of functional particles are increased from endogenous or exogenous sources. The data show that regression results from a combination of reduced plaque lipid and macrophage contents, as well as from a reduction in its inflammatory state. Although more research will be needed regarding basic mechanisms and to establish that these changes translate clinically to reduced cardiovascular disease events, that HDL can regress plaques suggests that the recent trial failures do not eliminate HDL from consideration as an atheroprotective agent but rather emphasizes the important distinction between HDL function and plasma levels of HDL-C.

  9. Reference values of clinical pathology parameters in cynomolgus monkeys (Macaca fascicularis) used in preclinical studies

    PubMed Central

    Park, Hyun-Kyu; Cho, Jae-Woo; Lee, Byoung-Seok; Park, Heejin; Han, Ji-Seok; Yang, Mi-Jin; Im, Wan-Jung; Park, Do-Yong; Kim, Woo-Jin; Han, Su-Cheol

    2016-01-01

    Nonhuman primates are increasingly used in biomedical research since they are highly homologous to humans compared to other rodent animals. However, there is limited reliable reference data of the clinical pathology parameters in cynomolgus monkeys, and in particular, only some coagulation and urinalysis parameters have been reported. Here, we reported the reference data of clinical chemical, hematological, blood coagulation, and urinalysis parameters in cynomolgus monkeys. The role of sex differences was analyzed and several parameters (including hematocrit, hemoglobin, red blood cell, blood urea nitrogen, total bilirubin, alkaline phosphatase, creatinine kinase, gamma-glutamyl tranferase, and lactate dehydrogenase) significantly differed between male and female subjects. In addition, compared to previous study results, lactate dehydrogenase, creatinine kinase, and aspartate aminotransferase showed significant variation. Interstudy differences could be affected by several factors, including age, sex, geographic origin, presence/absence of anesthetics, fasting state, and the analytical methods used. Therefore, it is important to deliberate with the overall reference indices. In conclusion, the current study provides a comprehensive and updated reference data of the clinical pathology parameters in cynomolgus monkeys and provides improved assessment criteria for evaluating preclinical studies or biomedical research. PMID:27382375

  10. Preclinical efficacy of N-substituted benztropine analogs as antagonists of methamphetamine self-administration in rats.

    PubMed

    Hiranita, Takato; Kohut, Stephen J; Soto, Paul L; Tanda, Gianluigi; Kopajtic, Theresa A; Katz, Jonathan L

    2014-01-01

    Atypical dopamine-uptake inhibitors have low abuse potential and may serve as leads for development of cocaine-abuse treatments. Among them, the benztropine (BZT) derivatives, N-butyl (JHW007), N-allyl (AHN2-005), and N-methyl (AHN1-055) analogs of 3α-[bis(4'-fluorophenyl)methoxy]-tropane dose-dependently decreased cocaine self-administration without effects on food-maintained responding. Our study examined selectivity by assessing their effects on self-administration of other drugs. As with cocaine, each BZT analog (1.0-10.0 mg/kg i.p.) dose-dependently decreased maximal self-administration of d-methamphetamine (0.01-0.32 mg/kg/infusion) but was inactive against heroin (1.0-32.0 µg/kg/infusion) and ketamine (0.032-1.0 mg/kg/infusion) self-administration. Further, standard dopamine indirect-agonists [WIN35,428 ((-)-3β-(4-fluorophenyl)-tropan-2-β-carboxylic acid methyl ester tartrate), d-amphetamine (0.1-1.0 mg/kg i.p., each)] dose-dependently left-shifted self-administration dose-effect curves for d-methamphetamine, heroin, and ketamine. Noncompetitive NMDA-glutamate receptor/channel antagonists [(+)-MK-801 (0.01-0.1 mg/kg i.p.), memantine (1.0-10.0 mg/kg i.p.)] also left-shifted dose-effect curves for d-methamphetamine and ketamine (but not heroin) self-administration. The µ-agonists [dl-methadone and morphine (1.0-10.0 mg/kg i.p., each)] dose-dependently decreased maximal self-administration of µ-agonists (heroin, remifentanil) but not d-methamphetamine or ketamine self-administration. The µ-agonist-induced decreases were similar to the effects of BZT analogs on stimulant self-administration and effects of food prefeeding on responding maintained by food reinforcement. Radioligand-binding and behavioral studies suggested that inhibition of dopamine transporters and σ receptors were critical for blocking stimulant self-administration by BZT-analogs. Thus, the present results suggest that the effects of BZT analogs on stimulant self-administration are

  11. Preclinical Efficacy of N-Substituted Benztropine Analogs as Antagonists of Methamphetamine Self-Administration in Rats

    PubMed Central

    Hiranita, Takato; Kohut, Stephen J.; Soto, Paul L.; Tanda, Gianluigi; Kopajtic, Theresa A.

    2014-01-01

    Atypical dopamine-uptake inhibitors have low abuse potential and may serve as leads for development of cocaine-abuse treatments. Among them, the benztropine (BZT) derivatives, N-butyl (JHW007), N-allyl (AHN2-005), and N-methyl (AHN1-055) analogs of 3α-[bis(4′-fluorophenyl)methoxy]-tropane dose-dependently decreased cocaine self-administration without effects on food-maintained responding. Our study examined selectivity by assessing their effects on self-administration of other drugs. As with cocaine, each BZT analog (1.0–10.0 mg/kg i.p.) dose-dependently decreased maximal self-administration of d-methamphetamine (0.01–0.32 mg/kg/infusion) but was inactive against heroin (1.0–32.0 µg/kg/infusion) and ketamine (0.032–1.0 mg/kg/infusion) self-administration. Further, standard dopamine indirect-agonists [WIN35,428 ((−)-3β-(4-fluorophenyl)-tropan-2-β-carboxylic acid methyl ester tartrate), d-amphetamine (0.1–1.0 mg/kg i.p., each)] dose-dependently left-shifted self-administration dose-effect curves for d-methamphetamine, heroin, and ketamine. Noncompetitive NMDA-glutamate receptor/channel antagonists [(+)-MK-801 (0.01–0.1 mg/kg i.p.), memantine (1.0–10.0 mg/kg i.p.)] also left-shifted dose-effect curves for d-methamphetamine and ketamine (but not heroin) self-administration. The µ-agonists [dl-methadone and morphine (1.0–10.0 mg/kg i.p., each)] dose-dependently decreased maximal self-administration of µ-agonists (heroin, remifentanil) but not d-methamphetamine or ketamine self-administration. The µ-agonist-induced decreases were similar to the effects of BZT analogs on stimulant self-administration and effects of food prefeeding on responding maintained by food reinforcement. Radioligand-binding and behavioral studies suggested that inhibition of dopamine transporters and σ receptors were critical for blocking stimulant self-administration by BZT-analogs. Thus, the present results suggest that the effects of BZT analogs on stimulant self

  12. Preclinical endodontic teaching

    PubMed Central

    Narayanaraopeta, Udaya; AlShwaimi, Emad

    2015-01-01

    Objectives: To provide an overview of the general curricula in preclinical endodontic training from 6 established dental schools in Saudi Arabia. Methods: This study was conducted in January 2014 including only schools that had more than 2 groups of student graduates prior to the study. We included 2 dental schools from the Central region, one from Qassim region, one from the Makkah region (west), one from Abha region (south west), and one from the eastern region. An internet-based questionnaire was sent to the course directors of preclinical endodontics department of the 6 schools. The survey comprised 20 questions that examined various aspects of preclinical endodontics. Results: It was demonstrated that a significant number of faculty members had Doctor of Philosophy (PhD) degrees (n=21), Master’s degrees (n=15), and Saudi board certifications (n=8). We determined that the faculty to student ratio varied from 2:1 to 8: 1 among the colleges. The participating dental schools were found to teach the Step Back, as well as the Step Down techniques for root canal preparation. Five of the 6 schools implemented the use of nickel titanium rotary instruments. All dental schools predominantly used radiographs as the means of the working length determination. Conclusion: The curriculum for preclinical endodontics in Saudi Arabia is comparable to that followed in most European countries. A more comprehensive survey is needed that would involve more schools to formulate generalized guidelines for preclinical endodontic training in Saudi Arabia. PMID:25630011

  13. 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…

  14. Behavioral models of impulsivity in relation to ADHD: Translation between clinical and preclinical studies

    PubMed Central

    Winstanley, Catharine A.; Eagle, Dawn M.; Robbins, Trevor W.

    2006-01-01

    Impulsivity, broadly defined as action without foresight, is a component of numerous psychiatric illnesses including attention deficit/hyperactivity disorder (ADHD), mania and substance abuse. In order to investigate the mechanisms underpinning impulsive behavior, the nature of impulsivity itself needs to be defined in operational terms that can be used as the basis for empirical investigation. Due to the range of behaviors that the term impulsivity describes, it has been suggested that impulsivity is not a unitary construct, but encompasses a variety of related phenomena that may differ in their biological basis. Through fractionating impulsivity into these component parts, it has proved possible to devise different behavioral paradigms to measure various aspects of impulsivity in both humans and laboratory animals. This review describes and evaluates some of the current behavioral models of impulsivity developed for use with rodents based on human neuropsychological tests, focusing on the five-choice serial reaction time task, the stop-signal reaction time task and delay-discounting paradigms. Furthermore, the contributions made by preclinical studies using such methodology to improve our understanding of the neural and neurochemical basis of impulsivity and ADHD are discussed, with particular reference to the involvement of both the serotonergic and dopaminergic systems, and frontostriatal circuitry. PMID:16504359

  15. Electrophysiological Mechanisms of Brugada Syndrome: Insights from Pre-clinical and Clinical Studies

    PubMed Central

    Tse, Gary; Liu, Tong; Li, Ka H. C.; Laxton, Victoria; Chan, Yin W. F.; Keung, Wendy; Li, Ronald A.; Yan, Bryan P.

    2016-01-01

    Brugada syndrome (BrS), is a primary electrical disorder predisposing affected individuals to sudden cardiac death via the development of ventricular tachycardia and fibrillation (VT/VF). Originally, BrS was linked to mutations in the SCN5A, which encodes for the cardiac Na+ channel. To date, variants in 19 genes have been implicated in this condition, with 11, 5, 3, and 1 genes affecting the Na+, K+, Ca2+, and funny currents, respectively. Diagnosis of BrS is based on ECG criteria of coved- or saddle-shaped ST segment elevation and/or T-wave inversion with or without drug challenge. Three hypotheses based on abnormal depolarization, abnormal repolarization, and current-load-mismatch have been put forward to explain the electrophysiological mechanisms responsible for BrS. Evidence from computational modeling, pre-clinical, and clinical studies illustrates that molecular abnormalities found in BrS lead to alterations in excitation wavelength (λ), which ultimately elevates arrhythmic risk. A major challenge for clinicians in managing this condition is the difficulty in predicting the subset of patients who will suffer from life-threatening VT/VF. Several repolarization risk markers have been used thus far, but these neglect the contributions of conduction abnormalities in the form of slowing and dispersion. Indices incorporating both repolarization and conduction and based on the concept of λ have recently been proposed. These may have better predictive values than the existing markers. PMID:27803673

  16. Autosomal Dominant Alzheimer Disease: A Unique Resource to Study CSF Biomarker Changes in Preclinical AD

    PubMed Central

    Schindler, Suzanne Elizabeth; Fagan, Anne M.

    2015-01-01

    Our understanding of the pathogenesis of Alzheimer disease (AD) has been greatly influenced by investigation of rare families with autosomal dominant mutations that cause early onset AD. Mutations in the genes coding for amyloid precursor protein (APP), presenilin 1 (PSEN-1), and presenilin 2 (PSEN-2) cause over-production of the amyloid-β peptide (Aβ) leading to early deposition of Aβ in the brain, which in turn is hypothesized to initiate a cascade of processes, resulting in neuronal death, cognitive decline, and eventual dementia. Studies of cerebrospinal fluid (CSF) from individuals with the common form of AD, late-onset AD (LOAD), have revealed that low CSF Aβ42 and high CSF tau are associated with AD brain pathology. Herein, we review the literature on CSF biomarkers in autosomal dominant AD (ADAD), which has contributed to a detailed road map of AD pathogenesis, especially during the preclinical period, prior to the appearance of any cognitive symptoms. Current drug trials are also taking advantage of the unique characteristics of ADAD and utilizing CSF biomarkers to accelerate development of effective therapies for AD. PMID:26175713

  17. Computed tomography-based rigidity analysis: a review of the approach in preclinical and clinical studies

    PubMed Central

    Villa-Camacho, Juan C; Iyoha-Bello, Otatade; Behrouzi, Shohreh; Snyder, Brian D; Nazarian, Ara

    2014-01-01

    The assessment of fracture risk in patients afflicted with osseous neoplasms has long presented a problem for orthopedic oncologists. These patients are at risk for developing pathologic fractures through lytic defects in the appendicular and axial skeleton with devastating consequences on their quality of life. Lesions with a high risk of fracture may require prophylactic surgical stabilization, whereas low-risk lesions can be treated conservatively. Therefore, effective prevention of pathologic fractures depends on accurate assessment of fracture risk and is a critical step to avoid debilitating complications. Given the complex nature of osseous neoplasms, treatment requires a multidisciplinary approach; yet, little consensus regarding fracture risk assessment exists among physicians involved in the care of these patients. In order to improve the overall standard of care, specific criteria must be adopted to formulate consistent and accurate fracture risk predictions. However, clinicians make subjective assessments about fracture risk on plain radiographs using guidelines now recognized to be inaccurate. Osseous neoplasms alter both the material and geometric properties of bone; failure to account for changes in both of these parameters limits the accuracy of current fracture risk assessments. Rigidity, the capacity to resist deformation upon loading, is a structural property that integrates both the material and geometric properties of bone. Therefore, rigidity can be used as a mechanical assay of the changes induced by lytic lesions to the structural competency of bone. Using this principle, computed tomography (CT)-based structural rigidity analysis (CTRA) was developed and validated in a series of preclinical and clinical studies. PMID:25396051

  18. Preclinical animal study and clinical trail of modified extraoral craniofacial implants.

    PubMed

    Petrovic, L; Schlegel, K A; Wiltfang, J; Neukam, F W; Rupprecht, S

    2007-01-01

    We report on our experience using a new endosseous implant designed to provide sufficient retention to various types of facial prostheses. In a preclinical animal experiment implants (N=12, 4 x 3.5 mm) were placed in the frontal calvarial region of nine adult pigs. The animals were sacrificed at 2, 4 and 8 weeks to evaluate the implant incorporation microradiographically. The clinical outcome and patient satisfaction of implant-retained prostheses were evaluated in a group of 10 patients with facial defects by using clinical assessment and standardized questionnaires for patients and relatives. In the prospective clinical study 33 identical modified implants for extraoral anchorage were placed for the fixation of various prostheses in the midfacial (eye, nose) and ear regions in the course of a clinical trial and observed over a follow-up period of 34 months. The bone-implant contact in the animal experiment reached 31% (+/-2) at 2 weeks, 39% (+/-1) after 4 weeks and 51% (+/-5) at 8 weeks. In the clinical trial, no implants were lost and all implants remained osseointegrated as confirmed clinically and radiographically, providing a stable prosthetic restoration. The analysis of the questionnaire indicates an improvement of the quality of life of patients with respect to aesthetic and psychological well-being. The results demonstrate that extraoral implants not only achieve sufficient osseointegration but also show good clinical handling and easy fixation possibilities for prosthetic anchorage. PMID:17392045

  19. Meta-Analysis and Systematic Review of Neural Stem Cells therapy for experimental ischemia stroke in preclinical studies

    PubMed Central

    Chen, Lukui; Zhang, Guilong; Gu, Yuchun; Guo, Xiaoyuan

    2016-01-01

    To evaluate the preclinical studies using NSCs transplantation therapy for experimental ischemic stroke, and determine the effect size of NSCs therapy and the correlations between different clinical measures. We firstly searched literatures to identify studies of NSCs therapy in animal cerebral ischemia models, and then calculated the quality score of studies, assessed the effect size of NSCs therapy relative to behavioral and histologic endpoints by meta-analysis. A total of 37 studies and 54 independent treated interventions were used for systematic review and meta-analysis. The median quality score was 5 of 10. 36 studies (53 intervention arms) reported functional outcome, 22 studies (34 intervention arms) reported structural outcome. After adjusted by subgroup and sensitivity analysis, the mean effect sizes were improved by 1.35 for mNSS, 1.84 for rotarod test, 0.61 for cylinder test, and 0.84 for infarct volume. Furthermore, effect size had a certain interaction with clinical variables, for example early NSCs therapy etc. In this preclinical studies, we demonstrated that transplanted NSCs significantly improved outcomes (both functional and structural outcome) in ischemic stroke. It is suggested that future preclinical animal model studies of stroke should improve study quality validity and reduce potentially confounded publication bias. PMID:27554433

  20. HD047703, a New Promising Anti-Diabetic Drug Candidate: In Vivo Preclinical Studies

    PubMed Central

    Kim, SoRa; Kim, Dae Hoon; Kim, Young-Seok; Ha, Tae-Young; Yang, Jin; Park, Soo Hyun; Jeong, Kwang Won; Rhee, Jae-Keol

    2014-01-01

    G-protein coupled receptor 119 (GPR119) has emerged as a novel target for the treatment of type 2 diabetes mellitus. GPR119 is involved in glucose-stimulated insulin secretion (GSIS) from the pancreatic β-cells and intestinal cells. In this study, we identified a novel small-molecule GPR119 agonist, HD047703, which raises intracellular cAMP concentrations in pancreatic β-cells and can be expected to potentiate glucose-stimulated insulin secretion from human GPR119 receptor stably expressing cells (CHO cells). We evaluated the acute efficacy of HD047703 by the oral glucose tolerance test (OGTT) in normal C57BL/6J mice. Then, chronic administrations of HD047703 were performed to determine its efficacy in various diabetic rodent models. Single administration of HD047703 caused improved glycemic control during OGTT in a dose-dependent manner in normal mice, and the plasma GLP-1 level was also increased. With respect to chronic efficacy, we observed a decline in blood glucose levels in db/db, ob/ob and DIO mice. These results suggest that HD047703 may be a potentially promising anti-diabetic agent. PMID:25414769

  1. Timing of Decompressive Surgery of Spinal Cord after Traumatic Spinal Cord Injury: An Evidence-Based Examination of Pre-Clinical and Clinical Studies

    PubMed Central

    Furlan, Julio C.; Noonan, Vanessa; Cadotte, David W.

    2011-01-01

    Abstract While the recommendations for spine surgery in specific cases of acute traumatic spinal cord injury (SCI) are well recognized, there is considerable uncertainty regarding the role of the timing of surgical decompression of the spinal cord in the management of patients with SCI. Given this, we sought to critically review the literature regarding the pre-clinical and clinical evidence on the potential impact of timing of surgical decompression of the spinal cord on outcomes after traumatic SCI. The primary literature search was performed using MEDLINE, CINAHL, EMBASE, and Cochrane databases. A secondary search strategy incorporated articles referenced in prior meta-analyses and systematic and nonsystematic review articles. Two reviewers independently assessed every study with regard to eligibility, level of evidence, and study quality. Of 198 abstracts of pre-clinical studies, 19 experimental studies using animal SCI models fulfilled our inclusion and exclusion criteria. Despite some discrepancies in the results of those pre-clinical studies, there is evidence for a biological rationale to support early decompression of the spinal cord. Of 153 abstracts of clinical studies, 22 fulfilled the inclusion and exclusion criteria. While the vast majority of the clinical studies were level-4 evidence, there were two studies of level-2b evidence. The quality assessment scores varied from 7 to 25 with a mean value of 12.41. While 2 of 22 clinical studies assessed feasibility and safety, 20 clinical studies examined efficacy of early surgical intervention to stabilize and align the spine and to decompress the spinal cord; the most common definitions of early operation used 24 and 72 h after SCI as timelines. A number of studies indicated that patients who undergo early surgical decompression can have similar outcomes to patients who received a delayed decompressive operation. However, there is evidence to suggest that early surgical intervention is safe and feasible

  2. Alterations in the rate of binge ethanol consumption: implications for preclinical studies in mice.

    PubMed

    Linsenbardt, David N; Boehm, Stephen L

    2014-09-01

    The rate at which alcohol (ethanol) is consumed has direct impact on its behavioral and subjective effects. For this reason, alterations in the pattern of ethanol consumption as a function of drinking history might be critical to the development and maintenance of alcoholism. Furthermore, because pharmacological interventions aimed at disrupting the motivation to consume ethanol are dependent on the brain/plasma concentrations present when an individual is most likely to engage in consumption of this substance, characterizing temporal drinking patterns might be useful to determine the timing of such treatments. The primary goal of the present study was to evaluate alterations in the timecourse of daily binge (drinking-in-the-dark; DID) ethanol consumption. We gave 14 daily 2 hour DID ethanol or water access sessions to male C57BL/6J (B6) mice using a state of the art volumetric drinking monitoring device. We then, primarily as a proof-of-principle, used the GABAB allosteric modulator GS39783 (GS) to determine how this compound influenced the timecourse of binge-like ethanol intake. The rate of ethanol consumption increased dramatically over sessions with the majority occurring in the first few minutes of the final session. Additionally, ethanol consumption occurring immediately following access was almost completely abolished in mice pre-treated with GS; an effect which was ethanol-specific only at this early time interval. These data characterize progressive alterations in the rate of ethanol intake using the DID model and suggest that careful consideration of prior ethanol history and timing of drug administration are warranted when interpreting results of pre-clinical drug administration studies.

  3. Nanomedicines for cancer therapy: state-of-the-art and limitations to pre-clinical studies that hinder future developments

    NASA Astrophysics Data System (ADS)

    Dawidczyk, Charlene; Russell, Luisa; Searson, Peter

    2014-08-01

    The ability to efficiently deliver a drug or gene to a tumor site is dependent on a wide range of factors including circulation time, interactions with the mononuclear phagocyte system, extravasation from circulation at the tumor site, targeting strategy, release from the delivery vehicle, and uptake in cancer cells. Nanotechnology provides the possibility of creating delivery systems where the design constraints are decoupled, allowing new approaches for reducing the unwanted side effects of systemic delivery, increasing tumor accumulation, and improving efficacy. The physico-chemical properties of nanoparticle-based delivery platforms introduce additional complexity associated with pharmacokinetics and tumor accumulation. To assess the impact of nanoparticle-based delivery systems, we first review the design strategies and pharmacokinetics of FDA-approved nanomedicines. Next we review nanomedicines under development, summarizing the range of nanoparticle platforms, strategies for targeting, and pharmacokinetics. We show how the lack of uniformity in preclinical trials prevents systematic comparison and hence limits advances in the field.

  4. Irinotecan delivery by microbubble-assisted ultrasound - A pilot preclinical study

    NASA Astrophysics Data System (ADS)

    Escoffre, Jean-Michel; Novell, Anthony; Serrière, Sophie; Bouakaz, Ayache

    2012-11-01

    Irinotecan is conventionally used for the treatment of colorectal cancer. However, its administration is associated with severe side effects. Targeted drug delivery using ultrasound (US) combined with microbubbles offers new opportunities to increase the therapeutic effectiveness of antitumor treatment and to reduce toxic exposure to healthy tissues. The objective of this study is to investigate the safety and efficacy of in-vivo delivery of irinotecan by microbubble-assisted US in human glioblastoma model (U-87 MG). In order to validate the potential of this new method in-vivo, subcutaneous tumors were implanted in the flank of nude mouse and treated when they reached a volume of 100 mm3. In the first study, the measured volumes with caliper and anatomic ultrasound imaging were compared for the monitoring and the quantification of tumor growth during 27 days. Ultrasound imaging measurements were positively correlated to caliper measurements. The tumor treatment consisted of an i.v. injection of irinotecan (20 mg/kg) followed one hour later by i.v. administration of MM1 microbubble and an US insonation using a single-element transducer operating at 1MHz (400 kPa, 10 kHz PRF 40% DC, 3 min). The therapeutic efficacy was evaluated for 39 days by measuring the tumor volume before and after treatment using a caliper and based on ultrasound images using an 18 MHz probe (Vevo 2100). Our results showed that anatomical ultrasound imaging was as efficient as caliper for the monitoring and the quantification of tumor growth. Moreover, irinotecan delivery by sonoporation induced a significant decrease of glioblastoma tumor volume and an increase of tumor-doubling time compared to the tumor treated by irinotecan alone. In conclusion, this novel therapeutic approach has promising features since it can be used to reduce the injected drug dose and to achieve a better therapeutic efficacy.

  5. In question: the scientific value of preclinical safety pharmacology and toxicology studies with cell-based therapies

    PubMed Central

    Broichhausen, Christiane; Riquelme, Paloma; Ahrens, Norbert; Wege, Anja K; Koehl, Gudrun E; Schlitt, Hans J; Banas, Bernhard; Fändrich, Fred; Geissler, Edward K; Hutchinson, James A

    2014-01-01

    A new cell-based medicinal product containing human regulatory macrophages, known as Mreg_UKR, has been developed and conforms to expectations of a therapeutic drug. Here, Mreg_UKR was subjected to pharmacokinetic, safety pharmacology, and toxicological testing, which identified no adverse reactions. These results would normally be interpreted as evidence of the probable clinical safety of Mreg_UKR; however, we contend that, owing to their uncertain biological relevance, our data do not fully support this conclusion. This leads us to question whether there is adequate scientific justification for preclinical safety testing of similar novel cell-based medicinal products using animal models. In earlier work, two patients were treated with regulatory macrophages prior to kidney transplantation. In our opinion, the absence of acute or chronic adverse effects in these cases is the most convincing available evidence of the likely safety of Mreg_UKR in future recipients. On this basis, we consider that safety information from previous clinical investigations of related cell products should carry greater weight than preclinical data when evaluating the safety profile of novel cell-based medicinal products. By extension, we argue that omitting extensive preclinical safety studies before conducting small-scale exploratory clinical investigations of novel cell-based medicinal products data may be justifiable in some instances. PMID:26015968

  6. Trajectories of memory decline in preclinical Alzheimer's disease: results from the Australian Imaging, Biomarkers and Lifestyle Flagship Study of ageing.

    PubMed

    Pietrzak, Robert H; Lim, Yen Ying; Ames, David; Harrington, Karra; Restrepo, Carolina; Martins, Ralph N; Rembach, Alan; Laws, Simon M; Masters, Colin L; Villemagne, Victor L; Rowe, Christopher C; Maruff, Paul

    2015-03-01

    Memory changes in preclinical Alzheimer's disease (AD) are often characterized by heterogenous trajectories. However, data regarding the nature and determinants of predominant trajectories of memory changes in preclinical AD are lacking. We analyzed data from 333 cognitively healthy older adults who participated in a multicenter prospective cohort study with baseline and 18-, 36-, and 54-month follow-up assessments. Latent growth mixture modeling revealed 3 predominant trajectories of memory change: a below average, subtly declining memory trajectory (30.9%); a below average, rapidly declining memory trajectory (3.6%); and an above average, stable memory trajectory (65.5%). Compared with the stable memory trajectory, high Αβ (relative risk ratio [RRR] = 2.1), and lower Mini-Mental State Examination (RRR = 0.6) and full-scale IQ (RRR = 0.9) scores were independently associated with the subtly declining memory trajectory; and high Αβ (RRR = 8.3), APOE ε4 carriage (RRR = 6.1), and greater subjective memory impairment (RRR = 1.2) were independently associated with the rapidly declining memory trajectory. Compared with the subtly declining memory trajectory group, APOE ε4 carriage (RRR = 8.4), and subjective memory complaints (RRR = 1.2) were associated with a rapidly declining memory trajectory. These results suggest that the preclinical phase of AD may be characterized by 2 predominant trajectories of memory decline that have common (e.g., high Αβ) and unique (e.g., APOE ε4 genotype) determinants. PMID:25585532

  7. Synergistic anti-tumor efficacy of immunogenic adenovirus ONCOS-102 (Ad5/3-D24-GM-CSF) and standard of care chemotherapy in preclinical mesothelioma model.

    PubMed

    Kuryk, Lukasz; Haavisto, Elina; Garofalo, Mariangela; Capasso, Cristian; Hirvinen, Mari; Pesonen, Sari; Ranki, Tuuli; Vassilev, Lotta; Cerullo, Vincenzo

    2016-10-15

    Malignant mesothelioma (MM) is a rare cancer type caused mainly by asbestos exposure. The median overall survival time of a mesothelioma cancer patient is less than 1-year from diagnosis. Currently there are no curative treatment modalities for malignant mesothelioma, however treatments such as surgery, chemotherapy and radiotherapy can help to improve patient prognosis and increase life expectancy. Pemetrexed-Cisplatin is the only standard of care (SoC) chemotherapy for malignant mesothelioma, but the median PFS/OS (progression-free survival/overall survival) from the initiation of treatment is only up to 12 months. Therefore, new treatment strategies against malignant mesothelioma are in high demand. ONCOS-102 is a dual targeting, chimeric oncolytic adenovirus, coding for human GM-CSF. The safety and immune activating properties of ONCOS-102 have already been assessed in phase 1 study (NCT01598129). In this preclinical study, we evaluated the antineoplastic activity of combination treatment with SoC chemotherapy (Pemetrexed, Cisplatin, Carboplatin) and ONCOS-102 in xenograft BALB/c model of human malignant mesothelioma. We demonstrated that ONCOS-102 is able to induce immunogenic cell death of human mesothelioma cell lines in vitro and showed anti-tumor activity in the treatment of refractory H226 malignant pleural mesothelioma (MPM) xenograft model. While chemotherapy alone showed no anti-tumor activity in the mesothelioma mouse model, ONCOS-102 was able to slow down tumor growth. Interestingly, a synergistic anti-tumor effect was seen when ONCOS-102 was combined with chemotherapy regimens. These findings give a rationale for the clinical testing of ONCOS-102 in combination with first-line chemotherapy in patients suffering from malignant mesothelioma. PMID:27287512

  8. 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

  9. Challenges for Preclinical Investigations of Human Biofield Modalities.

    PubMed

    Gronowicz, Gloria; Bengston, William; Yount, Garret

    2015-11-01

    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.

  10. Long-term drug administration in the adult zebrafish using oral gavage for cancer preclinical studies

    PubMed Central

    Dang, Michelle; Henderson, Rachel E.; Garraway, Levi A.

    2016-01-01

    ABSTRACT Zebrafish are a major model for chemical genetics, and most studies use embryos when investigating small molecules that cause interesting phenotypes or that can rescue disease models. Limited studies have dosed adults with small molecules by means of water-borne exposure or injection techniques. Challenges in the form of drug delivery-related trauma and anesthesia-related toxicity have excluded the adult zebrafish from long-term drug efficacy studies. Here, we introduce a novel anesthetic combination of MS-222 and isoflurane to an oral gavage technique for a non-toxic, non-invasive and long-term drug administration platform. As a proof of principle, we established drug efficacy of the FDA-approved BRAFV600E inhibitor, Vemurafenib, in adult zebrafish harboring BRAFV600E melanoma tumors. In the model, adult casper zebrafish intraperitoneally transplanted with a zebrafish melanoma cell line (ZMEL1) and exposed to daily sub-lethal dosing at 100 mg/kg of Vemurafenib for 2 weeks via oral gavage resulted in an average 65% decrease in tumor burden and a 15% mortality rate. In contrast, Vemurafenib-resistant ZMEL1 cell lines, generated in culture from low-dose drug exposure for 4 months, did not respond to the oral gavage treatment regimen. Similarly, this drug treatment regimen can be applied for treatment of primary melanoma tumors in the zebrafish. Taken together, we developed an effective long-term drug treatment system that will allow the adult zebrafish to be used to identify more effective anti-melanoma combination therapies and opens up possibilities for treating adult models of other diseases. PMID:27482819

  11. Synthesis, characterization and preclinical studies of two-photon-activated targeted PDT therapeutic triads

    NASA Astrophysics Data System (ADS)

    Spangler, C. W.; Starkey, J. R.; Rebane, A.; Meng, F.; Gong, A.; Drobizhev, M.

    2006-02-01

    Photodynamic therapy (PDT) continues to evolve into a mature clinical treatment of a variety of cancer types as well as age-related macular degeneration of the eye. However, there are still aspects of PDT that need to be improved in order for greater clinical acceptance. While a number of new PDT photo-sensitizers, sometimes referred to as second- or third- generation therapeutic agents, are currently under clinical investigation, the direct treatment through the skin of subcutaneous tumors deeper than 5 mm remains problematic. Currently approved PDT porphyrin photo-sensitizers, as well as several modified porphyrins (e.g. chlorins, bacteriochlorins, etc.) that are under clinical investigation can be activated at 630-730 nm, but none above 800 nm. It would be highly desirable if new PDT paradigms could be developed that would allow photo-activation deep in the tissue transparency window in the Near-infrared (NIR) above 800 nm to reduce scattering and absorption phenomena that reduce deep tissue PDT efficacy. Rasiris and MPA Technologies have developed new porphyrins that have greatly enhanced two-photon absorption ( P A ) cross-sections and can be activated deep in the NIR (ca. 780-850 nm). These porphyrins can be incorporated into a therapeutic triad that also employs an small molecule targeting agent that directs the triad to over-expressed tumor receptor sites, and a NIR onephoton imaging agent that allows tracking the delivery of the triad to the tumor site, as well as clearance of excess triad from healthy tissue prior to the start of PDT treatment. We are currently using these new triads in efficacy studies with a breast cancer cell line that has been transfected with luciferase genes that allow implanted tumor growth and post- PDT treatment efficacy studies in SCID mouse models by following the rise and decay of the bioluminescence signal. We have also designed highly absorbing and scattering collagen breast cancer phantoms in which we have demonstrated

  12. Systematic Approach to Remediation in Basic Science Knowledge for Preclinical Students: A case study

    NASA Astrophysics Data System (ADS)

    Amara, Francis

    Remediation of pre-clerkship students for deficits in basic science knowledge should help them overcome their learning deficiencies prior to clerkship. However, very little is known about remediation in basic science knowledge during pre-clerkship. This study utilized the program theory framework to collect and organize mixed methods data of the remediation plan for pre-clerkship students who failed their basic science cognitive examinations in a Canadian medical school. This plan was analyzed using a logic model narrative approach and compared to literature on the learning theories. The analysis showed a remediation plan that was strong on governance and verification of scores, but lacked: clarity and transparency of communication, qualified remedial tutors, individualized diagnosis of learner's deficits, and student centered learning. Participants admitted uncertainty about the efficacy of the remediation process. A remediation framework is proposed that includes student-centered participation, individualized learning plan and activities, deliberate practice, feedback, reflection, and rigorous reassessment.

  13. Preclinical assessment of the absorption and disposition of the phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor GDC-0980 and prediction of its pharmacokinetics and efficacy in human.

    PubMed

    Salphati, Laurent; Pang, Jodie; Plise, Emile G; Lee, Leslie B; Olivero, Alan G; Prior, Wei Wei; Sampath, Deepak; Wong, Susan; Zhang, Xiaolin

    2012-09-01

    (S)-1-{4-[2-(2-Amino-pyrimidin-5-yl)-7-methyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl]-piperazin-1-yl}-2-hydroxy-propan-1-one (GDC-0980) is a potent and selective inhibitor of phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin, two key components of the PI3K pathway, the deregulation of which is associated with the development of many cancers. The objectives of these studies were to characterize the absorption and disposition of GDC-0980 and assess its efficacy in an MCF7-neo/HER2 human breast cancer xenograft model in immunocompromised mice. Studies in parental Madin-Darby canine kidney cells indicated that GDC-0980 had high permeability (P(app) = 18 × 10⁻⁶ cm/s), suggesting good absorption potential. However, it was found to be a P-glycoprotein and breast cancer resistance protein substrate in transfected cells and in knockout mice studies. Plasma protein binding was low, with the fraction unbound ranging from 29 to 52% across species. GDC-0980 hepatic clearance (CL) was predicted to be low in all of the species tested from hepatocyte incubations. The plasma CL of GDC-0980 was low in mouse (6.30 ml · min⁻¹ · kg⁻¹), rat (15.4 ml · min⁻¹ · kg⁻¹), and dog (6.37 ml · min⁻¹ · kg⁻¹) and moderate in cynomolgus monkey (18.9 ml · min⁻¹ · kg⁻¹). Oral bioavailability ranged from 14.4% in monkey to 125% in dog. Predicted human plasma CL and volume of distribution using allometry were 5.1 ml · min⁻¹ · kg⁻¹ and 1.8 l/kg, respectively. Parameters estimated from the pharmacokinetic/pharmacodynamic modeling of the MCF7-neo/HER2 xenograft data indicated that the GDC-0980 plasma concentration required for tumor stasis was approximately 0.5 μM. These parameters, combined with the predicted human pharmacokinetic profile, suggested that 55 mg once daily may be a clinically efficacious dose. GDC-0980 preclinical characterization and the predictions of its human properties supported its clinical development; it

  14. A Selective Nociceptin Receptor Antagonist to Treat Depression: Evidence from Preclinical and Clinical Studies.

    PubMed

    Post, Anke; Smart, Trevor S; Krikke-Workel, Judith; Dawson, Gerard R; Harmer, Catherine J; Browning, Michael; Jackson, Kimberley; Kakar, Rishi; Mohs, Richard; Statnick, Michael; Wafford, Keith; McCarthy, Andrew; Barth, Vanessa; Witkin, Jeffrey M

    2016-06-01

    Nociceptin/Orphanin FQ (N/OFQ) is an endogenous ligand of the N/OFQ peptide (NOP) receptor, which is a G protein-coupled receptor in brain regions associated with mood disorders. We used a novel, potent, and selective orally bioavailable antagonist, LY2940094, to test the hypothesis that blockade of NOP receptors would induce antidepressant effects. In this study we demonstrate that targeting NOP receptors with LY2940094 translates to antidepressant-like effects in rodent models and, importantly, to antidepressant efficacy in patients with major depressive disorder (MDD). The proof-of-concept study (POC) was an 8-week, double-blind, placebo-controlled trial that evaluated LY2940094 as a novel oral medication for the treatment of patients with MDD. Once daily oral dosing of LY2940094 at 40 mg for 8 weeks vs placebo provided some evidence for an antidepressant effect based on the change from baseline to week 8 in the GRID-Hamilton Depression Rating Scale-17 item total score, although the predefined POC efficacy criterion (probability of LY2940094 being better than placebo⩾88%) was not met (82.9%). LY2940094 also had an early effect on the processing of emotional stimuli at Week 1 as shown by an increased recognition of positive relative to negative facial expressions in an emotional test battery. LY2940094 was safe and well tolerated. Overall, these are the first human data providing evidence that the blockade of NOP receptor signaling represents a promising strategy for the treatment of MDD.

  15. Metabonomics in the preclinical and environmental toxicity field.

    PubMed

    Colet, Jean-Marie

    2015-06-01

    Preclinical studies assess both efficacy and safety of new drugs through a series of assays used to identify potential target organs and determine safety thresholds. However, despite these efforts, too many drugs prove toxic to humans during clinical phases or later on the market. This paper reviews how metabonomics, one of the key players in systems biology, should be able to assist toxicologists in better predicting the adverse effects of xenobiotics.

  16. Preclinical Development of Ipilimumab and Nivolumab Combination Immunotherapy: Mouse Tumor Models, In Vitro Functional Studies, and Cynomolgus Macaque Toxicology.

    PubMed

    Selby, Mark J; Engelhardt, John J; Johnston, Robert J; Lu, Li-Sheng; Han, Minhua; Thudium, Kent; Yao, Dapeng; Quigley, Michael; Valle, Jose; Wang, Changyu; Chen, Bing; Cardarelli, Pina M; Blanset, Diann; Korman, Alan J

    2016-01-01

    The monoclonal antibodies ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) have shown remarkable antitumor activity in an increasing number of cancers. When combined, ipilimumab and nivolumab have demonstrated superior activity in patients with metastatic melanoma (CHECKMATE-067). Here we describe the preclinical development strategy that predicted these clinical results. Synergistic antitumor activity in mouse MC38 and CT26 colorectal tumor models was observed with concurrent, but not sequential CTLA-4 and PD-1 blockade. Significant antitumor activity was maintained using a fixed dose of anti-CTLA-4 antibody with decreasing doses of anti-PD-1 antibody in the MC38 model. Immunohistochemical and flow cytometric analyses confirmed that CD3+ T cells accumulated at the tumor margin and infiltrated the tumor mass in response to the combination therapy, resulting in favorable effector and regulatory T-cell ratios, increased pro-inflammatory cytokine secretion, and activation of tumor-specific T cells. Similarly, in vitro studies with combined ipilimumab and nivolumab showed enhanced cytokine secretion in superantigen stimulation of human peripheral blood lymphocytes and in mixed lymphocyte response assays. In a cynomolgus macaque toxicology study, dose-dependent immune-related gastrointestinal inflammation was observed with the combination therapy; this response had not been observed in previous single agent cynomolgus studies. Together, these in vitro assays and in vivo models comprise a preclinical strategy for the identification and development of highly effective antitumor combination immunotherapies. PMID:27610613

  17. Preclinical Development of Ipilimumab and Nivolumab Combination Immunotherapy: Mouse Tumor Models, In Vitro Functional Studies, and Cynomolgus Macaque Toxicology

    PubMed Central

    Selby, Mark J.; Engelhardt, John J.; Johnston, Robert J.; Lu, Li-Sheng; Han, Minhua; Thudium, Kent; Yao, Dapeng; Quigley, Michael; Valle, Jose; Wang, Changyu; Chen, Bing; Cardarelli, Pina M.; Blanset, Diann; Korman, Alan J.

    2016-01-01

    The monoclonal antibodies ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) have shown remarkable antitumor activity in an increasing number of cancers. When combined, ipilimumab and nivolumab have demonstrated superior activity in patients with metastatic melanoma (CHECKMATE-067). Here we describe the preclinical development strategy that predicted these clinical results. Synergistic antitumor activity in mouse MC38 and CT26 colorectal tumor models was observed with concurrent, but not sequential CTLA-4 and PD-1 blockade. Significant antitumor activity was maintained using a fixed dose of anti-CTLA-4 antibody with decreasing doses of anti-PD-1 antibody in the MC38 model. Immunohistochemical and flow cytometric analyses confirmed that CD3+ T cells accumulated at the tumor margin and infiltrated the tumor mass in response to the combination therapy, resulting in favorable effector and regulatory T-cell ratios, increased pro-inflammatory cytokine secretion, and activation of tumor-specific T cells. Similarly, in vitro studies with combined ipilimumab and nivolumab showed enhanced cytokine secretion in superantigen stimulation of human peripheral blood lymphocytes and in mixed lymphocyte response assays. In a cynomolgus macaque toxicology study, dose-dependent immune-related gastrointestinal inflammation was observed with the combination therapy; this response had not been observed in previous single agent cynomolgus studies. Together, these in vitro assays and in vivo models comprise a preclinical strategy for the identification and development of highly effective antitumor combination immunotherapies. PMID:27610613

  18. Cardiac arterial spin labeling using segmented ECG-gated Look-Locker FAIR: variability and repeatability in preclinical studies.

    PubMed

    Campbell-Washburn, Adrienne E; Price, Anthony N; Wells, Jack A; Thomas, David L; Ordidge, Roger J; Lythgoe, Mark F

    2013-01-01

    MRI is important for the assessment of cardiac structure and function in preclinical studies of cardiac disease. Arterial spin labeling techniques can be used to measure perfusion noninvasively. In this study, an electrocardiogram-gated Look-Locker sequence with segmented k-space acquisition has been implemented to acquire single slice arterial spin labeling data sets in 15 min in the mouse heart. A data logger was introduced to improve data quality by: (1) allowing automated rejection of respiration-corrupted images, (2) providing additional prospective gating to improve consistency of acquisition timing, and (3) allowing the recombination of uncorrupted k-space lines from consecutive data sets to reduce respiration corruption. Finally, variability and repeatability of perfusion estimation within-session, between-session, between-animal, and between image rejection criteria were assessed in mice. The criterion used to reject images from the T(1) fit was shown to affect the perfusion estimation. These data showed that the between-animal coefficient of variability (24%) was greater than the between-session variability (17%) and within-session variability (11%). Furthermore, the magnitude of change in perfusion required to detect differences was 30% (within-session) and 55% (between-session) according to Bland-Altman repeatability analysis. These technique developments and repeatability statistics will provide a platform for future preclinical studies applying cardiac arterial spin labeling.

  19. Pre-clinical and preliminary dose-finding and safety studies to identify candidate antivenoms for treatment of envenoming by saw-scaled or carpet vipers (Echis ocellatus) in northern Nigeria.

    PubMed

    Abubakar, S B; Abubakar, I S; Habib, A G; Nasidi, A; Durfa, N; Yusuf, P O; Larnyang, S; Garnvwa, J; Sokomba, E; Salako, L; Laing, G D; Theakston, R D G; Juszczak, E; Alder, N; Warrell, D A

    2010-04-01

    The aim of this study was to identify candidate antivenoms with specific activity against the venom of the saw-scaled or carpet viper (Echis ocellatus) in northern Nigeria, where bites by this species cause great morbidity and mortality but where effective antivenoms have become scarce and unaffordable. Selected antivenoms were destined to be compared by randomised controlled clinical trials (RCTs). Standard pre-clinical neutralisation assays were carried out in rodents. We included two licensed antivenoms of established clinical efficacy and 6 candidate antivenoms. Although 6 of the tested antivenoms showed promising efficacy, all but 3 were excluded from further study because of inadequate pre-clinical efficacy or because they were unavailable or unaffordable for the anticipated RCTs. Median effective doses (ED(50)) of the remaining three candidate antivenoms suggested that the following doses might neutralise the maximum observed venom yield of 24.8 mg (dry weight) of venom milked from captive E. ocellatus: 10 ml of MicroPharm "EchiTAb G" (ET-G) antivenom; 30 ml of Instituto Clodomiro Picado "EchiTAb-Plus-ICP" (ET-Plus) antivenom; 50 ml of VacSera, Cairo "EgyVac" antivenom. A preliminary clinical dose-finding and safety study of these three antivenoms was carried out in 24 patients with incoagulable blood after E. ocellatus bites who were not severely envenomed. A 3+3 dose escalation design was employed. Initial doses of 10 ml ET-G and 30 ml ET-Plus restored blood coagulability in groups of 6 patients with early mild reactions (pruritus only) in not more than one third of them. EgyVac antivenom did not fulfil efficacy or safety criteria in 12 patients. On the basis of these results, ET-G and ET-Plus were selected for comparison in a RCT. PMID:19874841

  20. Prazosin addition to fluvoxamine: A preclinical study and open clinical trial in OCD.

    PubMed

    Feenstra, Matthijs G P; Klompmakers, André; Figee, Martijn; Fluitman, Sjoerd; Vulink, Nienke; Westenberg, Herman G M; Denys, Damiaan

    2016-02-01

    The efficacy of selective serotonin reuptake inhibitors (SRIs) in psychiatric disorders may be "augmented" through the addition of atypical antipsychotic drugs. A synergistic increase in dopamine (DA) release in the prefrontal cortex has been suggested to underlie this augmentation effect, though the mechanism of action is not clear yet. We used in vivo microdialysis in rats to study DA release following the administration of combinations of fluvoxamine (10 mg/kg) and quetiapine (10 mg/kg) with various monoamine-related drugs. The results confirmed that the selective 5-HT1A antagonist WAY-100635 (0.05 mg/kg) partially blocked the fluvoxamine-quetiapine synergistic effect (maximum DA increase dropped from 325% to 214%). A novel finding is that the α1-adrenergic blocker prazosin (1 mg/kg), combined with fluvoxamine, partially mimicked the effect of augmentation (maximum DA increase 205%; area-under-the-curve 163%). As this suggested that prazosin augmentation might be tested in a clinical study, we performed an open clinical trial of prazosin 20 mg addition to SRI in therapy-resistant patients with obsessive-compulsive disorder applying for neurosurgery. A small, non-significant reduction in Yale Brown Obsessive Compulsive Scale (Y-BOCS) scores was observed in 10 patients and one patient was classified as a responder with a reduction in Y-BOCS scores of more than 25%. We suggest that future clinical studies augmenting SRIs with an α1-adrenergic blocker in less treatment resistant cases should be considered. The clinical trial "Prazosin in combination with a serotonin reuptake inhibitor for patients with Obsessive Compulsive disorder: an open label study" was registered at 24/05/2011 under trial number ISRCTN61562706: http://www.controlled-trials.com/ISRCTN61562706. PMID:26712326

  1. Methods to Evaluate the Antitumor Activity of Immune Checkpoint Inhibitors in Preclinical Studies.

    PubMed

    Allard, Bertrand; Allard, David; Stagg, John

    2016-01-01

    Immune checkpoint inhibitors (ICI) are a new class of drugs characterized by their ability to enhance antitumor immune responses through the blockade of critical cell surface receptors involved in the maintenance of peripheral tolerance. The recent approval of ICI targeting CTLA-4 or PD-1 for the treatment of cancer constitutes a major breakthrough in the field of oncology and demonstrates the potential of immune-mediated therapies in achieving durable cancer remissions. The identification of new immune regulatory pathways that could be targeted to reactivate or boost antitumor immunity is now a very active field of research. In this context, the use of syngeneic mouse models and immune monitoring techniques are the cornerstone of proof-of-concept studies. In this chapter, we describe the general methodology to evaluate antitumor activity of ICI in immunocompetent mice. We outline protocols to reliably establish tumors in mice and generate lung metastasis through tail vein injections with the aim of testing the efficacy of ICI. We also present methods to analyze the composition of the tumor immune-infiltrate by multicolor flow cytometry. PMID:27581021

  2. Preclinical Studies on the Pharmacokinetics, Safety and Toxicology of Oxfendazole: Toward First in Human Studies

    PubMed Central

    Codd, Ellen E.; Ng, Hanna H.; McFarlane, Claire; Riccio, Edward S.; Doppalapudi, Rupa; Mirsalis, Jon C.; Horton, R. John; Gonzalez, Armando E.; Garcia, H. Hugo; Gilman, Robert H.

    2015-01-01

    A two-week study in rats identified target organs of oxfendazole toxicity to be bone marrow, epididymis, liver, spleen, testis, and thymus. Female rats had greater oxfendazole exposure and exhibited toxicities at lower doses than did males. Decreased WBC levels, a class effect of benzimidazole anthelminthics, returned to normal during the recovery period. The NOAEL was determined to be >5 but < 25 mg/kg/d and the MTD 100 mg/kg/d. The highest dose, 200 mg/kg/d resulted in significant toxicity and mortality, leading to euthanization of the main study animals in this group after seven days. Oxfendazole did not exhibit genetic toxicology signals in standard Ames bacterial, mouse lymphoma or rat micronucleus assays, nor did it provoke safety concerns when evaluated for behavioral effects in rats or cardiovascular safety effects in dogs. These results support the transition of oxfendazole to First in Human safety studies preliminary to its evaluation in human helminth diseases. PMID:25701764

  3. Pharmacokinetics and tolerability of NSC23925b, a novel P-glycoprotein inhibitor: preclinical study in mice and rats

    PubMed Central

    Gao, Yan; Shen, Jacson K.; Choy, Edwin; Zhang, Zhan; Mankin, Henry J.; Hornicek, Francis J.; Duan, Zhenfeng

    2016-01-01

    Overexpression of P-glycoprotein (Pgp) increases multidrug resistance (MDR) in cancer, which greatly impedes satisfactory clinical treatment and outcomes of cancer patients. Due to unknown pharmacokinetics, the use of Pgp inhibitors to overcome MDR in the clinical setting remains elusive despite promising in vitro results. The purpose of our current preclinical study is to investigate the pharmacokinetics and tolerability of NSC23925b, a novel and potent P-glycoprotein inhibitor, in rodents. Plasma pharmacokinetic studies of single-dose NSC23925b alone or in combination with paclitaxel or doxorubicin were conducted in male BALB/c mice and Sprague-Dawley rats. Additionally, inhibition of human cytochrome P450 (CYP450) by NSC23925b was examined in vitro. Finally, the maximum tolerated dose (MTD) of NSC23925b was determined. NSC23925b displayed favorable pharmacokinetic profiles after intraperitoneal/intravenous (I.P./I.V.) injection alone or combined with chemotherapeutic drugs. The plasma pharmacokinetic characteristics of the chemotherapy drugs were not affected when co-administered with NSC23925b. All the animals tolerated the I.P./I.V. administration of NSC23925b. Moreover, the enzymatic activity of human CYP450 was not inhibited by NSC23925b. Our results demonstrated that Pgp inhibitor NSC23925b exhibits encouraging preclinical pharmacokinetic characteristics and limited toxicity in vivo. NSC23925b has the potential to treat cancer patients with MDR in the future. PMID:27157103

  4. Pre-clinical and clinical walking kinematics in female breeding pigs with lameness: A nested case-control cohort study.

    PubMed

    Stavrakakis, S; Guy, J H; Syranidis, I; Johnson, G R; Edwards, S A

    2015-07-01

    Gait profiles were investigated in a cohort of female pigs experiencing a lameness period prevalence of 29% over 17 months. Gait alterations before and during visually diagnosed lameness were evaluated to identify the best quantitative clinical lameness indicators and early predictors for lameness. Pre-breeding gilts (n= 84) were recruited to the study over a period of 6 months, underwent motion capture every 5 weeks and, depending on their age at entry to the study, were followed for up to three successive gestations. Animals were subject to motion capture in each parity at 8 weeks of gestation and on the day of weaning (28 days postpartum). During kinematic motion capture, the pigs walked on the same concrete walkway and an array of infra-red cameras was used to collect three dimensional coordinate data of reflective skin markers attached to the head, trunk and limb anatomical landmarks. Of 24 pigs diagnosed with lameness, 19 had preclinical gait records, whilst 18 had a motion capture while lame. Depending on availability, data from one or two preclinical motion capture 1-11 months prior to lameness and on the day of lameness were analysed. Lameness was best detected and evaluated using relative spatiotemporal gait parameters, especially vertical head displacement and asymmetric stride phase timing. Irregularity in the step-to-stride length ratio was elevated (deviation  ≥ 0.03) in young pigs which presented lameness in later life (odds ratio 7.2-10.8). PMID:25986130

  5. Rodents as pre-clinical models for predicting vaccine performance in humans.

    PubMed

    Riese, Peggy; Trittel, Stephanie; Schulze, Kai; Guzmán, Carlos A

    2015-01-01

    Vaccines represent a key building block for establishing a successful and sustainable control strategy against infectious diseases. Vaccine development often depends on the availability of correlates for protection and reliable animal models for the screening, selection and prioritization of potential vaccine candidates. This is performed according to their immunogenicity, efficacy and safety profiles in pre-clinical studies, which are also critical for identification of candidate antigens, selection of an optimal delivery system and design of appropriate vaccine formulations. Thus, pre-clinical studies in animal models are a prerequisite for addressing crucial issues and generating a solid pre-clinical package for the approval of clinical trials. This review addresses the strengths, limitations and perspectives of rodents as a vaccine development and pre-clinical validation tool. PMID:26268433

  6. Preclinical studies on the pharmacokinetics, safety, and toxicology of oxfendazole: toward first in human studies.

    PubMed

    Codd, Ellen E; Ng, Hanna H; McFarlane, Claire; Riccio, Edward S; Doppalapudi, Rupa; Mirsalis, Jon C; Horton, R John; Gonzalez, Armando E; Garcia, H Hugo; Gilman, Robert H

    2015-01-01

    A 2-week study in rats identified target organs of oxfendazole toxicity to be bone marrow, epididymis, liver, spleen, testis, and thymus. Female rats had greater oxfendazole exposure and exhibited toxicities at lower doses than did males. Decreased white blood cell levels, a class effect of benzimidazole anthelmintics, returned to normal during the recovery period. The no observed adverse effect level was determined to be >5 but <25 mg/kg/d and the maximum tolerated dose 100 mg/kg/d. The highest dose, 200 mg/kg/d, resulted in significant toxicity and mortality, leading to euthanization of the main study animals in this group after 7 days. Oxfendazole did not exhibit genetic toxicology signals in standard Ames bacterial, mouse lymphoma, or rat micronucleus assays nor did it provoke safety concerns when evaluated for behavioral effects in rats or cardiovascular safety effects in dogs. These results support the transition of oxfendazole to First in Human safety studies preliminary to its evaluation in human helminth diseases.

  7. Nanomedicines for cancer therapy: state-of-the-art and limitations to pre-clinical studies that hinder future developments

    PubMed Central

    Dawidczyk, Charlene M.; Russell, Luisa M.; Searson, Peter C.

    2014-01-01

    The ability to efficiently deliver a drug or gene to a tumor site is dependent on a wide range of factors including circulation time, interactions with the mononuclear phagocyte system, extravasation from circulation at the tumor site, targeting strategy, release from the delivery vehicle, and uptake in cancer cells. Nanotechnology provides the possibility of creating delivery systems where the design constraints are decoupled, allowing new approaches for reducing the unwanted side effects of systemic delivery, increasing tumor accumulation, and improving efficacy. The physico-chemical properties of nanoparticle-based delivery platforms introduce additional complexity associated with pharmacokinetics, tumor accumulation, and biodistribution. To assess the impact of nanoparticle-based delivery systems, we first review the design strategies and pharmacokinetics of FDA-approved nanomedicines. Next we review nanomedicines under development, summarizing the range of nanoparticle platforms, strategies for targeting, and pharmacokinetics. We show how the lack of uniformity in preclinical trials prevents systematic comparison and hence limits advances in the field. PMID:25202689

  8. 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

  9. Therapeutic vaccination and immunomodulation in the treatment of chronic hepatitis B: preclinical studies in the woodchuck.

    PubMed

    Kosinska, Anna D; Liu, Jia; Lu, Mengji; Roggendorf, Michael

    2015-02-01

    Infection with hepatitis B virus (HBV) may lead to subclinical, acute or chronic hepatitis. In the prevaccination era, HBV infections were endemic due to frequent mother to child transmission in large regions of the world. However, there are still estimated 240 million chronic HBV carriers today and ca. 620,000 patients die per year due to HBV-related liver diseases. Recommended treatment of chronic hepatitis B with interferon-α and/or nucleos(t)ide analogues does not lead to satisfactory results. Induction of HBV-specific T cells by therapeutic vaccination or immunomodulation may be an innovative strategy to overcome virus persistence. Vaccination with commercially available HBV vaccines in patients with or without therapeutic reduction of viral load did not result in effective immune control of HBV infection, suggesting that combination of antiviral treatment with new formulations of therapeutic vaccines is needed. The woodchuck (Marmota monax) and its HBV-like woodchuck hepatitis virus are a useful preclinical animal model for developing new therapeutic approaches in chronic hepadnaviral infections. Several innovative approaches combining antiviral treatments using nucleos(t)ide analogues, with prime-boost vaccination using DNA vaccines, new hepadnaviral antigens or recombinant adenoviral vectors were tested in the woodchuck model. In this review, we summarize these encouraging results obtained with these therapeutic vaccines. In addition, we present potential innovations in immunostimulatory strategies by blocking the interaction of the inhibitory programmed death receptor 1 with its ligand in this animal model. PMID:25535101

  10. Preclinical and clinical studies of the NEDD9 scaffold protein in cancer and other diseases

    PubMed Central

    Shagisultanova, Elena; Gaponova, Anna V.; Gabbasov, Rashid; Nicolas, Emmanuelle; Golemis, Erica A

    2015-01-01

    Cancer progression requires a significant reprogramming of cellular signaling to support the essential tumor-specific processes that include hyperproliferation, invasion (for solid tumors) and survival of metastatic colonies. NEDD9 (also known as CasL and HEF1) encodes a multi-domain scaffolding protein that assembles signaling complexes regulating multiple cellular processes relevant to cancer. These include responsiveness to signals emanating from the T and B cell receptors, integrins, chemokine receptors, and receptor tyrosine kinases, as well as cytoplasmic oncogenes such as BCR-ABL and FAK- and SRC-family kinases. Downstream, NEDD9 regulation of partners including CRKL, WAVE, PI3K/AKT, ERK, E-cadherin, Aurora-A (AURKA), HDAC6, and others allow NEDD9 to influence functions as pleiotropic as migration, invasion, survival, ciliary resorption, and mitosis. In this review, we summarize a growing body of preclinical and clinical data that indicate that while NEDD9 is itself non-oncogenic, changes in expression of NEDD9 (most commonly elevation of expression) are common features of tumors, and directly impact tumor aggressiveness, metastasis, and response to at least some targeted agents inhibiting NEDD9-interacting proteins. These data strongly support the relevance of further development of NEDD9 as a biomarker for therapeutic resistance. Finally, we briefly discuss emerging evidence supporting involvement of NEDD9 in additional pathological conditions, including stroke and polycystic kidney disease. PMID:25967390

  11. Therapeutic vaccination and immunomodulation in the treatment of chronic hepatitis B: preclinical studies in the woodchuck.

    PubMed

    Kosinska, Anna D; Liu, Jia; Lu, Mengji; Roggendorf, Michael

    2015-02-01

    Infection with hepatitis B virus (HBV) may lead to subclinical, acute or chronic hepatitis. In the prevaccination era, HBV infections were endemic due to frequent mother to child transmission in large regions of the world. However, there are still estimated 240 million chronic HBV carriers today and ca. 620,000 patients die per year due to HBV-related liver diseases. Recommended treatment of chronic hepatitis B with interferon-α and/or nucleos(t)ide analogues does not lead to satisfactory results. Induction of HBV-specific T cells by therapeutic vaccination or immunomodulation may be an innovative strategy to overcome virus persistence. Vaccination with commercially available HBV vaccines in patients with or without therapeutic reduction of viral load did not result in effective immune control of HBV infection, suggesting that combination of antiviral treatment with new formulations of therapeutic vaccines is needed. The woodchuck (Marmota monax) and its HBV-like woodchuck hepatitis virus are a useful preclinical animal model for developing new therapeutic approaches in chronic hepadnaviral infections. Several innovative approaches combining antiviral treatments using nucleos(t)ide analogues, with prime-boost vaccination using DNA vaccines, new hepadnaviral antigens or recombinant adenoviral vectors were tested in the woodchuck model. In this review, we summarize these encouraging results obtained with these therapeutic vaccines. In addition, we present potential innovations in immunostimulatory strategies by blocking the interaction of the inhibitory programmed death receptor 1 with its ligand in this animal model.

  12. First update of the International Xenotransplantation Association consensus statement on conditions for undertaking clinical trials of porcine islet products in type 1 diabetes--Chapter 4: pre-clinical efficacy and complication data required to justify a clinical trial.

    PubMed

    Cooper, David K C; Bottino, Rita; Gianello, Pierre; Graham, Melanie; Hawthorne, Wayne J; Kirk, Allan D; Korsgren, Olle; Park, Chung-Gyu; Weber, Collin

    2016-01-01

    In 2009, the International Xenotransplantation Association (IXA) published a consensus document that provided guidelines and "recommendations" (not regulations) for those contemplating clinical trials of porcine islet transplantation. These guidelines included the IXA's opinion on what constituted "rigorous pre-clinical studies using the most relevant animal models" and were based on "non-human primate testing." We now report our discussion following a careful review of the 2009 guidelines as they relate to pre-clinical testing. In summary, we do not believe there is a need to greatly modify the conclusions and recommendations of the original consensus document. Pre-clinical studies should be sufficiently rigorous to provide optimism that a clinical trial is likely to be safe and has a realistic chance of success, but need not be so demanding that success might only be achieved by very prolonged experimentation, as this would not be in the interests of patients whose quality of life might benefit immensely from a successful islet xenotransplant. We believe these guidelines will be of benefit to both investigators planning a clinical trial and to institutions and regulatory authorities considering a proposal for a clinical trial. In addition, we suggest consideration should be given to establishing an IXA Clinical Trial Advisory Committee that would be available to advise (but not regulate) researchers considering initiating a clinical trial of xenotransplantation. PMID:26916706

  13. [Classification of results of studying blood plasma with laser correlation spectroscopy based on semiotics of preclinical and clinical states].

    PubMed

    Ternovoĭ, K S; Kryzhanovskiĭ, G N; Musiĭchuk, Iu I; Noskin, L A; Klopov, N V; Noskin, V A; Starodub, N F

    1998-01-01

    The usage of laser correlation spectroscopy for verification of preclinical and clinical states is substantiated. Developed "semiotic" classifier for solving the problems of preclinical and clinical states is presented. The substantiation of biological algorithms as well as the mathematical support and software for the proposed classifier for the data of laser correlation spectroscopy of blood plasma are presented.

  14. Employing a gain-of-function factor IX variant R338L to advance the efficacy and safety of hemophilia B human gene therapy: preclinical evaluation supporting an ongoing adeno-associated virus clinical trial.

    PubMed

    Monahan, Paul E; Sun, Junjiang; Gui, Tong; Hu, Genlin; Hannah, William B; Wichlan, David G; Wu, Zhijian; Grieger, Joshua C; Li, Chengwen; Suwanmanee, Thipparat; Stafford, Darrel W; Booth, Carmen J; Samulski, Jade J; Kafri, Tal; McPhee, Scott W J; Samulski, R Jude

    2015-02-01

    , 100-500%). These preclinical studies demonstrate a safety:efficacy profile supporting an ongoing phase 1/2 human clinical trial of the scAAV8.FIXR338L vector (designated BAX335).

  15. Analysis of machine perfusion benefits in kidney grafts: a preclinical study

    PubMed Central

    2011-01-01

    Background Machine perfusion (MP) has potential benefits for marginal organs such as from deceased from cardiac death donors (DCD). However, there is still no consensus on MP benefits. We aimed to determine machine perfusion benefits on kidney grafts. Methods We evaluated kidney grafts preserved in ViaspanUW or KPS solutions either by CS or MP, in a DCD pig model (60 min warm ischemia + 24 h hypothermic preservation). Endpoints were: function recovery, quality of function during follow up (3 month), inflammation, fibrosis, animal survival. Results ViaspanUW-CS animals did not recover function, while in other groups early follow up showed similar values for kidney function. Alanine peptidase and β-NAG activities in the urine were higher in CS than in MP groups. Oxydative stress was lower in KPS-MP animals. Histology was improved by MP over CS. Survival was 0% in ViaspanUW-CS and 60% in other groups. Chronic inflammation, epithelial-to-mesenchymal transition and fibrosis were lowest in KPS-MP, followed by KPS-CS and ViaspanUW-MP. Conclusions With ViaspanUW, effects of MP are obvious as only MP kidney recovered function and allowed survival. With KPS, the benefits of MP over CS are not directly obvious in the early follow up period and only histological analysis, urinary tubular enzymes and red/ox status was discriminating. Chronic follow-up was more conclusive, with a clear superiority of MP over CS, independently of the solution used. KPS was proven superior to ViaspanUW in each preservation method in terms of function and outcome. In our pre-clinical animal model of DCD transplantation, MP offers critical benefits. PMID:21266040

  16. Are All Dentiform Teeth with Simulated Caries the Same? A Six-Year Retrospective Study in Preclinical Operative Dentistry.

    PubMed

    Delgado, Alex J; Walter, Ricardo; Behar-Horenstein, Linda S; Boushell, Lee W

    2015-11-01

    Dentiform teeth with simulated caries (DTSC), frequently used in preclinical courses, should show no variability in the amount of simulated caries from tooth to tooth. However, the level of caries variability among DTSC is currently unknown. The aim of this study was to assess the variation in simulated caries levels in one group of DTSC and determine whether variation among DTSC impacted the preclinical performance of dental students. In the study, 80 commercially available mandibular first molar DTSC with simulated mesio-occluso-distal caries were sectioned in coronal (n=40) and sagittal (n=40) planes where the caries depth/width was greatest. Section images were analyzed for variation in levels of simulated caries using image-processing software. Three years of practical performance data using DTSC were compared with three years of practical performance data using dentiform teeth without simulated caries, for a total of six years (students' performance on two exams, Practical 1 and Practical 2). The results showed that 70% of the coronally sectioned teeth had manufacturing defects that resulted in caries overextension at the dentino-enamel junctions (DEJs). Overextensions were found at the DEJ in 41.3% of the sagittally sectioned teeth. There was a statistically significant decrease in Practical 1 performance of the students who used DTSC as compared with students who used teeth without simulated caries (p=0.0001); there was no statistically significant difference on Practical 2 performance. Of the DTSC evaluated in this study, 56.6% contained manufacturing defects, and more than 80% were found to have excessive caries variation. Prediction of which DTSC will have caries overextension is not possible. Students preparing DTSC that contain caries overextension are therefore at increased risk of receiving undeserved negative summative assessment on practical examinations.

  17. (99m)Tc-amitrole as a novel selective imaging probe for solid tumor: In silico and preclinical pharmacological study.

    PubMed

    Essa, B M; Sakr, T M; Khedr, Mohammed A; El-Essawy, F A; El-Mohty, A A

    2015-08-30

    Lactoperoxidase (LPO) inhibitors are very selective for solid tumor due to their high binding affinity to the LPO enzyme. A computational study was used to select top-ranked LPO inhibitor (alone and in complex with (99m)Tc) with high in silico affinity. The novel prepared (99m)Tc-amitrole complex demonstrated both in silico and in vivo high affinity toward solid tumors.(99m)Tc-amitrole was radio-synthesized with a high radiochemical yield (89.7±3.25). It showed in vitro stability for up to 6h. Its preclinical evaluation in solid tumor-bearing mice showed high retention and biological accumulation in solid tumor cells with a high Target/Non-Target (T/NT) ratio equal to 4.9 at 60min post-injection. The data described previously could recommend (99m)Tc-amitrole as potential targeting scintigraphic probe for solid tumor imaging.

  18. (99m)Tc-amitrole as a novel selective imaging probe for solid tumor: In silico and preclinical pharmacological study.

    PubMed

    Essa, B M; Sakr, T M; Khedr, Mohammed A; El-Essawy, F A; El-Mohty, A A

    2015-08-30

    Lactoperoxidase (LPO) inhibitors are very selective for solid tumor due to their high binding affinity to the LPO enzyme. A computational study was used to select top-ranked LPO inhibitor (alone and in complex with (99m)Tc) with high in silico affinity. The novel prepared (99m)Tc-amitrole complex demonstrated both in silico and in vivo high affinity toward solid tumors.(99m)Tc-amitrole was radio-synthesized with a high radiochemical yield (89.7±3.25). It showed in vitro stability for up to 6h. Its preclinical evaluation in solid tumor-bearing mice showed high retention and biological accumulation in solid tumor cells with a high Target/Non-Target (T/NT) ratio equal to 4.9 at 60min post-injection. The data described previously could recommend (99m)Tc-amitrole as potential targeting scintigraphic probe for solid tumor imaging. PMID:25956074

  19. Cranberries and Cancer: An Update of Preclinical Studies Evaluating the Cancer Inhibitory Potential of Cranberry and Cranberry Derived Constituents.

    PubMed

    Weh, Katherine M; Clarke, Jennifer; Kresty, Laura A

    2016-01-01

    Cranberries are rich in bioactive constituents reported to influence a variety of health benefits, ranging from improved immune function and decreased infections to reduced cardiovascular disease and more recently cancer inhibition. A review of cranberry research targeting cancer revealed positive effects of cranberries or cranberry derived constituents against 17 different cancers utilizing a variety of in vitro techniques, whereas in vivo studies supported the inhibitory action of cranberries toward cancers of the esophagus, stomach, colon, bladder, prostate, glioblastoma and lymphoma. Mechanisms of cranberry-linked cancer inhibition include cellular death induction via apoptosis, necrosis and autophagy; reduction of cellular proliferation; alterations in reactive oxygen species; and modification of cytokine and signal transduction pathways. Given the emerging positive preclinical effects of cranberries, future clinical directions targeting cancer or premalignancy in high risk cohorts should be considered. PMID:27548236

  20. Cranberries and Cancer: An Update of Preclinical Studies Evaluating the Cancer Inhibitory Potential of Cranberry and Cranberry Derived Constituents.

    PubMed

    Weh, Katherine M; Clarke, Jennifer; Kresty, Laura A

    2016-08-18

    Cranberries are rich in bioactive constituents reported to influence a variety of health benefits, ranging from improved immune function and decreased infections to reduced cardiovascular disease and more recently cancer inhibition. A review of cranberry research targeting cancer revealed positive effects of cranberries or cranberry derived constituents against 17 different cancers utilizing a variety of in vitro techniques, whereas in vivo studies supported the inhibitory action of cranberries toward cancers of the esophagus, stomach, colon, bladder, prostate, glioblastoma and lymphoma. Mechanisms of cranberry-linked cancer inhibition include cellular death induction via apoptosis, necrosis and autophagy; reduction of cellular proliferation; alterations in reactive oxygen species; and modification of cytokine and signal transduction pathways. Given the emerging positive preclinical effects of cranberries, future clinical directions targeting cancer or premalignancy in high risk cohorts should be considered.

  1. Cranberries and Cancer: An Update of Preclinical Studies Evaluating the Cancer Inhibitory Potential of Cranberry and Cranberry Derived Constituents

    PubMed Central

    Weh, Katherine M.; Clarke, Jennifer; Kresty, Laura A.

    2016-01-01

    Cranberries are rich in bioactive constituents reported to influence a variety of health benefits, ranging from improved immune function and decreased infections to reduced cardiovascular disease and more recently cancer inhibition. A review of cranberry research targeting cancer revealed positive effects of cranberries or cranberry derived constituents against 17 different cancers utilizing a variety of in vitro techniques, whereas in vivo studies supported the inhibitory action of cranberries toward cancers of the esophagus, stomach, colon, bladder, prostate, glioblastoma and lymphoma. Mechanisms of cranberry-linked cancer inhibition include cellular death induction via apoptosis, necrosis and autophagy; reduction of cellular proliferation; alterations in reactive oxygen species; and modification of cytokine and signal transduction pathways. Given the emerging positive preclinical effects of cranberries, future clinical directions targeting cancer or premalignancy in high risk cohorts should be considered. PMID:27548236

  2. Two Years Later: Journals Are Not Yet Enforcing the ARRIVE Guidelines on Reporting Standards for Pre-Clinical Animal Studies

    PubMed Central

    Baker, David; Lidster, Katie; Sottomayor, Ana; Amor, Sandra

    2014-01-01

    There is growing concern that poor experimental design and lack of transparent reporting contribute to the frequent failure of pre-clinical animal studies to translate into treatments for human disease. In 2010, the Animal Research: Reporting of In Vivo Experiments (ARRIVE) guidelines were introduced to help improve reporting standards. They were published in PLOS Biology and endorsed by funding agencies and publishers and their journals, including PLOS, Nature research journals, and other top-tier journals. Yet our analysis of papers published in PLOS and Nature journals indicates that there has been very little improvement in reporting standards since then. This suggests that authors, referees, and editors generally are ignoring guidelines, and the editorial endorsement is yet to be effectively implemented. PMID:24409096

  3. Two years later: journals are not yet enforcing the ARRIVE guidelines on reporting standards for pre-clinical animal studies.

    PubMed

    Baker, David; Lidster, Katie; Sottomayor, Ana; Amor, Sandra

    2014-01-01

    There is growing concern that poor experimental design and lack of transparent reporting contribute to the frequent failure of pre-clinical animal studies to translate into treatments for human disease. In 2010, the Animal Research: Reporting of In Vivo Experiments (ARRIVE) guidelines were introduced to help improve reporting standards. They were published in PLOS Biology and endorsed by funding agencies and publishers and their journals, including PLOS, Nature research journals, and other top-tier journals. Yet our analysis of papers published in PLOS and Nature journals indicates that there has been very little improvement in reporting standards since then. This suggests that authors, referees, and editors generally are ignoring guidelines, and the editorial endorsement is yet to be effectively implemented.

  4. Evaluation of dietetic product innovations: the relative role of preclinical and clinical studies.

    PubMed

    Makrides, Maria; Gibson, Robert A

    2010-01-01

    A variety of systems are used to establish efficacy of food ingredients. Immortal human cell lines have the advantage of rapid throughput and often have the ability to point to mechanisms of action. Transgenic and natural variants of animals (usually rats and mice) have proven to be extremely useful in elucidating effects in vivo, although extrapolation of results to humans has risks. Animal models are also useful in establishing safety and toxic levels of ingredients. Human trials have the most relevance to society. Types of evidence for efficacy rise from improved status level in subjects as a result of eating food (long-chain polyunsaturated fatty acid, levels in erythrocytes), change in surrogate markers as a result of eating food (plasma cholesterol or glutathione peroxidase activity), change in a physiological outcome (such as visual evoked potential acuity or heart rate variability) through to the highest level of evidence, a change in a clinical outcome (improved global development, reduction in infections) established in randomized controlled trials. Ultimately, there is a need for tests of pragmatic interventions that can easily be incorporated into usual dietary practices of the culture in which it is tested. PMID:20664222

  5. Pexmetinib: A Novel Dual Inhibitor of Tie2 and p38 MAPK with Efficacy in Preclinical Models of Myelodysplastic Syndromes and Acute Myeloid Leukemia.

    PubMed

    Bachegowda, Lohith; Morrone, Kerry; Winski, Shannon L; Mantzaris, Ioannis; Bartenstein, Matthias; Ramachandra, Nandini; Giricz, Orsi; Sukrithan, Vineeth; Nwankwo, George; Shahnaz, Samira; Bhagat, Tushar D; Bhattacharyya, Sanchari; Assal, Amer; Shastri, Aditi; Gordon-Mitchell, Shanisha; Pellagatti, Andrea; Boultwood, Jacqueline; Schinke, Carolina; Yu, Yiting; Guha, Chandan; Rizzi, James; Garrus, Jennifer; Brown, Suzy; Wollenberg, Lance; Hogeland, Grant; Wright, Dale; Munson, Mark; Rodriguez, Mareli; Gross, Stefan; Chantry, David; Zou, Yiyu; Platanias, Leonidas C; Burgess, Laurence E; Pradhan, Kith; Steidl, Ulrich; Verma, Amit

    2016-08-15

    Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) suppress normal hematopoietic activity in part by enabling a pathogenic inflammatory milieu in the bone marrow. In this report, we show that elevation of angiopoietin-1 in myelodysplastic CD34(+) stem-like cells is associated with higher risk disease and reduced overall survival in MDS and AML patients. Increased angiopoietin-1 expression was associated with a transcriptomic signature similar to known MDS/AML stem-like cell profiles. In seeking a small-molecule inhibitor of this pathway, we discovered and validated pexmetinib (ARRY-614), an inhibitor of the angiopoietin-1 receptor Tie-2, which was also found to inhibit the proinflammatory kinase p38 MAPK (which is overactivated in MDS). Pexmetinib inhibited leukemic proliferation, prevented activation of downstream effector kinases, and abrogated the effects of TNFα on healthy hematopoietic stem cells. Notably, treatment of primary MDS specimens with this compound stimulated hematopoiesis. Our results provide preclinical proof of concept for pexmetinib as a Tie-2/p38 MAPK dual inhibitor applicable to the treatment of MDS/AML. Cancer Res; 76(16); 4841-9. ©2016 AACR. PMID:27287719

  6. Generation, characterization and preclinical studies of a human anti-L1CAM monoclonal antibody that cross-reacts with rodent L1CAM.

    PubMed

    Cho, Seulki; Park, Insoo; Kim, Haejung; Jeong, Mun Sik; Lim, Mooney; Lee, Eung Suk; Kim, Jin Hong; Kim, Semi; Hong, Hyo Jeong

    2016-01-01

    L1 cell adhesion molecule (L1CAM) is aberrantly expressed in malignant tumors and plays important roles in tumor progression. Thus, L1CAM could serve as a therapeutic target and anti-L1CAM antibodies may have potential as anticancer agents. However, L1CAM is expressed in neural cells and the druggability of anti-L1AM antibody must be validated at the earliest stages of preclinical study. Here, we generated a human monoclonal antibody that is cross-reactive with mouse L1CAM and evaluated its pharmacokinetic properties and anti-tumor efficacy in rodent models. First, we selected an antibody (Ab4) that binds human and mouse L1CAM from the human naïve Fab library using phage display, then increased its affinity 45-fold through mutation of 3 residues in the complementarity-determining regions (CDRs) to generate Ab4M. Next, the affinity of Ab4M was increased 1.8-fold by yeast display of single-chain variable fragment containing randomly mutated light chain CDR3 to generate Ab417. The affinities (KD) of Ab417 for human and mouse L1CAM were 0.24 nM and 79.16 pM, respectively. Ab417 specifically bound the Ig5 domain of L1CAM and did not exhibit off-target activity, but bound to the peripheral nerves embedded in normal human tissues as expected in immunohistochemical analysis. In a pharmacokinetics study, the mean half-life of Ab417 was 114.49 h when a single dose (10 mg/kg) was intravenously injected into SD rats. Ab417 significantly inhibited tumor growth in a human cholangiocarcinoma xenograft nude mouse model and did not induce any adverse effect in in vivo studies. Thus, Ab417 may have potential as an anticancer agent. PMID:26785809

  7. 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.

  8. 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. PMID:26644345

  9. Study Skills Course Impact on Academic Self-Efficacy

    ERIC Educational Resources Information Center

    Wernersbach, Brenna M.; Crowley, Susan L.; Bates, Scott C.; Rosenthal, Carol

    2014-01-01

    Although study skills courses improve student retention, the impact of study skills courses on students' academic self-efficacy has not been investigated. The present study examined pre- and posttest levels of academic self-efficacy in college students enrolled in a study skills course (n = 126) compared to students enrolled in a general education…

  10. Concise Review: Review and Perspective of Cell Dosage and Routes of Administration From Preclinical and Clinical Studies of Stem Cell Therapy for Heart Disease

    PubMed Central

    Golpanian, Samuel; Schulman, Ivonne H.; Ebert, Ray F.; Heldman, Alan W.; DiFede, Darcy L.; Yang, Phillip C.; Wu, Joseph C.; Bolli, Roberto; Perin, Emerson C.; Simari, Robert D.; Wolf, Ariel; Hare, Joshua M.

    2016-01-01

    An important stage in the development of any new therapeutic agent is establishment of the optimal dosage and route of administration. This can be particularly challenging when the treatment is a biologic agent that might exert its therapeutic effects via complex or poorly understood mechanisms. Multiple preclinical and clinical studies have shown paradoxical results, with inconsistent findings regarding the relationship between the cell dose and clinical benefit. Such phenomena can, at least in part, be attributed to variations in cell dosing or concentration and the route of administration (ROA). Although clinical trials of cell-based therapy for cardiovascular disease began more than a decade ago, specification of the optimal dosage and ROA has not been established. The present review summarizes what has been learned regarding the optimal cell dosage and ROA from preclinical and clinical studies of stem cell therapy for heart disease and offers a perspective on future directions. Significance Preclinical and clinical studies on cell-based therapy for cardiovascular disease have shown inconsistent results, in part because of variations in study-specific dosages and/or routes of administration (ROA). Future preclinical studies and smaller clinical trials implementing cell-dose and ROA comparisons are warranted before proceeding to pivotal trials. PMID:26683870

  11. Ramucirumab: preclinical research and clinical development.

    PubMed

    Aprile, Giuseppe; Rijavec, Erika; Fontanella, Caterina; Rihawi, Karim; Grossi, Francesco

    2014-01-01

    Ramucirumab (IMC-1121B, LY3009806), a fully humanized monoclonal antibody directed against the extracellular domain of vascular endothelial growth factor receptor 2 (VEGFR-2), is a new therapeutic option that selectively inhibits the human VEGFR-2 with a much greater affinity than its natural ligands. Based on the promising results of both preclinical and early clinical studies, ramucirumab has been tested in different tumor types either alone or in combination with chemotherapy. While it has recently been granted its first US Food and Drug Administration approval for use as a single agent in patients with advanced or metastatic gastric cancer or gastroesophageal junction carcinoma, its role for metastatic breast cancer or advanced non-small-cell lung cancer is still debated. The aims of this review are to recall and discuss the most significant preclinical and clinical studies that led to the development of ramucirumab and to present the results of the randomized clinical trials that have tested its efficacy in different malignancies, including gastric and lung cancer.

  12. Self-Efficacy and Statistics Performance among Sport Studies Students

    ERIC Educational Resources Information Center

    Lane, Andrew M.; Hall, Ross; Lane, John

    2004-01-01

    The present study explored predictive paths between performance accomplishments, self-efficacy, and performance among Sport Studies students taking a Level 1 statistics module. Fifty-eight Level 1 Sport Studies undergraduate degree students completed a 44-item self-efficacy measure and an assessment of perceived academic success at the start of…

  13. A novel ibuprofen derivative with anti-lung cancer properties: synthesis, formulation, pharmacokinetic and efficacy studies.

    PubMed

    Cheng, Ka-Wing; Nie, Ting; Ouyang, Nengtai; Alston, Ninche; Wong, Chi C; Mattheolabakis, George; Papayannis, Ioannis; Huang, Liqun; Rigas, Basil

    2014-12-30

    Phospho-non-steroidal anti-inflammatory drugs (phospho-NSAIDs) are a novel class of NSAID derivatives with potent antitumor activity. However, phospho-NSAIDs have limited stability in vivo due to their rapid hydrolysis by carboxylesterases at their carboxylic ester link. Here, we synthesized phospho-ibuprofen amide (PIA), a metabolically stable analog of phospho-ibuprofen, formulated it in nanocarriers, and evaluated its pharmacokinetics and anticancer efficacy in pre-clinical models of human lung cancer. PIA was 10-fold more potent than ibuprofen in suppressing the growth of human non-small-cell lung cancer (NSCLC) cell lines, an effect mediated by favorably altering cytokinetics and inducing oxidative stress. Pharmacokinetic studies in rats revealed that liposome-encapsulated PIA exhibited remarkable resistance to hydrolysis by carboxylesterases, remaining largely intact in the systemic circulation, and demonstrated selective distribution to the lungs. The antitumor activity of liposomal PIA was evaluated in a metastatic model of human NSCLC in mice. Liposomal PIA strongly inhibited lung tumorigenesis (>95%) and was significantly (p<0.05) more efficacious than ibuprofen. We observed a significant induction of urinary 8-iso-prostaglandin F2αin vivo, which indicates that ROS stress probably plays an important role in mediating the antitumor efficacy of PIA. Our findings suggest that liposomal PIA is a potent agent in the treatment of lung cancer and merits further evaluation.

  14. Erlotinib exhibits antineoplastic off-target effects in AML and MDS: a preclinical study.

    PubMed

    Boehrer, Simone; Adès, Lionel; Braun, Thorsten; Galluzzi, Lorenzo; Grosjean, Jennifer; Fabre, Claire; Le Roux, Génèviève; Gardin, Claude; Martin, Antoine; de Botton, Stéphane; Fenaux, Pierre; Kroemer, Guido

    2008-02-15

    Erlotinib, an inhibitor of the epidermal growth factor receptor (EGFR), induces differentiation, cell-cycle arrest, and apoptosis of EGFR-negative myeloblasts of patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), as well as in EGFR-negative cell lines representing these diseases (P39, KG-1, and HL 60). This off-target effect can be explained by inhibitory effects on JAK2. Apoptosis induction coupled to mitochondrial membrane permeabilization occurred independently from phenotypic differentiation. In apoptosis-sensitive AML cells, erlotinib caused a rapid (within less than 1 hour) nucleocytoplasmic translocation of nucleophosmin-1 (NPM-1) and p14(ARF). Apoptosis-insensitive myeloblasts failed to manifest this translocation yet became sensitive to apoptosis induction by erlotinib when NPM-1 was depleted by RNA interference. Moreover, erlotinib reduced the growth of xenografted human AML cells in vivo. Erlotinib also killed CD34(+) bone marrow blasts from MDS and AML patients while sparing normal CD34(+) progenitors. This ex vivo therapeutic effect was once more associated with the nucleocytoplasmic translocation of NPM-1 and p14(ARF). One patient afflicted with both MDS and non-small cell lung cancer manifested hematologic improvement in response to erlotinib. In summary, we here provide novel evidence in vitro, ex vivo, and in vivo for the potential therapeutic efficacy of erlotinib in the treatment of high-risk MDS and AML.

  15. Mesenchymal Stem Cell Therapy for the Treatment of Vocal Fold Scarring: A Systematic Review of Preclinical Studies

    PubMed Central

    Wingstrand, Vibe Lindeblad; Jensen, David H.; Bork, Kristian; Sebbesen, Lars; Balle, Jesper; Fischer-Nielsen, Anne; von Buchwald, Christian

    2016-01-01

    Objectives Therapy with mesenchymal stem cells exhibits potential for the development of novel interventions for many diseases and injuries. The use of mesenchymal stem cells in regenerative therapy for vocal fold scarring exhibited promising results to reduce stiffness and enhance the biomechanical properties of injured vocal folds. This study evaluated the biomechanical effects of mesenchymal stem cell therapy for the treatment of vocal fold scarring. Data Sources PubMed, Embase, the Cochrane Library and Google Scholar were searched. Methods Controlled studies that assessed the biomechanical effects of mesenchymal stem cell therapy for the treatment of vocal fold scarring were included. Primary outcomes were viscoelastic properties and mucosal wave amplitude. Results Seven preclinical animal studies (n = 152 single vocal folds) were eligible for inclusion. Evaluation of viscoelastic parameters revealed a decreased dynamic viscosity (η’) and elastic modulus (G’), i.e., decreased resistance and stiffness, in scarred vocal folds treated with mesenchymal stem cells compared to non-treated scarred vocal folds. Mucosal wave amplitude was increased in scarred vocal folds treated with mesenchymal stem cells vs. non-treated scarred vocal folds. Conclusion The results from these studies suggest an increased regenerative effect of therapy with mesenchymal stem cells for scarred vocal folds and are encouraging for further clinical studies. PMID:27631373

  16. Sequential therapy with JX-594, a targeted oncolytic poxvirus, followed by sorafenib in hepatocellular carcinoma: preclinical and clinical demonstration of combination efficacy.

    PubMed

    Heo, Jeong; Breitbach, Caroline J; Moon, Anne; Kim, Chang Won; Patt, Rick; Kim, Mi Kyung; Lee, Yu Kyung; Oh, Sung Yong; Woo, Hyun Young; Parato, Kelley; Rintoul, Julia; Falls, Theresa; Hickman, Theresa; Rhee, Byung-Geon; Bell, John C; Kirn, David H; Hwang, Tae-Ho

    2011-06-01

    JX-594 is a targeted and granulocyte-macrophage colony stimulating factor (GM-CSF) expressing oncolytic poxvirus designed to selectively replicate in and destroy cancer cells through viral oncolysis and tumor-specific immunity. In a phase 1 trial, JX-594 injection into hepatocellular carcinoma (HCC) was well-tolerated and associated with viral replication, decreased tumor perfusion, and tumor necrosis. We hypothesized that JX-594 and sorafenib, a small molecule inhibitor of B-raf and vascular endothelial growth factor receptor (VEGFR) approved for HCC, would have clinical benefit in combination given their demonstrated efficacy in HCC patients and their complementary mechanisms-of-action. HCC cell lines were uniformly sensitive to JX-594. Anti-raf kinase effects of concurrent sorafenib inhibited JX-594 replication in vitro, whereas sequential therapy was superior to either agent alone in murine tumor models. We therefore explored pilot safety and efficacy of JX-594 followed by sorafenib in three HCC patients. In all three patients, sequential treatment was (i) well-tolerated, (ii) associated with significantly decreased tumor perfusion, and (iii) associated with objective tumor responses (Choi criteria; up to 100% necrosis). HCC historical control patients on sorafenib alone at the same institutions had no objective tumor responses (0 of 15). Treatment of HCC with JX-594 followed by sorafenib has antitumoral activity, and JX-594 may sensitize tumors to subsequent therapy with VEGF/VEGFR inhibitors.

  17. Pre-clinical studies of Notch signaling inhibitor RO4929097 in inflammatory breast cancer cells.

    PubMed

    Debeb, Bisrat G; Cohen, Evan N; Boley, Kimberly; Freiter, Erik M; Li, Li; Robertson, Fredika M; Reuben, James M; Cristofanilli, Massimo; Buchholz, Thomas A; Woodward, Wendy A

    2012-07-01

    Basal breast cancer, common among patients presenting with inflammatory breast cancer (IBC), has been shown to be resistant to radiation and enriched in cancer stem cells. The Notch pathway plays an important role in self-renewal of breast cancer stem cells and contributes to inflammatory signaling which promotes the breast cancer stem cell phenotype. Herein, we inhibited Notch signaling using a gamma secretase inhibitor, RO4929097, in an in vitro model that enriches for cancer initiating cells (3D clonogenic assay) and conventional 2D clonogenic assay to compare the effect on radiosensitization of the SUM149 and SUM190 IBC cell lines. RO4929097 downregulated the Notch target genes Hes1, Hey1, and HeyL, and showed a significant reduction in anchorage independent growth in SUM190 and SUM149. However, the putative self-renewal assay mammosphere formation efficiency was increased with the drug. To assess radiosensitization of putative cancer stem cells, cells were exposed to increasing doses of radiation with or without 1 μM RO4929097 in their standard (2D) and self-renewal enriching (3D) culture conditions. In the conventional 2D clonogenic assay, RO4929097 significantly sensitized SUM190 cells to ionizing radiation and has a modest radiosensitization effect in SUM149 cells. In the 3D clonogenic assays, however, a radioprotective effect was seen in both SUM149 and SUM190 cells at higher doses. Both cell lines express IL-6 and IL-8 cytokines known to mediate the efficacy of Notch inhibition and to promote self-renewal of stem cells. We further showed that RO429097 inhibits normal T-cell synthesis of some inflammatory cytokines, including TNF-α, a potential mediator of IL-6 and IL-8 production in the microenvironment. These data suggest that additional targeting agents may be required to selectively target IBC stem cells through Notch inhibition, and that evaluation of microenvironmental influences may shed further light on the potential effects of this inhibitor.

  18. The Relationship between Lesson Study and Self-Efficacy

    ERIC Educational Resources Information Center

    Sibbald, Tim

    2009-01-01

    This article addresses a gap in the literature by developing a theory that bridges lesson study and self-efficacy. Since self-efficacy has been linked to student achievement, the theory is important as an explanatory mechanism linking lesson study to student achievement. The theory was developed using grounded theory based on primary source data…

  19. Retrospect and Prospect of Studies of Teacher Efficacy in China

    ERIC Educational Resources Information Center

    He, Ning; Miao, Danmin

    2006-01-01

    Teacher efficacy is a powerful variable in educational and psychological studies. And it aroused much attention and interest from Chinese scholars in the past decade, which led to an accumulation of documents in this field. Following an introduction of efficacy studies in the west, the article reviews the brief history of those in China,…

  20. Photodynamic therapy with the phthalocyanine photosensitizer Pc 4: The case experience with preclinical mechanistic and early clinical-translational studies

    SciTech Connect

    Miller, Janine D.; Scull, Heather

    2007-11-01

    Photodynamic therapy (PDT) is emerging as a promising non-invasive treatment for cancers. PDT involves either local or systemic administration of a photosensitizing drug, which preferentially localizes within the tumor, followed by illumination of the involved organ with light, usually from a laser source. Here, we provide a selective overview of our experience with PDT at Case Western Reserve University, specifically with the silicon phthalocyanine photosensitizer Pc 4. We first review our in vitro studies evaluating the mechanism of cell killing by Pc 4-PDT. Then we briefly describe our clinical experience in a Phase I trial of Pc 4-PDT and our preliminary translational studies evaluating the mechanisms behind tumor responses. Preclinical work identified (a) cardiolipin and the anti-apoptotic proteins Bcl-2 and Bcl-xL as targets of Pc 4-PDT, (b) the intrinsic pathway of apoptosis, with the key participation of caspase-3, as a central response of many human cancer cells to Pc 4-PDT, (c) signaling pathways that could modify apoptosis, and (d) a formulation by which Pc 4 could be applied topically to human skin and penetrate at least through the basal layer of the epidermis. Clinical-translational studies enabled us to develop an immunohistochemical assay for caspase-3 activation, using biopsies from patients treated with topical Pc 4 in a Phase I PDT trial for cutaneous T-cell lymphoma. Results suggest that this assay may be used as an early biomarker of clinical response.

  1. Does Bacillus anthracis Lethal Toxin Directly Depress Myocardial Function? A Review of Clinical Cases and Preclinical Studies.

    PubMed

    Suffredini, Dante A; Sampath-Kumar, Hanish; Li, Yan; Ohanjanian, Lernik; Remy, Kenneth E; Cui, Xizhong; Eichacker, Peter Q

    2015-12-01

    The US outbreak of B.anthracis infection in 2001 and subsequent cases in the US and Europe demonstrate that anthrax is a continuing risk for the developed world. While several bacterial components contribute to the pathogenesis of B. anthracis, production of lethal toxin (LT) is strongly associated with the development of hypotension and lethality. However, the mechanisms underlying the cardiovascular instability LT produces are unclear. Some evidence suggests that LT causes shock by impairing the peripheral vasculature, effects consistent with the substantial extravasation of fluid in patients dying with B. anthracis. Other data suggests that LT directly depresses myocardial function. However a clinical correlate for this latter possibility is less evident since functional studies and post-mortem examination in patients demonstrate absent or minimal cardiac changes. The purposes of this review were to first present clinical studies of cardiac functional and histologic pathology with B. anthracis infection and to then examine in vivo, in vitro, and ex vivo preclinical studies of LT's myocardial effects. Together, these data suggest that it is unclear whether that LT directly depresses cardiac function. This question is important for the clinical management and development of new therapies for anthrax and efforts should continue to be made to answer it. PMID:26703730

  2. Does Bacillus anthracis Lethal Toxin Directly Depress Myocardial Function? A Review of Clinical Cases and Preclinical Studies

    PubMed Central

    Suffredini, Dante A.; Sampath-Kumar, Hanish; Li, Yan; Ohanjanian, Lernik; Remy, Kenneth E.; Cui, Xizhong; Eichacker, Peter Q.

    2015-01-01

    The US outbreak of B.anthracis infection in 2001 and subsequent cases in the US and Europe demonstrate that anthrax is a continuing risk for the developed world. While several bacterial components contribute to the pathogenesis of B. anthracis, production of lethal toxin (LT) is strongly associated with the development of hypotension and lethality. However, the mechanisms underlying the cardiovascular instability LT produces are unclear. Some evidence suggests that LT causes shock by impairing the peripheral vasculature, effects consistent with the substantial extravasation of fluid in patients dying with B. anthracis. Other data suggests that LT directly depresses myocardial function. However a clinical correlate for this latter possibility is less evident since functional studies and post-mortem examination in patients demonstrate absent or minimal cardiac changes. The purposes of this review were to first present clinical studies of cardiac functional and histologic pathology with B. anthracis infection and to then examine in vivo, in vitro, and ex vivo preclinical studies of LT’s myocardial effects. Together, these data suggest that it is unclear whether that LT directly depresses cardiac function. This question is important for the clinical management and development of new therapies for anthrax and efforts should continue to be made to answer it. PMID:26703730

  3. A gender study investigating physics self-efficacy

    NASA Astrophysics Data System (ADS)

    Sawtelle, Vashti

    The underrepresentation of women in physics has been well documented and a source of concern for both policy makers and educators. My dissertation focuses on understanding the role self-efficacy plays in retaining students, particularly women, in introductory physics. I use an explanatory mixed methods approach to first investigate quantitatively the influence of self-efficacy in predicting success and then to qualitatively explore the development of self-efficacy. In the initial quantitative studies, I explore the utility of self-efficacy in predicting the success of introductory physics students, both women and men. Results indicate that self-efficacy is a significant predictor of success for all students. I then disaggregate the data to examine how self-efficacy develops differently for women and men in the introductory physics course. Results show women rely on different sources of self-efficacy than do men, and that a particular instructional environment, Modeling Instruction, has a positive impact on these sources of self-efficacy. In the qualitative phase of the project, this dissertation focuses on the development of self-efficacy. Using the qualitative tool of microanalysis, I introduce a methodology for understanding how self-efficacy develops moment-by-moment using the lens of self-efficacy opportunities. I then use the characterizations of self-efficacy opportunities to focus on a particular course environment and to identify and describe a mechanism by which Modeling Instruction impacts student self-efficacy. Results indicate that the emphasizing the development and deployment of models affords opportunities to impact self-efficacy. The findings of this dissertation indicate that introducing key elements into the classroom, such as cooperative group work, model development and deployment, and interaction with the instructor, create a mechanism by which instructors can impact the self-efficacy of their students. Results from this study indicate that

  4. Reform in Teaching Preclinical Pathophysiology

    ERIC Educational Resources Information Center

    Li, Yong-Yu; Li, Kun; Yao, Hong; Xu, Xiao-Juan; Cai, Qiao-Lin

    2015-01-01

    Pathophysiology is a scientific discipline that studies the onset and progression of pathological conditions and diseases, and pathophysiology is one of the core courses in most preclinical medical curricula. In China, most medical schools house a Department of Pathophysiology, in contrast to medical schools in many developed countries. The staff…

  5. The discovery of rivaroxaban: translating preclinical assessments into clinical practice

    PubMed Central

    Kubitza, Dagmar; Perzborn, Elisabeth; Berkowitz, Scott D.

    2013-01-01

    Direct oral anticoagulants that target a single coagulation factor (such as factor Xa or thrombin) have been developed in recent years in an attempt to address some of the limitations of traditional anticoagulants. Rivaroxaban is an oral, direct factor Xa inhibitor that inhibits free and clot-bound factor Xa and factor Xa in the prothrombinase complex. Preclinical studies demonstrated a potent anticoagulant effect of rivaroxaban in plasma as well as the ability of this agent to prevent and treat venous and arterial thrombosis in animal models. These studies led to an extensive phase I clinical development program that investigated the pharmacological properties of rivaroxaban in humans. In these studies, rivaroxaban was shown to exhibit predictable pharmacokinetics and pharmacodynamics and to have no clinically relevant interactions with many commonly prescribed co-medications. The pharmacodynamic effects of rivaroxaban (for example, inhibition of factor Xa and prolongation of prothrombin time) were closely correlated with rivaroxaban concentrations in plasma. The encouraging findings from preclinical and early clinical studies were expanded upon in large, randomized phase III studies, which demonstrated the clinical efficacy and safety of rivaroxaban in a broad spectrum of patients. This article provides an overview of the discovery and development of rivaroxaban, describing the pharmacodynamic profile established in preclinical studies and the optimal translation to clinical studies in healthy subjects and patient populations. PMID:24324436

  6. Volume cerebral blood flow reduction in pre-clinical stage of Alzheimer disease: evidence from an ultrasonographic study.

    PubMed

    Maalikjy Akkawi, Nabil; Borroni, B; Agosti, C; Magoni, M; Broli, M; Pezzini, A; Padovani, A

    2005-05-01

    The association of decreased cerebral blood flow with the development of Alzheimer's disease (AD) has been a recent target of interest. By using neuroimaging techniques, growing attention has been devoted to the identification of preclinical AD. In this study, color duplex sonography of cervical arteries was used to measure mean cerebral blood flow (CBF) on 55 amnestic Mild Cognitive Impairment (MCI) patients. Two years after enrollment, excluding patients who progressed to dementia other than AD, two subgroups were identified, patients who developed AD (MCI converters) and patients with preserved cognitive and functional level (MCI non-converters). Examining the mean difference of CBF measured at baseline in the two subgroups obtained, a significant difference was noticed (MCI converters 539.3 +/- 114.3 vs MCI non converters 636.0 +/- 143.9, p < 0.05). MCI patients with CBF higher than median value (558 ml/min) had lower risk of developing AD (specificity 72.2%, sensitivity 68.4%) within a two year follow-up. Ultrasonography of the cervical arteries is a simple, non invasive and widespread technique useful in detecting CBF decline during the MCI stage, thus identifying patients who later will convert to AD.

  7. Preclinical Pharmacokinetics Study of R- and S-Enantiomers of the Histone Deacetylase Inhibitor, AR-42 (NSC 731438), in Rodents.

    PubMed

    Cheng, Hao; Xie, Zhiliang; Jones, William P; Wei, Xiaohui Tracey; Liu, Zhongfa; Wang, Dasheng; Kulp, Samuel K; Wang, Jiang; Coss, Christopher C; Chen, Ching-Shih; Marcucci, Guido; Garzon, Ramiro; Covey, Joseph M; Phelps, Mitch A; Chan, Kenneth K

    2016-05-01

    AR-42, a new orally bioavailable, potent, hydroxamate-tethered phenylbutyrate class I/IIB histone deacetylase inhibitor currently is under evaluation in phase 1 and 2 clinical trials and has demonstrated activity in both hematologic and solid tumor malignancies. This report focuses on the preclinical characterization of the pharmacokinetics of AR-42 in mice and rats. A high-performance liquid chromatography-tandem mass spectrometry assay has been developed and applied to the pharmacokinetic study of the more active stereoisomer, S-AR-42, when administered via intravenous and oral routes in rodents, including plasma, bone marrow, and spleen pharmacokinetics (PK) in CD2F1 mice and plasma PK in F344 rats. Oral bioavailability was estimated to be 26 and 100% in mice and rats, respectively. R-AR-42 was also evaluated intravenously in rats and was shown to display different pharmacokinetics with a much shorter terminal half-life compared to that of S-AR-42. Renal clearance was a minor elimination pathway for parental S-AR-42. Oral administration of S-AR-42 to tumor-bearing mice demonstrated high uptake and exposure of the parent drug in the lymphoid tissues, spleen, and bone marrow. This is the first report of the pharmacokinetics of this novel agent, which is now in early phase clinical trials.

  8. Self-Efficacy and Interest: Experimental Studies of Optimal Incompetence.

    ERIC Educational Resources Information Center

    Silvia, Paul J.

    2003-01-01

    To test the optimal incompetence hypothesis (high self-efficacy lowers task interest), 30 subjects rated interest, perceived difficulty, and confidence of success in different tasks. In study 2, 33 subjects completed a dart-game task in easy, moderate, and difficult conditions. In both, interest was a quadratic function of self-efficacy,…

  9. Pre-clinical efficacy of PU-H71, a novel HSP90 inhibitor, alone and in combination with bortezomib in Ewing sarcoma.

    PubMed

    Ambati, Srikanth R; Lopes, Eloisi Caldas; Kosugi, Kohji; Mony, Ullas; Zehir, Ahmet; Shah, Smit K; Taldone, Tony; Moreira, Andre L; Meyers, Paul A; Chiosis, Gabriela; Moore, Malcolm A S

    2014-03-01

    Ewing sarcoma is characterized by multiple deregulated pathways that mediate cell survival and proliferation. Heat shock protein 90 (HSP90) is a critical component of the multi-chaperone complexes that regulate the disposition and activity of a large number of proteins involved in cell-signaling systems. We tested the efficacy of PU-H71, a novel HSP90 inhibitor in Ewing sarcoma cell lines, primary samples, benign mesenchymal stromal cells and hematopoietic stem cells. We performed cell cycle analysis, clonogenic assay, immunoblot analysis and reverse phase protein array in Ewing cell lines and in vivo experiments in NSG and nude mice using the A673 cell line. We noted a significant therapeutic window in the activity of PU-H71 against Ewing cell lines and benign cells. PU-H71 treatment resulted in G2/M phase arrest. Exposure to PU-H71 resulted in depletion of critical proteins including AKT, pERK, RAF-1, c-MYC, c-KIT, IGF1R, hTERT and EWS-FLI1 in Ewing cell lines. Our results indicated that Ewing sarcoma tumor growth and the metastatic burden were significantly reduced in the mice injected with PU-H71 compared to the control mice. We also investigated the effects of bortezomib, a proteasome inhibitor, alone and in combination with PU-H71 in Ewing sarcoma. Combination index (CI)-Fa plots and normalized isobolograms indicated synergism between PU-H71 and bortezomib. Ewing sarcoma xenografts were significantly inhibited when mice were treated with the combination compared to vehicle or either drug alone. This provides a strong rationale for clinical evaluation of PU-H71 alone and in combination with bortezomib in Ewing sarcoma.

  10. Metabolic phenotyping applied to pre-clinical and clinical studies of acetaminophen metabolism and hepatotoxicity.

    PubMed

    Coen, Muireann

    2015-02-01

    Acetaminophen (APAP, paracetamol, N-acetyl-p-aminophenol) is a widely used analgesic that is safe at therapeutic doses but is a major cause of acute liver failure (ALF) following overdose. APAP-induced hepatotoxicity is related to the formation of an electrophilic reactive metabolite, N-acetyl-p-benzoquinone imine (NAPQI), which is detoxified through conjugation with reduced glutathione (GSH). One method that has been applied to study APAP metabolism and hepatotoxicity is that of metabolic phenotyping, which involves the study of the small molecule complement of complex biological samples. This approach involves the use of high-resolution analytical platforms such as NMR spectroscopy and mass spectrometry to generate information-rich metabolic profiles that reflect both genetic and environmental influences and capture both endogenous and xenobiotic metabolites. Data modeling and mining and the subsequent identification of panels of candidate biomarkers are typically approached with multivariate statistical tools. We review the application of multi-platform metabolic profiling for the study of APAP metabolism in both in vivo models and humans. We also review the application of metabolic profiling for the study of endogenous metabolic pathway perturbations in response to APAP hepatotoxicity, with a particular focus on metabolites involved in the biosynthesis of GSH and those that reflect mitochondrial function such as long-chain acylcarnitines. Taken together, this body of work sheds much light on the mechanism of APAP-induced hepatotoxicity and provides candidate biomarkers that may prove of translational relevance for improved stratification of APAP-induced ALF.

  11. Comparative Studies Evaluating Mouse Models Used for Efficacy Testing of Experimental Drugs against Mycobacterium tuberculosis▿

    PubMed Central

    De Groote, Mary A.; Gilliland, Janet C.; Wells, Colby L.; Brooks, Elizabeth J.; Woolhiser, Lisa K.; Gruppo, Veronica; Peloquin, Charles A.; Orme, Ian M.; Lenaerts, Anne J.

    2011-01-01

    Methodologies for preclinical animal model testing of drugs against Mycobacterium tuberculosis vary from laboratory to laboratory; however, it is unknown if these variations result in different outcomes. Thus, a series of head-to-head comparisons of drug regimens in three commonly used mouse models (intravenous, a low-dose aerosol, and a high-dose aerosol infection model) and in two strains of mice are reported here. Treatment with standard tuberculosis (TB) drugs resulted in similar efficacies in two mouse species after a low-dose aerosol infection. When comparing the three different infection models, the efficacies in mice of rifampin and pyrazinamide were similar when administered with either isoniazid or moxifloxacin. Relapse studies revealed that the standard drug regimen showed a significantly higher relapse rate than the moxifloxacin-containing regimen. In fact, 4 months of the moxifloxacin-containing combination regimen showed similar relapse rates as 6 months of the standard regimen. The intravenous model showed slower bactericidal killing kinetics with the combination regimens tested and a higher relapse of infection than either aerosol infection models. All three models showed similar outcomes for in vivo efficacy and relapse of infection for the drug combinations tested, regardless of the mouse infection model used. Efficacy data for the drug combinations used also showed similar results, regardless of the formulation used for rifampin or timing of the drugs administered in combination. In all three infection models, the dual combination of rifampin and pyrazinamide was less sterilizing than the standard three-drug regimen, and therefore the results do not support the previously reported antagonism between standard TB agents. PMID:21135176

  12. Validation of the Filovirus Plaque Assay for Use in Preclinical Studies

    PubMed Central

    Shurtleff, Amy C.; Bloomfield, Holly A.; Mort, Shannon; Orr, Steven A.; Audet, Brian; Whitaker, Thomas; Richards, Michelle J.; Bavari, Sina

    2016-01-01

    A plaque assay for quantitating filoviruses in virus stocks, prepared viral challenge inocula and samples from research animals has recently been fully characterized and standardized for use across multiple institutions performing Biosafety Level 4 (BSL-4) studies. After standardization studies were completed, Good Laboratory Practices (GLP)-compliant plaque assay method validation studies to demonstrate suitability for reliable and reproducible measurement of the Marburg Virus Angola (MARV) variant and Ebola Virus Kikwit (EBOV) variant commenced at the United States Army Medical Research Institute of Infectious Diseases (USAMRIID). The validation parameters tested included accuracy, precision, linearity, robustness, stability of the virus stocks and system suitability. The MARV and EBOV assays were confirmed to be accurate to ±0.5 log10 PFU/mL. Repeatability precision, intermediate precision and reproducibility precision were sufficient to return viral titers with a coefficient of variation (%CV) of ≤30%, deemed acceptable variation for a cell-based bioassay. Intraclass correlation statistical techniques for the evaluation of the assay’s precision when the same plaques were quantitated by two analysts returned values passing the acceptance criteria, indicating high agreement between analysts. The assay was shown to be accurate and specific when run on Nonhuman Primates (NHP) serum and plasma samples diluted in plaque assay medium, with negligible matrix effects. Virus stocks demonstrated stability for freeze-thaw cycles typical of normal usage during assay retests. The results demonstrated that the EBOV and MARV plaque assays are accurate, precise and robust for filovirus titration in samples associated with the performance of GLP animal model studies. PMID:27110807

  13. Validation of the Filovirus Plaque Assay for Use in Preclinical Studies.

    PubMed

    Shurtleff, Amy C; Bloomfield, Holly A; Mort, Shannon; Orr, Steven A; Audet, Brian; Whitaker, Thomas; Richards, Michelle J; Bavari, Sina

    2016-04-01

    A plaque assay for quantitating filoviruses in virus stocks, prepared viral challenge inocula and samples from research animals has recently been fully characterized and standardized for use across multiple institutions performing Biosafety Level 4 (BSL-4) studies. After standardization studies were completed, Good Laboratory Practices (GLP)-compliant plaque assay method validation studies to demonstrate suitability for reliable and reproducible measurement of the Marburg Virus Angola (MARV) variant and Ebola Virus Kikwit (EBOV) variant commenced at the United States Army Medical Research Institute of Infectious Diseases (USAMRIID). The validation parameters tested included accuracy, precision, linearity, robustness, stability of the virus stocks and system suitability. The MARV and EBOV assays were confirmed to be accurate to ±0.5 log10 PFU/mL. Repeatability precision, intermediate precision and reproducibility precision were sufficient to return viral titers with a coefficient of variation (%CV) of ≤30%, deemed acceptable variation for a cell-based bioassay. Intraclass correlation statistical techniques for the evaluation of the assay's precision when the same plaques were quantitated by two analysts returned values passing the acceptance criteria, indicating high agreement between analysts. The assay was shown to be accurate and specific when run on Nonhuman Primates (NHP) serum and plasma samples diluted in plaque assay medium, with negligible matrix effects. Virus stocks demonstrated stability for freeze-thaw cycles typical of normal usage during assay retests. The results demonstrated that the EBOV and MARV plaque assays are accurate, precise and robust for filovirus titration in samples associated with the performance of GLP animal model studies.

  14. Issues in pharmaceutical development of thymosin alpha1 from preclinical studies through marketing.

    PubMed

    Tuthill, Cynthia

    2007-09-01

    SciClone Pharmaceuticals licensed the commercial and patent rights to thymosin alpha1, for geographical regions of the world excluding the United States and Europe, in the early 1990s. With this license, SciClone embarked on global drug development, and the issues encountered for thymosin alpha1 are reflective of the roller coaster of modern approval of pharmaceuticals. Most of the required toxicology studies had been completed prior to licensure, but some newer studies had to be conducted to obtain approvals in certain countries. The recent development of the "International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use" (ICH) guidelines allows for a clearer definition of the required battery of toxicology studies, although some countries still have not adopted these guidelines, and the local regulations have had to be understood and followed. Other hurdles include the complications that manufacturing requirements can differ between countries, and certain countries require local clinical experience trials in addition to SciClone's cumulative clinical data. A further obstacle was the pleiotropic nature of the mechanism of action of thymosin alpha1, with the resulting difficulty in the unraveling of its pharmacologic effects. With close attention to these regulatory details, SciClone has obtained approvals in more than 30 countries and has successfully begun commercial sales.

  15. Issues in pharmaceutical development of thymosin alpha1 from preclinical studies through marketing.

    PubMed

    Tuthill, Cynthia

    2007-09-01

    SciClone Pharmaceuticals licensed the commercial and patent rights to thymosin alpha1, for geographical regions of the world excluding the United States and Europe, in the early 1990s. With this license, SciClone embarked on global drug development, and the issues encountered for thymosin alpha1 are reflective of the roller coaster of modern approval of pharmaceuticals. Most of the required toxicology studies had been completed prior to licensure, but some newer studies had to be conducted to obtain approvals in certain countries. The recent development of the "International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use" (ICH) guidelines allows for a clearer definition of the required battery of toxicology studies, although some countries still have not adopted these guidelines, and the local regulations have had to be understood and followed. Other hurdles include the complications that manufacturing requirements can differ between countries, and certain countries require local clinical experience trials in addition to SciClone's cumulative clinical data. A further obstacle was the pleiotropic nature of the mechanism of action of thymosin alpha1, with the resulting difficulty in the unraveling of its pharmacologic effects. With close attention to these regulatory details, SciClone has obtained approvals in more than 30 countries and has successfully begun commercial sales. PMID:17947591

  16. Preclinical Magnetic Resonance Imaging and Spectroscopy Studies of Memory, Aging, and Cognitive Decline

    PubMed Central

    Febo, Marcelo; Foster, Thomas C.

    2016-01-01

    Neuroimaging provides for non-invasive evaluation of brain structure and activity and has been employed to suggest possible mechanisms for cognitive aging in humans. However, these imaging procedures have limits in terms of defining cellular and molecular mechanisms. In contrast, investigations of cognitive aging in animal models have mostly utilized techniques that have offered insight on synaptic, cellular, genetic, and epigenetic mechanisms affecting memory. Studies employing magnetic resonance imaging and spectroscopy (MRI and MRS, respectively) in animal models have emerged as an integrative set of techniques bridging localized cellular/molecular phenomenon and broader in vivo neural network alterations. MRI methods are remarkably suited to longitudinal tracking of cognitive function over extended periods permitting examination of the trajectory of structural or activity related changes. Combined with molecular and electrophysiological tools to selectively drive activity within specific brain regions, recent studies have begun to unlock the meaning of fMRI signals in terms of the role of neural plasticity and types of neural activity that generate the signals. The techniques provide a unique opportunity to causally determine how memory-relevant synaptic activity is processed and how memories may be distributed or reconsolidated over time. The present review summarizes research employing animal MRI and MRS in the study of brain function, structure, and biochemistry, with a particular focus on age-related cognitive decline. PMID:27468264

  17. Revising the high-density lipoprotein targeting strategies - insights from human and preclinical studies.

    PubMed

    Nesan, Dinushan; Ng, Dominic S

    2014-12-01

    In recent years, the high-density lipoprotein (HDL) hypothesis has been challenged. Several completed randomized clinical trials continue to fall short in demonstrating HDL, or at least HDL-cholesterol (HDL-C) levels, as being a consistent target in the prevention of cardiovascular diseases. However, population studies and findings in lipid modifying trials continue to strongly support HDL-C as a superb risk predictor. It is increasingly evident that the complexity of HDL metabolism confounds the use of HDL-C concentration as a unified target. However, important insights continue to emerge from the post hoc analyses of recently completed (i) fibrate-based FIELD and ACCORD trials, including the unexpected beneficial effect of fibrates in microvascular diseases, (ii) the niacin-based AIM-HIGH and HPS2-THRIVE studies, (iii) recombinant HDL-based as well as (iv) the completed CETP inhibitor-based trials. These together with on-going mechanistic studies on novel pathways, which include the unique roles of microRNAs, post-translational remodeling of HDL and novel pathways related to HDL modulators will provide valuable insights to guide how best to refocus and redesign the conceptual framework for selecting HDL-based targets. PMID:25115413

  18. Preclinical Magnetic Resonance Imaging and Spectroscopy Studies of Memory, Aging, and Cognitive Decline.

    PubMed

    Febo, Marcelo; Foster, Thomas C

    2016-01-01

    Neuroimaging provides for non-invasive evaluation of brain structure and activity and has been employed to suggest possible mechanisms for cognitive aging in humans. However, these imaging procedures have limits in terms of defining cellular and molecular mechanisms. In contrast, investigations of cognitive aging in animal models have mostly utilized techniques that have offered insight on synaptic, cellular, genetic, and epigenetic mechanisms affecting memory. Studies employing magnetic resonance imaging and spectroscopy (MRI and MRS, respectively) in animal models have emerged as an integrative set of techniques bridging localized cellular/molecular phenomenon and broader in vivo neural network alterations. MRI methods are remarkably suited to longitudinal tracking of cognitive function over extended periods permitting examination of the trajectory of structural or activity related changes. Combined with molecular and electrophysiological tools to selectively drive activity within specific brain regions, recent studies have begun to unlock the meaning of fMRI signals in terms of the role of neural plasticity and types of neural activity that generate the signals. The techniques provide a unique opportunity to causally determine how memory-relevant synaptic activity is processed and how memories may be distributed or reconsolidated over time. The present review summarizes research employing animal MRI and MRS in the study of brain function, structure, and biochemistry, with a particular focus on age-related cognitive decline. PMID:27468264

  19. Quality of Reporting and Adherence to ARRIVE Guidelines in Animal Studies for Chagas Disease Preclinical Drug Research: A Systematic Review.

    PubMed

    Gulin, Julián Ernesto Nicolás; Rocco, Daniela Marisa; García-Bournissen, Facundo

    2015-11-01

    Publication of accurate and detailed descriptions of methods in research articles involving animals is essential for health scientists to accurately interpret published data, evaluate results and replicate findings. Inadequate reporting of key aspects of experimental design may reduce the impact of studies and could act as a barrier to translation of research findings. Reporting of animal use must be as comprehensive as possible in order to take advantage of every study and every animal used. Animal models are essential to understanding and assessing new chemotherapy candidates for Chagas disease pathology, a widespread parasitic disease with few treatment options currently available. A systematic review was carried out to compare ARRIVE guidelines recommendations with information provided in publications of preclinical studies for new anti-Trypanosoma cruzi compounds. A total of 83 publications were reviewed. Before ARRIVE guidelines, 69% of publications failed to report any macroenvironment information, compared to 57% after ARRIVE publication. Similar proportions were observed when evaluating reporting of microenvironmental information (56% vs. 61%). Also, before ARRIVE guidelines publication, only 13% of papers described animal gender, only 18% specified microbiological status and 13% reported randomized treatment assignment, among other essential information missing or incomplete. Unfortunately, publication of ARRIVE guidelines did not seem to enhance reporting quality, compared to papers appeared before ARRIVE publication. Our results suggest that there is a strong need for the scientific community to improve animal use description, animal models employed, transparent reporting and experiment design to facilitate its transfer and application to the affected human population. Full compliance with ARRIVE guidelines, or similar animal research reporting guidelines, would be an excellent start in this direction.

  20. Quality of Reporting and Adherence to ARRIVE Guidelines in Animal Studies for Chagas Disease Preclinical Drug Research: A Systematic Review

    PubMed Central

    Gulin, Julián Ernesto Nicolás; Rocco, Daniela Marisa; García-Bournissen, Facundo

    2015-01-01

    Publication of accurate and detailed descriptions of methods in research articles involving animals is essential for health scientists to accurately interpret published data, evaluate results and replicate findings. Inadequate reporting of key aspects of experimental design may reduce the impact of studies and could act as a barrier to translation of research findings. Reporting of animal use must be as comprehensive as possible in order to take advantage of every study and every animal used. Animal models are essential to understanding and assessing new chemotherapy candidates for Chagas disease pathology, a widespread parasitic disease with few treatment options currently available. A systematic review was carried out to compare ARRIVE guidelines recommendations with information provided in publications of preclinical studies for new anti-Trypanosoma cruzi compounds. A total of 83 publications were reviewed. Before ARRIVE guidelines, 69% of publications failed to report any macroenvironment information, compared to 57% after ARRIVE publication. Similar proportions were observed when evaluating reporting of microenvironmental information (56% vs. 61%). Also, before ARRIVE guidelines publication, only 13% of papers described animal gender, only 18% specified microbiological status and 13% reported randomized treatment assignment, among other essential information missing or incomplete. Unfortunately, publication of ARRIVE guidelines did not seem to enhance reporting quality, compared to papers appeared before ARRIVE publication. Our results suggest that there is a strong need for the scientific community to improve animal use description, animal models employed, transparent reporting and experiment design to facilitate its transfer and application to the affected human population. Full compliance with ARRIVE guidelines, or similar animal research reporting guidelines, would be an excellent start in this direction. PMID:26587586

  1. Neural Stem Cell-Mediated Enzyme-Prodrug Therapy for Glioma: Preclinical Studies

    PubMed Central

    Aboody, Karen S.; Najbauer, Joseph; Metz, Marianne Z.; D’Apuzzo, Massimo; Gutova, Margarita; Annala, Alexander J.; Synold, Timothy W.; Couture, Larry A.; Blanchard, Suzette; Moats, Rex A.; Garcia, Elizabeth; Aramburo, Soraya; Valenzuela, Valerie V.; Frank, Richard T.; Barish, Michael E.; Brown, Christine E.; Kim, Seung U.; Badie, Behnam; Portnow, Jana

    2013-01-01

    High-grade gliomas are extremely difficult to treat because they are invasive and therefore are not curable by surgical resection; the toxicity of currently chemo- and radiation therapies limits the doses that can be used. Neural stem cells (NSCs) have inherent tumor-tropic properties that enable their use as delivery vehicles that can target enzyme/prodrug therapy selectively to tumors. We have used a cytosine deaminase (CD)-expressing clonal human NSC line, HB1.F3.CD, to home to gliomas in mice and locally convert the tumor-localized prodrug 5-fluorocytosine to the active chemotherapeutic 5-fluorouracil. In vitro studies confirmed that the NSCs have normal karyotype, tumor tropism, and CD expression, indicating that these cells are genetically and functionally stable. In vivo biodistribution studies demonstrated that these NSCs retained tumor tropism, even in mice pre-treated with radiation or dexamethasone to mimic clinically relevant adjuvant therapies. We evaluated safety and toxicity after intracerebral administration of the NSCs in non-tumor bearing, and in orthotopic glioma-bearing, immunocompetent and immunodeficient mice. We detected no difference in toxicity associated with conversion of 5-fluorocytosine to 5-fluorouracil, no NSCs outside the brain, and no histological evidence of pathology or tumorigenesis attributable to the NSCs. The average tumor volume in mice that received HB1.F3.CD NSCs and 5-fluorocytosine was approximately one-third that of the average volume in control mice. On the basis of these results, we conclude that combination therapy with HB1.F3.CD NSCs and 5-fluorocytosine is safe, non-toxic and effective in mice. These data have led to approval of a first-inhuman study of an allogeneic NSC-mediated enzyme/prodrug targeted cancer therapy in patients with recurrent high-grade glioma. PMID:23658244

  2. Transoral endoscopic thyroidectomy via the tri-vestibular routes: results of a preclinical cadaver feasibility study.

    PubMed

    Park, Jun-Ook; Kim, Choung Soo; Song, Jee-Nam; Kim, Ju-Eun; Nam, Inn-Chul; Lee, So-Yoon; Chun, Byung-Joon; Cho, Jung-Hae; Joo, Young-Hoon; Cho, Kwang-Jae; Park, Young Hak; Kim, Min-Sik; Sun, Dong-Il

    2014-12-01

    The concept of natural orifice transluminal endoscopic surgery (NOTES) is an emerging experimental alternative to conventional surgery that eliminates skin incisions using an endoscope passed through a natural orifice (e.g., mouth, urethra, or anus). This study was designed to evaluate the feasibility and safety of thyroid resection via an entirely transoral tri-vestibular route using endoscopy, and to introduce NOTES to the head and neck area of medicine. We performed ten complete endoscopic thyroid lobectomies with central lymph node dissection via a tri-vestibular approach in fresh-frozen cadavers. A 5-mm endoscope with a deflectable tip was used to visualize the surgical field. Three cannulas were inserted through the midline and bilateral incision sites in the vestibule to position the instruments and endoscope. We refined and described the surgical technique in each step using video clips. We identified and preserved neighboring critical structures during surgery. We also confirmed that there were no obvious remnant thyroid tissues and no injury to the neighboring structures after exploration. The transoral tri-vestibular approach seems to provide a good view and surgical field for endoscopic thyroidectomy. However, the transoral approach for thyroidectomy remains experimental, and the detailed surgical technique should be refined via further clinical studies.

  3. Treating the Developing versus Developed Brain: Translating Preclinical Mouse and Human Studies

    PubMed Central

    Casey, BJ; Glatt, Charles E.; Lee, Francis S.

    2015-01-01

    Summary Behaviors and underlying brain circuits show characteristic changes across the life-span that produce sensitive windows of vulnerability and resilience to psychopathology. Understanding the developmental course of these changes may inform which treatments are best at what ages. Focusing on behavioral domains and neurobiological substrates conserved from mouse to human supports reciprocal hypothesis generation and testing that leverages the strengths of each system in understanding their development. Introducing human genetic variants into mice can further define effects of individual variation on normative development, how they contribute to risk and resilience for mental illness, and inform personalized treatment opportunities. This article emphasizes the period of adolescence, when there is a peak in the emergence of mental illness, in particular, anxiety disorders. We present cross-species studies relating fear learning to anxiety across development, and discuss how clinical treatments can be optimized for individuals and targeted to the biological states of the developing brain. PMID:26087163

  4. Treating the Developing versus Developed Brain: Translating Preclinical Mouse and Human Studies.

    PubMed

    Casey, B J; Glatt, Charles E; Lee, Francis S

    2015-06-17

    Behaviors and underlying brain circuits show characteristic changes across the lifespan that produce sensitive windows of vulnerability and resilience to psychopathology. Understanding the developmental course of these changes may inform which treatments are best at what ages. Focusing on behavioral domains and neurobiological substrates conserved from mouse to human supports reciprocal hypothesis generation and testing that leverages the strengths of each system in understanding their development. Introducing human genetic variants into mice can further define effects of individual variation on normative development, how they contribute to risk and resilience for mental illness, and inform personalized treatment opportunities. This article emphasizes the period of adolescence, when there is a peak in the emergence of mental illness, anxiety disorders in particular. We present cross-species studies relating fear learning to anxiety across development and discuss how clinical treatments can be optimized for individuals and targeted to the biological states of the developing brain. PMID:26087163

  5. Preclinical studies of [61Cu]ATSM as a PET radiopharmaceutical for fibrosarcoma imaging.

    PubMed

    Jalilian, Amir R; Rostampour, Nima; Rowshanfarzad, Pejman; Shafaii, Kamaleddin; Kamali-Dehghan, Mohsen; Akhlaghi, Mehdi

    2009-03-01

    [61Cu]diacetyl-bis(N4-methylthiosemicarbazone) ([61Cu] ATSM) was prepared using in house-made diacetyl-bis(N4-methylthiosemicarbazone) (ATSM) ligand and [61Cu]CuCl2 produced via the natZn(p, x)61Cu (180 muA proton irradiation, 22 MeV, 3.2 h) and purified by a ion chromatography method. [61Cu]ATSM radiochemical purity was >98 %, as shown by HPLC and RTLC methods. [61Cu]ATSM was administered into normal and tumor bearing rodents for up to 210 minutes, followed by biodistribution and co-incidence imaging studies. Significant tumor/non-tumor accumulation was observed either by animal sacrification or imaging. [61Cu]ATSM is a positron emission tomography (PET) radiotracer for tumor hypoxia imaging.

  6. A Preclinical Study of Laryngeal Motor-Evoked Potentials as a Marker Vagus Nerve Activation.

    PubMed

    Grimonprez, Annelies; Raedt, Robrecht; De Taeye, Leen; Larsen, Lars Emil; Delbeke, Jean; Boon, Paul; Vonck, Kristl

    2015-12-01

    Vagus nerve stimulation (VNS) is a treatment for refractory epilepsy and depression. Previous studies using invasive recording electrodes showed that VNS induces laryngeal motor-evoked potentials (LMEPs) through the co-activation of the recurrent laryngeal nerve and subsequent contractions of the laryngeal muscles. The present study investigates the feasibility of recording LMEPs in chronically VNS-implanted rats, using a minimally-invasive technique, to assess effective current delivery to the nerve and to determine optimal VNS output currents for vagal fiber activation. Three weeks after VNS electrode implantation, signals were recorded using an electromyography (EMG) electrode in the proximity of the laryngeal muscles and a reference electrode on the skull. The VNS output current was gradually ramped up from 0.1 to 1.0 mA in 0.1 mA steps. In 13/27 rats, typical LMEPs were recorded at low VNS output currents (median 0.3 mA, IQR 0.2-0.3 mA). In 11/27 rats, significantly higher output currents were required to evoke electrophysiological responses (median 0.7 mA, IQR 0.5-0.7 mA, p < 0.001). The latencies of these responses deviated significantly from LMEPs (p < 0.05). In 3/27 rats, no electrophysiological responses to simulation were recorded. Minimally invasive LMEP recordings are feasible to assess effective current delivery to the vagus nerve. Furthermore, our results suggest that low output currents are sufficient to activate vagal fibers.

  7. Preclinical toxicity and teratogenicity studies with the narcotic antagonist analgesic drug TR5379M.

    PubMed

    Porter, M C; Hartnagel, R E; Clemens, G R; Kowalski, R L; Bare, J J; Halliwell, W E; Kitchen, D N

    1983-01-01

    The narcotic antagonist TR5379M had po LD50 values of 365 and 750 mg/kg and iv LD50 values of 35.0 and 22.3 mg/kg in the mouse and rat, respectively. Subchronic (one month) po administration to rats at 40, 120, or 400 mg/kg/day and to cynomolgus monkeys at 20, 45, or 100 mg/kg/day showed the compound to be well tolerated at doses of 40 and 45 mg/kg, respectively. Deaths during the subchronic studies included one monkey following a single dose of 100 mg/kg and six rats following repeated doses of 400 mg/kg. Signs of toxicosis in rats included clonic convulsions (high-dose animals only) and mild dose-related salivation and hyperactivity. Signs of toxicosis in monkeys were limited to sporadic emesis and transiently decreased food consumption at all three dose levels. Emesis was not observed at doses of 20 or 45 mg/kg after the first week. Slightly increased weights (not significant at 40 mg/kg) for thyroid and adrenal glands occurred in male rats. Gross, microscopic, and clinical pathologic examinations revealed no treatment-related adverse effects at any dose level for either species. Administration of TR5379M to pregnant rats (20, 70, or 250 mg/kg/day on Days 6-15 of gestation) caused no teratogenicity or embryotoxicity and did not adversely affect any of the reproductive parameters examined. Dams given TR5379M at doses of 70 and 250 mg/kg salivated and had reduced weight gain. It was concluded from these studies that TR5379M has an adequate margin of safety to begin clinical investigations.

  8. Virtual reality, augmented reality, and robotics applied to digestive operative procedures: from in vivo animal preclinical studies to clinical use

    NASA Astrophysics Data System (ADS)

    Soler, Luc; Marescaux, Jacques

    2006-04-01

    Technological innovations of the 20 th century provided medicine and surgery with new tools, among which virtual reality and robotics belong to the most revolutionary ones. Our work aims at setting up new techniques for detection, 3D delineation and 4D time follow-up of small abdominal lesions from standard mecial images (CT scsan, MRI). It also aims at developing innovative systems making tumor resection or treatment easier with the use of augmented reality and robotized systems, increasing gesture precision. It also permits a realtime great distance connection between practitioners so they can share a same 3D reconstructed patient and interact on a same patient, virtually before the intervention and for real during the surgical procedure thanks to a telesurgical robot. In preclinical studies, our first results obtained from a micro-CT scanner show that these technologies provide an efficient and precise 3D modeling of anatomical and pathological structures of rats and mice. In clinical studies, our first results show the possibility to improve the therapeutic choice thanks to a better detection and and representation of the patient before performing the surgical gesture. They also show the efficiency of augmented reality that provides virtual transparency of the patient in real time during the operative procedure. In the near future, through the exploitation of these systems, surgeons will program and check on the virtual patient clone an optimal procedure without errors, which will be replayed on the real patient by the robot under surgeon control. This medical dream is today about to become reality.

  9. Development of telmisartan in the therapy of spinal cord injury: pre-clinical study in rats

    PubMed Central

    Lin, Chien-Min; Tsai, Jo-Ting; Chang, Chen Kuei; Cheng, Juei-Tang; Lin, Jia-Wei

    2015-01-01

    Background Decrease of peroxisome proliferator-activated receptors-δ (PPARδ) expression has been observed after spinal cord injury (SCI). Increase of PPARδ may improve the damage in SCI. Telmisartan, the antihypertensive agent, has been mentioned to increase the expression of PPARδ. Thus, we are going to screen the effectiveness of telmisartan in SCI for the development of it in clinical application. Methods In the present study, we used compressive SCI in rats. Telmisartan was then used to evaluate the influence in rats after SCI. Change in PPARδ expression was identified by Western blots. Also, behavioral tests were performed to check the recovery of damage. Results Recovery of damage from SCI was observed in telmisartan-treated rats. Additionally, this action of telmisartan was inhibited by GSK0660 at the dose sufficient to block PPARδ. However, metformin at the dose enough to activate adenosine monophosphate-activated protein kinase failed to produce similar action as telmisartan. Thus, mediation of adenosine monophosphate-activated protein kinase in this action of telmisartan can be rule out. Moreover, telmisartan reversed the expressions of PPARδ in rats with SCI. Conclusion The obtained data suggest that telmisartan can improve the damage of SCI in rats through an increase in PPARδ expression. Thus, telmisartan is useful to be developed as an agent in the therapy of SCI. PMID:26316709

  10. The Tyrosine Kinase Inhibitor Sunitinib Affects Ovulation but Not Ovarian Reserve in Mouse: A Preclinical Study

    PubMed Central

    Bernard, Valérie; Bouilly, Justine; Kramer, Piet; Carré, Nadège; Schlumberger, Martin; Visser, Jenny A.; Young, Jacques; Binart, Nadine

    2016-01-01

    The aim of the study was to evaluate ovarian toxicity of tyrosine kinase inhibitor (TKI) sunitinib, since only scarce data are available on gonadal function after this treatment. Six-week-old female mice received orally, once daily, vehicle or sunitinib (50 mg/kg/d) during 5 weeks. Fertility parameters were analyzed from ovulation to litter assessment. Sunitinib exposure significantly reduced (i) corpora lutea number per ovary (1.1 ± 0.38 in sunitinib group versus 4 ± 0.79 in control group, p<0.01) and (ii) serum Anti Müllerian hormone (AMH) levels in sunitinib treated mice (12.01 ± 1.16) compared to control mice (14.33 ± 0.87 ng/ml, p< 0.05). However, primordial and growing follicles numbers per ovary were not different in both groups. After treatment withdrawal, female mice in both groups were able to obtain litters. These data could be helpful to counsel clinicians and patients, when fertility preservation methods are discussed, before TKI treatment in girls and young women. PMID:27035144

  11. The Tyrosine Kinase Inhibitor Sunitinib Affects Ovulation but Not Ovarian Reserve in Mouse: A Preclinical Study.

    PubMed

    Bernard, Valérie; Bouilly, Justine; Kramer, Piet; Carré, Nadège; Schlumberger, Martin; Visser, Jenny A; Young, Jacques; Binart, Nadine

    2016-01-01

    The aim of the study was to evaluate ovarian toxicity of tyrosine kinase inhibitor (TKI) sunitinib, since only scarce data are available on gonadal function after this treatment. Six-week-old female mice received orally, once daily, vehicle or sunitinib (50 mg/kg/d) during 5 weeks. Fertility parameters were analyzed from ovulation to litter assessment. Sunitinib exposure significantly reduced (i) corpora lutea number per ovary (1.1 ± 0.38 in sunitinib group versus 4 ± 0.79 in control group, p<0.01) and (ii) serum Anti Müllerian hormone (AMH) levels in sunitinib treated mice (12.01 ± 1.16) compared to control mice (14.33 ± 0.87 ng/ml, p< 0.05). However, primordial and growing follicles numbers per ovary were not different in both groups. After treatment withdrawal, female mice in both groups were able to obtain litters. These data could be helpful to counsel clinicians and patients, when fertility preservation methods are discussed, before TKI treatment in girls and young women. PMID:27035144

  12. Silver nanoparticle/chitosan oligosaccharide/poly(vinyl alcohol) nanofibers as wound dressings: a preclinical study

    PubMed Central

    Li, Chenwen; Fu, Ruoqiu; Yu, Caiping; Li, Zhuoheng; Guan, Haiyan; Hu, Daqiang; Zhao, Dehua; Lu, Laichun

    2013-01-01

    In this study, a mixture of poly(vinyl alcohol) (PVA) and chitosan oligosaccharides (COS) was electrospun with silver nanoparticles (AgNPs) to produce fibrous mats for use in wound healing. The AgNPs were reduced by COS prior to electrospinning or Ag+ was reduced via ultraviolet irradiation in nanofibers. The morphologies of the PVA/COS/AgNO3 and PVA/COS-AgNP nanofibers were analyzed by scanning electron microscopy. Formation of the AgNPs was investigated by field emission transmission electron microscopy, ultraviolet-visible spectroscopy, Fourier transform infrared spectroscopy, and X-ray diffraction. We also evaluated the biocompatibility of the nanofibers, particularly their cytotoxicity to human skin fibroblasts and potential to cause primary skin irritation. The in vitro antibacterial activity and in vivo wound healing capacity of the nanofibers were also investigated. The nanofibers had a smooth surface with an average diameter of 130–192 nm. The diameters of the AgNPs were in the range of 15–22 nm. The nanofibers significantly inhibited growth of Escherichia coli and Staphylococcus aureus bacteria. PVA/COS-AgNP nanofibers accelerated the rate of wound healing over that of the control (gauze). The results of our in vitro and in vivo animal experiments suggest that PVA/COS-AgNP nanofibers should be of greater interest than PVA/COS/AgNO3 nanofibers for clinical use as a bioactive wound dressing. PMID:24204142

  13. Silver nanoparticle/chitosan oligosaccharide/poly(vinyl alcohol) nanofibers as wound dressings: a preclinical study.

    PubMed

    Li, Chenwen; Fu, Ruoqiu; Yu, Caiping; Li, Zhuoheng; Guan, Haiyan; Hu, Daqiang; Zhao, Dehua; Lu, Laichun

    2013-01-01

    In this study, a mixture of poly(vinyl alcohol) (PVA) and chitosan oligosaccharides (COS) was electrospun with silver nanoparticles (AgNPs) to produce fibrous mats for use in wound healing. The AgNPs were reduced by COS prior to electrospinning or Ag(+) was reduced via ultraviolet irradiation in nanofibers. The morphologies of the PVA/COS/AgNO3 and PVA/COS-AgNP nanofibers were analyzed by scanning electron microscopy. Formation of the AgNPs was investigated by field emission transmission electron microscopy, ultraviolet-visible spectroscopy, Fourier transform infrared spectroscopy, and X-ray diffraction. We also evaluated the biocompatibility of the nanofibers, particularly their cytotoxicity to human skin fibroblasts and potential to cause primary skin irritation. The in vitro antibacterial activity and in vivo wound healing capacity of the nanofibers were also investigated. The nanofibers had a smooth surface with an average diameter of 130-192 nm. The diameters of the AgNPs were in the range of 15-22 nm. The nanofibers significantly inhibited growth of Escherichia coli and Staphylococcus aureus bacteria. PVA/COS-AgNP nanofibers accelerated the rate of wound healing over that of the control (gauze). The results of our in vitro and in vivo animal experiments suggest that PVA/COS-AgNP nanofibers should be of greater interest than PVA/COS/AgNO3 nanofibers for clinical use as a bioactive wound dressing.

  14. Electric field characteristics of electroconvulsive therapy with individualized current amplitude: a preclinical study.

    PubMed

    Lee, Won Hee; Lisanby, Sarah H; Laine, Andrew F; Peterchev, Angel V

    2013-01-01

    This study examines the characteristics of the electric field induced in the brain by electroconvulsive therapy (ECT) with individualized current amplitude. The electric field induced by bilateral (BL), bifrontal (BF), right unilateral (RUL), and frontomedial (FM) ECT electrode configurations was computed in anatomically realistic finite element models of four nonhuman primates (NHPs). We generated maps of the electric field strength relative to an empirical neural activation threshold, and determined the stimulation strength and focality at fixed current amplitude and at individualized current amplitudes corresponding to seizure threshold (ST) measured in the anesthetized NHPs. The results show less variation in brain volume stimulated above threshold with individualized current amplitudes (16-36%) compared to fixed current amplitude (30-62%). Further, the stimulated brain volume at amplitude-titrated ST is substantially lower than that for ECT with conventional fixed current amplitudes. Thus individualizing the ECT stimulus current could compensate for individual anatomical variability and result in more focal and uniform electric field exposure across different subjects compared to the standard clinical practice of using high, fixed current for all patients.

  15. The usefulness of systematic reviews of animal experiments for the design of preclinical and clinical studies.

    PubMed

    de Vries, Rob B M; Wever, Kimberley E; Avey, Marc T; Stephens, Martin L; Sena, Emily S; Leenaars, Marlies

    2014-01-01

    The question of how animal studies should be designed, conducted, and analyzed remains underexposed in societal debates on animal experimentation. This is not only a scientific but also a moral question. After all, if animal experiments are not appropriately designed, conducted, and analyzed, the results produced are unlikely to be reliable and the animals have in effect been wasted. In this article, we focus on one particular method to address this moral question, namely systematic reviews of previously performed animal experiments. We discuss how the design, conduct, and analysis of future (animal and human) experiments may be optimized through such systematic reviews. In particular, we illustrate how these reviews can help improve the methodological quality of animal experiments, make the choice of an animal model and the translation of animal data to the clinic more evidence-based, and implement the 3Rs. Moreover, we discuss which measures are being taken and which need to be taken in the future to ensure that systematic reviews will actually contribute to optimizing experimental design and thereby to meeting a necessary condition for making the use of animals in these experiments justified.

  16. Khat (Catha edulis F.) and cannabinoids: Parallel and contrasting behavioral effects in preclinical and clinical studies.

    PubMed

    Geresu, Berhanu

    2015-11-01

    After a brief outline of Catha edulis F. (khat) and the cannabinoid systems, the interactions between the pharmacological effects of khat and cannabinoids will be reviewed. Khat chewing is a widespread habit that has a deep-rooted sociocultural tradition in Africa and the Middle East. Experimental studies conducted to investigate khat's central and peripheral effects have revealed an amphetamine-like mechanism of action mediated through the dopaminergic system. The endocannabinoid system comprises the receptors, the endogenous agonists and the related biochemical machinery responsible for synthesizing these substances and terminating their actions. Endocannabinoids are synthesized "on demand" from membrane phospholipids and then rapidly cleared by cellular uptake and enzymatic degradation. Khat and cannabinoids produce a body of parallel and contrasting behavioral effects. Concurrent consumption of khat and cannabinoids may increase the risk of getting or precipitating psychosis, has rewarding and motivational effect, increases the threshold of pain perception and impairs learning and memory. On the other hand, the action of cannabis to enhance food intake is likely to reduce khat's appetite suppressant effects. PMID:26469212

  17. Confidentiality in preclinical Alzheimer disease studies: when research and medical records meet.

    PubMed

    Arias, Jalayne J; Karlawish, Jason

    2014-02-25

    Clinical trials to advance the diagnosis and treatment of Alzheimer disease (AD) may expose research subjects to discrimination risks. An individual enrolled in a research study that uses positive test results from amyloid PET imaging or CSF measures of β-amyloid 42 as inclusion criteria has biomarkers indicative of AD pathology. If insurers and employers learn this information, it could expose subjects to discrimination. Unfortunately, current legal and regulatory mechanisms are not sufficient to protect against harms that have significant consequences for subjects. Existing law that prohibits employment and insurance discrimination based on genetic status does not apply to amyloid biomarkers or any other biomarkers for neurodegenerative diseases. Gaps in legal protections fail to protect research subjects from discrimination by long-term care and disability insurers. This risk is particularly concerning because individuals with AD dementia ultimately need long-term care services. To maximize subject protections and advance valuable research, policymakers, investigators, and research institutions must address shortcomings in the design of the electronic medical record, revise laws to limit discrimination, and develop practices that inform research participants of risks associated with loss of confidentiality.

  18. GABAergic contributions to alcohol responsivity during adolescence: insights from preclinical and clinical studies.

    PubMed

    Silveri, Marisa M

    2014-08-01

    There is a considerable body of literature demonstrating that adolescence is a unique age period, which includes rapid and dramatic maturation of behavioral, cognitive, hormonal and neurobiological systems. Most notably, adolescence is also a period of unique responsiveness to alcohol effects, with both hyposensitivity and hypersensitivity observed to the various effects of alcohol. Multiple neurotransmitter systems are undergoing fine-tuning during this critical period of brain development, including those that contribute to the rewarding effects of drugs of abuse. The role of developmental maturation of the γ-amino-butyric acid (GABA) system, however, has received less attention in contributing to age-specific alcohol sensitivities. This review integrates GABA findings from human magnetic resonance spectroscopy studies as they may translate to understanding adolescent-specific responsiveness to alcohol effects. Better understanding of the vulnerability of the GABA system both during adolescent development, and in psychiatric conditions that include alcohol dependence, could point to a putative mechanism, boosting brain GABA, that may have increased effectiveness for treating alcohol use disorders.

  19. Preclinical Studies Suggest Complex Nutraceutical Strategies May Have Potential for Preventing and Managing Sepsis.

    PubMed

    McCarty, Mark F

    2015-01-01

    An analysis of signaling mechanisms triggered by toll receptor 4 (TLR4) in macrophages, as well as of pertinent cell-culture and rodent studies, suggests that various nutraceuticals may have clinical potential for preventing and treating Gram-negative sepsis. Endotoxin activation of TLR4 results in induction of nitric oxide synthase (iNOS); cyclooxygenase 2 (COX-2); tissue factor (TF); and a range of proinflammatory cytokines, such as tumor necrosis factor α (TNF-α), interleukin-1 β (IL-1β), and interleukin 6 (IL-6), that collaborate to generate the clinical picture of sepsis. Upstream activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase contributes importantly to those effects by inducing superoxide production that promotes activation of p38 mitogen-activated protein (MAP) kinase and nuclear factor (NF) κΒ. Bilirubin generated intracellularly by activation of heme oxygenase 1 (HO-1) functions to provide feedback inhibition of NAPDH-oxidase complexes. Exogenous bilirubin, or its precursor, biliverdin, is protective in rodent models of sepsis. One nutraceutical, phycocyanobilin (PhyCB), is a biliverdin derivative that functions as a light-gathering chromophore in cyanobacteria such as spirulina and can be converted intracellularly to a compound structurally homologous to bilirubin that likewise inhibits NADPH-oxidase complexes. In rodent studies, administration of phycocyanin, to which PhyCB is covalently attached, has likewise been shown to be protective in rodent models of sepsis. Other nutraceuticals provide benefits in counteracting the effects of TLR4. Phase 2-inductive nutraceuticals, such as lipoic acid, have the potential to induce HO-1 activity in macrophages, promoting bilirubin production. They may also antagonize the upregulatory impact of reactive oxygen species (ROS) on macrophage signaling by boosting glutathione synthesis. Another nutraceutical, glycine, helps counter the TLR4-triggered calcium influx that occurs through

  20. Molecular actions and therapeutic potential of lithium in preclinical and clinical studies of CNS disorders.

    PubMed

    Chiu, Chi-Tso; Chuang, De-Maw

    2010-11-01

    Lithium has been used clinically to treat bipolar disorder for over half a century, and remains a fundamental pharmacological therapy for patients with this illness. Although lithium's therapeutic mechanisms are not fully understood, substantial in vitro and in vivo evidence suggests that it has neuroprotective/neurotrophic properties against various insults, and considerable clinical potential for the treatment of several neurodegenerative conditions. Evidence from pharmacological and gene manipulation studies support the notion that glycogen synthase kinase-3 inhibition and induction of brain-derived neurotrophic factor-mediated signaling are lithium's main mechanisms of action, leading to enhanced cell survival pathways and alteration of a wide variety of downstream effectors. By inhibiting N-methyl-D-aspartate receptor-mediated calcium influx, lithium also contributes to calcium homeostasis and suppresses calcium-dependent activation of pro-apoptotic signaling pathways. In addition, lithium decreases inositol 1,4,5-trisphosphate by inhibiting phosphoinositol phosphatases, a process recently identified as a novel mechanism for inducing autophagy. Through these mechanisms, therapeutic doses of lithium have been demonstrated to defend neuronal cells against diverse forms of death insults and to improve behavioral as well as cognitive deficits in various animal models of neurodegenerative diseases, including stroke, amyotrophic lateral sclerosis, fragile X syndrome, as well as Huntington's, Alzheimer's, and Parkinson's diseases, among others. Several clinical trials are also underway to assess the therapeutic effects of lithium for treating these disorders. This article reviews the most recent findings regarding the potential targets involved in lithium's neuroprotective effects, and the implication of these findings for the treatment of a variety of diseases.

  1. Molecular actions and therapeutic potential of lithium in preclinical and clinical studies of CNS disorders

    PubMed Central

    Chiu, Chi-Tso; Chuang, De-Maw

    2011-01-01

    Lithium has been used clinically to treat bipolar disorder for over half a century, and remains a fundamental pharmacological therapy for patients with this illness. Although lithium’s therapeutic mechanisms are not fully understood, substantial in vitro and in vivo evidence suggests that it has neuroprotective/neurotrophic properties against various insults, and considerable clinical potential for the treatment of several neurodegenerative conditions. Evidence from pharmacological and gene manipulation studies support the notion that glycogen synthase kinase-3 inhibition and induction of brain-derived neurotrophic factor-mediated signaling are lithium’s main mechanisms of action, leading to enhanced cell survival pathways and alteration of a wide variety of downstream effectors. By inhibiting N-methyl-D-aspartate receptor-mediated calcium influx, lithium also contributes to calcium homeostasis and suppresses calcium-dependent activation of pro-apoptotic signaling pathways. In addition, lithium decreases inositol 1,4,5-trisphosphate by inhibiting phosphoinositol phosphatases, a process recently identified as a novel mechanism for inducing autophagy. Through these mechanisms, therapeutic doses of lithium have been demonstrated to defend neuronal cells against diverse forms of death insults and to improve behavioral as well as cognitive deficits in various animal models of neurodegenerative diseases, including stroke, amyotrophic lateral sclerosis, fragile X syndrome, as well as Huntington’s, Alzheimer’s, and Parkinson’s diseases, among others. Several clinical trials are also underway to assess the therapeutic effects of lithium for treating these disorders. This article reviews the most recent findings regarding the potential targets involved in lithium’s neuroprotective effects, and the implication of these findings for the treatment of a variety of diseases. PMID:20705090

  2. Microrobotized blasting improves the bone-to-textured implant response. A preclinical in vivo biomechanical study.

    PubMed

    Coelho, Paulo G; Gil, Luiz F; Neiva, Rodrigo; Jimbo, Ryo; Tovar, Nick; Lilin, Thomas; Bonfante, Estevam A

    2016-03-01

    This study evaluated the effect of microrobotized blasting of titanium endosteal implants relative to their manually blasted counterparts. Two different implant systems were utilized presenting two different implant surfaces. Control surfaces (Manual) were fabricated by manually grit blasting the implant surfaces while experimental surfaces (Microblasted) were fabricated through a microrobotized system that provided a one pass grit blasting routine. Both surfaces were created with the same ~50µm average particle size alumina powder at ~310KPa. Surfaces were then etched with 37% HCl for 20min, washed, and packaged through standard industry procedures. The surfaces were characterized through scanning electron microscopy (SEM) and optical interferometry, and were then placed in a beagle dog radius model remaining in vivo for 3 and 6 weeks. The implant removal torque was recorded and statistical analysis evaluated implant system and surface type torque levels as a function of time in vivo. Histologic sections were qualitatively evaluated for tissue response. Electron microscopy depicted textured surfaces for both manual and microblasted surfaces. Optical interferometry showed significantly higher Sa, Sq, values for the microblasted surface and no significant difference for Sds and Sdr values between surfaces. In vivo results depicted that statistically significant gains in biomechanical fixation were obtained for both implant systems tested at 6 weeks in vivo, while only one system presented significant biomechanical gain at 3 weeks. Histologic sections showed qualitative higher amounts of new bone forming around microblasted implants relative to the manually blasted group. Microrobotized blasting resulted in higher biomechanical fixation of endosteal dental implants and should be considered as an alternative for impant surface manufacturing.

  3. Confocal Raman microspectroscopy of stratum corneum: a pre-clinical validation study.

    PubMed

    Wu, J; Polefka, T G

    2008-02-01

    significantly more hydrated than non-emollient shower gel washed skin. The unique and direct quantitative water content information provided by confocal Raman microspectroscopy offers a whole new perspective for fundamental skin moisturization studies and will play an important role in evaluating moisturizing profiles and the hydration potential of products designed for personal care in the cosmetic industry.

  4. A transplantable TH-MYCN transgenic tumor model in C57Bl/6 mice for preclinical immunological studies in neuroblastoma.

    PubMed

    Kroesen, Michiel; Nierkens, Stefan; Ansems, Marleen; Wassink, Melissa; Orentas, Rimas J; Boon, Louis; den Brok, Martijn H; Hoogerbrugge, Peter M; Adema, Gosse J

    2014-03-15

    Current multimodal treatments for patients with neuroblastoma (NBL), including anti-disialoganglioside (GD2) monoclonal antibody (mAb) based immunotherapy, result in a favorable outcome in around only half of the patients with advanced disease. To improve this, novel immunocombinational strategies need to be developed and tested in autologous preclinical NBL models. A genetically well-explored autologous mouse model for NBL is the TH-MYCN model. However, the immunobiology of the TH-MYCN model remains largely unexplored. We developed a mouse model using a transplantable TH-MYCN cell line in syngeneic C57Bl/6 mice and characterized the immunobiology of this model. In this report, we show the relevance and opportunities of this model to study immunotherapy for human NBL. Similar to human NBL cells, syngeneic TH-MYCN-derived 9464D cells endogenously express the tumor antigen GD2 and low levels of MHC Class I. The presence of the adaptive immune system had little or no influence on tumor growth, showing the low immunogenicity of the NBL cells. In contrast, depletion of NK1.1+ cells resulted in enhanced tumor outgrowth in both wild-type and Rag1(-/-) mice, showing an important role for NK cells in the natural anti-NBL immune response. Analysis of the tumor infiltrating leukocytes ex vivo revealed the presence of both tumor associated myeloid cells and T regulatory cells, thus mimicking human NBL tumors. Finally, anti-GD2 mAb mediated NBL therapy resulted in ADCC in vitro and delayed tumor outgrowth in vivo. We conclude that the transplantable TH-MYCN model represents a relevant model for the development of novel immunocombinatorial approaches for NBL patients.

  5. A Cre-conditional MYCN-driven neuroblastoma mouse model as an improved tool for preclinical studies.

    PubMed

    Althoff, K; Beckers, A; Bell, E; Nortmeyer, M; Thor, T; Sprüssel, A; Lindner, S; De Preter, K; Florin, A; Heukamp, L C; Klein-Hitpass, L; Astrahantseff, K; Kumps, C; Speleman, F; Eggert, A; Westermann, F; Schramm, A; Schulte, J H

    2015-06-01

    Neuroblastoma, a childhood cancer that originates from neural crest-derived cells, is the most common deadly solid tumor of infancy. Amplification of the MYCN oncogene, which occurs in approximately 20-25% of human neuroblastomas, is the most prominent genetic marker of high-stage disease. The availability of valid preclinical in vivo models is a prerequisite to develop novel targeted therapies. We here report on the generation of transgenic mice with Cre-conditional induction of MYCN in dopamine β-hydroxylase-expressing cells, termed LSL-MYCN;Dbh-iCre. These mice develop neuroblastic tumors with an incidence of >75%, regardless of strain background. Molecular profiling of tumors revealed upregulation of the MYCN-dependent miR-17-92 cluster as well as expression of neuroblastoma marker genes, including tyrosine hydroxylase and the neural cell adhesion molecule 1. Gene set enrichment analyses demonstrated significant correlation with MYC-associated expression patterns. Array comparative genome hybridization showed that chromosomal aberrations in LSL-MYCN;Dbh-iCre tumors were syntenic to those observed in human neuroblastomas. Treatment of a cell line established from a tumor derived from a LSL-MYCN;Dbh-iCre mouse with JQ1 or MLN8237 reduced cell viability and demonstrated oncogene addiction to MYCN. Here we report establishment of the first Cre-conditional human MYCN-driven mouse model for neuroblastoma that closely recapitulates the human disease with respect to tumor localization, histology, marker expression and genomic make up. This mouse model is a valuable tool for further functional studies and to assess the effect of targeted therapies. PMID:25174395

  6. Preclinical Comparative Study of (68)Ga-Labeled DOTA, NOTA, and HBED-CC Chelated Radiotracers for Targeting PSMA.

    PubMed

    Ray Banerjee, Sangeeta; Chen, Zhengping; Pullambhatla, Mrudula; Lisok, Ala; Chen, Jian; Mease, Ronnie C; Pomper, Martin G

    2016-06-15

    (68)Ga-labeled, low-molecular-weight imaging agents that target the prostate-specific membrane antigen (PSMA) are increasingly used clinically to detect prostate and other cancers with positron emission tomography (PET). The goal of this study was to compare the pharmacokinetics of three PSMA-targeted radiotracers: (68)Ga-1, using DOTA-monoamide as the chelating agent; (68)Ga-2, containing the macrocyclic chelating agent p-SCN-Bn-NOTA; and (68)Ga-DKFZ-PSMA-11, currently in clinical trials, which uses the acyclic chelating agent, HBED-CC. The PSMA-targeting scaffold for all three agents utilized a similar Glu-urea-Lys-linker construct. Each radiotracer enabled visualization of PSMA+ PC3 PIP tumor, kidney, and urinary bladder as early as 15 min post-injection using small animal PET/computed tomography (PET/CT). (68)Ga-2 demonstrated the fastest rate of clearance from all tissues in this series and displayed higher uptake in PSMA+ PC3 PIP tumor compared to (68)Ga-1 at 1 h post-injection. There was no significant difference in PSMA+ PC3 PIP tumor uptake for the three agents at 2 and 3 h post-injection. (68)Ga-DKFZ-PSMA-11 demonstrated the highest uptake and retention in normal tissues, including kidney, blood, spleen, and salivary glands and PSMA-negative PC3 flu tumors up to 3 h post-injection. In this preclinical evaluation (68)Ga-2 had the most advantageous characteristics for PSMA-targeted PET imaging. PMID:27076393

  7. The prevalence and correlations of medical student burnout in the pre-clinical years: a cross-sectional study.

    PubMed

    Mazurkiewicz, Rebecca; Korenstein, Deborah; Fallar, Robert; Ripp, Jonathan

    2012-01-01

    Burnout is a psychological syndrome of emotional exhaustion, depersonalization, and impaired personal accomplishment induced by repeated workplace stressors. Current research suggests that physician burnout may have its origins in medical school. The consequences of medical student burnout include both personal and professional distress, loss of empathy, and poor health. We hypothesized that burnout occurs prior to the initiation of the clinical years of medical education. This was a cross-sectional survey administered to third-year medical students at the Mount Sinai School of Medicine (MSSM) in New York, New York (a traditional-style medical school with a marked division between pre-clinical and clinical training occurring at the beginning of the third year). Survey included an instrument used to measure job burnout, a sleep deprivation screen, and questions related to demographic information, current rotation, psychiatric history, time spent working/studying, participation in extracurricular activities, social support network, autonomy and isolation. Of the 86 medical students who participated, 71% met criteria for burnout. Burnt out students were significantly more likely to suffer from sleep deprivation (p = 0.0359). They were also more likely to disagree with the following statements: "I have control over my daily schedule" (p = 0.0286) and "I am confident that I will have the knowledge and skills necessary to become an intern when I graduate" (p = 0.0263). Our findings show that burnout is present at the beginning of the third year of medical school, prior to the initiation of the clinical years of medical training. Medical student burnout is quite common, and early efforts should be made to empower medical students to both build the knowledge and skills necessary to become capable physicians, as well as withstand the emotional, mental, and physical challenges inherent to medical school. PMID:21781020

  8. Inter-study variability of preclinical in vivo safety studies and translational exposure–QTc relationships – a PKPD meta-analysis

    PubMed Central

    Gotta, V; Cools, F; van Ammel, K; Gallacher, D J; Visser, S A G; Sannajust, F; Morissette, P; Danhof, M; van der Graaf, P H

    2015-01-01

    Background and Purpose Preclinical cardiovascular safety studies (CVS) have been compared between facilities with respect to their sensitivity to detect drug-induced QTc prolongation (ΔQTc). Little is known about the consistency of quantitative ΔQTc predictions that are relevant for translation to humans. Experimental Approach We derived typical ΔQTc predictions at therapeutic exposure (ΔQTcTHER) with 95% confidence intervals (95%CI) for 3 Kv11.1 (hERG) channel blockers (moxifloxacin, dofetilide and sotalol) from a total of 14 CVS with variable designs in the conscious dog. Population pharmacokinetic-pharmacodynamic (PKPD) analysis of each study was followed by a meta-analysis (pooling 2–6 studies including 10–32 dogs per compound) to derive meta-predictions of typical ΔQTcTHER. Meta-predictions were used as a reference to evaluate the consistency of study predictions and to relate results to those found in the clinical literature. Key Results The 95%CIs of study-predicted ΔQTcTHER comprised in 13 out of 14 cases the meta-prediction. Overall inter-study variability (mean deviation from meta-prediction at upper level of therapeutic exposure) was 30% (range: 1–69%). Meta-ΔQTcTHER predictions for moxifloxacin, dofetilide and sotalol overlapped with reported clinical QTc prolongation when expressed as %-prolongation from baseline. Conclusions and Implications Consistent exposure-ΔQTc predictions were obtained from single preclinical dog studies of highly variable designs by systematic PKPD analysis, which is suitable for translational purposes. The good preclinical–clinical pharmacodynamic correlations obtained suggest that such an analysis should be more routinely applied to increase the informative and predictive value of results obtained from animal experiments. PMID:26076100

  9. Preclinical and clinical studies of photodynamic action on some pathogenic micro-organisms of the oral cavity

    NASA Astrophysics Data System (ADS)

    Ovchinnikov, Ilya S.; Tuchin, Valery V.; Ivanov, Krill I.; Titorenko, Vladimir A.

    2001-10-01

    The work is devoted to an analysis of pre-clinical and clinical experiments on photodynamic action of HeNe laser radiation in aggregate with a cation thiazinium dye Methylene Blue (MB) on a mix of pathogenic and conditionally pathogenic aerobic bacteria being activators of pyoinflammatory diseases of oral cavity. Concentration of photosensitizes at which there is no own bactericidal influence on dying microflora, and parameters of influence at which the efficiency of irradiated microflora defeat reaches 99% are determined.

  10. Efficacy and mechanism of action of the tyrosine kinase inhibitors gefitinib, lapatinib and neratinib in the treatment of HER2-positive breast cancer: preclinical and clinical evidence

    PubMed Central

    Segovia-Mendoza, Mariana; González-González, María E; Barrera, David; Díaz, Lorenza; García-Becerra, Rocío

    2015-01-01

    An increasing number of tumors, including breast cancer, overexpress proteins of the epidermal growth factor receptor (EGFR) family. The interaction between family members activates signaling pathways that promote tumor progression and resistance to treatment. Human epidermal growth factor receptor type II (HER2) positive breast cancer represents a clinical challenge for current therapy. It has motivated the development of novel and more effective therapeutic EGFR family target drugs, such as tyrosine kinase inhibitors (TKIs). This review focuses on the effects of three TKIs mostly studied in HER2- positive breast cancer, lapatinib, gefitinib and neratinib. Herein, we discuss the mechanism of action, therapeutic advantages and clinical applications of these TKIs. To date, TKIs seem to be promising therapeutic agents for the treatment of HER2-overexpressing breast tumors, either as monotherapy or combined with other pharmacological agents. PMID:26609467

  11. 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

  12. Pre-Clinical Lupus

    PubMed Central

    Bourn, Rebecka; James, Judith A.

    2015-01-01

    Purpose of review Systemic lupus erythematosus (SLE) is often preceded by immune dysregulation and clinical manifestations below the threshold for SLE classification. This review discusses current and evolving concepts about the pre-classification period of SLE, including clinical and mechanistic observations, and potential avenues for early identification and intervention. Recent findings Although incomplete lupus erythematosus (ILE) involves fewer clinical manifestations than SLE, ILE can cause organ damage and mortality. Common clinical features in ILE include antinuclear antibody seropositivity, polyarthritis, immunologic manifestations, and hematological disorders. Despite having lower disease activity and damage scores than SLE patients, ILE patients may develop pulmonary arterial hypertension or renal, neurological, or peripheral vascular damage. The recently proposed SLICC SLE classification criteria could shift the period considered “preclinical SLE”. Murine studies suggest that the balance of T helper/T regulatory cells, peroxisome proliferator-activated receptor γ activity, and plasmacytoid dendritic cell pathways may be valuable targets for early intervention. Summary Advances in our understanding of early SLE, including stages before clinical features are fully developed, will improve our ability to identify individuals at high risk of classification for potential prevention trials, provide necessary information to improve diagnostic testing, and perhaps identify novel targets for directed therapeutics in clinical SLE. PMID:26125103

  13. Self-Efficacy Perceptions of Social Studies Candidate Teachers

    ERIC Educational Resources Information Center

    Simsek, Nihat

    2011-01-01

    The aim of this study was to determine the self efficacy beliefs of pre-service social studies teachers. For this purpose, the scales developed in various areas were examined, the opinions of experts were taken and a final scale was created to be used for this study. The validity and reliability of the scale were checked. The validity coefficient…

  14. 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

  15. Safety and efficacy field study of artesunate for dogs with non-resectable tumours.

    PubMed

    Rutteman, Gerard R; Erich, Suzanne A; Mol, Jan A; Spee, Bart; Grinwis, Guy C M; Fleckenstein, Lawrence; London, Cheryl A; Efferth, Thomas

    2013-05-01

    The anti-malarial drug artesunate has shown anticancer activity in vitro and in preliminary animal experiments, but experience in patients with cancer is very limited. Pre-clinical studies in dogs indicated morbidity at high dosage levels. This study evaluated the effects of artesunate in canine cancer cell lines and in canine cancer patients. Four canine cell lines were tested in vitro for sensitivity towards artesunate and dihydroartemisinin (DHA; active metabolite of artesunate). The half-maximal inhibitory concentration (IC50) values for artesunate or DHA were 2-60 μM in three cell lines, while one cell line was much less sensitive to artesunate (IC50 337 μM) than to DHA (IC50 50 μM). A safety/efficacy field study with artesunate was conducted in 23 dogs with non-resectable tumours. Artesunate was administered for 7-385 days at a dosage of 651-1178 (median 922) mg/m(2). No neurological or cardiac toxicity was observed and seven dogs exhibited no adverse effects at all. Fever and haematological/gastrointestinal toxicity, mostly transient, occurred in 16 dogs. One dog died from pneumonia. Plasma artesunate and DHA levels fell below the limit of detection within 8-12 h after artesunate administration, while levels after two hours were close to 1 μM. Artesunate produced a long-lasting complete remission in one case of cancer and short-term stabilization of another seven cases. PMID:23645726

  16. Sources of variation in the design of preclinical studies assessing the effects of amphetamine-type stimulants in pregnancy and lactation.

    PubMed

    McDonnell-Dowling, Kate; Kelly, John P

    2015-02-15

    The prevalence of drug use during pregnancy has increased in recent years and the amount of drug-exposed babies has therefore increased. In order to assess the risk associated with this there has been an increase in the amount of preclinical studies investigating the effects of prenatal and postnatal drug exposure on the offspring. There are many challenges associated with investigating the developmental and behavioural effects of drugs of abuse in animal models and ensuring that such models are appropriate and clinically relevant. The purpose of this review is to illustrate the variation in the design of preclinical studies investigating the effects of the amphetamine-type stimulants taken during pregnancy and/or lactation in animal models. Methamphetamine, methylendioxymethamphetamine and amphetamine were included in this review. The protocols used for exploring the effects of these drugs when taking during pregnancy and/or lactation were investigated and summarised into maternal experimental variables and offspring experimental variables. Maternal experimental variables include animals used, mating procedures and drug treatment and offspring experimental variables include litter standardisation, cross fostering, weaning and behaviours and parameters assessed. The findings in this paper suggest that there is a large diversity and little consistency among these studies and so the interpretation of these results may not be as clinically relevant as previously thought. For this reason, the importance of steering the preclinical studies in a direction that is most clinically relevant will be an important future recommendation. This will also allow us to be more confident in the results obtained and confident that the human situation is being replicated as closely as possible.

  17. Preclinical Studies of Mesenchymal Stem Cell (MSC) Administration in Chronic Obstructive Pulmonary Disease (COPD): A Systematic Review and Meta-Analysis

    PubMed Central

    Liu, Xiangde; Fang, Qiuhong; Kim, Huijung

    2016-01-01

    Background In the last two decades, mesenchymal stem cells (MSCs) have been pre-clinically utilized in the treatment of a variety of kinds of diseases including chronic obstructive pulmonary disease (COPD). The aim of the current study was to systematically review and conduct a meta-analysis on the published pre-clinical studies of MSC administration in the treatment of COPD in animal models. Methods and Results A systematic search of electronic databases was performed. Statistical analysis was performed using the Comprehensive Meta-Analysis software (Version 3). The pooled Hedges’s g with 95% confidence intervals (95% CIs) was adopted to assess the effect size. Random effect model was used due to the heterogeneity between the studies. A total of 20 eligible studies were included in the current systematic review. The overall meta-analysis showed that MSC administration was significantly in favor of attenuating acute lung injury (Hedges’s g = -2.325 ± 0.145 with 95% CI: -2.609 ~ -2.040, P < 0.001 for mean linear intercept, MLI; Hedges’s g = -3.488 ± 0.504 with 95% CI: -4.476 ~ -2.501, P < 0.001 for TUNEL staining), stimulating lung tissue repair (Hedges’s g = 3.249 ± 0.586 with 95% CI: 2.103~ 4.394, P < 0.001) and improving lung function (Hedges’s g = 2.053 ± 0.408 with 95% CI: 1.253 ~ 2.854, P< 0.001). The mechanism of MSC therapy in COPD is through ameliorating airway inflammation (Hedges’s g = -2.956 ± 0.371 with 95% CI: -3.683 ~ -2.229, P< 0.001) and stimulating cytokine synthesis that involves lung tissue repair (Hedges’s g = 3.103 ± 0.734 with 95% CI: 1.664 ~ 4.541, P< 0.001). Conclusion This systematic review and meta-analysis suggest a promising role for MSCs in COPD treatment. Although the COPD models may not truly mimic COPD patients, these pre-clinical studies demonstrate that MSC hold promise in the treatment of chronic lung diseases including COPD. The mechanisms of MSCs role in preclinical COPD treatment may be associated with

  18. Spatial Navigation in Preclinical Alzheimer's Disease

    PubMed Central

    Allison, Samantha L.; Fagan, Anne M.; Morris, John C.; Head, Denise

    2016-01-01

    Although several previous studies have demonstrated navigational deficits in early-stage symptomatic Alzheimer's disease (AD), navigational abilities in preclinical AD have not been examined. The present investigation examined the effects of preclinical AD and early-stage symptomatic AD on spatial navigation performance. Performance on tasks of wayfinding and route learning in a virtual reality environment were examined. Comparisons were made across the following three groups: Clinically normal without preclinical AD (n = 42), clinically normal with preclinical AD (n = 13), and early-stage symptomatic AD (n = 16) groups. Preclinical AD was defined based on cerebrospinal fluid Aβ42 levels below 500 pg/ml. Preclinical AD was associated with deficits in the use of a wayfinding strategy, but not a route learning strategy. Moreover, post-hoc analyses indicated that wayfinding performance had moderate sensitivity and specificity. Results also confirmed early-stage symptomatic AD-related deficits in the use of both wayfinding and route learning strategies. The results of this study suggest that aspects of spatial navigation may be particularly sensitive at detecting the earliest cognitive deficits of AD. PMID:26967209

  19. Studies on the Efficacy of Child Psychoanalysis.

    ERIC Educational Resources Information Center

    Fonagy, Peter; Moran, George S.

    1990-01-01

    Summarizes three studies on psychoanalytic psychotherapeutic treatment of diabetic children and adolescents with grossly abnormal blood glucose profiles necessitating repeated admissions to hospital. Used time series analysis, comparative analysis, and single-case experimental design to illustrate effectiveness of psychotherapeutic intervention…

  20. Orazipone, a locally acting immunomodulator, ameliorates intestinal radiation injury: A preclinical study in a novel rat model

    SciTech Connect

    Boerma, Marjan; Wang, Junru; Richter, Konrad K.; Hauer-Jensen, Martin . E-mail: mhjensen@life.uams.edu

    2006-10-01

    Purpose: Intestinal radiation injury (radiation enteropathy) is relevant to cancer treatment, as well as to radiation accidents and radiation terrorism scenarios. This study assessed the protective efficacy of orazipone, a locally-acting small molecule immunomodulator. Methods and Materials: Male rats were orchiectomized, a 4-cm segment of small bowel was sutured to the inside of the scrotum, a proximal anteperistaltic ileostomy was created for intraluminal drug administration, and intestinal continuity was re-established by end-to-side anastomosis. After three weeks postoperative recovery, the intestine in the 'scrotal hernia' was exposed locally to single-dose or fractionated X-radiation. Orazipone (30 mg/kg/day) or vehicle was administered daily through the ileostomy, either during and after irradiation, or only after irradiation. Structural, cellular, and molecular aspects of intestinal radiation toxicity were assessed two weeks after irradiation. Results: Orazipone significantly ameliorated histologic injury and transforming growth factor-{beta} immunoreactivity levels, both after single-dose and fractionated irradiation. Intestinal wall thickness was significantly reduced after single-dose and nonsignificantly after fractionated irradiation. Mucosal surface area and numbers of mast cells were partially restored by orazipone after single-dose irradiation. Conclusions: This work (1) demonstrates the utility of the ileostomy rat model for intraluminal administration of response modifiers in single-dose and fractionated radiation studies; (2) shows that mucosal immunomodulation during and/or after irradiation ameliorates intestinal toxicity; and (3) highlights important differences between single-dose and fractionated radiation regimens.

  1. A preclinical evaluation of an autologous living hyaline-like cartilaginous graft for articular cartilage repair: a pilot study

    PubMed Central

    Peck, Yvonne; He, Pengfei; Chilla, Geetha Soujanya V. N.; Poh, Chueh Loo; Wang, Dong-An

    2015-01-01

    In this pilot study, an autologous synthetic scaffold-free construct with hyaline quality, termed living hyaline cartilaginous graft (LhCG), was applied for treating cartilage lesions. Implantation of autologous LhCG was done at load-bearing regions of the knees in skeletally mature mini-pigs for 6 months. Over the course of this study, significant radiographical improvement in LhCG treated sites was observed via magnetic resonance imaging. Furthermore, macroscopic repair was effected by LhCG at endpoint. Microscopic inspection revealed that LhCG engraftment restored cartilage thickness, promoted integration with surrounding native cartilage, produced abundant cartilage-specific matrix molecules, and re-established an intact superficial tangential zone. Importantly, the repair efficacy of LhCG was quantitatively shown to be comparable to native, unaffected cartilage in terms of biochemical composition and biomechanical properties. There were no complications related to the donor site of cartilage biopsy. Collectively, these results imply that LhCG engraftment may be a viable approach for articular cartilage repair. PMID:26549401

  2. The Efficacy of Self-Paced Study in Multitrial Learning

    ERIC Educational Resources Information Center

    de Jonge, Mario; Tabbers, Huib K.; Pecher, Diane; Jang, Yoonhee; Zeelenberg, René

    2015-01-01

    In 2 experiments we investigated the efficacy of self-paced study in multitrial learning. In Experiment 1, native speakers of English studied lists of Dutch-English word pairs under 1 of 4 imposed fixed presentation rate conditions (24 × 1 s, 12 × 2 s, 6 × 4 s, or 3 × 8 s) and a self-paced study condition. Total study time per list was equated for…

  3. The Efficacy of Math Coaching: An Evaluative Case Study

    ERIC Educational Resources Information Center

    Dobbins, C. Neelie

    2010-01-01

    There is a lack of implementation of instructional strategies to assist middle school teachers in improving mathematics education for their students. Coaching is one solution to this problem, but its impact on student achievement is unclear. This case study evaluated the relationship between coaching and teacher efficacy and the impact of these…

  4. Self-Efficacy and IPS: An Empirical Study

    ERIC Educational Resources Information Center

    McLeod, Linda P.

    2015-01-01

    The fact that some learners learn language more successfully than others who are at the same level of aptitude and capabilities is inevitable. To understand why, the researcher has focused her attention on individual differences among learners. The ones that have been taken into account in this study are namely called self-efficacy and identity…

  5. Year 3 ASK/FOSS Efficacy Study. CRESST Report 782

    ERIC Educational Resources Information Center

    Osmundson, Ellen; Dai, Yunyun; Herman, Joan

    2011-01-01

    This efficacy study was designed to examine the traditional FOSS curriculum (Delta Publishing, Full Option Science System/FOSS, magnetism and electricity, structures of life, and water modules, 2005), and the new ASK/FOSS curriculum (magnetism and electricity, structures of life, and water modules, 2005), a revised version of the original FOSS…

  6. Optimization and qualification of an 8-color intracellular cytokine staining assay for quantifying T cell responses in rhesus macaques for pre-clinical vaccine studies

    PubMed Central

    Donaldson, Mitzi M.; Kao, Shing-Fen; Eslamizar, Leila; Gee, Connie; Koopman, Gerrit; Lifton, Michelle; Schmitz, Joern E.; Sylwester, Andrew W.; Wilson, Aaron; Hawkins, Natalie; Self, Steve G.; Roederer, Mario; Foulds, Kathryn E.

    2013-01-01

    Vaccination and SIV challenge of macaque species is the best animal model for evaluating candidate HIV vaccines in pre-clinical studies. As such, robust assays optimized for use in nonhuman primates are necessary for reliable ex vivo measurement of immune responses and identification of potential immune correlates of protection. We optimized and qualified an 8-color intracellular cytokine staining assay for the measurement of IFNγ, IL-2, and TNF from viable CD4 and CD8 T cells from cryopreserved rhesus macaque PBMC stimulated with peptides. After optimization, five laboratories tested assay performance using the same reagents and PBMC samples; similar results were obtained despite the use of flow cytometers with different configurations. The 8-color assay was then subjected to a pre-qualification study to quantify specificity and precision. These data were used to set positivity thresholds and to design the qualification protocol. Upon completion of the qualification study, the assay was shown to be highly reproducible with low inter-aliquot, inter-day, and inter-operator variability according to the qualification criteria with an overall variability of 20–40% for each outcome measurement. Thus, the 8-color ICS assay was formally qualified according to the ICH guidelines Q2 (R1) for specificity and precision indicating that it is considered a standardized/robust assay acceptable for use in pre-clinical trial immunogenicity testing. PMID:22955212

  7. ISO 12189 standard for the preclinical evaluation of posterior spinal stabilization devices--II: A parametric comparative study.

    PubMed

    La Barbera, Luigi; Costa, Francesco; Villa, Tomaso

    2016-02-01

    The International Standardization Organization (ISO) 12189 standard was recently introduced to preclinically evaluate and compare the mechanical properties of posterior stabilization devices. This scenario presents some new significant steps ahead over the vertebrectomy model recommended by American Society for Testing and Materials (ASTM) F1717 standard: the modular anterior support allows for describing a closer scenario to the effective clinical use as well as to test very flexible and dynamic posterior stabilization devices. Despite these significant advantages, ISO 12189 received little attention in the literature. Anatomical parameters depending on the spinal level were compared to the published data or original measurements on biplanar stereoradiography on 13 patients. Other mechanical variables, describing the test set-up design, were considered and all parameters were investigated using a numerical parametric finite element model. Stress values were calculated by also considering their worst-case combination. The standard set-up represents quite well the anatomy of an instrumented average thoracolumbar segment. The parametric comparative analysis demonstrates a significant (even beyond +350%) maximum increase in the stress on the device, compared to the standard currently in use. The anterior support stiffness plays the most detrimental effect (maximum stress increases up to 396%). The initial precompression step has an important role in determining the final stress values achieved at peak load (up to +76%). Moreover, when combining these two contributions, an even higher stress increase may be achieved (up to 473%). Despite the other anatomical parameters playing a secondary role, their worst-case combination demonstrates that a device could potentially undergo higher stresses than those reached according to standard suggestions (maximum increase of 22.4% at L1). Any user/designer should be aware of these effects when using ISO 12189 standard for the

  8. Preclinical and first-in-human phase I studies of KW-2450, an oral tyrosine kinase inhibitor with insulin-like growth factor receptor-1/insulin receptor selectivity.

    PubMed

    Schwartz, Gary K; Dickson, Mark A; LoRusso, Patricia M; Sausville, Edward A; Maekawa, Yoshimi; Watanabe, Yasuo; Kashima, Naomi; Nakashima, Daisuke; Akinaga, Shiro

    2016-04-01

    Numerous solid tumors overexpress or have excessively activated insulin-like growth factor receptor-1 (IGF-1R). We summarize preclinical studies and the first-in-human study of KW-2450, an oral tyrosine kinase inhibitor with IGF-1R and insulin receptor (IR) inhibitory activity. Preclinical activity of KW-2450 was evaluated in various in vitro and in vivo models. It was then evaluated in a phase I clinical trial in 13 patients with advanced solid tumors (NCT00921336). In vitro, KW-2450 inhibited human IGF-1R and IR kinases (IC50 7.39 and 5.64 nmol/L, respectively) and the growth of various human malignant cell lines. KW-2450 40 mg/kg showed modest growth inhibitory activity and inhibited IGF-1-induced signal transduction in the murine HT-29/GFP colon carcinoma xenograft model. The maximum tolerated dose of KW-2450 was 37.5 mg once daily continuously; dose-limiting toxicity occurred in two of six patients at 50 mg/day (both grade 3 hyperglycemia) and in one of seven patients at 37.5 mg/day (grade 3 rash). Four of 10 evaluable patients showed stable disease. Single-agent KW-2450 was associated with modest antitumor activity in heavily pretreated patients with solid tumors and is being further investigated in combination therapy with lapatinib/letrozole in patients with human epidermal growth factor receptor 2-postive metastatic breast cancer. PMID:26850678

  9. Multiple vaginal exposures to low doses of R5 simian-human immunodeficiency virus: strategy to study HIV preclinical interventions in nonhuman primates.

    PubMed

    Otten, Ron A; Adams, Debra R; Kim, Caryn N; Jackson, Eddie; Pullium, Jennifer K; Lee, Kemba; Grohskopf, Lisa A; Monsour, Michael; Butera, Sal; Folks, Thomas M

    2005-01-15

    A nonhuman-primate model of human immunodeficiency virus type 1 (HIV-1) infection that more closely emulates human heterosexual transmission by use of multiple exposures to low doses of virus is critical to better evaluate intervention strategies that include microbicides or vaccines. In this report, we describe such a system that uses female pig-tailed macaques exposed vaginally to a CCR5-using simian-human immunodeficiency virus (SHIV(SF162P3)) at weekly intervals. Results of dose-titration experiments indicated that 3 once-weekly exposures to 10 tissue culture infectious doses of SHIV(SF162P3) resulted in consistent transmission of virus and establishment of systemic infection. The efficacy of cellulose acetate phthalate (CAP) as a vaginal microbicide was evaluated by applying it to the vaginal vault of macaques (n = 4) 15 min before each weekly exposure to SHIV(SF162P3). One conclusion that can be drawn from the data derived from multiple exposures to virus is that CAP prevented infection in 12 of 13 possible chances for infection, over the course of 39 total exposures. Our findings provide a basis to refine monkey models for transmission of HIV-1, which may be relevant to preclinical evaluation for therapeutic interventions.

  10. Towards developing standard operating procedures for pre-clinical testing in the mdx mouse model of Duchenne muscular dystrophy

    PubMed Central

    Grounds, Miranda D.; Radley, Hannah G.; Lynch, Gordon S.; Nagaraju, Kanneboyina; De Luca, Annamaria

    2008-01-01

    This review discusses various issues to consider when developing standard operating procedures for pre-clinical studies in the mdx mouse model of Duchenne muscular dystrophy (DMD). The review describes and evaluates a wide range of techniques used to measure parameters of muscle pathology in mdx mice and identifies some basic techniques that might comprise standardised approaches for evaluation. While the central aim is to provide a basis for the development of standardised procedures to evaluate efficacy of a drug or a therapeutic strategy, a further aim is to gain insight into pathophysiological mechanisms in order to identify other therapeutic targets. The desired outcome is to enable easier and more rigorous comparison of pre-clinical data from different laboratories around the world, in order to accelerate identification of the best pre-clinical therapies in the mdx mouse that will fast-track translation into effective clinical treatments for DMD. PMID:18499465

  11. Essentials for starting a pediatric clinical study (4): Clinical pediatric safety planning based on preclinical toxicity studies and pediatric pharmacovigilance guidance.

    PubMed

    Sheth, Neha

    2009-01-01

    Juvenile toxicology studies in animals provide useful information to guide monitoring of potential adverse effects in children especially on growth and development. In order to continue to gain knowledge and build upon these preclinical studies, recent experience has suggested that additional approaches for monitoring of safety concerns in the pediatric population may be required. Recently, pediatric guidance has become available from the health authorities which provide pharmacovigilance concepts as they specifically relate to drugs being developed for pediatric indications. Clinical trials are typically not robust enough to detect rare or delayed safety effects as the pediatric trials are relatively short-term. Furthermore, such long term or rare effects may not be detected via standard voluntary postmarketing surveillance. Safety monitoring of children with Juvenile Inflammatory Arthritis (JIA) taking nonsteroid anti-inflammatory drug (NSAID)s will be used as an example to describe a post-marketing risk management and pharmacovigilance program that serves to better evaluate safety data from various sources. The intent of this program is to identify adverse events (AE), including events with longer latency, which may be associated with NSAID use in a pediatric population. In this presentation, the 4 major components of the program are to be addressed. Such a program may serve as a model to proactively generate and monitor safety data in order to identify AEs that may be associated with new therapeutics for a pediatric population. PMID:19571487

  12. White matter changes in preclinical Alzheimer's disease: a magnetic resonance imaging-diffusion tensor imaging study on cognitively normal older people with positive amyloid β protein 42 levels.

    PubMed

    Molinuevo, José Luis; Ripolles, Pablo; Simó, Marta; Lladó, Albert; Olives, Jaume; Balasa, Mircea; Antonell, Anna; Rodriguez-Fornells, Antoni; Rami, Lorena

    2014-12-01

    The aim of this study was to use diffusion tensor imaging measures to determine the existence of white matter microstructural differences in the preclinical phases of Alzheimer's disease, assessing cognitively normal older individuals with positive amyloid β protein (Aβ42) levels (CN_Aβ42+) on the basis of normal cognition and cerebrospinal fluid Aβ42 levels below 500 pg/mL. Nineteen CN_Aβ42+ and 19 subjects with Aβ42 levels above 500 pg/mL (CN_Aβ42-) were included. We encountered increases in axial diffusivity (AxD) in CN_Aβ42+ relative to CN_Aβ42- in the corpus callosum, corona radiata, internal capsule, and superior longitudinal fasciculus bilaterally, and also in the left fornix, left uncinate fasciculus, and left inferior fronto-occipital fasciculus. However, no differences were found in other diffusion tensor imaging indexes. Cognitive reserve scores were positively associated with AxD exclusively in the CN_Aβ42+ group. The finding of AxD alteration together with preserved fractional anisotropy, mean diffusivity, and radial diffusivity indexes in the CN_Aβ42+ group may indicate that, subtle axonal changes may be happening in the preclinical phases of Alzheimer's disease, whereas white matter integrity is still widely preserved.

  13. Study of Self-Efficacy Perceptions of Social Studies Teacher Candidates on Educational Internet Usage

    ERIC Educational Resources Information Center

    Akman, Özkan

    2016-01-01

    This study aimed at examining the self-efficacy perceptions of social studies teacher candidates with respect to educational internet use. This research was conducted on a sample of 174 social studies teacher candidates enrolled in Gaziantep University Nizip Faculty of Education. The "Educational Internet Self-Efficacy Scale," developed…

  14. Challenges in preclinical to clinical translation for anticancer carrier-mediated agents.

    PubMed

    Lucas, Andrew T; Madden, Andrew J; Zamboni, William C

    2016-09-01

    Major advances in carrier-mediated agents (CMAs), which include nanoparticles and conjugates, have revolutionized drug delivery capabilities over the past decade. While providing numerous advantages over their small-molecule counterparts, there is substantial variability in how individual CMA formulations and patient characteristics affect the pharmacology, pharmacokinetics (PK), and pharmacodynamics (PD) (efficacy and toxicity) of these agents. Development or selection of animal models is used to predict the effects within a particular human disease. A breadth of studies have begun to emphasize the importance of preclinical animal models in understanding and evaluating the interaction between CMAs and the immune system and tumor matrix, which ultimately influences CMA PK (clearance and distribution) and PD (efficacy and toxicity). It is fundamental to study representative preclinical tumor models that recapitulate patients with diseases (e.g., cancer) and evaluate the interplay between CMAs and the immune system, including the mononuclear phagocyte system (MPS), chemokines, hormones, and other immune modulators. Furthermore, standard allometric scaling using body weight does not accurately predict drug clearance in humans. Future studies are warranted to better understand the complex pharmacology and interaction of CMA carriers within individual preclinical models and their biological systems, such as the MPS and tumor microenvironment, and their application to allometric scaling across species. WIREs Nanomed Nanobiotechnol 2016, 8:642-653. doi: 10.1002/wnan.1394 For further resources related to this article, please visit the WIREs website. PMID:26846457

  15. Challenges in preclinical to clinical translation for anticancer carrier-mediated agents.

    PubMed

    Lucas, Andrew T; Madden, Andrew J; Zamboni, William C

    2016-09-01

    Major advances in carrier-mediated agents (CMAs), which include nanoparticles and conjugates, have revolutionized drug delivery capabilities over the past decade. While providing numerous advantages over their small-molecule counterparts, there is substantial variability in how individual CMA formulations and patient characteristics affect the pharmacology, pharmacokinetics (PK), and pharmacodynamics (PD) (efficacy and toxicity) of these agents. Development or selection of animal models is used to predict the effects within a particular human disease. A breadth of studies have begun to emphasize the importance of preclinical animal models in understanding and evaluating the interaction between CMAs and the immune system and tumor matrix, which ultimately influences CMA PK (clearance and distribution) and PD (efficacy and toxicity). It is fundamental to study representative preclinical tumor models that recapitulate patients with diseases (e.g., cancer) and evaluate the interplay between CMAs and the immune system, including the mononuclear phagocyte system (MPS), chemokines, hormones, and other immune modulators. Furthermore, standard allometric scaling using body weight does not accurately predict drug clearance in humans. Future studies are warranted to better understand the complex pharmacology and interaction of CMA carriers within individual preclinical models and their biological systems, such as the MPS and tumor microenvironment, and their application to allometric scaling across species. WIREs Nanomed Nanobiotechnol 2016, 8:642-653. doi: 10.1002/wnan.1394 For further resources related to this article, please visit the WIREs website.

  16. Effect of Stem Cell Therapy on Bone Mineral Density: A Meta-Analysis of Preclinical Studies in Animal Models of Osteoporosis

    PubMed Central

    Li, Feng; Zhou, Changlin; Xu, Liang; Tao, Shuqing; Zhao, Jingyi; Gu, Qun

    2016-01-01

    Background Preclinical studies of the therapeutic role of stem cell based therapy in animal models of osteoporosis have largely yielded inconsistent results. We performed a meta-analysis to provide an overview of the currently available evidence. Methods Pubmed, Embase and Cochrane Library databases were systematically searched for relevant controlled studies. A random-effect model was used for pooled analysis of the effect of stem cell based therapy on bone mineral density (BMD). Stratified analyses were performed to explore the effect of study characteristics on the outcomes. Results Pooled results from 12 preclinical studies (110 animals in stem cell treatment groups, and 106 animals in control groups) indicated that stem cell based treatment was associated with significantly improved BMD (standardized mean difference [SMD] = 1.29, 95% Confidence Interval [CI]: 0.84–1.74, P < 0.001) with moderate heterogeneity (Cochrane’s Q test: P = 0.02, I2 = 45%) among the constituent studies. Implantation of bone marrow cells, bone marrow mesenchymal stem cells, adipose-derived stem cells, and human umbilical cord blood-derived CD34+ cells, were all associated with improved BMD as compared to that in the controls (P < 0.05 for all); the only exception being the use of embryonic stem cell transplantation (P > 0.05). Egger’s test detected potential publication bias (P = 0.055); however, ‘trim and fill’ analysis yielded similar results after statistically incorporating the hypothetical studies in the analysis (SMD = 1.24, 95% CI: 0.32–2.16, P < 0.001). Conclusions Stem cell transplantation may improve BMD in animal models of osteoporosis. Our meta-analysis indicates a potential therapeutic role of stem cell based therapy for osteoporosis, and serves to augment the rationale for clinical studies. PMID:26882451

  17. A meta-analysis of threats to valid clinical inference in preclinical research of sunitinib.

    PubMed

    Henderson, Valerie C; Demko, Nadine; Hakala, Amanda; MacKinnon, Nathalie; Federico, Carole A; Fergusson, Dean; Kimmelman, Jonathan

    2015-10-13

    Poor study methodology leads to biased measurement of treatment effects in preclinical research. We used available sunitinib preclinical studies to evaluate relationships between study design and experimental tumor volume effect sizes. We identified published animal efficacy experiments where sunitinib monotherapy was tested for effects on tumor volume. Effect sizes were extracted alongside experimental design elements addressing threats to valid clinical inference. Reported use of practices to address internal validity threats was limited, with no experiments using blinded outcome assessment. Most malignancies were tested in one model only, raising concerns about external validity. We calculate a 45% overestimate of effect size across all malignancies due to potential publication bias. Pooled effect sizes for specific malignancies did not show apparent relationships with effect sizes in clinical trials, and we were unable to detect dose-response relationships. Design and reporting standards represent an opportunity for improving clinical inference.

  18. Monitoring of anti-cancer treatment with (18)F-FDG and (18)F-FLT PET: a comprehensive review of pre-clinical studies.

    PubMed

    Jensen, Mette Munk; Kjaer, Andreas

    2015-01-01

    Functional imaging of solid tumors with positron emission tomography (PET) imaging is an evolving field with continuous development of new PET tracers and discovery of new applications for already implemented PET tracers. During treatment of cancer patients, a general challenge is to measure treatment effect early in a treatment course and by that to stratify patients into responders and non-responders. With 2-deoxy-2-[(18)F]fluoro-D-glucose ((18)F-FDG) and 3'-deoxy-3'-[(18)F]fluorothymidine((18)F-FLT) two of the cancer hallmarks, altered energy metabolism and increased cell proliferation, can be visualized and quantified non-invasively by PET. With (18)F-FDG and (18)F-FLT PET changes in energy metabolism and cell proliferation can thereby be determined after initiation of cancer treatment in both clinical and pre-clinical studies in order to predict, at an early time-point, treatment response. It is hypothesized that decreases in glycolysis and cell proliferation may occur in tumors that are sensitive to the applied cancer therapeutics and that tumors that are resistant to treatment will show unchanged glucose metabolism and cell proliferation. Whether (18)F-FDG and/or (18)F-FLT PET can be used for prediction of treatment response has been analyzed in many studies both following treatment with conventional chemotherapeutic agents but also following treatment with different targeted therapies, e.g. monoclonal antibodies and small molecules inhibitors. The results from these studies have been most variable; in some studies early changes in (18)F-FDG and (18)F-FLT uptake predicted later tumor regression whereas in other studies no change in tracer uptake was observed despite the treatment being effective. The present review gives an overview of pre-clinical studies that have used (18)F-FDG and/or (18)F-FLT PET for response monitoring of cancer therapeutics.

  19. Monitoring of anti-cancer treatment with 18F-FDG and 18F-FLT PET: a comprehensive review of pre-clinical studies

    PubMed Central

    Jensen, Mette Munk; Kjaer, Andreas

    2015-01-01

    Functional imaging of solid tumors with positron emission tomography (PET) imaging is an evolving field with continuous development of new PET tracers and discovery of new applications for already implemented PET tracers. During treatment of cancer patients, a general challenge is to measure treatment effect early in a treatment course and by that to stratify patients into responders and non-responders. With 2-deoxy-2-[18F]fluoro-D-glucose (18F-FDG) and 3’-deoxy-3’-[18F]fluorothymidine(18F-FLT) two of the cancer hallmarks, altered energy metabolism and increased cell proliferation, can be visualized and quantified non-invasively by PET. With 18F-FDG and 18F-FLT PET changes in energy metabolism and cell proliferation can thereby be determined after initiation of cancer treatment in both clinical and pre-clinical studies in order to predict, at an early time-point, treatment response. It is hypothesized that decreases in glycolysis and cell proliferation may occur in tumors that are sensitive to the applied cancer therapeutics and that tumors that are resistant to treatment will show unchanged glucose metabolism and cell proliferation. Whether 18F-FDG and/or 18F-FLT PET can be used for prediction of treatment response has been analyzed in many studies both following treatment with conventional chemotherapeutic agents but also following treatment with different targeted therapies, e.g. monoclonal antibodies and small molecules inhibitors. The results from these studies have been most variable; in some studies early changes in 18F-FDG and 18F-FLT uptake predicted later tumor regression whereas in other studies no change in tracer uptake was observed despite the treatment being effective. The present review gives an overview of pre-clinical studies that have used 18F-FDG and/or 18F-FLT PET for response monitoring of cancer therapeutics. PMID:26550536

  20. Preclinical pharmacokinetics of MHAA4549A, a human monoclonal antibody to influenza A virus, and the prediction of its efficacious clinical dose for the treatment of patients hospitalized with influenza A.

    PubMed

    Gupta, Priyanka; Kamath, Amrita V; Park, Summer; Chiu, Henry; Lutman, Jeff; Maia, Mauricio; Tan, Man-Wah; Xu, Min; Swem, Lee; Deng, Rong

    2016-07-01

    MHAA4549A is a human immunoglobulin G1 (IgG1) monoclonal antibody that binds to a highly conserved epitope on the stalk of influenza A hemagglutinin and blocks the hemagglutinin-mediated membrane fusion in the endosome, neutralizing all known human influenza A strains. Pharmacokinetics (PK) of MHAA4549A and its related antibodies were determined in DBA/2J and Balb-c mice at 5 mg/kg and in cynomolgus monkeys at 5 and 100 mg/kg as a single intravenous dose. Serum samples were analyzed for antibody concentrations using an ELISA and the PK was evaluated using WinNonlin software. Human PK profiles were projected based on the PK in monkeys using species-invariant time method. The human efficacious dose projection was based on in vivo nonclinical pharmacological active doses, exposure in mouse infection models and expected human PK. The PK profiles of MHAA4549A and its related antibody showed a linear bi-exponential disposition in mice and cynomolgus monkeys. In mice, clearance and half-life ranged from 5.77 to 9.98 mL/day/kg and 10.2 to 5.76 days, respectively. In cynomolgus monkeys, clearance and half-life ranged from 4.33 to 4.34 mL/day/kg and 11.3 to 11.9 days, respectively. The predicted clearance in humans was ∼2.60 mL/day/kg. A single intravenous dose ranging from 15 to 45 mg/kg was predicted to achieve efficacious exposure in humans. In conclusion, the PK of MHAA4549A was as expected for a human IgG1 monoclonal antibody that lacks known endogenous host targets. The predicted clearance and projected efficacious doses in humans for MHAA4549A have been verified in a Phase 1 study and Phase 2a study, respectively.

  1. [Studies of biologic activation associated with molecular receptor increase and tumor response in ChL6/L6 protocol patients; Studies in phantoms; Quantitative SPECT; Preclinical studies; and Clinical studies]. DOE annual report, 1994--95

    SciTech Connect

    DeNardo, S.J.

    1995-12-31

    The authors describe results which have not yet been published from their associated studies listed in the title. For the first, they discuss Lym-1 single chain genetically engineered molecules, analysis of molecular genetic coded messages to enhance tumor response, and human dosimetry and therapeutic human use radiopharmaceuticals. Studies in phantoms includes a discussion of planar image quantitation, counts coincidence correction, organ studies, tumor studies, and {sup 90}Y quantitation with Bremsstrahlung imaging. The study on SPECT discusses attenuation correction and scatter correction. Preclinical studies investigated uptake of {sup 90}Y-BrE-3 in mice using autoradiography. Clinical studies discuss image quantitation verses counts from biopsy samples, S factors for radiation dose calculation, {sup 67}Cu imaging studies for lymphoma cancer, and {sup 111}In MoAb imaging studies for breast cancer to predict {sup 90}Y MoAb therapy.

  2. Antagonism of haloperidol-induced swim impairment in L-dopa and caffeine treated mice: a pre-clinical model to study Parkinson's disease.

    PubMed

    Luthra, Pratibha Mehta; Barodia, Sandeep Kumar; Raghubir, Ram

    2009-04-15

    Parkinson's disease (PD) exhibits symptoms of motor dysfunction such as tremor, akinesia and rigidity. Agents that selectively disrupt or destroy catecholaminergic systems, such as reserpine, methamphetamine, 6-hydroxydopamine and 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine, have been used to develop PD models and to study the animal behavior like catalepsy, akinesia, swim-test, etc. The major apprehension while working with these chemicals is their irreversible neuro-toxic effect. Haloperidol is a classical antipsychotic drug, which produces extra-pyrimidal Parkinson's symptoms (EPS). Measuring catalepsy and akinesia in the treated mice monitored the haloperidol-induced EPS. Alternatively, swimming disability was tested as a new parameter to monitor haloperidol-induced EPS. The results showed that the restoration of swimming disability in haloperidol-induced L-dopa and caffeine pre-treated mice could be used as pre-clinical model to study PD.

  3. The isolation, Characterization and Preclinical Studies of Metal Complex of Thespesia populnea for the Potential Peroxisome Proliferator-activated Receptors-γ Agonist Activity

    PubMed Central

    Phanse, Mohini Ashok; Patil, Manohar Janardhan; Abbulu, Konde

    2015-01-01

    Background: Diabetes mellitus is an international public health problem since ancient days. The condition is predominantly more severe in developing countries like India where, life is more sedentary due to the even changing lifestyles in this fast-paced global scenario. Thespesia populnea is widely used in the ayurvedic system of medicine for treatment of diabetes mellitus in India for years. The aim of this work is to explore the anti-diabetic activity of the isolated compound. Materials and Methods: The sesquiterpene isolated from hexane fraction of bark of T. populnea modified synthetically then identified by using analytical techniques such as electron paramagnetic resonance spectra for confirmation and the anti-diabetic activity was evaluated by anti-hyperglycemic, hypoglycemic potential. Result: In the present work, we have studied the anti-hyperglycemic and hypoglycemic activity of the vanadium complex in glucose loaded and normal animals were shown significantly decreased in plasma blood glucose level. The results derived from preclinical studies confirm the potential of new sesquiterpene. Conclusion: The findings could provide evidence regarding the anti-diabetic potential of T. populnea by lowering blood glucose level. SUMMARY Thespesia populnea is widely used in the ayurvedic system of medicine for treatment of diabetes in India. Present study aimed to explore the anti diabetic potential of isolated compound. Isolation of sesquiterpene from hexane fraction of bark of Thespesia populnea and modified synthetically then authenticated by using analytical techniques such as electron paramagnetic resonance spectra for confirmation. The modified complex was further assessed for its anti diabetic property in glucose loaded rats. Vanadium complex demonstrated significant reduction in plasma blood glucose level in glucose loaded animals. The results derived from preclinical studies confirm the potential of new sesquiterpene. The present findings conclude that

  4. A Decade of Experience in Developing Preclinical Models of Advanced- or Early-Stage Spontaneous Metastasis to Study Antiangiogenic Drugs, Metronomic Chemotherapy, and the Tumor Microenvironment.

    PubMed

    Kerbel, Robert S

    2015-01-01

    The clinical circumstance of treating spontaneous metastatic disease, after resection of primary tumors, whether advanced/overt or microscopic in nature, is seldom modeled in mice and may be a major factor in explaining the frequent discordance between preclinical and clinical therapeutic outcomes where the trend is "overprediction" of positive results in preclinical mouse model studies. To evaluate this hypothesis, a research program was initiated a decade ago to develop multiple models of metastasis in mice, using variants of human tumor cell lines selected in vivo for enhanced spontaneous metastatic aggressiveness after surgical resection of established orthotopic primary tumors. These models have included breast, renal, and colorectal carcinomas; ovarian cancer (but without prior surgery); and malignant melanoma. They have been used primarily for experimental therapeutic investigations involving various antiangiogenic drugs alone or with chemotherapy, especially "metronomic" low-dose chemotherapy. The various translational studies undertaken have revealed a number of clinically relevant findings. These include the following: (i) the potential of metronomic chemotherapy, especially when combined with a vascular endothelial growth factor pathway targeting drug to successfully treat advanced metastatic disease; (ii) the development of relapsed spontaneous brain metastases in mice with melanoma or breast cancer whose systemic metastatic disease is successfully controlled for a period with a given therapy; (iii) foreshadowing the failure of adjuvant antiangiogenic drug-based phase III trials; (iv) recapitulating the failure of oral antiangiogenic tyrosine kinase inhibitors plus standard chemotherapy in contrast to the modest successes of antiangiogenic antibodies plus chemotherapy in metastatic breast cancer; and (v) revealing "vessel co-option" and absence of angiogenesis as a determinant of intrinsic resistance or minimal responsiveness to antiangiogenic therapy

  5. The role of metabotropic glutamate receptor 5 in the pathogenesis of mood disorders and addiction: combining preclinical evidence with human Positron Emission Tomography (PET) studies

    PubMed Central

    Terbeck, Sylvia; Akkus, Funda; Chesterman, Laurence P.; Hasler, Gregor

    2015-01-01

    In the present review, we deliver an overview of the involvement of metabotropic glutamate receptor 5 (mGluR5) activity and density in pathological anxiety, mood disorders and addiction. Specifically, we will describe mGluR5 studies in humans that employed Positron Emission Tomography (PET) and combined the findings with preclinical animal research. This combined view of different methodological approaches—from basic neurobiological approaches to human studies—might give a more comprehensive and clinically relevant view of mGluR5 function in mental health than the view on preclinical data alone. We will also review the current research data on mGluR5 along the Research Domain Criteria (RDoC). Firstly, we found evidence of abnormal glutamate activity related to the positive and negative valence systems, which would suggest that antagonistic mGluR5 intervention has prominent anti-addictive, anti-depressive and anxiolytic effects. Secondly, there is evidence that mGluR5 plays an important role in systems for social functioning and the response to social stress. Finally, mGluR5's important role in sleep homeostasis suggests that this glutamate receptor may play an important role in RDoC's arousal and modulatory systems domain. Glutamate was previously mostly investigated in non-human studies, however initial human clinical PET research now also supports the hypothesis that, by mediating brain excitability, neuroplasticity and social cognition, abnormal metabotropic glutamate activity might predispose individuals to a broad range of psychiatric problems. PMID:25852460

  6. The Economics of Reproducibility in Preclinical Research

    PubMed Central

    Freedman, Leonard P.; Cockburn, Iain M.; Simcoe, Timothy S.

    2015-01-01

    Low reproducibility rates within life science research undermine cumulative knowledge production and contribute to both delays and costs of therapeutic drug development. An analysis of past studies indicates that the cumulative (total) prevalence of irreproducible preclinical research exceeds 50%, resulting in approximately US$28,000,000,000 (US$28B)/year spent on preclinical research that is not reproducible—in the United States alone. We outline a framework for solutions and a plan for long-term improvements in reproducibility rates that will help to accelerate the discovery of life-saving therapies and cures. PMID:26057340

  7. Murine Model for Preclinical Studies of Var2CSA-Mediated Pathology Associated with Malaria in Pregnancy.

    PubMed

    de Moraes, Luciana V; Dechavanne, Sebastien; Sousa, Patrícia M; Barateiro, André; Cunha, Sónia F; Nunes-Silva, Sofia; Lima, Flávia A; Murillo, Oscar; Marinho, Claudio R F; Gangnard, Stephane; Srivastava, Anand; Braks, Joanna A; Janse, Chris J; Gamain, Benoit; Franke-Fayard, Blandine; Penha-Gonçalves, Carlos

    2016-06-01

    Plasmodium falciparum infection during pregnancy leads to abortions, stillbirth, low birth weight, and maternal mortality. Infected erythrocytes (IEs) accumulate in the placenta by adhering to chondroitin sulfate A (CSA) via var2CSA protein exposed on the P. falciparum IE membrane. Plasmodium berghei IE infection in pregnant BALB/c mice is a model for severe placental malaria (PM). Here, we describe a transgenic P. berghei parasite expressing the full-length var2CSA extracellular region (domains DBL1X to DBL6ε) fused to a P. berghei exported protein (EMAP1) and characterize a var2CSA-based mouse model of PM. BALB/c mice were infected at midgestation with different doses of P. berghei-var2CSA (P. berghei-VAR) or P. berghei wild-type IEs. Infection with 10(4) P. berghei-VAR IEs induced a higher incidence of stillbirth and lower fetal weight than P. berghei At doses of 10(5) and 10(6) IEs, P. berghei-VAR-infected mice showed increased maternal mortality during pregnancy and fetal loss, respectively. Parasite loads in infected placentas were similar between parasite lines despite differences in maternal outcomes. Fetal weight loss normalized for parasitemia was higher in P. berghei-VAR-infected mice than in P. berghei-infected mice. In vitro assays showed that higher numbers of P. berghei-VAR IEs than P. berghei IEs adhered to placental tissue. Immunization of mice with P. berghei-VAR elicited IgG antibodies reactive to DBL1-6 recombinant protein, indicating that the topology of immunogenic epitopes is maintained between DBL1-6-EMAP1 on P. berghei-VAR and recombinant DBL1-6 (recDBL1-6). Our data suggested that impairments in pregnancy caused by P. berghei-VAR infection were attributable to var2CSA expression. This model provides a tool for preclinical evaluation of protection against PM induced by approaches that target var2CSA. PMID:27045035

  8. Murine Model for Preclinical Studies of Var2CSA-Mediated Pathology Associated with Malaria in Pregnancy.

    PubMed

    de Moraes, Luciana V; Dechavanne, Sebastien; Sousa, Patrícia M; Barateiro, André; Cunha, Sónia F; Nunes-Silva, Sofia; Lima, Flávia A; Murillo, Oscar; Marinho, Claudio R F; Gangnard, Stephane; Srivastava, Anand; Braks, Joanna A; Janse, Chris J; Gamain, Benoit; Franke-Fayard, Blandine; Penha-Gonçalves, Carlos

    2016-06-01

    Plasmodium falciparum infection during pregnancy leads to abortions, stillbirth, low birth weight, and maternal mortality. Infected erythrocytes (IEs) accumulate in the placenta by adhering to chondroitin sulfate A (CSA) via var2CSA protein exposed on the P. falciparum IE membrane. Plasmodium berghei IE infection in pregnant BALB/c mice is a model for severe placental malaria (PM). Here, we describe a transgenic P. berghei parasite expressing the full-length var2CSA extracellular region (domains DBL1X to DBL6ε) fused to a P. berghei exported protein (EMAP1) and characterize a var2CSA-based mouse model of PM. BALB/c mice were infected at midgestation with different doses of P. berghei-var2CSA (P. berghei-VAR) or P. berghei wild-type IEs. Infection with 10(4) P. berghei-VAR IEs induced a higher incidence of stillbirth and lower fetal weight than P. berghei At doses of 10(5) and 10(6) IEs, P. berghei-VAR-infected mice showed increased maternal mortality during pregnancy and fetal loss, respectively. Parasite loads in infected placentas were similar between parasite lines despite differences in maternal outcomes. Fetal weight loss normalized for parasitemia was higher in P. berghei-VAR-infected mice than in P. berghei-infected mice. In vitro assays showed that higher numbers of P. berghei-VAR IEs than P. berghei IEs adhered to placental tissue. Immunization of mice with P. berghei-VAR elicited IgG antibodies reactive to DBL1-6 recombinant protein, indicating that the topology of immunogenic epitopes is maintained between DBL1-6-EMAP1 on P. berghei-VAR and recombinant DBL1-6 (recDBL1-6). Our data suggested that impairments in pregnancy caused by P. berghei-VAR infection were attributable to var2CSA expression. This model provides a tool for preclinical evaluation of protection against PM induced by approaches that target var2CSA.

  9. Anti-Plaque Efficacy of Herbal and 0.2% Chlorhexidine Gluconate Mouthwash: A Comparative Study

    PubMed Central

    Prasad, K A Ravi Varma; John, Sajil; Deepika, V; Dwijendra, K S; Reddy, Babu Ram; Chincholi, Siddharth

    2015-01-01

    Background: Mouthwashes are an adjunct to, not a substitute for, regular brushing and flossing. Chlorohexidine is cationic bis-biguanide broad spectrum antiseptic with both anti-plaque and antibacterial properties. It has side-effects like brownish discoloration of teeth and dorsum of the tongue, taste perturbation, oral mucosal ulceration, etc. To compare the antiplaque efficacy of herbal and chlorohexidine gluconate mouthwash. Materials and Methods: A double-blinded parallel, randomized controlled clinical trial was conducted in the Department of Periodontics, MNR Dental College. Totally 100 preclinical dental students were randomized into three groups (0.2% chlorohexidine, Saline and herbal mouthwash). All the groups were made to refrain from their regular mechanical oral hygiene measures and were asked to rinse with given respective mouthwashes for 4 days. The gingival and plaque scores are evaluated on 1st day, and 5th day, and differences were compared statistically. Results: There was no significant difference in the gingival index (GI) and plaque index (PI) scores of the pre-rinsing scores of three groups and mean age of subjects in the three age groups, suggesting selected population for the three groups was homogenous. Mean GI and PI scores at the post rinsing stage were least for the Group A, followed by B and C. The difference of post rinsing PI and GI scores between Group A and Group B were statistically non-significant, which means anti-gingivitis and plaque inhibiting properties are similar for both. Conclusion: Within the limitations of this study chlorhexidine gluconate and herbal mouthwash (Hiora) showed similar anti plaque activity with latter showing no side effects. PMID:26464549

  10. Preclinical studies on targeted delivery of multiple IFNα2b to HLA-DR in diverse hematologic cancers

    PubMed Central

    Rossi, Diane L.; Cardillo, Thomas M.; Stein, Rhona; Chang, Chien-Hsing

    2011-01-01

    The short circulating half-life and side effects of IFNα affect its dosing schedule and efficacy. Fusion of IFNα to a tumor-targeting mAb (mAb-IFNα) can enhance potency because of increased tumor localization and improved pharmacokinetics. We used the Dock-and-Lock method to generate C2-2b-2b, a mAb-IFNα comprising tetrameric IFNα2b site-specifically linked to hL243 (humanized anti–HLA-DR). In vitro, C2-2b-2b inhibited various B-cell lymphoma leukemia and myeloma cell lines. In most cases, this immunocytokine was more effective than CD20-targeted mAb-IFNα or a mixture comprising the parental mAb and IFNα. Our findings indicate that responsiveness depends on HLA-DR expression/density and sensitivity to IFNα and hL243. C2-2b-2b induced more potent and longer-lasting IFNα signaling compared with nontargeted IFNα. Phosphorylation of STAT1 was more robust and persistent than that of STAT3, which may promote apoptosis. C2-2b-2b efficiently depleted lymphoma and myeloma cells from whole human blood but also exhibited some toxicity to B cells, monocytes, and dendritic cells. C2-2b-2b showed superior efficacy compared with nontargeting mAb-IFNα, peginterferonalfa-2a, or a combination of hL243 and IFNα, using human lymphoma and myeloma xenografts. These results suggest that C2-2b-2b should be useful in the treatment of various hematopoietic malignancies. PMID:21680794

  11. Clinical Traumatic Brain Injury in the Preclinical Setting.

    PubMed

    Berkner, Justin; Mannix, Rebekah; Qiu, Jianhua

    2016-01-01

    Traumatic brain injury (TBI) is the leading cause of death and disability for people under 45 years of age. Clinical TBI is often the result of disparate forces resulting in heterogeneous injuries. Preclinical modeling of TBI is a vital tool for studying the complex cascade of metabolic, cellular, and molecular post-TBI events collectively termed secondary injury. Preclinical models also provide an important platform for studying therapeutic interventions. However, modeling TBI in the preclinical setting is challenging, and most models replicate only certain aspects of clinical TBI. This chapter details the most widely used models of preclinical TBI, including the controlled cortical impact, fluid percussion, blast, and closed head models. Each of these models replicates particular critical aspects of clinical TBI. Prior to selecting a preclinical TBI model, it is important to address what aspect of human TBI is being sought to evaluate. PMID:27604710

  12. A Descriptive Correlational Study of Teacher Participation in Professional Development and Teacher Efficacy

    ERIC Educational Resources Information Center

    Tupou, Samuel F.

    2013-01-01

    This study examines teacher efficacy within the context of professional development to understand the relationship between teacher efficacy and teacher collaboration. Two theoretical frameworks framed this teacher efficacy study based on "locus of control" and "social cognitive theory." A 29-item questionnaire was e-mailed to…

  13. Reform in teaching preclinical pathophysiology.

    PubMed

    Li, Yong-Yu; Li, Kun; Yao, Hong; Xu, Xiao-Juan; Cai, Qiao-Lin

    2015-12-01

    Pathophysiology is a scientific discipline that studies the onset and progression of pathological conditions and diseases, and pathophysiology is one of the core courses in most preclinical medical curricula. In China, most medical schools house a Department of Pathophysiology, in contrast to medical schools in many developed countries. The staff in Chinese Departments of Pathophysiology generally consists of full-time instructors or lecturers who teach medical students. These lecturers are sometimes lacking in clinic knowledge and experiences. To overcome this, in recent years, we have been trying to bring new trends in teaching pathophysiology into our curriculum. Our purpose in writing this article was to share our experiences with our colleagues and peers worldwide in the hope that the insights we have gained in pathophysiology teaching will be of some value to educators who advocate teaching reform in medical schools.

  14. Preclinical assessment of infant formula.

    PubMed

    Lönnerdal, Bo

    2012-01-01

    Infant formulas are the sole or predominant source of nutrition for many infants and are fed during a sensitive period of development and may therefore have short- and long-term consequences for infant health. Preclinical safety assessment therefore needs to include both short-term and long-term studies in animals. It is recommended that procedures are instituted by which experts may serve as independent scientists for companies developing novel products, without having their integrity compromised, and later serve the legislative institutions. A two-level assessment approach to determine the potential toxicity of a novel ingredient, its metabolites, and their effects in the matrix on developing organ systems has been suggested by IOM. This appears reasonable, as novel ingredients can be of different levels of concern. The use of modern methods in genomics and proteomics should be considered in these evaluation processes as well as novel methods to evaluate outcomes, including metabolomics and molecular techniques to assess the microbiome.

  15. A randomized, double-blind, positive-controlled, 3-way cross-over human experimental pain study of a TRPV1 antagonist (V116517) in healthy volunteers and comparison with preclinical profile.

    PubMed

    Arendt-Nielsen, Lars; Harris, Steve; Whiteside, Garth T; Hummel, Michele; Knappenberger, Terri; OʼKeefe, Sarah; Kapil, Ram; Kyle, Don

    2016-09-01

    This experimental, translational, experimental pain, single-center, randomized, double-blind, single-dose, 3-treatment, 3-period cross-over proof-of-concept volunteer trial studied the efficacy of a novel TRPV1 antagonist (V116517) on capsaicin- and UV-B-induced hyperalgesia. Heat and pressure pain thresholds, von Frey stimulus-response functions, and neurogenic inflammation were assessed together with safety. Each treatment period was 4 days. The 3 single oral treatments were 300 mg V116517, 400 mg celecoxib (a COX-2 inhibitor), and placebo. The heat pain detection and tolerance thresholds were increased significantly (P < 0.0001) by V116517. Heat pain detection and tolerance thresholds showed significantly less capsaicin hyperalgesia after V116517 (P = 0.004 and P < 0.0001, respectively). Celecoxib reduced UV-B-provoked pressure pain sensitization (P = 0.01). Laser Doppler flowmetry and erythema index after UV-B were significantly (P < 0.0001) reduced by celecoxib. Stimulus-response function in capsaicin-treated areas showed significant differences between both celecoxib and placebo and between V116517 and placebo. The body temperature showed no change, and no side effects were reported for any of the treatments. The TRPV1 antagonists and the COX-2 inhibitor showed different antihyperalgesic profiles indicating different clinical targets. In addition, the preclinical profile of V116517 in rat models of UV-B and capsaicin-induced hypersensitivity was compared with the human experimental data and overall demonstrated an alignment between 2 of the 3 end points tested. The TRPV1 antagonist showed a potent antihyperalgesic action without changing the body temperature but heat analgesia may be a potential safety issue. PMID:27168361

  16. Preclinical Molecular Imaging of Tumor Angiogenesis

    PubMed Central

    Zhu, Lei; Niu, Gang; Fang, Xuexun; Chen, Xiaoyuan

    2010-01-01

    Angiogenesis, a course that new blood vessels grow from the existing vasculature, plays important roles both physiologically and pathologically. Angiogenesis can be switched on by growth factors secreted by tumor cells, and in turn supplies more oxygen and nutrition to the tumor. More and more preclinical studies and clinical trials have shown that inhibition of angiogenesis is an effective way to inhibit tumor growth, substantiating the development of anti-angiogenesis therapeutics. Imaging technologies accelerate the translation of preclinical research to the clinic. In oncology, various imaging modalities are widely applied to drug development, tumor early detection and therapy response monitoring. So far, several angiogenesis related imaging agents are promising in cancer diagnosis. However, more effective imaging agents with less side-effect still need to be pursued to visualize angiogenesis process non-invasively. The main purpose of this review is to summarize the recent progresses in preclinical molecular imaging of angiogenesis and to discuss the potential of the current preclinical probes specific to various angiogenesis targets including vascular endothelial growth factor and its receptors (VEGF/VEGFRs), integrin αvβ3 and matrix metalloproteinases (MMPs). It is predicable that related investigations in the field will benefit cancer research and quicken the anti-angiogenic drug development. PMID:20639815

  17. Teacher Self-Efficacy and Teacher Burnout: A Study of Relations

    ERIC Educational Resources Information Center

    Skaalvik, Einar M.; Skaalvik, Sidsel

    2010-01-01

    The purpose of this study was partly to test the factor structure of a recently developed Norwegian scale for measuring teacher self-efficacy and partly to explore relations between teachers' perception of the school context, teacher self-efficacy, collective teacher efficacy, teacher burnout, teacher job satisfaction, and teachers' beliefs that…

  18. Preservice Elementary Teachers' Perceived Efficacy in Teaching Environmental Education: A Preliminary Study.

    ERIC Educational Resources Information Center

    Sia, Archibald P.

    This study was designed to develop an instrument that would measure preservice teachers' belief efficacy in teaching environmental education (EE). This belief efficacy includes a person's perception of ability to perform the behavior (self-efficacy) and a person's expectation that a specific behavior will result in desirable outcomes (outcome…

  19. Impact of Simulation and Clinical Experience on Self-efficacy in Nursing Students: Intervention Study.

    PubMed

    Kimhi, Einat; Reishtein, Judith L; Cohen, Miri; Friger, Michael; Hurvitz, Nancy; Avraham, Rinat

    2016-01-01

    This study compared the effect of simulation and clinical experience timing on self-confidence/self-efficacy for the nursing process. Using a randomized, double-crossover design, self-efficacy was measured 3 times. Although self-efficacy was significantly higher at time 1 for students who had clinical experience, there was no difference between the groups at the end of the course (time 2). Thus, simulation increased self-confidence/self-efficacy equivalently if placed either before or after clinical experience.

  20. Ultrasound guided fluorescence molecular tomography with improved quantification by an attenuation compensated born-normalization and in vivo preclinical study of cancer

    NASA Astrophysics Data System (ADS)

    Li, Baoqiang; Berti, Romain; Abran, Maxime; Lesage, Frédéric

    2014-05-01

    Ultrasound imaging, having the advantages of low-cost and non-invasiveness over MRI and X-ray CT, was reported by several studies as an adequate complement to fluorescence molecular tomography with the perspective of improving localization and quantification of fluorescent molecular targets in vivo. Based on the previous work, an improved dual-modality Fluorescence-Ultrasound imaging system was developed and then validated in imaging study with preclinical tumor model. Ultrasound imaging and a profilometer were used to obtain the anatomical prior information and 3D surface, separately, to precisely extract the tissue boundary on both sides of sample in order to achieve improved fluorescence reconstruction. Furthermore, a pattern-based fluorescence reconstruction on the detection side was incorporated to enable dimensional reduction of the dataset while keeping the useful information for reconstruction. Due to its putative role in the current imaging geometry and the chosen reconstruction technique, we developed an attenuation compensated Born-normalization method to reduce the attenuation effects and cancel off experimental factors when collecting quantitative fluorescence datasets over large area. Results of both simulation and phantom study demonstrated that fluorescent targets could be recovered accurately and quantitatively using this reconstruction mechanism. Finally, in vivo experiment confirms that the imaging system associated with the proposed image reconstruction approach was able to extract both functional and anatomical information, thereby improving quantification and localization of molecular targets.

  1. Ultrasound guided fluorescence molecular tomography with improved quantification by an attenuation compensated born-normalization and in vivo preclinical study of cancer

    SciTech Connect

    Li, Baoqiang; Berti, Romain; Abran, Maxime; Lesage, Frédéric

    2014-05-15

    Ultrasound imaging, having the advantages of low-cost and non-invasiveness over MRI and X-ray CT, was reported by several studies as an adequate complement to fluorescence molecular tomography with the perspective of improving localization and quantification of fluorescent molecular targets in vivo. Based on the previous work, an improved dual-modality Fluorescence-Ultrasound imaging system was developed and then validated in imaging study with preclinical tumor model. Ultrasound imaging and a profilometer were used to obtain the anatomical prior information and 3D surface, separately, to precisely extract the tissue boundary on both sides of sample in order to achieve improved fluorescence reconstruction. Furthermore, a pattern-based fluorescence reconstruction on the detection side was incorporated to enable dimensional reduction of the dataset while keeping the useful information for reconstruction. Due to its putative role in the current imaging geometry and the chosen reconstruction technique, we developed an attenuation compensated Born-normalization method to reduce the attenuation effects and cancel off experimental factors when collecting quantitative fluorescence datasets over large area. Results of both simulation and phantom study demonstrated that fluorescent targets could be recovered accurately and quantitatively using this reconstruction mechanism. Finally, in vivo experiment confirms that the imaging system associated with the proposed image reconstruction approach was able to extract both functional and anatomical information, thereby improving quantification and localization of molecular targets.

  2. The in vivo efficacy and side effect pharmacology of GS-5759, a novel bifunctional phosphodiesterase 4 inhibitor and long-acting β 2-adrenoceptor agonist in preclinical animal species.

    PubMed

    Salmon, Michael; Tannheimer, Stacey L; Gentzler, Terry T; Cui, Zhi-Hua; Sorensen, Eric A; Hartsough, Kimberly C; Kim, Musong; Purvis, Lafe J; Barrett, Edward G; McDonald, Jacob D; Rudolph, Karin; Doyle-Eisele, Melanie; Kuehl, Philip J; Royer, Christopher M; Baker, William R; Phillips, Gary B; Wright, Clifford D

    2014-08-01

    Bronchodilators are a central therapy for symptom relief in respiratory diseases such as chronic obstructive pulmonary disease (COPD) and asthma, with inhaled β 2-adrenoceptor agonists and anticholinergics being the primary treatments available. The present studies evaluated the in vivo pharmacology of (R)-6-[[3-[[4-[5-[[2-Hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino]pent-1-ynyl]phenyl]carbamoyl]phenyl]sulfonyl]-4-[(3-methoxyphenyl)amino]-8-methylquinoline-3-carboxamide (GS-5759), a novel bifunctional compound with both phosphodiesterase 4 (PDE4) inhibitor and long-acting β 2-adrenoceptor agonist (LABA) activity, which has been optimized for inhalation delivery. GS-5759 dose-dependently inhibited pulmonary neutrophilia in a lipopolysaccharide (LPS) aerosol challenge model of inflammation in rats with an ED50 ≤ 10 μg/kg. GS-5759 was also a potent bronchodilator with an ED50 of 0.09 μg/kg in guinea pigs and 3.4 μg/kg in dogs after methylcholine (MCh) and ragweed challenges respectively. In cynomolgus monkeys, GS-5759 was dosed as a fine-particle dry powder and was efficacious in the same dose range in both MCh and LPS challenge models, with an ED50 = 70 μg/kg for bronchodilation and ED50 = 4.9 μg/kg for inhibition of LPS-induced pulmonary neutrophilia. In models to determine therapeutic index (T.I.), efficacy for bronchodilation was evaluated against increased heart rate and GS-5759 had a T.I. of 700 in guinea pigs and >31 in dogs. In a ferret model of emesis, no emesis was seen at doses several orders of magnitude greater than the ED50 observed in the rat LPS inflammation model. GS-5759 is a bifunctional molecule developed for the treatment of COPD, which has both bronchodilator and anti-inflammatory activity and has the potential for combination as a triple therapy with a second compound, within a single inhalation device.

  3. Rapid and sensitive ultra-high-pressure liquid chromatography method for quantification of antichagasic benznidazole in plasma: application in a preclinical pharmacokinetic study.

    PubMed

    Davanço, Marcelo Gomes; de Campos, Michel Leandro; Peccinini, Rosângela Gonçalves

    2015-07-01

    Benznidazole (BNZ) and nifurtimox are the only drugs available for treating Chagas disease. In this work, we validated a bioanalytical method for the quantification of BNZ in plasma aimed at improving sensitivity and time of analysis compared with the assays already published. Furthermore, we demonstrated the application of the method in a preclinical pharmacokinetic study after administration of a single oral dose of BNZ in Wistar rats. A Waters® Acquity UHPLC system equipped with a UV-vis detector was employed. The method was established using an Acquity® UHPLC HSS SB C18 protected by an Acquity® UHPLC HSS SB C18 VanGuard guard column and detection at 324 nm. The mobile phase consisted of ultrapure water-acetonitrile (65:35), and elution was isocratic. The mobile phase flow rate was 0.55 mL/min, the volume of injection was 1 μL, and the run time was just 2 min. The samples were kept at 25°C until injection and the column at 45°C for the chromatographic separation. The sample preparation was performed by a rapid protein precipitation with acetonitrile. The linear concentration range was 0.15-20 µg/mL. The pharmacokinetic parameters of BNZ in rats were determined and the method was considered sensitive, fast and suitable for application in pharmacokinetic studies.

  4. 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

  5. Histopathological study of the hepatic and renal toxicity associated with the co-administration of imatinib and acetaminophen in a preclinical mouse model.

    PubMed

    Nassar, Inthisham; Pasupati, Thanikachalam; Judson, John Paul; Segarra, Ignacio

    2010-06-01

    Imatinib, a selective tyrosine kinase inhibitor, is the first line treatment against chronic myelogenous leukaemia (CML) and gastrointestinal stromal tumors (GIST). Several fatal cases have been associated with imatinib hepatotoxicity. Acetaminophen, an over-the-counter analgesic, anti-pyretic drug, which can cause hepatotoxicity, is commonly used in cancer pain management. We assessed renal and hepatic toxicity after imatinib and acetaminophen co-administration in a preclinical model. Four groups of male ICR mice (30-35 g) were fasted overnight and administered either saline solution orally (baseline control), imatinib 100 mg/kg orally (control), acetaminophen 700 mg/kg intraperitoneally (positive control) or co-administered imatinib 100 mg/kg orally and acetaminophen 700 mg/kg intraperitoneally (study group), and sacrificed at 15 min, 30 min, 1 h, 2 h, 4 h and 6 h post-administration (n = 4 per time point). The liver and kidneys were harvested for histopathology assessment. The liver showed reversible cell damage like feathery degeneration, microvesicular fatty change, sinusoidal congestion and pyknosis, when imatinib or acetaminophen were administered separately. The damage increased gradually with time, peaked at 2 h but resolved by 4 h. When both drugs were administered concurrently, the liver showed irreversible damage (cytolysis, karyolysis and karyorrhexis) which did not resolve by 6 h. Very minor renal changes were observed. Acetaminophen and imatinib co-administration increased hepatoxicity which become irreversible, probably due to shared P450 biotransformation pathways and transporters in the liver.

  6. Autofluorescence imaging device for real-time detection and tracking of pathogenic bacteria in a mouse skin wound model: preclinical feasibility studies

    NASA Astrophysics Data System (ADS)

    Wu, Yichao Charlie; Kulbatski, Iris; Medeiros, Philip J.; Maeda, Azusa; Bu, Jiachuan; Xu, Lizhen; Chen, Yonghong; DaCosta, Ralph S.

    2014-08-01

    Bacterial infection significantly impedes wound healing. Clinical diagnosis of wound infections is subjective and suboptimal, in part because bacteria are invisible to the naked eye during clinical examination. Moreover, bacterial infection can be present in asymptomatic patients, leading to missed opportunities for diagnosis and treatment. We developed a prototype handheld autofluorescence (AF) imaging device (Portable Real-time Optical Detection, Identification and Guidance for Intervention-PRODIGI) to noninvasively visualize and measure bacterial load in wounds in real time. We conducted preclinical pilot studies in an established nude mouse skin wound model inoculated with bioluminescent Staphylococcus aureus bacteria. We tested the feasibility of longitudinal AF imaging for in vivo visualization of bacterial load in skin wounds, validated by bioluminescence imaging. We showed that bacteria (S. aureus), occult to standard examination, can be visualized in wounds using PRODIGI. We also detected quantitative changes in wound bacterial load over time based on the antibiotic treatment and the correlation of bacterial AF intensity with bacterial load. AF imaging of wounds offers a safe, noninvasive method for visualizing the presence, location, and extent of bacteria as well as measuring relative changes in bacterial load in wounds in real time.

  7. Uruguay eHealth initiative: preliminary studies regarding an integrated approach to evaluate vascular age and preclinical atherosclerosis (CUiiDARTE project).

    PubMed

    Armentano, Ricardo L; Bia, Daniel; Zócalo, Yanina; Torrado, Juan; Farro, Ignacio; Farro, Federico; Florio, Lucía; Olascoaga, Alicia; Alallon, Walter; Negreira, Carlos; Lluberas, Ricardo

    2011-01-01

    In this work we present an initiative to develop a national (Uruguayan) program to evaluate vascular age and to detect pre-clinical atherosclerosis using: gold-standard technologies; complimentary and integrative approaches to asses arterial functional and structural indexes; data bases systems to process, analyze and determine normal and reference values and to identify the most sensitive markers of vascular changes for different ages. We evaluated, in a Uruguayan population complementary structural and functional vascular parameters that associate aging-related changes and are considered markers of sub-clinical atherosclerosis. Traditional CV risk factors were assessed. The subjects (n=281) were submitted to non-invasive vascular studies to evaluate: 1) Common carotid artery (CCA) intima-media thickness and diameter waveforms, 2) CCA stiffness, 3) aortic stiffness (pulse wave velocity) and 4) peripheral and central pressure pulse wave derived parameters. Age groups: 21-30, 31-40, 41-50, 51-60, and 61-70 years-old. Age-related profiles were obtained for the different vascular parameters, and their utility to assess vascular changes in young, middle-aged and old subjects was evaluated. The work has the strength of being the first that uses, in Latin-America an integrative approach to characterize vascular aging-related changes.

  8. In vitro and in vivo evaluation of a dry powder endotracheal insufflator device for use in dose-dependent preclinical studies in mice.

    PubMed

    Duret, Christophe; Wauthoz, Nathalie; Merlos, Romain; Goole, Jonathan; Maris, Calliope; Roland, Isabelle; Sebti, Thami; Vanderbist, Francis; Amighi, Karim

    2012-08-01

    The aim of this study was to evaluate the ability of the Penn-Century Dry Powder Insufflator for mice (DP-4M) to reproducibly, uniformly, and deeply deliver dry powders for inhalation in the mouse lung. Itraconazole-based dry powder formulations produced by spray-drying were different in terms of composition (different ratios of drug and mannitol, with or without phospholipids), but relatively similar in terms of particle size and mass median aerodynamic diameter. The ability of the dry powder insufflator to disaggregate each formulation was the same, indicated by the absence of a statistically significant difference between the particle size distribution parameters, as measured by laser scattering. The emitted fraction varied in vivo compared to the in vitro condition. Fluorescent particle distribution in the lungs was uniform and reached the alveolar spaces, as visualized by fluorescent microscopy. In terms of drug recovery in lung tissue, a minimum administered powder mass (in this case ∼1 mg) was necessary to recover at least 30% of the emitted dose in the lung and to obtain reproducible pulmonary concentrations. To reduce the dose administered in the lung, it was preferable to dilute the active ingredient within the carrier instead of reducing the dry powder mass inserted in the sampling chamber. Dry powder insufflators are devices usable in dose-dependent preclinical trials but have critical parameters to efficiently deliver reproducible doses depending on the type of formulation. PMID:22538097

  9. Universal Hand-held Three-dimensional Optoacoustic Imaging Probe for Deep Tissue Human Angiography and Functional Preclinical Studies in Real Time

    PubMed Central

    Deán-Ben, Xosé; Fehm, Thomas Felix; Razansky, Daniel

    2014-01-01

    The exclusive combination of high optical contrast and excellent spatial resolution makes optoacoustics (photoacoustics) ideal for simultaneously attaining anatomical, functional and molecular contrast in deep optically opaque tissues. While enormous potential has been recently demonstrated in the application of optoacoustics for small animal research, vast efforts have also been undertaken in translating this imaging technology into clinical practice. We present here a newly developed optoacoustic tomography approach capable of delivering high resolution and spectrally enriched volumetric images of tissue morphology and function in real time. A detailed description of the experimental protocol for operating with the imaging system in both hand-held and stationary modes is provided and showcased for different potential scenarios involving functional and molecular studies in murine models and humans. The possibility for real time visualization in three dimensions along with the versatile handheld design of the imaging probe make the newly developed approach unique among the pantheon of imaging modalities used in today’s preclinical research and clinical practice. PMID:25408083

  10. Sibutramine in weight control: a dose-ranging, efficacy study.

    PubMed

    Weintraub, M; Rubio, A; Golik, A; Byrne, L; Scheinbaum, M L

    1991-09-01

    We tested the safety and efficacy of sibutramine, 5 and 20 mg, and placebo on weight loss. Medication was added to caloric restriction, behavior modification, and exercise in a parallel-group, double-blind clinical trial. Participants were 130% to 180% of ideal body weight and in good health. The study lasted 12 weeks over Thanksgiving, Christmas, and New Year's Day. Weight loss during 8 weeks of study medication was: placebo, 1.4 +/- 2.1 kg (n = 19); 5 mg sibutramine, 2.9 +/- 2.3 kg (n = 18); and 20 mg sibutramine, 5.0 +/- 2.7 kg (n = 18) (p less than 0.05 sibutramine, 5 and 20 mg, versus placebo; p less than 0.05 sibutramine, 20 mg versus 5 mg). There is a significant dose-effect relationship. Five participants left the study before completion, all because of adverse events; placebo (one patient), 5 mg sibutramine (one patient), and 20 mg sibutramine (three patients). Sleep difficulties were noted by eight participants (20 mg sibutramine, seven patients; 5 mg, one patient; and placebo, no patients). Six of 21 participants receiving 20 mg complained of irritability, unusual impatience, or "excitation." Sibutramine, 5 and 20 mg, added to a multimodal program assisted participants in losing weight.

  11. Preclinical and Toxicology Studies of 1263W94, a Potent and Selective Inhibitor of Human Cytomegalovirus Replication

    PubMed Central

    Koszalka, George W.; Johnson, Nelson W.; Good, Steven S.; Boyd, Leslie; Chamberlain, Stanley C.; Townsend, Leroy B.; Drach, John C.; Biron, Karen K.

    2002-01-01

    1263W94 is a novel benzimidazole compound being developed for treatment of human cytomegalovirus infection. No adverse pharmacological effects were demonstrated in safety pharmacology studies with 1263W94. The minimal-effect dose in a 1-month rat study was 100 mg/kg/day, and the no-effect dose in a 1-month monkey study was 180 mg/kg/day. Toxic effects were limited to increases in liver weights, neutrophils, and monocytes at higher doses in female rats. 1263W94 was not genotoxic in the Ames or micronucleus assays. In the mouse lymphoma assay, 1263W94 was mutagenic in the absence of the rat liver S-9 metabolic activation system, with equivocal results in the presence of the S-9 mix. Mean oral bioavailability of 1263W94 was >90% in rats and ∼50% in monkeys. Clearance in rats and monkeys was primarily by biliary secretion, with evidence of enterohepatic recirculation. In 1-month studies in rats and monkeys, mean peak concentrations and exposures to 1263W94 increased in near proportion to dose. Metabolism of 1263W94 to its primary metabolite, an N-dealkylated analog, appeared to be mediated via the isozyme CYP3A4 in humans. 1263W94 was primarily distributed in the gastrointestinal tract of rats but did not cross the blood-brain barrier. In monkeys, 1263W94 levels in the brain, cerebrospinal fluid, and vitreous humor ranged from 4 to 20%, 1 to 2%, and <1%, of corresponding concentrations in plasma, respectively. The high level of binding by 1263W94 to human plasma proteins (primarily albumin) was readily reversible, with less protein binding seen in the monkey, rat, and mouse. Results of these studies demonstrate a favorable safety profile for 1263W94. PMID:12121907

  12. 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.

  13. 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. PMID:27445276

  14. Adjuvant anticholinesterase therapy for the management of epilepsy-induced memory deficit: a critical pre-clinical study.

    PubMed

    Mishra, Awanish; Goel, Rajesh Kumar

    2014-12-01

    Epilepsy is one of the major neurological disorders still awaiting safer drugs with improved antiepileptic effect and lesser side effects. Apart from epilepsy itself, AEDs also have been shown to induce cognitive impairment in patients with epilepsy. There are limited data for the treatment of this menace. As cholinergic approach has widely been practiced for the restoration of memory in various neurodegenerative disorders, this study was envisaged to evaluate add on effect of acetylcholinesterase inhibitor (tacrine) with phenytoin in pentylenetetrazole-kindling-induced learning and memory deficit in mice. In this study, mice were kindled using subconvulsive dose of pentylenetetrazole (35 mg/kg, i.p.; at interval of 48 ± 2 hr) and successfully kindled animals were divided into different groups and treated with vehicle, phenytoin and phenytoinin in combination with tacrine (0.3 mg/kg), atropine (1 mg/kg) and tacrine + atropine. Effect of different interventions on learning and memory was evaluated using elevated plus maze and passive shock avoidance on days 5, 10, 15 and 20. Phenytoin-treated kindled animals were associated with learning and memory deficit, while tacrine supplementation improved memory deficit with increased seizure severity score. Atropine treatment significantly reversed the protective effect of tacrine. Neurochemical findings also support the behavioural finding of the study. Our results suggest the use of anticholinesterases, with better seizure tolerance, for the management of cognitive impairment of epilepsy, as adjunct therapy.

  15. Mouse models for studies of HLA-G functions in basic science and pre-clinical research.

    PubMed

    Nguyen-Lefebvre, Anh Thu; Ajith, Ashwin; Portik-Dobos, Vera; Horuzsko, Daniel D; Mulloy, Laura L; Horuzsko, Anatolij

    2016-09-01

    HLA-G was described originally as a tolerogenic molecule that allows the semiallogeneic fetus to escape from recognition by the maternal immune response. This review will discuss different steps in the study of HLA-G expression and functions in vivo, starting with analyses of expression of the HLA-G gene and its receptors in transgenic mice, and continuing with applications of HLA-G and its receptors in prevention of allograft rejection, transplantation tolerance, and controlling the development of infection. Humanized mouse models have been discussed for developing in vivo studies of HLA-G in physiological and pathological conditions. Collectively, animal models provide an opportunity to evaluate the importance of the interaction between HLA-G and its receptors in terms of its ability to regulate immune responses during maternal-fetal tolerance, survival of allografts, tumor-escape mechanisms, and development of infections when both HLA-G and its receptors are expressed. In addition, in vivo studies on HLA-G also offer novel approaches to achieve a reproducible transplantation tolerance and to develop personalized medicine to prevent allograft rejection.

  16. Plaque removal efficacy of Colgate 360 toothbrush: A clinical study

    PubMed Central

    Iyer, Nageshwar; Chandna, Shalu; Dhindsa, Abhishek; Damle, Dhanashree; Loomba, Ashish

    2016-01-01

    Aim: The aim of this clinical study was to confirm the plaque removal efficacy of the Colgate 360 Whole Mouth Clean Toothbrush. Study Design: This was a single-center, monadic, case–controlled study with the 7 days duration. Materials and Methods: A total of eighty participants (56 male and 24 female) aged between 18 and 45 years with a minimum of 20 permanent teeth (excluding the third molars) without any prosthetic crowns and an initial plaque score of minimum 1.5 as determined by Modified Quigley-Hein Plaque Index (1970) participated in the study. There were two dropouts during the study duration, one male and one female. The participants were instructed to brush for 1 min, after which plaque index was recorded again. They were then instructed to brush their teeth twice a day for 1 min with the assigned toothbrush (Colgate 360 Whole Mouth Clean Toothbrush) and a commercially available fluoride toothpaste for the next 7 days. On the 7th day, all the participants were recalled for follow-up and plaque examination. The plaque index scores (pre- and post-brushing) were recorded, tabulated, and analyzed statistically. Results: The mean plaque indices reduced after brushing both on day 1 and day 7. There was also a reduction in mean plaque indices from day 1 to day 7. All these reductions were statistically significant (P < 0.001). The reduction in plaque scores was independent of the gender of the participants however female participants showed lower scores as compared to male participants (P < 0.001). Conclusion: The present study demonstrated a significant reduction in plaque scores with the use of Colgate 360 Whole Mouth Clean Soft Toothbrush throughout the study period. Continued use resulted in a further significant reduction in plaque scores irrespective of the gender of participants.

  17. Plaque removal efficacy of Colgate 360 toothbrush: A clinical study

    PubMed Central

    Iyer, Nageshwar; Chandna, Shalu; Dhindsa, Abhishek; Damle, Dhanashree; Loomba, Ashish

    2016-01-01

    Aim: The aim of this clinical study was to confirm the plaque removal efficacy of the Colgate 360 Whole Mouth Clean Toothbrush. Study Design: This was a single-center, monadic, case–controlled study with the 7 days duration. Materials and Methods: A total of eighty participants (56 male and 24 female) aged between 18 and 45 years with a minimum of 20 permanent teeth (excluding the third molars) without any prosthetic crowns and an initial plaque score of minimum 1.5 as determined by Modified Quigley-Hein Plaque Index (1970) participated in the study. There were two dropouts during the study duration, one male and one female. The participants were instructed to brush for 1 min, after which plaque index was recorded again. They were then instructed to brush their teeth twice a day for 1 min with the assigned toothbrush (Colgate 360 Whole Mouth Clean Toothbrush) and a commercially available fluoride toothpaste for the next 7 days. On the 7th day, all the participants were recalled for follow-up and plaque examination. The plaque index scores (pre- and post-brushing) were recorded, tabulated, and analyzed statistically. Results: The mean plaque indices reduced after brushing both on day 1 and day 7. There was also a reduction in mean plaque indices from day 1 to day 7. All these reductions were statistically significant (P < 0.001). The reduction in plaque scores was independent of the gender of the participants however female participants showed lower scores as compared to male participants (P < 0.001). Conclusion: The present study demonstrated a significant reduction in plaque scores with the use of Colgate 360 Whole Mouth Clean Soft Toothbrush throughout the study period. Continued use resulted in a further significant reduction in plaque scores irrespective of the gender of participants. PMID:27630494

  18. Quantile Regression with a Change-point Model for Longitudinal Data: An Application to the Study of Cognitive Changes in Preclinical Alzheimer’s Disease

    PubMed Central

    Li, Chenxi; Dowling, N. Maritza; Chappell, Rick

    2015-01-01

    Summary Progressive and insidious cognitive decline that interferes with daily life is the defining characteristic of Alzheimer’s disease (AD). Epidemiological studies have found that the pathological process of AD begins years before a clinical diagnosis is made and can be highly variable within a given population. Characterizing cognitive decline in the preclinical phase of AD is critical for the development of early intervention strategies when disease-modifying therapies may be most effective. In the last decade, there has been an increased interest in the application of change-point models to longitudinal cognitive outcomes prior to and after diagnosis. Most of the proposed statistical methodology for describing decline relies upon distributional assumptions that may not hold. In this paper, we introduce a quantile regression with a change-point model for longitudinal data of cognitive function in persons bound to develop AD. A change-point in our model reflects the transition from the cognitive decline due to normal aging to the accelerated decline due to disease progression. Quantile regression avoids common distributional assumptions on cognitive outcomes and allows the covariate effects and the change-point to vary for different quantiles of the response. We provided an approach for estimating the model parameters, including the change-point, and presented inferential procedures based on the asymptotic properties of the estimators. A simulation study showed that the estimation and inferential procedures perform reasonably well in finite samples. The practical use of our model was illustrated by an application to longitudinal episodic memory outcomes from two cohort studies of aging and AD. PMID:25892034

  19. Quantile regression with a change-point model for longitudinal data: An application to the study of cognitive changes in preclinical alzheimer's disease.

    PubMed

    Li, Chenxi; Dowling, N Maritza; Chappell, Rick

    2015-09-01

    Progressive and insidious cognitive decline that interferes with daily life is the defining characteristic of Alzheimer's disease (AD). Epidemiological studies have found that the pathological process of AD begins years before a clinical diagnosis is made and can be highly variable within a given population. Characterizing cognitive decline in the preclinical phase of AD is critical for the development of early intervention strategies when disease-modifying therapies may be most effective. In the last decade, there has been an increased interest in the application of change-point models to longitudinal cognitive outcomes prior to and after diagnosis. Most of the proposed statistical methodology for describing decline relies upon distributional assumptions that may not hold. In this article, we introduce a quantile regression with a change-point model for longitudinal data of cognitive function in persons bound to develop AD. A change-point in our model reflects the transition from the cognitive decline due to normal aging to the accelerated decline due to disease progression. Quantile regression avoids common distributional assumptions on cognitive outcomes and allows the covariate effects and the change-point to vary for different quantiles of the response. We provided an approach for estimating the model parameters, including the change-point, and presented inferential procedures based on the asymptotic properties of the estimators. A simulation study showed that the estimation and inferential procedures perform reasonably well in finite samples. The practical use of our model was illustrated by an application to longitudinal episodic memory outcomes from two cohort studies of aging and AD.

  20. Preclinical Evaluation of DMA, a Bisbenzimidazole, as Radioprotector: Toxicity, Pharmacokinetics, and Biodistribution Studies in Balb/c Mice.

    PubMed

    Nimesh, Hemlata; Tiwari, Vinod; Yang, Chunhua; Gundala, Sushma R; Chuttani, Krishna; Hazari, Puja P; Mishra, Anil K; Sharma, Abhisheak; Lal, Jawahar; Katyal, Anju; Aneja, Ritu; Tandon, Vibha

    2015-10-01

    Radiotherapy, a therapeutic modality of cancer treatment, nonselectively damages normal tissues as well as tumor tissues. The search is ongoing for therapeutic agents that selectively reduce radiation-induced normal tissue injury without reducing tumoricidal effect, thereby increasing the therapeutic ratio of radiation therapy. Our laboratory established 5-(4-methylpiperazin-1-yl)-2-[2'-(3,4-dimethoxyphenyl)-5'benzimidazolyl] benzimidazole (DMA) as noncytotoxic radioprotector in mammalian cells. DMA showed an excellent radioprotection in mice at single nontoxic oral dose by a dose-reduction factor of 1.28. An oxygen radical absorbing capacity assay confirmed its free-radical quenching ability. Single bolus dose and 28-days of repeated administration of DMA in mice for toxicity studies determined an LD50 of >2000 mg/kg body weight (bw) and 225 mg/kg bw, respectively, suggesting DMA is safe. Histopathology, biochemical parameters, and relative organ weight analysis revealed insignificant changes in the DMA-treated animals. The pharmacokinetic study of DMA at oral and intravenous doses showed its C(max) = 1 hour, bioavailability of 8.84%, elimination half-life of 4 hours, and an enterohepatic recirculation. Biodistribution study in mice with Ehrlich ascites tumors showed that (99m)Tc-DMA achieved its highest concentration in 1 hour and was retained up to 4 hours in the lungs, liver, kidneys, and spleen, and in a low concentration in the tumor, a solicited property of any radioprotector to protect normal cells over cancerous cells. We observed that the single-dose treatment of tumor-bearing mice with DMA 2 hours before 8 Gy total body irradiation showed an impressive rescue of radiation-induced morbidity in terms of weight loss and mortality without a change in tumor response. PMID:26240287

  1. In vivo measurement of gadolinium diffusivity by dynamic contrast-enhanced MRI: a preclinical study of human xenografts.

    PubMed

    Koh, T S; Hartono, S; Thng, C H; Lim, T K H; Martarello, L; Ng, Q S

    2013-01-01

    Compartmental tracer kinetic models currently used for analysis of dynamic contrast-enhanced MRI data yield poor fittings or parameter values that are unphysiological in necrotic regions of the tumor, as these models only describe microcirculation in perfused tissue. In this study, we explore the use of Fick's law of diffusion as an alternative method for analysis of dynamic contrast-enhanced MRI data in the necrotic regions. Xenografts of various human cancer cell lines were implanted in 14 mice that were subjected to dynamic contrast-enhanced MRI performed using a spoiled gradient recalled sequence. Tracer concentration was estimated using the variable flip angle technique. Poorly perfused and necrotic tumor regions exhibiting delayed and slow enhancement were identified using a k-means clustering algorithm. Tracer behavior in necrotic regions was shown to be consistent with Fick's diffusion equation and the in vivo gadolinium diffusivity was estimated to be 2.08 (±0.88) × 10(-4) mm(2)/s. This study proposes the use of gadolinium diffusivity as an alternative parameter for quantifying tracer transport within necrotic tumor regions.

  2. Accurate guidance for percutaneous access to a specific target in soft tissues: preclinical study of computer-assisted pericardiocentesis.

    PubMed

    Chavanon, O; Barbe, C; Troccaz, J; Carrat, L; Ribuot, C; Noirclerc, M; Maitrasse, B; Blin, D

    1999-06-01

    In the field of percutaneous access to soft tissues, our project was to improve classical pericardiocentesis by performing accurate guidance to a selected target, according to a model of the pericardial effusion acquired through three-dimensional (3D) data recording. Required hardware is an echocardiographic device and a needle, both linked to a 3D localizer, and a computer. After acquiring echographic data, a modeling procedure allows definition of the optimal puncture strategy, taking into consideration the mobility of the heart, by determining a stable region, whatever the period of the cardiac cycle. A passive guidance system is then used to reach the planned target accurately, generally a site in the middle of the stable region. After validation on a dynamic phantom and a feasibility study in dogs, an accuracy and reliability analysis protocol was realized on pigs with experimental pericardial effusion. Ten consecutive successful punctures using various trajectories were performed on eight pigs. Nonbloody liquid was collected from pericardial effusions in the stable region (5 to 9 mm wide) within 10 to 15 minutes from echographic acquisition to drainage. Accuracy of at least 2.5 mm was demonstrated. This study demonstrates the feasibility of computer-assisted pericardiocentesis. Beyond the simple improvement of the current technique, this method could be a new way to reach the heart or a new tool for percutaneous access and image-guided puncture of soft tissues. Further investigation will be necessary before routine human application.

  3. A Novel Pre-Clinical Murine Model to Study the Life Cycle and Progression of Cervical and Anal Papillomavirus Infections

    PubMed Central

    Cladel, Nancy M.; Budgeon, Lynn R.; Balogh, Karla K.; Cooper, Timothy K.; Hu, Jiafen; Christensen, Neil D.

    2015-01-01

    Background Papillomavirus disease and associated cancers remain a significant health burden in much of the world. The current protective vaccines, Gardasil and Cervarix, are expensive and not readily available to the underprivileged. In addition, the vaccines have not gained wide acceptance in the United States nor do they provide therapeutic value. Papillomaviruses are strictly species specific and thus human viruses cannot be studied in an animal host. An appropriate model for mucosal disease has long been sought. We chose to investigate whether the newly discovered mouse papillomavirus, MmuPV1, could infect mucosal tissues in Foxn1nu/Foxn1nu mice. Methods The vaginal and anal canals of Foxn1nu/Foxn1nu mice were gently abraded using Nonoxynol-9 and “Doctor’s BrushPicks” and MmuPV1 was delivered into the vaginal tract or the anal canal. Results Productive vaginal, cervical and anal infections developed in all mice. Vaginal/cervical infections could be monitored by vaginal lavage. Dysplasias were evident in all animals. Conclusions Anogenital tissues of a common laboratory mouse can be infected with a papillomavirus unique to that animal. This observation will pave the way for fundamental virological and immunological studies that have been challenging to carry out heretofore due to lack of a suitable model system. PMID:25803616

  4. Time Course for Onset and Recovery from Effects of a Novel Male Reproductive Toxicant: Implications for Apical Preclinical Study Designs.

    PubMed

    Powles-Glover, Nicola; Mitchard, Terri; Stewart, Jane

    2015-06-01

    In the pharmaceutic ICH S5(R2) guidelines for reproductive toxicity testing, a premating dose duration of 14 days is considered sufficient for assessment of male fertility for compounds that are not testicular toxicants. A novel α7 subtype of nicotinic acetylcholine receptor (α7nAChR) agonist, originally intended for treatment of Alzheimer's disease, did not cause changes in sperm counts, motility, or testicular histopathology in rat toxicity studies of up to 6 months duration. However, profound decrements in male fertility (reduced pregnancy rates and litter sizes) occurred after 11 weeks of dosing in male rats. In two time-course investigations, dosed male rats were paired with undosed females after 5, 14, and 28 daily doses and again after 2 and 4 weeks off-dose. Effects on male fertility were undetectable after 5 days. After 14 days, there was no effect on pregnancy rate, but preimplantation losses were increased. Effects on both pregnancy rates and preimplantation losses were clearly detectable after 28 days, but were of lesser magnitude than after 11 weeks of dosing. Fertility recovered rapidly after dose cessation. These studies illustrate the sensitivity of a long premating dose period at revealing hazard and determining the magnitude of effect on male fertility for compounds that are intended for chronic administration and do not affect testicular histopathology. PMID:26194980

  5. Efficacy of Zolpidem for Dystonia: A Study Among Different Subtypes

    PubMed Central

    Miyazaki, Yoshimichi; Sako, Wataru; Asanuma, Kotaro; Izumi, Yuishin; Miki, Tetsuro; Kaji, Ryuji

    2012-01-01

    Although there are some newly developed options to treat dystonia, its medical treatment is not always satisfactory. Zolpidem, an imidazopyridine agonist with a high affinity on benzodiazepine subtype receptor BZ1 (ω1), was found to improve clinical symptoms of dystonia in a limited number of case reports. To investigate what subtype of dystonia is responsive to the therapy, we conducted an open label study to assess the efficacy of zolpidem (5–20 mg) in 34 patients suffering from miscellaneous types of dystonia using the Burke–Fahn–Marsden Dystonia Rating Scale (BFMDRS). Patients were entered into the study if they had been refractory to other medications as evaluated by BFMDRS (no change in the previous two successive visits). After zolpidem therapy, the scores in the patients as a whole were decreased from 7.2 ± 7.9 to 5.5 ± 5.0 (P = 0.042). Patients with generalized dystonia, Meige syndrome/blepharospasm, and hand dystonia improved in the scale by 27.8, 17.8, and 31.0%, respectively, whereas no improvement was found in cervical dystonia patients. Overall response rate among patients were comparable to that of trihexyphenidyl. Zolpidem may be a therapeutic option for generalized dystonia, Meige syndrome, and hand dystonia including musician’s. Drowsiness was the dose-limiting factor. PMID:22529836

  6. Preclinical study of treatment response in HCT-116 cells and xenografts with (1) H-decoupled (31) P MRS.

    PubMed

    Darpolor, Moses M; Kennealey, Peter T; Le, H Carl; Zakian, Kristen L; Ackerstaff, Ellen; Rizwan, Asif; Chen, Jin-Hong; Sambol, Elliot B; Schwartz, Gary K; Singer, Samuel; Koutcher, Jason A

    2011-11-01

    The topoisomerase I inhibitor, irinotecan, and its active metabolite SN-38 have been shown to induce G(2) /M cell cycle arrest without significant cell death in human colon carcinoma cells (HCT-116). Subsequent treatment of these G(2) /M-arrested cells with the cyclin-dependent kinase inhibitor, flavopiridol, induced these cells to undergo apoptosis. The goal of this study was to develop a noninvasive metabolic biomarker for early tumor response and target inhibition of irinotecan followed by flavopiridol treatment in a longitudinal study. A total of eleven mice bearing HCT-116 xenografts were separated into two cohorts where one cohort was administered saline and the other treated with a sequential course of irinotecan followed by flavopiridol. Each mouse xenograft was longitudinally monitored with proton ((1) H)-decoupled phosphorus ((31) P) magnetic resonance spectroscopy (MRS) before and after treatment. A statistically significant decrease in phosphocholine (p = 0.0004) and inorganic phosphate (p = 0.0103) levels were observed in HCT-116 xenografts following treatment, which were evidenced within twenty-four hours of treatment completion. Also, a significant growth delay was found in treated xenografts. To discern the underlying mechanism for the treatment response of the xenografts, in vitro HCT-116 cell cultures were investigated with enzymatic assays, cell cycle analysis, and apoptotic assays. Flavopiridol had a direct effect on choline kinase as measured by a 67% reduction in the phosphorylation of choline to phosphocholine. Cells treated with SN-38 alone underwent 83 ± 5% G(2) /M cell cycle arrest compared to untreated cells. In cells, flavopiridol alone induced 5 ± 1% apoptosis while the sequential treatment (SN-38 then flavopiridol) resulted in 39 ± 10% apoptosis. In vivo (1) H-decoupled (31) P MRS indirectly measures choline kinase activity. The decrease in phosphocholine may be a potential indicator of early tumor response to

  7. Fluorine-18-fluorodeoxygglucose-guided breast cancer surgery with a positron-sensitive probe: Validation in preclinical studies

    SciTech Connect

    Raylman, R.R.; Fisher, S.J.; Brown, R.S.; Ethier, S.P.; Wahl, R.L.

    1995-10-01

    In this study, the feasibility of utilizing 2-deoxy-2-fluoro-d-glucose (FDG) in conjunction with a positron-sensitive intraoperative probe to guide breast tumor excision was investigated. The probe was constructed with a plastic scintillator tip coupled to a photomultiplier tube with fiber optic cable. Anticipated resolution degradation was evaluated by measurement of line spread functions in the presence of background radiation. Realistic photon background distributions were simulated with a human torso phantom and a cardiac insert. The relationship between resolution and energy threshold was measured to find the optimal discriminator settings. In addition, probe sensitivity as a function of energy threshold was determined for various size-simulated tumors. Finally, the ability to localize breast cancers in vivo was tested in a rodent model. Mammary rat tumors implanted in Lewis rats were examined after injection with FDG; these results were correlated with those of histologic analyses. Measurements of line spread functions indicated that resolution could be maximized in a realistic background photon environment by increasing the energy threshold to levels at or above the Compton continuum edge (340 keV). At this setting, the probe`s sensitivity was determined to be 58 and 11 cps/{mu}Ci for 3.18- and 6.35-mm diameter simulated tumors, respectively. Probe readings correlated well with histologic results; the probe was generally able to discriminate between tumor and normal tissue. This study indicates that breast cancer surgery guided by a positron-sensitive probe warrants future evaluation in breast-conserving surgery of patients with breast cancer. 23 refs., 5 figs.

  8. Development of Immunoassays for the Quantitative Assessment of Amyloid-β in the Presence of Therapeutic Antibody: Application to Pre-Clinical Studies

    PubMed Central

    Bogstedt, Anna; Groves, Maria; Tan, Keith; Narwal, Rajesh; McFarlane, Mary; Höglund, Kina

    2015-01-01

    Abstract Utilizing decision making biomarkers in drug development requires thorough assay validation. Special considerations need to be taken into account when monitoring biomarkers using immunoassays in the presence of therapeutic antibodies. We have developed robust and sensitive assays to assess target engagement and proof of mechanism to support the clinical progression of a human monoclonal antibody against the neurotoxic amyloid-β (Aβ)42 peptide. Here we present the introduction of novel pre-treatment steps to ensure drug-tolerant immunoassays and describe the validation of the complete experimental procedures to measure total Aβ42 concentration (bound and unbound) in cerebrospinal fluid (CSF) and plasma, free Aβ42 concentration (unbound) in CSF, and Aβ40 concentration in CSF. The difference in composition of the matrices (CSF and plasma) and antigen levels therein, in combination with the hydrophobic properties of Aβ protein, adds to the complexity of validation. Monitoring pharmacodynamics of an Aβ42 specific monoclonal antibody in a non-human primate toxicology study using these assays, we demonstrated a 1500-fold and a 3000-fold increase in total Aβ42 in plasma, a 4-fold and 8-fold increase in total Aβ42 in CSF together with a 95% and 96% reduction of free Aβ42 in CSF following weekly intravenous injections of 10 mg/kg and 100 mg/kg, respectively. Levels of Aβ40 were unchanged. The accuracy of these data is supported by previous pre-clinical studies as well as predictive pharmacokinetic/pharmacodynamics modeling. In contrast, when analyzing the same non-human primate samples excluding the pre-treatment steps, we were not able to distinguish between free and total Aβ42. Our data clearly demonstrate the importance of thorough evaluation of antibody interference and appropriate validation to monitor different types of biomarkers in the presence of a therapeutic antibody. PMID:26402635

  9. In situ study of the impact of inter- and intra-reader variability on region of interest (ROI) analysis in preclinical molecular imaging

    PubMed Central

    Habte, Frezghi; Budhiraja, Shradha; Keren, Shay; Doyle, Timothy C; Levin, Craig S; Paik, David S

    2013-01-01

    We estimated reader-dependent variability of region of interest (ROI) analysis and evaluated its impact on preclinical quantitative molecular imaging. To estimate reader variability, we used five independent image datasets acquired each using microPET and multispectral fluorescence imaging (MSFI). We also selected ten experienced researchers who utilize molecular imaging in the same environment that they typically perform their own studies. Nine investigators blinded to the data type completed the ROI analysis by drawing ROIs manually that delineate the tumor regions to the best of their knowledge and repeated the measurements three times, non-consecutively. Extracted mean intensities of voxels within each ROI are used to compute the coefficient of variation (CV) and characterize the inter- and intra-reader variability. The impact of variability was assessed through random samples iterated from normal distributions for control and experimental groups on hypothesis testing and computing statistical power by varying subject size, measured difference between groups and CV. The results indicate that inter-reader variability was 22.5% for microPET and 72.2% for MSFI. Additionally, mean intra-reader variability was 10.1% for microPET and 26.4% for MSFI. Repeated statistical testing showed that a total variability of CV < 50% may be needed to detect differences < 50% between experimental and control groups when six subjects (n = 6) or more are used and statistical power is adequate (80%). Surprisingly high variability has been observed mainly due to differences in the ROI placement and geometry drawn between readers, which may adversely affect statistical power and erroneously lead to negative study outcomes. PMID:23526701

  10. Safety data on 19 vehicles for use in 1 month oral rodent pre-clinical studies: administration of hydroxypropyl-ß-cyclodextrin causes renal toxicity.

    PubMed

    Healing, Guy; Sulemann, Tabassum; Cotton, Peter; Harris, Jayne; Hargreaves, Adam; Finney, Rowena; Kirk, Sarah; Schramm, Carolin; Garner, Clare; Pivette, Perrine; Burdett, Lisa

    2016-01-01

    Potential new drugs are assessed in pre-clinical in vivo studies to determine their safety profiles. The drugs are formulated in vehicles suitable for the route of administration and the physicochemical properties of the drug, aiming to achieve optimal exposure in the test species. The availability of safety data on vehicles is often limited (incomplete data, access restricted/private databases). Nineteen potentially useful vehicles that contained new and/or increased concentrations of excipients and for which little safety data have been published were tested. Vehicles were dosed orally once daily to HanWistar rats for a minimum of 28 days and a wide range of toxicological parameters were assessed. Only 30% (w/v) hydroxypropyl-ß-cyclodextrin was found unsuitable owing to effects on liver enzymes (AST, ALT and GLDH), urinary volume and the kidneys (tubular vacuolation and tubular pigment). 20% (v/v) oleic acid caused increased salivation and hence this vehicle should be used with caution. As 40% (v/v) tetraethylene glycol affected urinary parameters, its use should be carefully considered, particularly for compounds suspected to impact the renal system and studies longer than 1 month. There were no toxicologically significant findings with 10% (v/v) dimethyl sulphoxide, 20% (v/v) propylene glycol, 33% (v/v) Miglyol®812, 20% (w/v) Kolliphor®RH40, 10% (w/v) Poloxamer 407, 5% (w/v) polyvinylpyrrolidone K30 or 10% (v/v) Labrafil®M1944. All other vehicles tested caused isolated or low magnitude effects which would not prevent their use. The aim of sharing these data, including adverse findings, is to provide meaningful information for vehicle selection, thereby avoiding repetition of animal experimentation.

  11. Development and validation of a method for the analysis of hydroxyzine hydrochloride in extracellular solution used in in vitro preclinical safety studies.

    PubMed

    Briône, Willy; Brekelmans, Mari; Eijndhoven, Freek van; Schenkel, Eric; Noij, Theo

    2015-11-10

    In the process of drug development, preclinical safety studies are to be performed that require the analysis of the compound at very low concentrations with high demands on the performance of the analytical methods. In the current study, a UPLC-MS/MS method was developed and validated to quantify hydroxyzine hydrochloride in an extracellular solution used in a hERG assay in concentrations ranging from 0.01 to 10μM (4.5ng/ml-4.5μg/ml). Chromatographic separation was achieved isocratically on an Acquity BEH C18 analytical column. The assay was validated at concentrations of 0.11-1.1ng/ml in end solution for hydroxyzine hydrochloride. Linearity was demonstrated over the range of concentrations of 0.06-0.17ng/ml and over the range of concentrations of 0.6-1.7ng/ml in end solution with the coefficient of correlation r>0.99. Accuracy of the achieved concentration, intra-run, and inter-run precision of the method were well within the acceptance criteria (being mean recovery of 80-120% and relative standard deviation ≤10.0%). The limit of quantification in extracellular solution was 0.09ng/ml. Hydroxyzine hydrochloride in extracellular solution proved to be stable when stored in the fridge at 4-8°C for at least 37 days, at room temperature for at least 16 days and at +35°C for at least 16 days. The analytical method was successfully applied in hERG assay.

  12. Universal wet-milling technique to prepare oral nanosuspension focused on discovery and preclinical animal studies - Development of particle design method.

    PubMed

    Niwa, Toshiyuki; Miura, Satoru; Danjo, Kazumi

    2011-02-28

    Simple and easy methods to prepare oral nanosuspension of a poorly water-soluble pharmaceutical candidate compound, called a candidate, have been developed to support the discovery and preclinical studies using animals. The different wet-milling processes in miniature, middle and large preparation scales have been established in order to cover the various types of studies with wide scale. The powder of phenytoin, a poorly water-soluble model drug candidate, was suspended in the aqueous medium, in which the appropriate dispersing agents were dissolved, and milled by agitating together with small hard beads made of zirconia. Three general-purpose equipments with stirring, oscillating and turbulent motions were applied instead of the specific milling machine with high power to avoid much investment at such early development stage. The operational condition and dispersing agents were optimized to obtain finer particles using the middle-scaled oscillating beads-milling apparatus in particular. It was found that the nanosuspension, which whole particle distribution was in the submicron range, was successfully produced within the running time around 10min. By applying the newly developed dispersing medium, the nanoparticles with identical size distribution were also prepared using the stirring and turbulent methods on miniature and large scales, respectively; indicating only 50mg to 30g or more amount of candidate could be milled to nanosuspension using three equipments. The crystalline analysis indicated that the both crystal form and crystallinity of the original bulk drug completely remained after wet-milling process. The results demonstrated that the wet-milling methods developed in this research would be a fundamental technique to produce nanosuspension for poorly water-soluble and oral absorbable drug candidates. PMID:21167922

  13. Development of Immunoassays for the Quantitative Assessment of Amyloid-β in the Presence of Therapeutic Antibody: Application to Pre-Clinical Studies.

    PubMed

    Bogstedt, Anna; Groves, Maria; Tan, Keith; Narwal, Rajesh; McFarlane, Mary; Höglund, Kina

    2015-01-01

    Utilizing decision making biomarkers in drug development requires thorough assay validation. Special considerations need to be taken into account when monitoring biomarkers using immunoassays in the presence of therapeutic antibodies. We have developed robust and sensitive assays to assess target engagement and proof of mechanism to support the clinical progression of a human monoclonal antibody against the neurotoxic amyloid-β (Aβ)42 peptide. Here we present the introduction of novel pre-treatment steps to ensure drug-tolerant immunoassays and describe the validation of the complete experimental procedures to measure total Aβ42 concentration (bound and unbound) in cerebrospinal fluid (CSF) and plasma, free Aβ42 concentration (unbound) in CSF, and Aβ40 concentration in CSF. The difference in composition of the matrices (CSF and plasma) and antigen levels therein, in combination with the hydrophobic properties of Aβ protein, adds to the complexity of validation. Monitoring pharmacodynamics of an Aβ42 specific monoclonal antibody in a non-human primate toxicology study using these assays, we demonstrated a 1500-fold and a 3000-fold increase in total Aβ42 in plasma, a 4-fold and 8-fold increase in total Aβ42 in CSF together with a 95% and 96% reduction of free Aβ42 in CSF following weekly intravenous injections of 10 mg/kg and 100 mg/kg, respectively. Levels of Aβ40 were unchanged. The accuracy of these data is supported by previous pre-clinical studies as well as predictive pharmacokinetic/pharmacodynamics modeling. In contrast, when analyzing the same non-human primate samples excluding the pre-treatment steps, we were not able to distinguish between free and total Aβ42. Our data clearly demonstrate the importance of thorough evaluation of antibody interference and appropriate validation to monitor different types of biomarkers in the presence of a therapeutic antibody. PMID:26402635

  14. In situ study of the impact of inter- and intra-reader variability on region of interest (ROI) analysis in preclinical molecular imaging.

    PubMed

    Habte, Frezghi; Budhiraja, Shradha; Keren, Shay; Doyle, Timothy C; Levin, Craig S; Paik, David S

    2013-01-01

    We estimated reader-dependent variability of region of interest (ROI) analysis and evaluated its impact on preclinical quantitative molecular imaging. To estimate reader variability, we used five independent image datasets acquired each using microPET and multispectral fluorescence imaging (MSFI). We also selected ten experienced researchers who utilize molecular imaging in the same environment that they typically perform their own studies. Nine investigators blinded to the data type completed the ROI analysis by drawing ROIs manually that delineate the tumor regions to the best of their knowledge and repeated the measurements three times, non-consecutively. Extracted mean intensities of voxels within each ROI are used to compute the coefficient of variation (CV) and characterize the inter- and intra-reader variability. The impact of variability was assessed through random samples iterated from normal distributions for control and experimental groups on hypothesis testing and computing statistical power by varying subject size, measured difference between groups and CV. The results indicate that inter-reader variability was 22.5% for microPET and 72.2% for MSFI. Additionally, mean intra-reader variability was 10.1% for microPET and 26.4% for MSFI. Repeated statistical testing showed that a total variability of CV < 50% may be needed to detect differences < 50% between experimental and control groups when six subjects (n = 6) or more are used and statistical power is adequate (80%). Surprisingly high variability has been observed mainly due to differences in the ROI placement and geometry drawn between readers, which may adversely affect statistical power and erroneously lead to negative study outcomes. PMID:23526701

  15. Universal wet-milling technique to prepare oral nanosuspension focused on discovery and preclinical animal studies - Development of particle design method.

    PubMed

    Niwa, Toshiyuki; Miura, Satoru; Danjo, Kazumi

    2011-02-28

    Simple and easy methods to prepare oral nanosuspension of a poorly water-soluble pharmaceutical candidate compound, called a candidate, have been developed to support the discovery and preclinical studies using animals. The different wet-milling processes in miniature, middle and large preparation scales have been established in order to cover the various types of studies with wide scale. The powder of phenytoin, a poorly water-soluble model drug candidate, was suspended in the aqueous medium, in which the appropriate dispersing agents were dissolved, and milled by agitating together with small hard beads made of zirconia. Three general-purpose equipments with stirring, oscillating and turbulent motions were applied instead of the specific milling machine with high power to avoid much investment at such early development stage. The operational condition and dispersing agents were optimized to obtain finer particles using the middle-scaled oscillating beads-milling apparatus in particular. It was found that the nanosuspension, which whole particle distribution was in the submicron range, was successfully produced within the running time around 10min. By applying the newly developed dispersing medium, the nanoparticles with identical size distribution were also prepared using the stirring and turbulent methods on miniature and large scales, respectively; indicating only 50mg to 30g or more amount of candidate could be milled to nanosuspension using three equipments. The crystalline analysis indicated that the both crystal form and crystallinity of the original bulk drug completely remained after wet-milling process. The results demonstrated that the wet-milling methods developed in this research would be a fundamental technique to produce nanosuspension for poorly water-soluble and oral absorbable drug candidates.

  16. Preclinical Safety Evaluation of ASCs Engineered by FLPo/Frt-Based Hybrid Baculovirus: In Vitro and Large Animal Studies.

    PubMed

    Li, Kuei-Chang; Chang, Yu-Han; Lin, Chin-Yu; Hwang, Shiaw-Min; Wang, Tzu-Hao; Hu, Yu-Chen

    2015-05-01

    We recently developed hybrid baculovirus (BV) vectors that exploited FLPo/Frt-mediated DNA minicircle formation. Engineering of adipose-derived stem cells (ASCs) with the FLPo/Frt-based BV vectors enabled prolonged transgene expression and, after cell implantation into rabbits, ameliorated cartilage regeneration and bone repair. To translate the hybrid BV one step further toward clinical applications, here we assessed the biosafety profiles of the hybrid BV-engineered human ASCs (hASCs) in vitro and evaluated the immune responses elicited by the engineered porcine ASCs (pASCs) in large animals. We confirmed that the hybrid BV did not compromise the hASCs viability, immunosuppressive capacity, and surface characteristics. Neither did the hybrid BV cause chromosomal abnormality/transgene integration in vitro nor did it induce tumorigenicity in vivo. In the large animal study, pASCs were engineered with the hybrid BV expressing bone morphogenetic protein 2 (BMP2) and vascular endothelial growth factor (VEGF) and implanted into femoral bone defects in mini pigs. The hybrid BV-engineered pASCs enabled prolonged BMP2/VEGF expression and triggered the healing of massive segmental bone defects, while only eliciting transient antibody, cytokine, and local cellular immune responses stemming from the implantation procedure itself. These data altogether demonstrated the safety of the hybrid BV vectors for ASCs engineering and bone healing in large animals, hence implicating the potential in clinical applications.

  17. Percutaneous left atrial appendage closure with a novel self-modelizing device: a pre-clinical feasibility study.

    PubMed

    Park, Jai-Wun; Sherif, Mohammad A; Zintl, Konstantin; Lam, Yat-Yin; Goedde, Martin; Scharnweber, Tim; Jung, Friedrich; Franke, Ralf Peter; Brachmann, Johannes

    2014-12-20

    The aim of the study is to evaluate the feasibility and safety of a new left atrial appendage (LAA) occluder. Twelve pigs were included. In 2 pigs the implantation process failed due to pericardial tamponade in 1 pig and device embolization in the other pig. The placement of the devices was controlled via TEE and fluoroscopy. After 6 weeks of implantation the hearts were explanted. The devices were found to be easy to deploy and showed a very good adaptation to the LAA tissue. Eight out of 10 pigs had full closure of the LAA directly after implantation. After six weeks, due to the self-modelizing properties of the device, all pigs had a full closure of the LAA. The macroscopic evaluation of the explanted hearts showed that all devices were securely integrated in LAA tissues. There was one case of mild pericarditis but no macroscopic signs of inflammation on the device surrounding endocardium. The explantation revealed that device loops had penetrated the LAA tissue in three pigs. However, no signs of bleeding, pericardial effusion, or other damage to the LAA wall could be detected and the pigs were in good condition with normal weight gain and no clinical symptoms. The Occlutech® LAA occluder achieved complete closure of the LAA in all pigs, and remained in the LAA, with benign healing and no evidence of new thrombus or damage to surrounding structures. Moreover, the uncompromised survival of all implanted pigs demonstrates the feasibility and safety of the device.

  18. Resilience to the effects of social stress: Evidence from clinical and preclinical studies on the role of coping strategies

    PubMed Central

    Wood, Susan K.; Bhatnagar, Seema

    2014-01-01

    The most common form of stress encountered by people stems from one's social environment and is perceived as more intense than other types of stressors. One feature that may be related to differential resilience or vulnerability to stress is the type of strategy used to cope with the stressor, either active or passive coping. This review focuses on models of social stress in which individual differences in coping strategies produce resilience or vulnerability to the effects of stress. Neurobiological mechanisms underlying these individual differences are discussed. Overall, the literature suggests that there are multiple neural mechanisms that underlie individual differences in stress-induced resilience and vulnerability. How these mechanisms interact with one another to produce a resilient or vulnerable phenotype is not understood and such mechanisms have been poorly studied in females and in early developmental periods. Finally, we propose that resilience may be stress context specific and resilience phenotypes may need to be fine-tuned to suit a shifting environment. PMID:25580450

  19. Balance of the Sexes: Addressing Sex Differences in Preclinical Research

    PubMed Central

    Zakiniaeiz, Yasmin; Cosgrove, Kelly P.; Potenza, Marc N.; Mazure, Carolyn M.

    2016-01-01

    Preclinical research is fundamental for the advancement of biomedical sciences and enhancing healthcare. Considering sex differences in all studies throughout the entire biomedical research pipeline is necessary to adequately inform clinical research and improve health outcomes. However, there is a paucity of information to date on sex differences in preclinical work. As of 2009, most (about 80 percent) rodent studies across 10 fields of biology were still conducted with only male animals. In 2016, the National Institutes of Health implemented a policy aimed to address this concern by requiring the consideration of sex as a biological variable in preclinical research grant applications. This perspective piece aims to (1) provide a brief history of female inclusion in biomedical research, (2) describe the importance of studying sex differences, (3) explain possible reasons for opposition of female inclusion, and (4) present potential additional solutions to reduce sex bias in preclinical research. PMID:27354851

  20. Pre-clinical study of in vivo magnetic resonance-guided bubble-enhanced heating in pig liver.

    PubMed

    Elbes, Delphine; Denost, Quentin; Laurent, Christophe; Trillaud, Hervé; Rullier, Anne; Quesson, Bruno

    2013-08-01

    Bubble-enhanced heating (BEH) can be exploited to increase heating efficiency in treatment of liver tumors with non-invasive high-intensity focused ultrasound (HIFU). The objectives of this study were: (i) to demonstrate the feasibility of increasing the heating efficiency of sonication exploiting BEH in pig liver in vivo using a clinical platform; (ii) to determine the acoustic threshold for such effects with real-time, motion-compensated magnetic resonance-guided thermometry; and (iii) to compare the heating patterns and thermal lesion characteristics resulting from continuous sonication and sonication including a burst pulse. The threshold acoustic power for generation of BEH in pig liver in vivo was determined using sonication of 0.5-s duration ("burst pulse") under real-time magnetic resonance thermometry. In a second step, experimental sonication composed of a burst pulse followed by continuous sonication (14.5 s) was compared with conventional sonication (15 s) of identical energy (1.8 kJ). Modification of the heating pattern at the targeted region located at a liver depth between 20 and 25 mm required 600-800 acoustic watts. The experimental group exhibited near-spherical heating with 40% mean enhancement of the maximal temperature rise as compared with the conventional sonication group, a mean shift of 7 ± 3.3 mm toward the transducer and reduction of the post-focal temperature increase. Magnetic resonance thermometry can be exploited to control acoustic BEH in vivo in the liver. By use of experimental sonication, more efficient heating can be achieved while protecting tissues located beyond the focal point.

  1. SU-E-J-156: Preclinical Inverstigation of Dynamic Tumor Tracking Using Vero SBRT Linear Accelerator: Motion Phantom Dosimetry Study

    SciTech Connect

    Mamalui-Hunter, M; Wu, J; Li, Z; Su, Z

    2014-06-01

    Purpose: Following the ‘end-to-end testing’ paradigm of Dynamic Target Tracking option in our Image-Guided dedicated SBRT VeroTM linac, we verify the capability of the system to deliver planned dose to moving targets in the heterogeneous thorax phantom (CIRSTM). The system includes gimbaled C-band linac head, robotic 6 degree of freedom couch and a tumor tracking method based on predictive modeling of target position using fluoroscopically tracked implanted markers and optically tracked infrared reflecting external markers. Methods: 4DCT scan of the motion phantom with the VisicoilTM implanted marker in the close vicinity of the target was acquired, the ‘exhale’=most prevalent phase was used for planning (iPlan by BrainLabTM). Typical 3D conformal SBRT treatment plans aimed to deliver 6-8Gy/fx to two types of targets: a)solid water-equivalent target 3cm in diameter; b)single VisicoilTM marker inserted within lung equivalent material. The planning GTV/CTV-to-PTV margins were 2mm, the block margins were 3 mm. The dose calculated by MonteCarlo algorithm with 1% variance using option Dose-to-water was compared to the ion chamber (CC01 by IBA Dosimetry) measurements in case (a) and GafchromicTM EBT3 film measurements in case (b). During delivery, the target 6 motion patterns available as a standard on CIRSTM motion phantom were investigated: in case (a), the target was moving along the designated sine or cosine4 3D trajectory; in case (b), the inserted marker was moving sinusoidally in 1D. Results: The ion chamber measurements have shown the agreement with the planned dose within 1% under all the studied motion conditions. The film measurements show 98.1% agreement with the planar calculated dose (gamma criteria: 3%/3mm). Conclusion: We successfully verified the capability of the SBRT VeroTM linac to perform real-time tumor tracking and accurate dose delivery to the target, based on predictive modeling of the correlation between implanted marker motion and

  2. A Novel Inherently Radiopaque Bead for Transarterial Embolization to Treat Liver Cancer - A Pre-clinical Study

    PubMed Central

    Duran, Rafael; Sharma, Karun; Dreher, Matthew R.; Ashrafi, Koorosh; Mirpour, Sahar; Lin, MingDe; Schernthaner, Ruediger E.; Schlachter, Todd R.; Tacher, Vania; Lewis, Andrew L.; Willis, Sean; den Hartog, Mark; Radaelli, Alessandro; Negussie, Ayele H.; Wood, Bradford J.; Geschwind, Jean-François H.

    2016-01-01

    Purpose: Embolotherapy using microshperes is currently performed with soluble contrast to aid in visualization. However, administered payload visibility dimishes soon after delivery due to soluble contrast washout, leaving the radiolucent bead's location unknown. The objective of our study was to characterize inherently radiopaque beads (RO Beads) in terms of physicomechanical properties, deliverability and imaging visibility in a rabbit VX2 liver tumor model. Materials and Methods: RO Beads, which are based on LC Bead® platform, were compared to LC Bead. Bead size (light microscopy), equilibrium water content (EWC), density, X-ray attenuation and iodine distribution (micro-CT), suspension (settling times), deliverability and in vitro penetration were investigated. Fifteen rabbits were embolized with either LC Bead or RO Beads + soluble contrast (iodixanol-320), or RO Beads+dextrose. Appearance was evaluated with fluoroscopy, X-ray single shot, cone-beam CT (CBCT). Results: Both bead types had a similar size distribution. RO Beads had lower EWC (60-72%) and higher density (1.21-1.36 g/cc) with a homogeneous iodine distribution within the bead's interior. RO Beads suspension time was shorter than LC Bead, with durable suspension (>5 min) in 100% iodixanol. RO Beads ≤300 µm were deliverable through a 2.3-Fr microcatheter. Both bead types showed similar penetration. Soluble contrast could identify target and non-target embolization on fluoroscopy during administration. However, the imaging appearance vanished quickly for LC Bead as contrast washed-out. RO Beads+contrast significantly increased visibility on X-ray single shot compared to LC Bead+contrast in target and non-target arteries (P=0.0043). Similarly, RO beads demonstrated better visibility on CBCT in target arteries (P=0.0238) with a trend in non-target arteries (P=0.0519). RO Beads+dextrose were not sufficiently visible to monitor embolization using fluoroscopy. Conclusion: RO Beads provide better

  3. A Novel Aminotetralin-Type Serotonin (5-HT) 2C Receptor-Specific Agonist and 5-HT2A Competitive Antagonist/5-HT2B Inverse Agonist with Preclinical Efficacy for Psychoses

    PubMed Central

    Morgan, Drake; Felsing, Daniel; Kondabolu, Krishnakanth; Rowland, Neil E.; Robertson, Kimberly L.; Sakhuja, Rajeev; Booth, Raymond G.

    2014-01-01

    Development of 5-HT2C agonists for treatment of neuropsychiatric disorders, including psychoses, substance abuse, and obesity, has been fraught with difficulties, because the vast majority of reported 5-HT2C selective agonists also activate 5-HT2A and/or 5-HT2B receptors, potentially causing hallucinations and/or cardiac valvulopathy. Herein is described a novel, potent, and efficacious human 5-HT2C receptor agonist, (−)-trans-(2S,4R)-4-(3′[meta]-bromophenyl)-N,N-dimethyl-1,2,3,4-tetrahydronaphthalen-2-amine (−)-MBP), that is a competitive antagonist and inverse agonist at human 5-HT2A and 5-HT2B receptors, respectively. (−)-MBP has efficacy comparable to the prototypical second-generation antipsychotic drug clozapine in three C57Bl/6 mouse models of drug-induced psychoses: the head-twitch response elicited by [2,5]-dimethoxy-4-iodoamphetamine; hyperlocomotion induced by MK-801 [(5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate (dizocilpine maleate)]; and hyperlocomotion induced by amphetamine. (−)-MBP, however, does not alter locomotion when administered alone, distinguishing it from clozapine, which suppresses locomotion. Finally, consumption of highly palatable food by mice was not increased by (−)-MBP at a dose that produced at least 50% maximal efficacy in the psychoses models. Compared with (−)-MBP, the enantiomer (+)-MBP was much less active across in vitro affinity and functional assays using mouse and human receptors and also translated in vivo with comparably lower potency and efficacy. Results indicate a 5-HT2C receptor-specific agonist, such as (−)-MBP, may be pharmacotherapeutic for psychoses, without liability for obesity, hallucinations, heart disease, sedation, or motoric disorders. PMID:24563531

  4. SU-D-304-04: Pre-Clinical Feasibility Study for Intensity Modulated Grid Proton Therapy (IMgPT) Using a Newly Developed Delivery System

    SciTech Connect

    Tsiamas, P; Moskvin, V; Shin, J; Axente, M; Pirlepesov, F; Krasin, M; Merchant, T; Farr, J

    2015-06-15

    Purpose: The purpose of the current study was to characterize and evaluate intensity-modulated proton grid therapy (IMgPT) using a clinical proton beam. Methods: A TOPAS MC model of a new developmental mode (pre-clinical) of the Hitachi proton therapy system (PROBEAT) was used for simulation and characterization of proton grid therapy. TOPAS simulations of different energy ranges, depths and spot separation distances were performed. LET spectra for various energies and depths were produced with FLUKA MC code for evaluation potential interplay between planning parameters and their effect on the characterization of areas (valley) between spots. IMgPT planning aspects (spot spacing, skin dose, peak-to-valley ratios, beam selection, etc.) were evaluated for different phantom and patient cases. Raysearch software (v4.51) was used to perform the evaluation. Results: Calculated beam peak-to-valley ratios scenarios showed strong energy and depth dependence with ratios to be larger for higher energies and shallower depths. Peak-to-valley ratios for R90 range and for spot spacing of 1cm varied from 30% (E = 221.3 MeV, depth 30.6 cm) to 80% (E = 70.3 MeV, depth 4 cm). LET spectra calculations showed spectral hardening with depth, which might potential increase, spot separation distance and improve peak-to-valley ratios. IMgPT optimization, using constant spot spacing, showed skin dose reduction between peak regions of dose due to the irradiation of less skin. Single beam for bulky shallower tumors might be a potential candidate for proton grid therapy. Conclusions: Proton grid therapy using a clinical beam is a promising technique that reduces skin dose between peak regions of dose and may be suitable for the treatment of shallow tumors. IMgPT may be considered for use when bystander effects in off peak regions would be appropriate.

  5. Function and redox state of peritoneal leukocytes as preclinical and prodromic markers in a longitudinal study of triple-transgenic mice for Alzheimer's disease.

    PubMed

    Maté, Ianire; Cruces, Julia; Giménez-Llort, Lydia; De la Fuente, Mónica

    2015-01-01

    The aging process involves the impairment of the immune system (immunosenescence), based on the imbalance of the redox status, as occurs in neurodegenerative diseases such as Alzheimer's disease (AD). Since in AD there is a systemic disorder, we aimed to assess longitudinally, from before the onset until the complete establishment of AD, cell populations, several functions, and oxidative stress parameters in peritoneal leukocytes of triple transgenic mice for AD (3xTgAD). These animals mimic the human AD pathophysiology. The results indicate a premature immunosenescence in 3xTgAD at 4 months of age, when the immunoreactivity against intracellular amyloid-β fibrils appears. Thus, decreases in functions such as chemotaxis, phagocytosis, and lymphoproliferation, as well as a lower reduced glutathione content and higher xanthine oxidase activity, appear in leukocytes. Moreover, NK percentage and cytotoxic activity, CD25+ B and naïve CD8 T cells percentage, GSSG/GSH ratio, and GSH content were already changed before the onset of AD, at the age of 2 months. Furthermore, the changes in some parameters such as CD5+ B1 cells, phagocytosis, lymphoproliferation, and xanthine oxidase activity continue at 15 months of age, when AD pathophysiology is completely established. Because the immune system parameters studied are markers of health and longevity, the premature immunosenescence could explain the shorter life span shown by 3xTgAD observed in the present work. These results suggest that peripheral immune cell functions and their oxidative stress status could be good early peripheral markers of the preclinical and prodromal stages and progression of AD.

  6. Preclinical assessment of infant formula.

    PubMed

    Lönnerdal, Bo

    2012-01-01

    Infant formulas are the sole or predominant source of nutrition for many infants and are fed during a sensitive period of development and may therefore have short- and long-term consequences for infant health. Preclinical safety assessment therefore needs to include both short-term and long-term studies in animals. It is recommended that procedures are instituted by which experts may serve as independent scientists for companies developing novel products, without having their integrity compromised, and later serve the legislative institutions. A two-level assessment approach to determine the potential toxicity of a novel ingredient, its metabolites, and their effects in the matrix on developing organ systems has been suggested by IOM. This appears reasonable, as novel ingredients can be of different levels of concern. The use of modern methods in genomics and proteomics should be considered in these evaluation processes as well as novel methods to evaluate outcomes, including metabolomics and molecular techniques to assess the microbiome. PMID:22699767

  7. Methodological Standardization for the Preclinical Evaluation of Renal Sympathetic Denervation

    PubMed Central

    Sakakura, Kenichi; Ladich, Elena; Edelman, Elazer R.; Markham, Peter; Stanley, James R.L.; Keating, John; Kolodgie, Frank D.; Virmani, Renu; Joner, Michael

    2015-01-01

    Transcatheter ablation of renal autonomic nerves is a viable option for the treatment of resistent arterial hypertension; however, structured preclinical evaluation with standardization of analytical procedures remains a clear gap in this field. Here we discuss the topics relevant to the preclinical model for the evaluation of renal denervation (RDN) devices and report methodologies and criteria towards standardization of the safety and efficacy assessment, including histopathological evaluations of the renal artery, peri-arterial nerves, and associated peri-adventitial tissues. The preclinical swine renal artery model can be used effectively to assess both the safety and efficacy of RDN technologies. Assessment of the efficacy of RDN modalities primarily focuses on the determination of the depth of penetration of treatment-related injury (eg, necrosis) of the peri-arterial tissues and its relationship (ie, location and distance) and affect on the associated renal nerves and the correlation thereof with proxy biomarkers including renal norepinephrine concentrations and nerve-specific immunohistochemical stains (eg, tyrosine hydroxylase). The safety evaluation of RDN technologies involves assessing for adverse effects on tissues local to the site of treatment (ie, on the arterial wall) as well as tissues at a distance (eg, soft tissue, veins, arterial branches, skeletal muscle, adrenal gland, ureters). Increasing experience will help to create a standardized means of examining all arterial beds subject to ablative energy and in doing so enable us to proceed to optimize development and assessment of these emerging technologies. PMID:25240550

  8. The prevalence and consequences of burnout on a group of preclinical dental students

    PubMed Central

    Atalayin, Cigdem; Balkis, Murat; Tezel, Huseyin; Onal, Banu; Kayrak, Gul

    2015-01-01

    Objective: The aim of this study is to investigate the prevalence of burnout among a group of Turkish preclinical dental students, to compare the level of burnout and to determine the consequences in structural equation model. Materials and Methods: Preclinical dental students (n = 329, 50.5% of females and 49.5% of males) aged between 18 and 24 took part in the study. Maslach burnout inventory student version, academic satisfaction scale, and personal information sheet were used to gather data. Pearson correlation analyses, t-test, and one-way ANOVA were used for statistical analysis. The proposed theoretical model was tested via observed variable path analysis using maximum likelihood parameter estimation with AMOS 7.0. Results: About 22.3% of students had high level of emotional exhaustion, 16.7% of students had high level of cynicism, and 17.9% of students suffered from high level of reduced academic efficacy. While the students attending the first grade reported higher level of reduced academic efficacy, the students in the third grade reported higher level of emotional exhaustion. Academic workload played an important role in the development of burnout. As consequences of burnout, students with high levels of burnout intended to change their current major and did not to plan to continue to postgraduate education. Students with high level of burnout reported less level of academic satisfaction and academic achievement. Conclusions: Creating awareness on the burnout of dental students from the preclinical period may be useful for prevention and more compatible dental education environment. PMID:26430363

  9. Preclinical electrogastrography in experimental pigs

    PubMed Central

    Květina, Jaroslav; Varayil, Jithinraj Edakkanambeth; Ali, Shahzad Marghoob; Kuneš, Martin; Bureš, Jan; Tachecí, Ilja; Rejchrt, Stanislav; Kopáčová, Marcela

    2010-01-01

    Surface electrogastrography (EGG) is a non-invasive means of recording gastric myoelectric activity or slow waves from cutaneous leads placed over the stomach. This paper provides a comprehensive review of preclinical EGG. Our group recently set up and worked out the methods for EGG in experimental pigs. We gained our initial experience in the use of EGG in assessment of porcine gastric myoelectric activity after volume challenge and after intragastric administration of itopride and erythromycin. The mean dominant frequency in pigs is comparable with that found in humans. EGG in experimental pigs is feasible. Experimental EGG is an important basis for further preclinical projects in pharmacology and toxicology. PMID:21217873

  10. A Study of Efficacy and Professional Development among Alternatively-Certified Teachers in Arizona

    ERIC Educational Resources Information Center

    Ludlow, Carlyn

    2010-01-01

    The purpose of this descriptive and comparative study was to investigate the self-assessed efficacy levels of alternatively-certified teachers in Arizona. More specifically, this study examined the teachers' perceived ability to influence student learning and the extent to which, if at all, their self-reported efficacy levels differed based on the…

  11. A Study Investigating Relationships between Elementary Principals' and Teachers' Self-Efficacy and Student Achievement

    ERIC Educational Resources Information Center

    Domsch, Gayle D.

    2009-01-01

    In order to examine effective behaviors and efficacy, this study examined the relationships between the self-reflection of effective practices by principals and teachers, as assessed by self-efficacy scales, and student achievement, as evaluated by the state assessment program. Other studies determined that effective behaviors preceded and…

  12. A Study on the Relationship between Teacher Self Efficacy and Burnout

    ERIC Educational Resources Information Center

    Savas, Ahmet Cezmi; Bozgeyik, Yunus; Eser, Ismail

    2014-01-01

    The major purpose of the study was to examine the relationship between teacher self efficacy and burnout. In order to collect the related data, "Maslach Burnout Inventory" and "Teacher Sense of Efficacy Scale" were used. The sample of the study consisted of 163 randomly chosen teachers who worked in various primary and…

  13. Clinical Self-Efficacy in Senior Nursing Students: A Mixed- Methods Study

    PubMed Central

    Abdal, Marzieh; Masoudi Alavi, Negin; Adib-Hajbaghery, Mohsen

    2015-01-01

    Background: Clinical education has a basic role in nursing education, and effective clinical training establishes a sense of clinical self-efficacy in senior nursing students. Self-efficacy is a key component for acting independently in the nursing profession. Objectives: This study was designed to outline senior nursing students’ views about clinical self-efficacy and to determine its level in nursing students. Patients and Methods: A mixed-methods approach, including a quantitative cross-sectional study and qualitative content analysis,was used in this study. Participants were senior nursing students who were in their two last semesters. During the initial quantitative stage, all students in the 7th and 8th semesters of the nursing major were invited to participate. They were asked to complete the Nursing Clinical Self-Efficacy Scale (NCSES) and, during the subsequent qualitative stage, the 14 students in the 7th and 8th semesters were asked to participate in semi-structured interviews. Results: In the quantitative part, 58 students completed the self-efficacy questionnaire; the mean score was 219.28 ± 35.8, which showed moderate self-efficacy in students. Self-efficacy was different across skills. In the qualitative part, the 355 open codes that were extracted from the interviews were clustered to 12 categories and 3 themes. The main themes included the factors related to self-efficacy, outcomes of self-efficacy, and ways to improve self-efficacy. Conclusions: Students had moderate self-efficacy. Several factors such as environment, nursing colleagues, and clinical educators could influence the creation of clinical self-efficacy in nursing students. PMID:26576443

  14. Comparative in vitro efficacy of antimicrobial shampoos: a pilot study.

    PubMed

    Young, Rebecca; Buckley, Laura; McEwan, Neil; Nuttall, Tim

    2012-02-01

    This study compared the antimicrobial efficacy of shampoos against meticillin-sensitive Staphylococcus pseudintermedius (MSSP), meticillin-resistant S. pseudintermedius (MRSP), antibiotic-sensitive Pseudomonas aeruginosa (PA), multidrug-resistant P. aeruginosa (MDR-PA) and Malassezia pachydermatis. Three isolates were incubated for 10, 30 and 60 min with each shampoo diluted in phosphate-buffered saline. Aliquots were then incubated for 16-18 h on sheep blood agar (bacteria) or for 3 days on Sabouraud's dextrose agar (Malassezia). The minimal bactericidal concentrations (MBCs) for chlorhexidine products (Malaseb(®), Pyoderm(®)/Microbex(®) and Hibiscrub(®)) were 1:1,024-1:2,048 for MSSP and MRSP, 1:512-1:1,024 for PA and MDR-PA, and 1:2,048-1:5,096 for Malassezia at all time points. The MBCs for benzoyl peroxide (Paxcutol(®)) for MSSP and MRSP were 1:2-1:8 at 10 min, and 1:256 after 30 and 60 min. A 1:2 dilution was effective against Pseudomonas, and 1:512-1:1,024 dilutions were effective against Malassezia at all time points. The MBCs for ethyl lactate (Etiderm(®)) for MSSP and MRSP were 1:2 at 10 min, and 1:2-1:16 after 30 and 60 min. A 1:2 dilution was effective against Pseudomonas, and a 1:512 dilution was effective against Malassezia at all time points. Chloroxylenol (Coatex(®)) and acetic acid-boric acid (Malacetic(®)) were not effective against MSSP, MRSP or Pseudomonas. Both were effective against Malassezia at 1:8-1:16 dilution at 10 min, and at 1:8-1:32 dilution after 30 and 60 min. In conclusion, chlorhexidine appeared to be the most effective topical biocide, and MRSP and MDR-PA were no less susceptible than antibiotic-sensitive organisms. These results should, however, be confirmed with larger numbers of isolates.

  15. Preclinical pharmacology and toxicology study of Ad-hTERT-E1a-Apoptin, a novel dual cancer-specific oncolytic adenovirus

    SciTech Connect

    Qi, Yanxin; Guo, Huanhuan; Hu, Ningning; He, Dongyun; Zhang, Shi; Chu, Yunjie; Huang, Yubin; Li, Xiao; Sun, LiLi; Jin, Ningyi

    2014-10-15

    Clinical studies have demonstrated that conditionally replicating adenovirus is safe. We constructed an oncolytic adenovirus, Ad-hTERT-E1a-Apoptin, using a cancer-specific promoter (human telomerase reverse transcriptase promoter, hTERTp) and a cancer cell-selective apoptosis-inducing gene (Apoptin). Ad-hTERT-E1a-Apoptin was proven effective both in vitro and in vivo in our previous study. In this study, the preclinical safety profiles of Ad-hTERT-E1a-Apoptin in animal models were investigated. At doses of 5.0 × 10{sup 8}, 2.5 × 10{sup 9}, and 1.25 × 10{sup 10} viral particles (VP)/kg, Ad-hTERT-E1a-Apoptin had no adverse effects on mouse behavior, muscle cooperation, sedative effect, digestive system, and nervous systems, or on beagle cardiovascular and respiratory systems at 5.0 × 10{sup 8}, 2.5 × 10{sup 9}, and 1.25 × 10{sup 10} VP/kg doses. In acute toxicity tests in mice, the maximum tolerated dose > 5 × 10{sup 10} VP/kg. There was no inflammation or ulceration at the injection sites within two weeks. In repeat-dose toxicological studies, the no observable adverse effect levels of Ad-hTERT-E1a-Apoptin in rats (1.25 × 10{sup 10} VP/kg) and beagles (2.5 × 10{sup 9} VP/kg) were 62.5- and 12.5-fold of the proposed clinical dose, respectively. The anti-virus antibody was produced in animal sera. Bone marrow examination revealed no histopathological changes. Guinea pigs sensitized by three repeated intraperitoneal injections of 1.35 × 10{sup 10} VP/mL Ad-hTERT-E1a-Apoptin each and challenged by one intravenous injection of 1.67 × 10{sup 8} VP/kg Ad-hTERT-E1a-Apoptin did not exhibit any sign of systemic anaphylaxis. Our data from different animal models suggest that Ad-hTERT-E1a-Apoptin is a safe anti-tumor therapeutic agent. - Highlights: • We use the rodents and non-rodents animal models to evaluation Ad-hTERT-E1a-Apoptin. • Ad-hTERT-E1a-Apoptin is a safe anti-tumor therapeutic agent. • Demonstrate the safety and feasibility dose of injected Ad

  16. A Gender Study Investigating Physics Self-Efficacy

    ERIC Educational Resources Information Center

    Sawtelle, Vashti

    2011-01-01

    The underrepresentation of women in physics has been well documented and a source of concern for both policy makers and educators. My dissertation focuses on understanding the role self-efficacy plays in retaining students, particularly women, in introductory physics. I use an explanatory mixed methods approach to first investigate quantitatively…

  17. An Exploratory Study into the Efficacy of Learning Objects

    ERIC Educational Resources Information Center

    Farha, Nicholas W.

    2009-01-01

    Learning objects have quickly become a widely accepted approach to instructional technology, particularly in on-line and computer-based learning environments. While there is a substantial body of literature concerning learning objects, very little of it verifies their efficacy. This research investigated the effectiveness of learning objects by…

  18. Methods to Evaluate the Preclinical Safety and Immunogenicity of Genetically Modified Live-Attenuated Leishmania Parasite Vaccines.

    PubMed

    Gannavaram, Sreenivas; Bhattacharya, Parna; Dey, Ranadhir; Ismail, Nevien; Avishek, Kumar; Salotra, Poonam; Selvapandiyan, Angamuthu; Satoskar, Abhay; Nakhasi, Hira L

    2016-01-01

    Live-attenuated parasite vaccines are being explored as potential vaccine candidates since other approaches of vaccination have not produced an effective vaccine so far. In order for live-attenuated parasite vaccines to be tested in preclinical studies and possibly in clinical studies, the safety and immunogenicity of these organisms must be rigorously evaluated. Here we describe methods to test persistence in the immunized host and immunogenicity, and to identify biomarkers of vaccine safety and efficacy with particular reference to genetically attenuated Leishmania parasites.

  19. Methods to Evaluate the Preclinical Safety and Immunogenicity of Genetically Modified Live-Attenuated Leishmania Parasite Vaccines.

    PubMed

    Gannavaram, Sreenivas; Bhattacharya, Parna; Dey, Ranadhir; Ismail, Nevien; Avishek, Kumar; Salotra, Poonam; Selvapandiyan, Angamuthu; Satoskar, Abhay; Nakhasi, Hira L

    2016-01-01

    Live-attenuated parasite vaccines are being explored as potential vaccine candidates since other approaches of vaccination have not produced an effective vaccine so far. In order for live-attenuated parasite vaccines to be tested in preclinical studies and possibly in clinical studies, the safety and immunogenicity of these organisms must be rigorously evaluated. Here we describe methods to test persistence in the immunized host and immunogenicity, and to identify biomarkers of vaccine safety and efficacy with particular reference to genetically attenuated Leishmania parasites. PMID:27076157

  20. Organizational Structure, Collegial Trust, and College Faculty Teaching Efficacy: A Case Study

    ERIC Educational Resources Information Center

    Okpogba, Desmond

    2011-01-01

    The purpose of this mixed-method study was to explore the relationship between faculty self-efficacy, organizational structure, and collegial trust. The concepts of teacher self-efficacy, organizational structure, and collegial trust were used to investigate any possible empirical relationships existing between these variables in a private,…

  1. A Confirmatory Study of Rating Scale Category Effectiveness for the Coaching Efficacy Scale

    ERIC Educational Resources Information Center

    Myers, Nicholas D.; Feltz, Deborah L.; Wolfe, Edward W.

    2008-01-01

    This study extended validity evidence for measures of coaching efficacy derived from the Coaching Efficacy Scale (CES) by testing the rating scale categorizations suggested in previous research. Previous research provided evidence for the effectiveness of a four-category (4-CAT) structure for high school and collegiate sports coaches; it also…

  2. Self-Efficacy and Creative Productivity: Three Studies of above Average Ability Children.

    ERIC Educational Resources Information Center

    Schack, Gina D.; And Others

    1991-01-01

    Three studies involving a total of 918 students of above average ability in grades 3 through 8 confirm the importance of self-efficacy in students' decisions to initiate creative productivity and reinforce the value of performance accomplishments for increasing self-efficacy and creative productivity. (SLD)

  3. A Survey Study of Chinese In-Service Teachers' Self-Efficacy about Inclusive Education

    ERIC Educational Resources Information Center

    Wang, Mian; Zan, Fei; Liu, Jiaqiu; Liu, Chunling; Sharma, Umesh

    2012-01-01

    A survey study was conducted to a total of 323 in-service teachers (110 special education teachers and 213 general education teachers) in Shanghai regarding their self-efficacy and concerns about inclusive education. Multivariate analysis results reveal that special teachers have significantly higher self-efficacy about inclusive education than…

  4. A Qualitative Case Study Exploring Self-Efficacy and Its Influence on Fourth Grade Mathematics Students

    ERIC Educational Resources Information Center

    Prindle, Catherine M.

    2014-01-01

    The perception of higher self-efficacy in young children has been determined to be a better predictor of intellectual and academic performance than simply the acquisition of skills alone. This empirical qualitative single-case study was conducted in order to explore the influence of self-efficacy instruction on perceptions toward and achievement…

  5. Turkish Version of the Principals' Sense of Efficacy Scale: Validity and Reliability Study

    ERIC Educational Resources Information Center

    Isik, Ayse Negis; Derinbay, Deniz

    2015-01-01

    Problem Statement: Principals are known as important actors in effective schools. So it is important to know which variables influence principals' success. One of these predictors can be self-efficacy. However, there is very few research about principals' sense of efficacy. Purpose of the Study: The purpose of this research was to test the…

  6. Emotional Intelligence and Teacher Efficacy: A Study of Turkish EFL Pre-Service Teachers

    ERIC Educational Resources Information Center

    Kocoglu, Zeynep

    2011-01-01

    This study investigated the relationship between emotional intelligence and teacher efficacy among 90 English language pre-service teachers from a university in Turkey. Data sources included Tschannen-Moran and Woolfolk-Hoy's Teachers' Sense of Efficacy Scale and Reuven Bar-On's Emotional Quotient Inventory. The findings indicated that Turkish EFL…

  7. Gender, Group Composition, Cooperation, and Self-Efficacy in Computer Studies.

    ERIC Educational Resources Information Center

    Busch, Tor

    1996-01-01

    Describes a study of Norwegian college students that investigated whether gender, group composition, or self-efficacy in computing has any impact on cooperation, giving or getting task-related help, and level of activity in student groups. Results confirms gender differences in self-efficacy in computing. (Author/LRW)

  8. Developing Teaching Self-Efficacy in Research Institutions: A Study of Award-Winning Professors

    ERIC Educational Resources Information Center

    Morris, David B.; Usher, Ellen L.

    2011-01-01

    The purpose of this study was to assess the sources of award-wining research professors' (six women; six men) teaching self-efficacy through the framework of Bandura's (1986) social cognitive theory. Semi-structured interviews revealed that mastery experiences and social persuasions were particularly influential sources of self-efficacy and that…

  9. Agricultural Education Perceived Teacher Self-Efficacy: A Descriptive Study of Beginning Agricultural Education Teachers

    ERIC Educational Resources Information Center

    Wolf, Kattlyn J.

    2011-01-01

    The purpose of this study was to describe beginning agriculture teachers' perceived agricultural education teacher self-efficacy. Additionally, the researcher sought to describe the relationship among teachers' demographic characteristics and their agricultural education teacher self-efficacy. An instrument specific to agricultural education was…

  10. A Longitudinal Study on Mathematics Teaching Efficacy: Which Factors (Un)Support the Development?

    ERIC Educational Resources Information Center

    Isiksal-Bostan, Mine

    2016-01-01

    The aim of this longitudinal study was to examine prospective teachers' mathematics teaching efficacy belief during their enrollment in teacher education program and at the end of their first year of teaching. In addition, the factors that enhance or inhibit participants' efficacy belief and how these factors affect their mathematics teaching…

  11. Education for Sustainability: A Case Study of Preservice Primary Teachers' Knowledge and Efficacy

    ERIC Educational Resources Information Center

    Effeney, Gerard; Davis, Julie

    2013-01-01

    This study investigated the relationships between knowledge and efficacy for teaching sustainability in a sample of 266 pre-service primary teachers at a large, metropolitan university in Australia. A survey gathered information about the participant's attitudes and self-efficacy for education for sustainability, along with their perceived…

  12. Comparative study of the neurotrophic effects elicited by VEGF-B and GDNF in preclinical in vivo models of Parkinson's disease.

    PubMed

    Yue, X; Hariri, D J; Caballero, B; Zhang, S; Bartlett, M J; Kaut, O; Mount, D W; Wüllner, U; Sherman, S J; Falk, T

    2014-01-31

    Vascular endothelial growth factor B (VEGF-B) has recently been shown to be a promising novel neuroprotective agent for several neurodegenerative conditions. In the current study we extended previous work on neuroprotective potential for Parkinson's disease (PD) by testing an expanded dose range of VEGF-B (1 and 10 μg) and directly comparing both neuroprotective and neurorestorative effects of VEGF-B in progressive unilateral 6-hydroxydopamine (6-OHDA) PD models to a single dose of glial cell line-derived neurotrophic factor (GDNF, 10 μg), that has been established by several groups as a standard in both preclinical PD models. In the amphetamine-induced rotational tests the treatment with 1 and 10 μg VEGF-B resulted in significantly improved motor function of 6-OHDA-lesioned rats compared to vehicle-treated 6-OHDA-lesioned rats in the neuroprotection paradigm. Both doses of VEGF-B caused an increase in tyrosine hydroxylase (TH)-positive cell and fiber count in the substantia nigra (SN) and striatum in the neuroprotective experiment. The effect size was comparable to the effects seen with GDNF. In the neurorestoration paradigm, VEGF-B injection had no significant effect in either the behavioral or the immunohistochemical analyses, whereas GDNF injection significantly improved the amphetamine-induced rotational behavior and reduced TH-positive neuronal cell loss in the SN. We also present a strong positive correlation (p=1.9e-50) of the expression of VEGF-B with nuclear-encoded mitochondrial genes involved in fatty acid metabolism in rat midbrain, pointing to the mitochondria as a site of action of VEGF-B. GDNF showed a positive correlation with nuclear-encoded mitochondrial genes that was not nearly as strong (p=0.018). VEGF-B counteracted rotenone-induced reduction of (a) fatty acid transport protein 1 and 4 levels and (b) both Akt protein and phosphorylation levels in SH-SY5Y cells. We further verified VEGF-B expression in the human SN pars compacta of healthy

  13. Electronic Cigarettes Efficacy and Safety at 12 Months: Cohort Study

    PubMed Central

    Fiore, Maria; La Vecchia, Carlo; Marzuillo, Carolina; Gualano, Maria Rosaria; Liguori, Giorgio; Cicolini, Giancarlo; Capasso, Lorenzo; D'Amario, Claudio; Boccia, Stefania; Siliquini, Roberta; Ricciardi, Walter; Villari, Paolo

    2015-01-01

    Objective To evaluate the safety and efficacy as a tool of smoking cessation of electronic cigarettes (e-cigarettes), directly comparing users of e-cigarettes only, smokers of tobacco cigarettes only, and smokers of both. Design Prospective cohort study. Final results are expected in 2019, but given the urgency of data to support policies on electronic smoking, we report the results of the 12-month follow-up. Data Sources Direct contact and structured questionnaires by phone or via internet. Methods Adults (30–75 years) were included if they were smokers of ≥1 tobacco cigarette/day (tobacco smokers), users of any type of e-cigarettes, inhaling ≥50 puffs weekly (e-smokers), or smokers of both tobacco and e-cigarettes (dual smokers). Carbon monoxide levels were tested in a sample of those declaring tobacco smoking abstinence. Main Outcome Measures Sustained smoking abstinence from tobacco smoking at 12 months, reduction in the number of tobacco cigarettes smoked daily. Data Synthesis We used linear and logistic regression, with region as cluster unit. Results Follow-up data were available for 236 e-smokers, 491 tobacco smokers, and 232 dual smokers (overall response rate 70.8%). All e-smokers were tobacco ex-smokers. At 12 months, 61.9% of the e-smokers were still abstinent from tobacco smoking; 20.6% of the tobacco smokers and 22.0% of the dual smokers achieved tobacco abstinence. Adjusting for potential confounders, tobacco smoking abstinence or cessation remained significantly more likely among e-smokers (adjusted OR 5.19; 95% CI: 3.35–8.02), whereas adding e-cigarettes to tobacco smoking did not enhance the likelihood of quitting tobacco and did not reduce tobacco cigarette consumption. E-smokers showed a minimal but significantly higher increase in self-rated health than other smokers. Non significant differences were found in self-reported serious adverse events (eleven overall). Conclusions Adding e-cigarettes to tobacco smoking did not facilitate

  14. Influence of freeze-drying and γ-irradiation in preclinical studies of flurbiprofen polymeric nanoparticles for ocular delivery using d-(+)-trehalose and polyethylene glycol

    PubMed Central

    Ramos Yacasi, Gladys Rosario; García López, María Luisa; Espina García, Marta; Parra Coca, Alexander; Calpena Campmany, Ana Cristina

    2016-01-01

    This study investigated the suspension of poly(ε-caprolactone) nanoparticles as an ocular delivery system for flurbiprofen (FB-PεCL-NPs) in order to overcome the associated problems, such as stability, sterility, tolerance, and efficacy, with two different FB-PεCL-NP formulations. The formulations were stabilized with poloxamer 188 (1.66% and 3.5%) and submitted individually for freeze-drying and γ-irradiation with polyethylene glycol 3350 (PEG3350) and d-(+)-trehalose (TRE). Both formulations satisfied criteria according to all physicochemical parameters required for ocular pharmaceuticals. The FB-PεCL-NP formulations showed non-Newtonian behavior and sustained drug release. Ex vivo permeation analysis using isolated ocular pig tissues suggested that the presence of PEG3350 results in a reduction of FB transcorneal permeation. Moreover, TRE improved the penetration of FB across the cornea, especially after γ-irradiation. In addition, both formulations did not show a significant affinity in increasing FB transscleral permeation. Both formulations were classified as nonirritating, safe products for ophthalmic administration according to hen’s egg test-chorioallantoic membrane and Draize eye test. Furthermore, an in vivo anti-inflammatory efficacy test showed that irradiated FB-PεCL-NPs prepared with PEG3350 (IR-NPsPEG) have longer anti-inflammatory effects than those presented with irradiated FB-PεCL-NPs prepared with TRE (IR-NPsTRE). IR-NPsPEG showed a suitable physical stability after an aqueous reconstitution over >30 days. This study concludes that both formulations meet the Goldman’s criteria and demonstrate how irradiated nanoparticles, with innovative permeation characteristics, could be used as a feasible alternative to a flurbiprofen solution for ocular application in clinical trials. PMID:27601897

  15. Influence of freeze-drying and γ-irradiation in preclinical studies of flurbiprofen polymeric nanoparticles for ocular delivery using d-(+)-trehalose and polyethylene glycol.

    PubMed

    Ramos Yacasi, Gladys Rosario; García López, María Luisa; Espina García, Marta; Parra Coca, Alexander; Calpena Campmany, Ana Cristina

    2016-01-01

    This study investigated the suspension of poly(ε-caprolactone) nanoparticles as an ocular delivery system for flurbiprofen (FB-PεCL-NPs) in order to overcome the associated problems, such as stability, sterility, tolerance, and efficacy, with two different FB-PεCL-NP formulations. The formulations were stabilized with poloxamer 188 (1.66% and 3.5%) and submitted individually for freeze-drying and γ-irradiation with polyethylene glycol 3350 (PEG3350) and d-(+)-trehalose (TRE). Both formulations satisfied criteria according to all physicochemical parameters required for ocular pharmaceuticals. The FB-PεCL-NP formulations showed non-Newtonian behavior and sustained drug release. Ex vivo permeation analysis using isolated ocular pig tissues suggested that the presence of PEG3350 results in a reduction of FB transcorneal permeation. Moreover, TRE improved the penetration of FB across the cornea, especially after γ-irradiation. In addition, both formulations did not show a significant affinity in increasing FB transscleral permeation. Both formulations were classified as nonirritating, safe products for ophthalmic administration according to hen's egg test-chorioallantoic membrane and Draize eye test. Furthermore, an in vivo anti-inflammatory efficacy test showed that irradiated FB-PεCL-NPs prepared with PEG3350 (IR-NPsPEG) have longer anti-inflammatory effects than those presented with irradiated FB-PεCL-NPs prepared with TRE (IR-NPsTRE). IR-NPsPEG showed a suitable physical stability after an aqueous reconstitution over >30 days. This study concludes that both formulations meet the Goldman's criteria and demonstrate how irradiated nanoparticles, with innovative permeation characteristics, could be used as a feasible alternative to a flurbiprofen solution for ocular application in clinical trials. PMID:27601897

  16. Influence of freeze-drying and γ-irradiation in preclinical studies of flurbiprofen polymeric nanoparticles for ocular delivery using d-(+)-trehalose and polyethylene glycol

    PubMed Central

    Ramos Yacasi, Gladys Rosario; García López, María Luisa; Espina García, Marta; Parra Coca, Alexander; Calpena Campmany, Ana Cristina

    2016-01-01

    This study investigated the suspension of poly(ε-caprolactone) nanoparticles as an ocular delivery system for flurbiprofen (FB-PεCL-NPs) in order to overcome the associated problems, such as stability, sterility, tolerance, and efficacy, with two different FB-PεCL-NP formulations. The formulations were stabilized with poloxamer 188 (1.66% and 3.5%) and submitted individually for freeze-drying and γ-irradiation with polyethylene glycol 3350 (PEG3350) and d-(+)-trehalose (TRE). Both formulations satisfied criteria according to all physicochemical parameters required for ocular pharmaceuticals. The FB-PεCL-NP formulations showed non-Newtonian behavior and sustained drug release. Ex vivo permeation analysis using isolated ocular pig tissues suggested that the presence of PEG3350 results in a reduction of FB transcorneal permeation. Moreover, TRE improved the penetration of FB across the cornea, especially after γ-irradiation. In addition, both formulations did not show a significant affinity in increasing FB transscleral permeation. Both formulations were classified as nonirritating, safe products for ophthalmic administration according to hen’s egg test-chorioallantoic membrane and Draize eye test. Furthermore, an in vivo anti-inflammatory efficacy test showed that irradiated FB-PεCL-NPs prepared with PEG3350 (IR-NPsPEG) have longer anti-inflammatory effects than those presented with irradiated FB-PεCL-NPs prepared with TRE (IR-NPsTRE). IR-NPsPEG showed a suitable physical stability after an aqueous reconstitution over >30 days. This study concludes that both formulations meet the Goldman’s criteria and demonstrate how irradiated nanoparticles, with innovative permeation characteristics, could be used as a feasible alternative to a flurbiprofen solution for ocular application in clinical trials.

  17. Influence of freeze-drying and γ-irradiation in preclinical studies of flurbiprofen polymeric nanoparticles for ocular delivery using d-(+)-trehalose and polyethylene glycol.

    PubMed

    Ramos Yacasi, Gladys Rosario; García López, María Luisa; Espina García, Marta; Parra Coca, Alexander; Calpena Campmany, Ana Cristina

    2016-01-01

    This study investigated the suspension of poly(ε-caprolactone) nanoparticles as an ocular delivery system for flurbiprofen (FB-PεCL-NPs) in order to overcome the associated problems, such as stability, sterility, tolerance, and efficacy, with two different FB-PεCL-NP formulations. The formulations were stabilized with poloxamer 188 (1.66% and 3.5%) and submitted individually for freeze-drying and γ-irradiation with polyethylene glycol 3350 (PEG3350) and d-(+)-trehalose (TRE). Both formulations satisfied criteria according to all physicochemical parameters required for ocular pharmaceuticals. The FB-PεCL-NP formulations showed non-Newtonian behavior and sustained drug release. Ex vivo permeation analysis using isolated ocular pig tissues suggested that the presence of PEG3350 results in a reduction of FB transcorneal permeation. Moreover, TRE improved the penetration of FB across the cornea, especially after γ-irradiation. In addition, both formulations did not show a significant affinity in increasing FB transscleral permeation. Both formulations were classified as nonirritating, safe products for ophthalmic administration according to hen's egg test-chorioallantoic membrane and Draize eye test. Furthermore, an in vivo anti-inflammatory efficacy test showed that irradiated FB-PεCL-NPs prepared with PEG3350 (IR-NPsPEG) have longer anti-inflammatory effects than those presented with irradiated FB-PεCL-NPs prepared with TRE (IR-NPsTRE). IR-NPsPEG showed a suitable physical stability after an aqueous reconstitution over >30 days. This study concludes that both formulations meet the Goldman's criteria and demonstrate how irradiated nanoparticles, with innovative permeation characteristics, could be used as a feasible alternative to a flurbiprofen solution for ocular application in clinical trials.

  18. EDRN Breast and Ovary Cancer CVC, Study 3: Phase 3 Validation of screening decision rules in preclinical UKCTOCS serial samples — EDRN Public Portal

    Cancer.gov

    We will collaborate with investigators from University College London to test a screening decision rule in preclinical serial samples from the U.K. Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) to learn if the panel can do better than CA125 alone. The UKCTOCS is an ideal setting for retrospective validation of an early detection marker panel and decision rule because it offers serial samples collected annually and use of imaging in women with rising CA125. Multi-modal strategies using serum markers HE4, MSLN, MMP7, and CA125 will be compared to strategies relying exclusively on CA125 and transvaginal sonography (TVS).

  19. Preclinical evaluation of three polyspecific antivenoms against the venom of Echis ocellatus: Neutralization of toxic activities and antivenomics.

    PubMed

    Calvete, Juan J; Arias, Ana Silvia; Rodríguez, Yania; Quesada-Bernat, Sarai; Sánchez, Laura V; Chippaux, Jean Philippe; Pla, Davinia; Gutiérrez, José María

    2016-09-01

    Snakebite envenoming has a heavy burden in the public health in sub-Saharan Africa. The viperid species Echis ocellatus (carpet viper or saw-scaled viper) is the medically most important snake in the savannahs of western sub-Saharan Africa. Several antivenoms are being distributed and used in this region for the treatment of envenomings by E. ocellatus, but the preclinical efficacy of some of these antivenoms has not been assessed. The present study evaluated the preclinical efficacy against E. ocellatus venom of three polyspecific antivenoms: (a) Snake Venom Antiserum (Pan Africa), manufactured by Premium Serums and Vaccines (India); (b) Snake Venom Antiserum (Africa), manufactured by VINS Bioproducts (India); and (c) Antivipmyn(®) Africa, manufactured by Instituto Bioclon (Mexico). Antivenomics analysis revealed the ability of the three antivenoms to immunocapture the majority of components of the venoms of E. ocellatus from Cameroon, Nigeria and Mali, although their maximal immunocapturing capability varied. Bioclon and Premium Serums antivenoms were effective in the neutralization of lethal, hemorrhagic and in vitro coagulant activities of the venom of E. ocellatus from Cameroon, albeit with different potencies. VINS antivenom neutralized hemorrhagic activity of this venom, but failed to neutralize lethality at the highest antivenom dose tested, and had a low neutralizing efficacy against in vitro coagulant effect.

  20. Preclinical evaluation of three polyspecific antivenoms against the venom of Echis ocellatus: Neutralization of toxic activities and antivenomics.

    PubMed

    Calvete, Juan J; Arias, Ana Silvia; Rodríguez, Yania; Quesada-Bernat, Sarai; Sánchez, Laura V; Chippaux, Jean Philippe; Pla, Davinia; Gutiérrez, José María

    2016-09-01

    Snakebite envenoming has a heavy burden in the public health in sub-Saharan Africa. The viperid species Echis ocellatus (carpet viper or saw-scaled viper) is the medically most important snake in the savannahs of western sub-Saharan Africa. Several antivenoms are being distributed and used in this region for the treatment of envenomings by E. ocellatus, but the preclinical efficacy of some of these antivenoms has not been assessed. The present study evaluated the preclinical efficacy against E. ocellatus venom of three polyspecific antivenoms: (a) Snake Venom Antiserum (Pan Africa), manufactured by Premium Serums and Vaccines (India); (b) Snake Venom Antiserum (Africa), manufactured by VINS Bioproducts (India); and (c) Antivipmyn(®) Africa, manufactured by Instituto Bioclon (Mexico). Antivenomics analysis revealed the ability of the three antivenoms to immunocapture the majority of components of the venoms of E. ocellatus from Cameroon, Nigeria and Mali, although their maximal immunocapturing capability varied. Bioclon and Premium Serums antivenoms were effective in the neutralization of lethal, hemorrhagic and in vitro coagulant activities of the venom of E. ocellatus from Cameroon, albeit with different potencies. VINS antivenom neutralized hemorrhagic activity of this venom, but failed to neutralize lethality at the highest antivenom dose tested, and had a low neutralizing efficacy against in vitro coagulant effect. PMID:27377229

  1. Shared Relationship Efficacy of Dyad Can Increase Life Satisfaction in Close Relationships: Multilevel Study

    PubMed Central

    Ito, Kenichi; Yoshida, Toshikazu

    2016-01-01

    Characteristics of relationship itself play an important role in determining well-being of individuals who participate in the relationship. We used efficacy expectations mutually shared between close friends or romantic partners as a characteristic of relationship and investigated its impact on their life satisfaction. In Study 1, we conducted a cross-sectional study among 137 pairs of close same-sex friends to test whether the efficacy expectations shared between friends are associated with levels of life satisfaction. In Study 2, we conducted a longitudinal study among 114 heterosexual romantic couples to test predictive validity of the efficacy expectations shared between couples predict levels of life satisfaction 2 month later. In both studies we found a consistent result that as degrees of the efficacy expectations shared between individuals in a relationship increased, the degree of their life satisfaction also increased. Underlying mechanisms that explain how characteristics of relationship itself increase life satisfaction are discussed. PMID:27437946

  2. [Studies on the efficacy of five repellents against Phlebotomus alexandri].

    PubMed

    Jia, J X; Guan, L R; Xu, Y X; Wang, G; Hao, K F

    1990-01-01

    The efficacy of five repellents were tested against Phlebotomus alexandri both in the laboratory and in the field in Meiyaogou, Turfan City, Xinjiang Uygur Autonomous Region during 1986-1987. A total of 3,301 female Ph. alexandri were used in the laboratory and 306 man-times of volunteers were tested in the field. At a dose of 0.25 microliters/cm2, the protective durations of mosquito repellent perfume (MRP), N, N-diethyl-mtaluamide (DETA), mosquito repellent liquid (MRL), dimethyl phthalate (DMP) and dibutyl phthalate (DBP) were 7.50 h, 5.00 h, 3.75 h, 1.25 h and 1.00 h, respectively. At a dose of 0.75 mg/cm2, the protective durations of the essential balms of DETA, DMP and DBP were 5.50 h, 3.50 h and 3.00 h, respectively. The repelling effect on volunteers in the field was the same as that tested in the laboratory. The relative efficacy of the five repellents was in the order of MRP greater than DETA greater than MRL greater than DMP greater than DBP. The above-mentioned repellents may be of practical use for individual protection against kala-azar transmission in the field.

  3. The Exploration of Elementary School Teachers' Internet Self-Efficacy and Information Commitments: A Study in Taiwan

    ERIC Educational Resources Information Center

    Wu, Ying-Tien; Wang, Li-Jen

    2015-01-01

    This study aimed to explore teachers' Internet self-efficacy and information commitments. More importantly, this study also attempted to identify possible factors that affect the teachers' Internet self-efficacy. The participants were 301 elementary school teachers. In this study, the Internet Self-efficacy Survey (ISS) and the Information…

  4. A multilevel study on the relationships between work characteristics, self-efficacy, collective efficacy, and organizational citizenship behavior: the case of Taiwanese police duty-executing organizations.

    PubMed

    Chen, Chun-Hsi Vivian; Kao, Rui-Hsin

    2011-01-01

    Public security, traffic management, and service for the people are the 3 major functions of policing in Taiwan. This definition encompasses not only the traditional job characteristics, but also the level of contextual characteristics and social characteristics because of police work's characteristics and its frequent interaction with the public. Thus, the present study conducted a multilevel model analysis by taking self-efficacy and collective efficacy as the mediating variables. The purpose was to investigate the influences of motivational work characteristics (knowledge-oriented) and social work characteristics (socially and contextually oriented) of work-design model on the police officers' organizational citizenship behavior (OCB), by using first-line police officers in Taiwan as the research objects. The study showed not only that knowledge characteristics will influence the self-efficacy of a police officer and that self-efficacy can in turn influence individual police officers' OCB, but also the contextual effect of social characteristics, contextual characteristics, and collective efficacy on self-efficacy and individuals' OCB. Additionally, there was a crosslevel moderating effect from contextual characteristics on the relationship between knowledge characteristics and self-efficacy and the relationship between self-efficacy and the individuals' OCB. The authors conclude the article with research implications.

  5. Two preclinical tests to evaluate anticancer activity and to help validate drug candidates for clinical trials

    PubMed Central

    López-Lázaro, Miguel

    2015-01-01

    Current approaches to assessing preclinical anticancer activity do not reliably predict drug efficacy in cancer patients. Most of the compounds that show remarkable anticancer effects in preclinical models actually fail when tested in clinical trials. We blame these failures on the complexity of the disease and on the limitations of the preclinical tools we require for our research. This manuscript argues that this lack of clinical response may also be caused by poor in vitro and in vivo preclinical designs, in which cancer patients' needs are not fully considered. Then, it proposes two patient-oriented tests to assess in vitro and in vivo anticancer activity and to help validate drug candidates for clinical evaluation. PMID:25859551

  6. Joint modeling of clinical efficacy and safety with an application to diabetes studies.

    PubMed

    Zhao, Yang; Shen, Wei; Fu, Haoda

    2013-01-01

    The purpose of drug development is to evaluate a drug's efficacy and safety profile. For a personalized medicine, it is important for patients and health care providers to understand the efficacy and safety trade-off when selecting a dose for a patient. In this article, we propose three different methods for jointly modeling the clinical safety and efficacy endpoints. These three methods model the correlation relationship in three different ways: modeling the joint distribution by a copula method, modeling conditional distributions, and modeling their correlations through individual means by a hierarchical model. We compare these three methods through simulations and apply these methods to a data set from a diabetes study.

  7. Development of a Preclinical Therapeutic Model of Human Brain Metastasis with Chemoradiotherapy

    PubMed Central

    Martínez-Aranda, Antonio; Hernández, Vanessa; Picón, Cristina; Modolell, Ignasi; Sierra, Angels

    2013-01-01

    Currently, survival of breast cancer patients with brain metastasis ranges from 2 to 16 months. In experimental brain metastasis studies, only 10% of lesions with the highest permeability exhibited cytotoxic responses to paclitaxel or doxorubicin. Therefore, radiation is the most frequently used treatment, and sensitizing agents, which synergize with radiation, can improve the efficacy of the therapy. In this study we used 435-Br1 cells containing the fluorescent protein (eGFP) gene and the photinus luciferase (PLuc) gene to develop a new brain metastatic cell model in mice through five in vivo/in vitro rounds. BR-eGFP-CMV/Luc-V5 brain metastatic cells induce parenchymal brain metastasis within 60.8 ± 13.8 days of intracarotid injection in all mice. We used this model to standardize a preclinical chemoradiotherapy protocol comprising three 5.5 Gy fractions delivered on consecutive days (overall dose of 16.5 Gy) which improved survival with regard to controls (60.29 ± 8.65 vs. 47.20 ± 11.14). Moreover, the combination of radiotherapy with temozolomide, 60 mg/Kg/day orally for five consecutive days doubled survival time of the mice 121.56 ± 52.53 days (Kaplan-Meier Curve, p < 0.001). This new preclinical chemoradiotherapy protocol proved useful for the study of radiation response/resistance in brain metastasis, either alone or in combination with new sensitizing agents. PMID:23591844

  8. Typhoid fever vaccines: a meta-analysis of studies on efficacy and toxicity.

    PubMed Central

    Engels, E. A.; Falagas, M. E.; Lau, J.; Bennish, M. L.

    1998-01-01

    OBJECTIVE: To estimate the efficacy and toxicity of typhoid fever vaccines. DESIGN: Meta-analysis of randomised efficacy trials and both randomised and non-randomised toxicity studies of the parenteral whole cell, oral Ty21a, and parenteral Vi vaccines. SUBJECTS: 1,866,951 subjects in 17 efficacy trials; 11,204 subjects in 20 toxicity studies. MAIN OUTCOME MEASURES: Pooled estimates of three year cumulative efficacy, year specific efficacy, and incidence of adverse events. RESULTS: Three year cumulative efficacy was 73% (95% confidence interval 65% to 80%) for two doses of whole cell vaccines (based on seven trials); 51% (35% to 63%) for three doses of Ty21a vaccine (four trials); and 55% (30% to 71%) for one dose of Vi vaccine (one trial). For whole cell and Ty21a vaccines, regimens of fewer doses were less effective. Efficacy was shown to be significant for five years for whole cell vaccines, four years for Ty21a vaccine, and two years for Vi vaccine. Neither the age of vaccine recipient nor the incidence of typhoid fever in the control group (varying from 6 to 810 cases per 100,000 person years) affected the efficacy of the whole cell or Ty21a vaccines. After vaccination, fever occurred in 15.7% (11.5% to 21.2%) of whole cell vaccine recipients, 2.0% (0.7% to 5.3%) of Ty21a vaccine recipients, and 1.1% (0.1% to 12.3%) of Vi vaccine recipients. CONCLUSIONS: Whole cell vaccines are more effective than the Ty21a and Vi vaccines but are more frequently associated with adverse events. Whether the added efficacy of the whole cell vaccines outweighs their toxicity will depend on the setting in which vaccination is used. PMID:9462316

  9. The Relationship between Pedagogical Beliefs and Teacher Efficacy: A Case Study of Chinese Foreign Language Teachers in Texas

    ERIC Educational Resources Information Center

    Liu, I-Chun

    2012-01-01

    This study investigated an emerging language learning culture by examining the relationship between teachers' pedagogical beliefs and perceived efficacy in two cities in southern Texas. Drawing on Bandura's (1994) theory of self-efficacy and Ashton and Webb's (1986) notions about teacher efficacy, a multi-sited case study was…

  10. Evaluation Of Microdosing Strategies For Studies In Preclinical Drug Development: Demonstration Of Linear Pharmacokinetics In Dogs Of A Nucleoside Analogue Over A 50-Fold Dose Range

    SciTech Connect

    Sandhu, P; Vogel, J S; Rose, M J; Ubick, E A; Brunner, J E; Wallace, M A; Adelsberger, J K; Baker, M P; Henderson, P T; Pearson, P G; Baillie, T A

    2004-04-22

    The technique of accelerator mass spectrometry (AMS) was validated successfully and utilized to study the pharmacokinetics and disposition in dogs of a preclinical drug candidate (Compound A), after oral and intravenous administration. The primary objective of this study was to examine whether Compound A displayed linear kinetics across sub-pharmacological (microdose) and pharmacological dose ranges in an animal model, prior to initiation of a human microdose study. The AMS-derived disposition properties of Compound A were comparable to data obtained via conventional techniques such as LC-MS/MS and liquid scintillation counting analyses. Thus, Compound A displayed multiphasic kinetics and possessed low plasma clearance (4.4 mL/min/kg), a long terminal elimination half-life (19.4 hr) and high oral bioavailability (82%). Currently there are no published comparisons of the kinetics of a pharmaceutical compound at pharmacological versus sub-pharmacological doses employing microdosing strategies. The present study thus provides the first description of the pharmacokinetics of a drug candidate assessed under these two dosing regimens. The data demonstrated that the pharmacokinetic properties of Compound A were similar following dosing at 0.02 mg/kg as at 1 mg/kg, indicating that in the case of Compound A, the kinetics of absorption, distribution and elimination in the dog appear to be linear across this 50-fold dose range. Moreover, the exceptional sensitivity of AMS provided a pharmacokinetic profile of Compound A, even following a microdose, which revealed aspects of the disposition of this agent that were inaccessible by conventional techniques. The applications of accelerator mass spectrometry (AMS) are broad ranging and vary from studying environmental and ecological issues such as the isotopic composition of the atmosphere, soil and water (Hughen et al., 2000; Beck et al., 2001; Keith-Roach et al., 2001; Mironov et al., 2002), to archaeology and volcanology

  11. Induction and Efficacy: A Case Study of New Zealand Newly Qualified Secondary Science Teachers

    NASA Astrophysics Data System (ADS)

    Haigh, Mavis A.; Anthony, Glenda J.

    2012-10-01

    This paper reports on 20 newly qualified secondary science teachers (NQSSTs) participating in a New Zealand study on teachers' early professional learning. The focus of our study is how these new teachers were nurtured to become competent science teachers, confident of their ability to positively influence student learning. Based on responses to a graduating questionnaire and three interviews across their first 18 months of teaching, we look at the effect of induction and contextual factors on the teachers' efficacy. While the NQSSTs overall reported relatively constant ratings of self-efficacy, they demonstrated different patterns of declared efficacy across this 18-month period. Findings regarding the influence of induction practices and contextual factors on the efficacy of these teachers are mixed.

  12. Preclinical animal study and human clinical trial data of co-electrospun poly(l-lactide-co-caprolactone) and fibrinogen mesh for anterior pelvic floor reconstruction

    PubMed Central

    Wu, Xujun; Wang, Yuru; Zhu, Cancan; Tong, Xiaowen; Yang, Ming; Yang, Li; Liu, Zhang; Huang, Weihong; Wu, Feng; Zong, Honghai; Li, Huaifang; He, Hongbing

    2016-01-01

    Synthetic and biological materials are commonly used for pelvic floor reconstruction. In this study, host tissue response and biomechanical properties of mesh fabricated from co-electrospun poly(l-lactide-co-caprolactone) (PLCL) and fibrinogen (Fg) were compared with those of polypropylene mesh (PPM) in a canine abdominal defect model. Macroscopic, microscopic, histological, and biomechanical evaluations were performed over a 24-week period. The results showed that PLCL/Fg mesh had similar host tissue responses but better initial vascularization and graft site tissue organization than PPM. The efficacy of the PLCL/Fg mesh was further examined in human pelvic floor reconstruction. Operation time, intraoperative blood loss, and pelvic organ prolapse quantification during 6-month follow-up were compared for patients receiving PLCL/Fg mesh versus PPM. According to the pelvic organ prolapse quantification scores, the anterior vaginal wall 3 cm proximal to the hymen point (Aa point), most distal edge of the cervix or vaginal cuff scar point (C point), and posterior fornix point (D point) showed significant improvement (P<0.01) at 1, 3, and 6 months for both groups compared with preoperatively. At 6 months, improvements at the Aa point in the PLCL/Fg group were significantly more (P<0.005) than the PPM group, indicating that, while both materials improve the patient symptoms, PLCL/Fg mesh resulted in more obvious improvement. PMID:26893556

  13. Preclinical animal study and human clinical trial data of co-electrospun poly(L-lactide-co-caprolactone) and fibrinogen mesh for anterior pelvic floor reconstruction.

    PubMed

    Wu, Xujun; Wang, Yuru; Zhu, Cancan; Tong, Xiaowen; Yang, Ming; Yang, Li; Liu, Zhang; Huang, Weihong; Wu, Feng; Zong, Honghai; Li, Huaifang; He, Hongbing

    2016-01-01

    Synthetic and biological materials are commonly used for pelvic floor reconstruction. In this study, host tissue response and biomechanical properties of mesh fabricated from co-electrospun poly(L-lactide-co-caprolactone) (PLCL) and fibrinogen (Fg) were compared with those of polypropylene mesh (PPM) in a canine abdominal defect model. Macroscopic, microscopic, histological, and biomechanical evaluations were performed over a 24-week period. The results showed that PLCL/Fg mesh had similar host tissue responses but better initial vascularization and graft site tissue organization than PPM. The efficacy of the PLCL/Fg mesh was further examined in human pelvic floor reconstruction. Operation time, intraoperative blood loss, and pelvic organ prolapse quantification during 6-month follow-up were compared for patients receiving PLCL/Fg mesh versus PPM. According to the pelvic organ prolapse quantification scores, the anterior vaginal wall 3 cm proximal to the hymen point (Aa point), most distal edge of the cervix or vaginal cuff scar point (C point), and posterior fornix point (D point) showed significant improvement (P<0.01) at 1, 3, and 6 months for both groups compared with preoperatively. At 6 months, improvements at the Aa point in the PLCL/Fg group were significantly more (P<0.005) than the PPM group, indicating that, while both materials improve the patient symptoms, PLCL/Fg mesh resulted in more obvious improvement. PMID:26893556

  14. Self-Efficacy After Life Skills Training: A Case-Control Study

    PubMed Central

    Rezayat, Fatemeh; Dehghan Nayeri, Nahid

    2013-01-01

    Background: Nursing students’ self-efficacy is a predictor for their educational progress. Students, who believe that they can be successful in their studies, are more confident. Therefore, many universities have focused on life skills training programs to improve the mental health of their students. Objectives: This study was conducted to evaluate and compare self-efficacy in two groups of nursing students of Tehran University of Medical Sciences (TUMS). One group of students was trained on life skill programs, and the second group was not trained on the issue. Materials and Methods: A case-control study was conducted on two groups of nursing students in TUMS in the late 2012. The case group (n = 112) had passed life skills training course, and the control group (n = 139) was not trained on the issue. Data was collected using a questionnaire containing 12 questions about demographic features, and the Sherer’s general self-efficacy questionnaire. Data analysis was performed using independent sample t-test, Chi-square, odds ratio, and Fisher’s exact test. Results: In the untrained and trained groups, 23% and 8% of the students had very high self-efficacy, respectively. The overall mean scores of self-efficacy were 41.99 ± 9.31 and 38.99 ± 10.48 in the trained and untrained groups, respectively (P = 0.015), and the higher mean score indicates lower level of self-efficacy. A significant difference was also found between the self-efficacy and family income (P = 0.029). Conclusions: The present study showed that life skills training program did not affect self-efficacy of nursing students. Perhaps, the methods used in education were influencing and then, more effective techniques such as role-play and group discussion should be substituted in life skills training. PMID:25414884

  15. Pharmacoeconomic evaluation of new treatments: efficacy versus effectiveness studies?

    PubMed Central

    Bombardier, C; Maetzel, A

    1999-01-01

    The juxtaposition of economic and clinical evaluation raises new issues in the design of clinical trials. Recent pharmacoeconomic guidelines provide some direction, but do not deal with the appropriate timing of economic evaluations in the drug developmental process. Ideally, pharmacoeconomic data should be available at the time of the regulatory and formulary decision making. Current pivotal phase III trials do not provide these data; they are designed to test safety and efficacy (does the drug work under optimal circumstances?) and not to answer questions about the effectiveness of a drug, the more relevant question for economic analysis (does the drug work in usual care?). The use of more "naturalistic" designs for some phase III randomised trials has been suggested. These so called "effectiveness trials" more closely reflect routine clinical practice. They use a more flexible dosage regimen, and a "usual care" instead of a placebo comparator. Patients randomised are more representative of actual practice and outcomes include quality of life and utility measures. They are more suited to provide the data needed to estimate the real benefit of the treatment in actual care. When costs are applied and compared with these benefits, you can estimate the efficiency of allocating resources to this new drug. Increasing the use of effectiveness trials in phase III would decrease the need for economic modelling.

 PMID:10577979

  16. Five decades of progress in hematopoietic cell transplantation based on the preclinical canine model

    PubMed Central

    Lupu, Marilena; Storb, Rainer

    2009-01-01

    The preclinical canine model has proved valuable for the development of principles and techniques of hematopoietic cell transplantation (HCT) applicable to human patients. Studies in random-bred dogs concerning the impact of histocompatibility barriers on engraftment and graft-versus-host disease, the kinetics of immunological reconstitution, the efficacy of various pre-transplant conditioning regimens, post-transplantation immunosuppression protocols, treatment of malignant diseases, and graft-versus-tumor effects have advanced HCT from an investigational therapy with uncertain clinical benefit half a century ago to an important treatment choice for thousands of patients treated annually in transplantation centers worldwide. More recent preclinical canine studies have resulted in the clinical translation of nonmyeloablative, minimally invasive transplantation protocols that have extended allogeneic HCT to include older human patients with malignant and non-malignant, acquired or inherited hematological disorders, and those with comorbid conditions. Here we review the contributions of the canine model to modern HCT and describe the usefulness of HCT for the treatment of canine hematological disorders. PMID:19754798

  17. Preclinical and clinical evaluation of intraductally administered agents in early breast cancer.

    PubMed

    Stearns, Vered; Mori, Tsuyoshi; Jacobs, Lisa K; Khouri, Nagi F; Gabrielson, Edward; Yoshida, Takahiro; Kominsky, Scott L; Huso, David L; Jeter, Stacie; Powers, Penny; Tarpinian, Karineh; Brown, Regina J; Lange, Julie R; Rudek, Michelle A; Zhang, Zhe; Tsangaris, Theodore N; Sukumar, Saraswati

    2011-10-26

    Most breast cancers originate in the epithelial cells lining the breast ducts. Intraductal administration of cancer therapeutics would lead to high drug exposure to ductal cells and eliminate preinvasive neoplasms while limiting systemic exposure. We performed preclinical studies in N-methyl-N'-nitrosourea-treated rats to compare the effects of 5-fluorouracil, carboplatin, nanoparticle albumin-bound paclitaxel, and methotrexate to the previously reported efficacy of pegylated liposomal doxorubicin (PLD) on treatment of early and established mammary tumors. Protection from tumor growth was observed with all five agents, with extensive epithelial destruction present only in PLD-treated rats. Concurrently, we initiated a clinical trial to establish the feasibility, safety, and maximum tolerated dose of intraductal PLD. In each eligible woman awaiting mastectomy, we visualized one ductal system and administered dextrose or PLD using a dose-escalation schema (2 to 10 mg). Intraductal administration was successful in 15 of 17 women with no serious adverse events. Our preclinical studies suggest that several agents are candidates for intraductal therapy. Our clinical trial supports the feasibility of intraductal administration of agents in the outpatient setting. If successful, administration of agents directly into the ductal system may allow for "breast-sparing mastectomy" in select women.

  18. A De Novo Tool to Measure the Preclinical Learning Climate of Medical Faculties in Turkey

    ERIC Educational Resources Information Center

    Yilmaz, Nilufer Demiral; Velipasaoglu, Serpil; Sahin, Hatice; Basusta, Bilge Uzun; Midik, Ozlem; Coskun, Ozlem; Budakoglu, Isil Irem; Mamakli, Sumer; Tengiz, Funda Ifakat; Durak, Halil Ibrahim; Ozan, Sema

    2015-01-01

    Although several scales are used to measure general and clinical learning climates, there are no scales that assess the preclinical learning climate. Therefore, the purpose of this study was to develop an effective measurement tool in order to assess the preclinical learning climate. In this cross-sectional study, data were collected from 3,540…

  19. Micro-ultrasound for preclinical imaging

    PubMed Central

    Foster, F. Stuart; Hossack, John; Adamson, S. Lee

    2011-01-01

    Over the past decade, non-invasive preclinical imaging has emerged as an important tool to facilitate biomedical discovery. Not only have the markets for these tools accelerated, but the numbers of peer-reviewed papers in which imaging end points and biomarkers have been used have grown dramatically. High frequency ‘micro-ultrasound’ has steadily evolved in the post-genomic era as a rapid, comparatively inexpensive imaging tool for studying normal development and models of human disease in small animals. One of the fundamental barriers to this development was the technological hurdle associated with high-frequency array transducers. Recently, new approaches have enabled the upper limits of linear and phased arrays to be pushed from about 20 to over 50 MHz enabling a broad range of new applications. The innovations leading to the new transducer technology and scanner architecture are reviewed. Applications of preclinical micro-ultrasound are explored for developmental biology, cancer, and cardiovascular disease. With respect to the future, the latest developments in high-frequency ultrasound imaging are described. PMID:22866232

  20. Micro-ultrasound for preclinical imaging.

    PubMed

    Foster, F Stuart; Hossack, John; Adamson, S Lee

    2011-08-01

    Over the past decade, non-invasive preclinical imaging has emerged as an important tool to facilitate biomedical discovery. Not only have the markets for these tools accelerated, but the numbers of peer-reviewed papers in which imaging end points and biomarkers have been used have grown dramatically. High frequency 'micro-ultrasound' has steadily evolved in the post-genomic era as a rapid, comparatively inexpensive imaging tool for studying normal development and models of human disease in small animals. One of the fundamental barriers to this development was the technological hurdle associated with high-frequency array transducers. Recently, new approaches have enabled the upper limits of linear and phased arrays to be pushed from about 20 to over 50 MHz enabling a broad range of new applications. The innovations leading to the new transducer technology and scanner architecture are reviewed. Applications of preclinical micro-ultrasound are explored for developmental biology, cancer, and cardiovascular disease. With respect to the future, the latest developments in high-frequency ultrasound imaging are described.

  1. Mitigating risk in academic preclinical drug discovery.

    PubMed

    Dahlin, Jayme L; Inglese, James; Walters, Michael A

    2015-04-01

    The number of academic drug discovery centres has grown considerably in recent years, providing new opportunities to couple the curiosity-driven research culture in academia with rigorous preclinical drug discovery practices used in industry. To fully realize the potential of these opportunities, it is important that academic researchers understand the risks inherent in preclinical drug discovery, and that translational research programmes are effectively organized and supported at an institutional level. In this article, we discuss strategies to mitigate risks in several key aspects of preclinical drug discovery at academic drug discovery centres, including organization, target selection, assay design, medicinal chemistry and preclinical pharmacology.

  2. Mitigating risk in academic preclinical drug discovery.

    PubMed

    Dahlin, Jayme L; Inglese, James; Walters, Michael A

    2015-04-01

    The number of academic drug discovery centres has grown considerably in recent years, providing new opportunities to couple the curiosity-driven research culture in academia with rigorous preclinical drug discovery practices used in industry. To fully realize the potential of these opportunities, it is important that academic researchers understand the risks inherent in preclinical drug discovery, and that translational research programmes are effectively organized and supported at an institutional level. In this article, we discuss strategies to mitigate risks in several key aspects of preclinical drug discovery at academic drug discovery centres, including organization, target selection, assay design, medicinal chemistry and preclinical pharmacology. PMID:25829283

  3. Efficacy of Five Standards in Raising Student Achievement: Findings from Three Studies

    ERIC Educational Resources Information Center

    Doherty, R. William; Hilberg, R. Soleste

    2008-01-01

    The authors reported findings from 3 studies examining the efficacy of Five Standards pedagogy in raising student achievement. Studies 1 and 2 were randomized designs; Study 3 was a quasi-experimental design. Samples included 53 teachers and 622 predominantly low-income Latino students in Grades 1-4. Studies assessed model fidelity with the…

  4. Preclinical impact of bevacizumab on brain and tumor distribution of irinotecan and temozolomide.

    PubMed

    Goldwirt, Lauriane; Beccaria, Kevin; Carpentier, Alexandre; Idbaih, Ahmed; Schmitt, Charlotte; Levasseur, Camille; Labussiere, Marianne; Milane, Aline; Farinotti, Robert; Fernandez, Christine

    2015-04-01

    Glioblastoma (GBM) is the most common primary malignant brain tumour in adults. Prognosis of GBM patients is poor with median overall survival around 15 months. Temozolomide is the chemotherapeutic agent used in the standard of care of newly diagnosed GBM patients relying on radiotherapy with concurrent chemotherapy followed by chemotherapy alone. Irinotecan has shown some efficacy in recurrent malignant gliomas. Bevacizumab has been combined with irinotecan in the treatment of recurrent GBM and with temozolomide in newly diagnosed GBM. As the efficacy of GBM treatments relies on their brain distribution through the blood brain barrier, the aim of the present preclinical work was to study, in in vivo models, the impact of bevacizumab on brain and tumor distribution of temozolomide and irinotecan. Our results show that bevacizumab pre-treatment was associated with a reduced temozolomide brain distribution in tumor-free mice. In tumor bearing mice, bevacizumab increased temozolomide tumor distribution, although not statistically significant. In both tumor-free and tumor-bearing mice, bevacizumab does not modify brain distribution of irinotecan and its metabolite SN-38. Bevacizumab impacts brain distribution of some anti-tumor drugs and potentially their efficacy in GBM. Further studies are warranted to investigate other therapeutic combination.

  5. A Comparative Study of Pre-Service Teachers' Teaching Efficacy Beliefs before and after Work-Integrated Learning: Part Two

    ERIC Educational Resources Information Center

    Junqueira, K. E.; Matoti, S. N.

    2013-01-01

    The study, which is grounded in Bandura's concept of self-efficacy, assessed the teaching efficacy beliefs of student teachers before and after completing six months of work-integrated learning. This was necessitated by research which shows that self-efficacy is an important aspect which influences a teacher's ability to teach as well as the…

  6. Influences of Self-Efficacy, Response Efficacy, and Reactance on Responses to Cigarette Health Warnings: A Longitudinal Study of Adult Smokers in Australia and Canada

    PubMed Central

    Thrasher, James F.; Swayampakala, Kamala; Borland, Ron; Nagelhout, Gera; Yong, Hua-Hie; Hammond, David; Bansal-Travers, Maansi; Thompson, Mary; Hardin, James

    2016-01-01

    ABSTRACT Guided by the extended parallel process model (EPPM) and reactance theory, this study examined the relationship between efficacy beliefs, reactance, and adult smokers’ responses to pictorial health warning labels (HWL) on cigarette packaging, including whether efficacy beliefs or reactance modify the relationship between HWL responses and subsequent smoking cessation behavior. Four waves of data were analyzed from prospective cohorts of smokers in Australia and Canada (n = 7,120 observations) over a period of time after implementation of more prominent, pictorial HWLs. Three types of HWL responses were studied: psychological threat responses (i.e., thinking about risks from smoking), forgoing cigarettes due to HWLs, and avoiding HWLs. The results from Generalized Estimating Equation models indicated that stronger efficacy beliefs and lower trait reactance were significantly associated with greater psychological threat responses to HWLs. Similar results were found for models predicting forgoing behavior, although response efficacy was inversely associated with it. Only response efficacy was significantly associated with avoiding HWLs, showing a positive relationship. Higher self-efficacy and stronger responses to HWLs, no matter the type, were associated with attempting to quit in the follow-up period; reactance was unassociated. No statistically significant interactions were found. These results suggest that stronger efficacy beliefs and lower trait reactance are associated with some stronger responses to fear-arousing HWL responses; however, these HWL responses appear no less likely to lead to cessation attempts among smokers with different levels of self-efficacy to quit, of response efficacy beliefs, or of trait reactance against attempts to control their behavior. PMID:27135826

  7. Influences of Self-Efficacy, Response Efficacy, and Reactance on Responses to Cigarette Health Warnings: A Longitudinal Study of Adult Smokers in Australia and Canada.

    PubMed

    Thrasher, James F; Swayampakala, Kamala; Borland, Ron; Nagelhout, Gera; Yong, Hua-Hie; Hammond, David; Bansal-Travers, Maansi; Thompson, Mary; Hardin, James

    2016-12-01

    Guided by the extended parallel process model (EPPM) and reactance theory, this study examined the relationship between efficacy beliefs, reactance, and adult smokers' responses to pictorial health warning labels (HWL) on cigarette packaging, including whether efficacy beliefs or reactance modify the relationship between HWL responses and subsequent smoking cessation behavior. Four waves of data were analyzed from prospective cohorts of smokers in Australia and Canada (n = 7,120 observations) over a period of time after implementation of more prominent, pictorial HWLs. Three types of HWL responses were studied: psychological threat responses (i.e., thinking about risks from smoking), forgoing cigarettes due to HWLs, and avoiding HWLs. The results from Generalized Estimating Equation models indicated that stronger efficacy beliefs and lower trait reactance were significantly associated with greater psychological threat responses to HWLs. Similar results were found for models predicting forgoing behavior, although response efficacy was inversely associated with it. Only response efficacy was significantly associated with avoiding HWLs, showing a positive relationship. Higher self-efficacy and stronger responses to HWLs, no matter the type, were associated with attempting to quit in the follow-up period; reactance was unassociated. No statistically significant interactions were found. These results suggest that stronger efficacy beliefs and lower trait reactance are associated with some stronger responses to fear-arousing HWL responses; however, these HWL responses appear no less likely to lead to cessation attempts among smokers with different levels of self-efficacy to quit, of response efficacy beliefs, or of trait reactance against attempts to control their behavior. PMID:27135826

  8. Advantages of Papio anubis for preclinical testing of immunotoxicity of candidate therapeutic antagonist antibodies targeting CD28.

    PubMed

    Poirier, Nicolas; Mary, Caroline; Le Bas-Bernardet, Stephanie; Daguin, Veronique; Belarif, Lyssia; Chevalier, Melanie; Hervouet, Jeremy; Minault, David; Ville, Simon; Charpy, Vianney; Blancho, Gilles; Vanhove, Bernard

    2014-01-01

    Antagonist anti-CD28 antibodies prevent T-cell costimulation and are functionally different from CTLA4Ig since they cannot block CTLA-4 and PDL-1 co-inhibitory signals. They demonstrated preclinical efficacy in suppressing effector T cells while enhancing immunoregulatory mechanisms. Because a severe cytokine release syndrome was observed during the Phase 1 study with the superagonist anti-CD28 TGN1412, development of other anti-CD28 antibodies requires careful preclinical evaluation to exclude any potential immunotoxicity side-effects. The failure to identify immunological toxicity of TGN1412 using macaques led us to investigate more relevant preclinical models. We report here that contrary to macaques, and like in man, all baboon CD4-positive T lymphocytes express CD28 in their effector memory cells compartment, a lymphocyte subtype that is the most prone to releasing cytokines after reactivation. Baboon lymphocytes are able to release pro-inflammatory cytokines in vitro in response to agonist or superagonist anti-CD28 antibodies. Furthermore, we compared the reactivity of human and baboon lymphocytes after transfer into non obese diabetic/severe combined immunodeficiency (NOD/SCID) interleukin-2rγ knockout mice and confirmed that both cell types could release inflammatory cytokines in situ after injection of agonistic anti-CD28 antibodies. In contrast, FR104, a monovalent antagonistic anti-CD28 antibody, did not elicit T cell activation in these assays, even in the presence of anti-drug antibodies. Infusion to baboons also resulted in an absence of cytokine release. In conclusion, the baboon represents a suitable species for preclinical immunotoxicity evaluation of anti-CD28 antibodies because their effector memory T cells do express CD28 and because cytokine release can be assessed in vitro and trans vivo.

  9. Review. Facts and fiction of phytotherapy for prostate cancer: a critical assessment of preclinical and clinical data.

    PubMed

    Von Löw, Eva C; Perabo, Frank G E; Siener, Roswitha; Müller, Stefan C

    2007-01-01

    The objective of this work was to substantially review all preclinical and clinical data on phytochemicals, such as genistein, lycopene, curcumin, epigallocatechin-gallate, and resveratrol, in terms of their effects as a potential treatment of prostate cancer. It is known, that prostate cancer patients increasingly use complementary and alternative medicines in the hope of preventing or curing cancer. The preclinical data for the phytochemicals presented in this review show a remarkable efficacy against prostate cancer cells in vitro, with molecular targets ranging from cell cycle regulation to induction of apoptosis. In addition, well-conducted animal experiments support the belief that these substances might have a clinical activity on human cancer. However, it is impossible to make definite statements or conclusions on the clinical efficacy in cancer patients because of the great variability and differences of the study designs, small patient numbers, short treatment duration and lack of a standardised drug formulation. Although some results from these clinical studies seem encouraging, reliable or long-term data on tumor recurrence, disease progression and survival are unknown. At present, there is no convincing clinical proof or evidence that the cited phythochemicals might be used in an attempt to cure cancer of the prostate. PMID:17436567

  10. An Oral Salmonella-Based Vaccine Inhibits Liver Metastases by Promoting Tumor-Specific T-Cell-Mediated Immunity in Celiac and Portal Lymph Nodes: A Preclinical Study.

    PubMed

    Vendrell, Alejandrina; Mongini, Claudia; Gravisaco, María José; Canellada, Andrea; Tesone, Agustina Inés; Goin, Juan Carlos; Waldner, Claudia Inés

    2016-01-01

    Primary tumor excision is one of the most widely used therapies of cancer. However, the risk of metastases development still exists following tumor resection. The liver is a common site of metastatic disease for numerous cancers. Breast cancer is one of the most frequent sources of metastases to the liver. The aim of this work was to evaluate the efficacy of the orally administered Salmonella Typhi vaccine strain CVD 915 on the development of liver metastases in a mouse model of breast cancer. To this end, one group of BALB/c mice was orogastrically immunized with CVD 915, while another received PBS as a control. After 24 h, mice were injected with LM3 mammary adenocarcinoma cells into the spleen and subjected to splenectomy. This oral Salmonella-based vaccine produced an antitumor effect, leading to a decrease in the number and volume of liver metastases. Immunization with Salmonella induced an early cellular immune response in mice. This innate stimulation rendered a large production of IFN-γ by intrahepatic immune cells (IHIC) detected within 24 h. An antitumor adaptive immunity was found in the liver and celiac and portal lymph nodes (LDLN) 21 days after oral bacterial inoculation. The antitumor immune response inside the liver was associated with increased CD4(+) and dendritic cell populations as well as with an inflammatory infiltrate located around liver metastatic nodules. Enlarged levels of inflammatory cytokines (IFN-γ and TNF) were also detected in IHIC. Furthermore, a tumor-specific production of IFN-γ and TNF as well as tumor-specific IFN-γ-producing CD8 T cells (CD8(+)IFN-γ(+)) were found in the celiac and portal lymph nodes of Salmonella-treated mice. This study provides first evidence for the involvement of LDLN in the development of an efficient cellular immune response against hepatic tumors, which resulted in the elimination of liver metastases after oral Salmonella-based vaccination. PMID:26973649

  11. An Oral Salmonella-Based Vaccine Inhibits Liver Metastases by Promoting Tumor-Specific T-Cell-Mediated Immunity in Celiac and Portal Lymph Nodes: A Preclinical Study

    PubMed Central

    Vendrell, Alejandrina; Mongini, Claudia; Gravisaco, María José; Canellada, Andrea; Tesone, Agustina Inés; Goin, Juan Carlos; Waldner, Claudia Inés

    2016-01-01

    Primary tumor excision is one of the most widely used therapies of cancer. However, the risk of metastases development still exists following tumor resection. The liver is a common site of metastatic disease for numerous cancers. Breast cancer is one of the most frequent sources of metastases to the liver. The aim of this work was to evaluate the efficacy of the orally administered Salmonella Typhi vaccine strain CVD 915 on the development of liver metastases in a mouse model of breast cancer. To this end, one group of BALB/c mice was orogastrically immunized with CVD 915, while another received PBS as a control. After 24 h, mice were injected with LM3 mammary adenocarcinoma cells into the spleen and subjected to splenectomy. This oral Salmonella-based vaccine produced an antitumor effect, leading to a decrease in the number and volume of liver metastases. Immunization with Salmonella induced an early cellular immune response in mice. This innate stimulation rendered a large production of IFN-γ by intrahepatic immune cells (IHIC) detected within 24 h. An antitumor adaptive immunity was found in the liver and celiac and portal lymph nodes (LDLN) 21 days after oral bacterial inoculation. The antitumor immune response inside the liver was associated with increased CD4+ and dendritic cell populations as well as with an inflammatory infiltrate located around liver metastatic nodules. Enlarged levels of inflammatory cytokines (IFN-γ and TNF) were also detected in IHIC. Furthermore, a tumor-specific production of IFN-γ and TNF as well as tumor-specific IFN-γ-producing CD8 T cells (CD8+IFN-γ+) were found in the celiac and portal lymph nodes of Salmonella-treated mice. This study provides first evidence for the involvement of LDLN in the development of an efficient cellular immune response against hepatic tumors, which resulted in the elimination of liver metastases after oral Salmonella-based vaccination. PMID:26973649

  12. An Oral Salmonella-Based Vaccine Inhibits Liver Metastases by Promoting Tumor-Specific T-Cell-Mediated Immunity in Celiac and Portal Lymph Nodes: A Preclinical Study.

    PubMed

    Vendrell, Alejandrina; Mongini, Claudia; Gravisaco, María José; Canellada, Andrea; Tesone, Agustina Inés; Goin, Juan Carlos; Waldner, Claudia Inés

    2016-01-01

    Primary tumor excision is one of the most widely used therapies of cancer. However, the risk of metastases development still exists following tumor resection. The liver is a common site of metastatic disease for numerous cancers. Breast cancer is one of the most frequent sources of metastases to the liver. The aim of this work was to evaluate the efficacy of the orally administered Salmonella Typhi vaccine strain CVD 915 on the development of liver metastases in a mouse model of breast cancer. To this end, one group of BALB/c mice was orogastrically immunized with CVD 915, while another received PBS as a control. After 24 h, mice were injected with LM3 mammary adenocarcinoma cells into the spleen and subjected to splenectomy. This oral Salmonella-based vaccine produced an antitumor effect, leading to a decrease in the number and volume of liver metastases. Immunization with Salmonella induced an early cellular immune response in mice. This innate stimulation rendered a large production of IFN-γ by intrahepatic immune cells (IHIC) detected within 24 h. An antitumor adaptive immunity was found in the liver and celiac and portal lymph nodes (LDLN) 21 days after oral bacterial inoculation. The antitumor immune response inside the liver was associated with increased CD4(+) and dendritic cell populations as well as with an inflammatory infiltrate located around liver metastatic nodules. Enlarged levels of inflammatory cytokines (IFN-γ and TNF) were also detected in IHIC. Furthermore, a tumor-specific production of IFN-γ and TNF as well as tumor-specific IFN-γ-producing CD8 T cells (CD8(+)IFN-γ(+)) were found in the celiac and portal lymph nodes of Salmonella-treated mice. This study provides first evidence for the involvement of LDLN in the development of an efficient cellular immune response against hepatic tumors, which resulted in the elimination of liver metastases after oral Salmonella-based vaccination.

  13. Malaria Vaccine Adjuvants: Latest Update and Challenges in Preclinical and Clinical Research

    PubMed Central

    Mata, Elena; Salvador, Aiala; Igartua, Manoli; Hernández, Rosa María; Pedraz, José Luis

    2013-01-01

    There is no malaria vaccine currently available, and the most advanced candidate has recently reported a modest 30% efficacy against clinical malaria. Although many efforts have been dedicated to achieve this goal, the research was mainly directed to identify antigenic targets. Nevertheless, the latest progresses on understanding how immune system works and the data recovered from vaccination studies have conferred to the vaccine formulation its deserved relevance. Additionally to the antigen nature, the manner in which it is presented (delivery adjuvants) as well as the immunostimulatory effect of the formulation components (immunostimulants) modulates the immune response elicited. Protective immunity against malaria requires the induction of humoral, antibody-dependent cellular inhibition (ADCI) and effector and memory cell responses. This review summarizes the status of adjuvants that have been or are being employed in the malaria vaccine development, focusing on the pharmaceutical and immunological aspects, as well as on their immunization outcomings at clinical and preclinical stages. PMID:23710439

  14. MEMS-enabled implantable drug infusion pumps for laboratory animal research, preclinical, and clinical applications

    PubMed Central

    Meng, Ellis; Hoang, Tuan

    2012-01-01

    Innovation in implantable drug delivery devices is needed for novel pharmaceutical compounds such as certain biologics, gene therapy, and other small molecules that are not suitable for administration by oral, topical, or intravenous routes. This invasive dosing scheme seeks to directly bypass physiological barriers presented by the human body, release the appropriate drug amount at the site of treatment, and maintain the drug bioavailability for the required duration of administration to achieve drug efficacy. Advances in microtechnologies have led to novel MEMS-enabled implantable drug infusion pumps with unique performance and feature sets. In vivo demonstration of micropumps for laboratory animal research and preclinical studies include acute rapid radiolabeling, short-term delivery of nanomedicine for cancer treatment, and chronic ocular drug dosing. Investigation of MEMS actuators, valves, and other microstructures for on-demand dosing control may enable next generation implantable pumps with high performance within a miniaturized form factor for clinical applications. PMID:22926321

  15. Measles vaccine efficacy study in a Canberra high school: a study following a measles outbreak.

    PubMed

    Cheah, D; Lane, J M; Passaris, I

    1993-12-01

    An outbreak of measles which occurred in Canberra between October and December, 1991, was investigated to estimate the public health utility of the vaccine. The measles vaccine efficacy was determined for the 13-15 year old children in a selected high school. During the outbreak, at least 82 Canberra children contracted measles. Teenage males accounted for 56% of total cases, and 22% of cases were confirmed by serology. The vaccine coverage in the high school studied decreased with increasing school years, varying from 85.8% in Grade 8 to 79.2% in Grade 10. The highest attack rate occurred in Grade 10 (66/1000). The vaccine efficacy for age 13-15 was estimated to be 72% (95% Cl, 45-86%) but varied from 67 to 73%. Measles remains a serious disease of childhood in Australia. The elimination of measles is only partly dependent on the vaccine coverage of children. Issues relating to the effectiveness of vaccine are also important. A two dose vaccine strategy with the second dose of measles, mumps, rubella vaccine (MMR), given preferably in the last year of primary school or the first year of high school, is supported by the findings of this study.

  16. Clinical research and diagnostic efficacy studies in the oral and maxillofacial radiology literature: 1996–2005

    PubMed Central

    Kim, IH; Patel, MJ; Hirt, SL; Kantor, ML

    2011-01-01

    Objectives The aim of this study was to determine the level of evidence that is published in the oral and maxillofacial radiology (OMR) literature. Methods OMR papers published in Dentomaxillofacial Radiology and Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology and Endodontology between 1996 and 2005 were classified using epidemiological study design and diagnostic efficacy hierarchies. The country of origin and number of authors were noted. Results Of the 725 articles, 384 could be classified with the epidemiological study design hierarchy: 155 (40%) case reports/series and 207 (54%) cross-sectional studies. The distribution of study designs was not statistically significant across time (Fisher's exact test, P = 0.06) or regions (P = 0.89). The diagnostic efficacy hierarchy was applicable to 246 articles: 71 (29%) technical efficacy and 166 (67%) diagnostic accuracy studies. The distribution of efficacy levels was not statistically significant across time (P = 0.22) but was significant across regions (P < 0.01). Authors from Japan produced 26% of the papers with a mean ± standard deviation of 5.78 ± 1.98 authors per paper (APP); American authors, 23% (3.78 ± 1.72 APP); and all others, 51% (3.76 ± 1.51 APP). Conclusion The OMR literature consisted mostly of case reports/series, cross-sectional, technical efficacy and diagnostic accuracy studies. Such studies do not provide strong evidence for clinical decision making nor do they address the impact of diagnostic imaging on patient care. More studies at the higher end of the study design and efficacy hierarchies are needed in order to make wise choices regarding clinical decisions and resource allocations. PMID:21697152

  17. The basics of preclinical drug development for neurodegenerative disease indications

    PubMed Central

    Steinmetz, Karen L; Spack, Edward G

    2009-01-01

    Preclinical development encompasses the activities that link drug discovery in the laboratory to initiation of human clinical trials. Preclinical studies can be designed to identify a lead candidate from several hits; develop the best procedure for new drug scale-up; select the best formulation; determine the route, frequency, and duration of exposure; and ultimately support the intended clinical trial design. The details of each preclinical development package can vary, but all have some common features. Rodent and nonrodent mammalian models are used to delineate the pharmacokinetic profile and general safety, as well as to identify toxicity patterns. One or more species may be used to determine the drug's mean residence time in the body, which depends on inherent absorption, distribution, metabolism, and excretion properties. For drugs intended to treat Alzheimer's disease or other brain-targeted diseases, the ability of a drug to cross the blood brain barrier may be a key issue. Toxicology and safety studies identify potential target organs for adverse effects and define the Therapeutic Index to set the initial starting doses in clinical trials. Pivotal preclinical safety studies generally require regulatory oversight as defined by US Food and Drug Administration (FDA) Good Laboratory Practices and international guidelines, including the International Conference on Harmonisation. Concurrent preclinical development activities include developing the Clinical Plan and preparing the new drug product, including the associated documentation to meet stringent FDA Good Manufacturing Practices regulatory guidelines. A wide range of commercial and government contract options are available for investigators seeking to advance their candidate(s). Government programs such as the Small Business Innovative Research and Small Business Technology Transfer grants and the National Institutes of Health Rapid Access to Interventional Development Pilot Program provide funding and

  18. The basics of preclinical drug development for neurodegenerative disease indications.

    PubMed

    Steinmetz, Karen L; Spack, Edward G

    2009-01-01

    Preclinical development encompasses the activities that link drug discovery in the laboratory to initiation of human clinical trials. Preclinical studies can be designed to identify a lead candidate from several hits; develop the best procedure for new drug scale-up; select the best formulation; determine the route, frequency, and duration of exposure; and ultimately support the intended clinical trial design. The details of each preclinical development package can vary, but all have some common features. Rodent and nonrodent mammalian models are used to delineate the pharmacokinetic profile and general safety, as well as to identify toxicity patterns. One or more species may be used to determine the drug's mean residence time in the body, which depends on inherent absorption, distribution, metabolism, and excretion properties. For drugs intended to treat Alzheimer's disease or other brain-targeted diseases, the ability of a drug to cross the blood brain barrier may be a key issue. Toxicology and safety studies identify potential target organs for adverse effects and define the Therapeutic Index to set the initial starting doses in clinical trials. Pivotal preclinical safety studies generally require regulatory oversight as defined by US Food and Drug Administration (FDA) Good Laboratory Practices and international guidelines, including the International Conference on Harmonization. Concurrent preclinical development activities include developing the Clinical Plan and preparing the new drug product, including the associated documentation to meet stringent FDA Good Manufacturing Practices regulatory guidelines. A wide range of commercial and government contract options are available for investigators seeking to advance their candidate(s). Government programs such as the Small Business Innovative Research and Small Business Technology Transfer grants and the National Institutes of Health Rapid Access to Interventional Development Pilot Program provide funding and

  19. Assessing the Effects of Collaborative Professional Learning: Efficacy Shifts in a Three-Year Mathematics Study

    ERIC Educational Resources Information Center

    Bruce, Catherine D.; Flynn, Tara

    2012-01-01

    Researchers examine the outcomes of professional collaborative inquiry in mathematics on teacher efficacy in a three-year study of teacher professional learning in Canada. The study applies a mixed methods approach involving over 200 teachers and 1000 students as well as case study sites in English and French. The collaborative inquiry-based…

  20. A Study on Physical Education Teachers: The Correlation between Self-Efficacy and Job Satisfaction

    ERIC Educational Resources Information Center

    Yildirim, Irfan

    2015-01-01

    The aim of the study was to determine the correlation between self-efficacy and job satisfaction among the physical education teachers. The study was carried out in correlational survey model and the study sample was made up by 306 physical education teachers who worked in different geographical regions of Turkey. The data were assessed using SPSS…

  1. Lesson Study: Professional Development and Its Impact on Science Teacher Self-Efficacy

    ERIC Educational Resources Information Center

    Roberts, Megan Rae

    2010-01-01

    This study focuses on an analysis of a professional development program known as lesson study via data obtained during an in-service professional development program for secondary school science teachers. The purpose of this study was to examine the self-efficacy beliefs of one group of science teachers related to their experiences in a lesson…

  2. ICT Competence and Lecturers' Job Efficacy: A Study of Two Universities in Nigeria

    ERIC Educational Resources Information Center

    Akpan, Charles P.

    2014-01-01

    The study sought to establish the influence of ICT competence on lecturers' job efficacy in two universities in Nigeria. The sample of the study consisted of 500 university teachers randomly sampled from a population of 1,795 teachers. The results of the study revealed that male and female lecturers did not differ significantly in their level of…

  3. Preservice Elementary Teachers' Development of Self-Efficacy and Confidence to Teach Science: A Case Study

    NASA Astrophysics Data System (ADS)

    Gunning, Amanda M.; Mensah, Felicia Moore

    2011-03-01

    This study examines the self-efficacy of one preservice elementary school teacher (Kasey) during and after her participation in Science in Childhood Education—a 16-week, elementary preservice science methods course. The case study of this teacher is situated in the context of the class as a whole. This is accomplished through interviewing the one teacher and examining artifacts and observations of the entire class. The results of these experiences are studied to determine what changes have taken place in the participants' self-efficacy in science teaching as well as the one preservice teacher in greater detail. Because self efficacy is influential to student learning, the results of this study have significant implications for the design of elementary teacher education programs and the support of elementary teachers in teaching science.

  4. Lesson study: Professional development and its impact on science teacher self-efficacy

    NASA Astrophysics Data System (ADS)

    Roberts, Megan Rae

    This study focuses on an analysis of a professional development program known as lesson study via data obtained during an in-service professional development program for secondary school science teachers. The purpose of this study was to examine the self-efficacy beliefs of one group of science teachers related to their experiences in a lesson study. Another purpose for this research, aligned with the first, included a theoretical analysis of the lesson study construct to see if its design promoted positive self-efficacy beliefs of its participants. The research is framed within the context of social constructivism and self-efficacy and is qualitative in nature and utilized descriptive analysis as a means of research. Case studies were conducted detailing two of the six participants. Data sources included researcher field notes and transcriptions of all planning and debriefing sessions; individual interviews with each participant and the schools' principal; a participant questionnaire, and the Science Teaching Efficacy Belief Instrument. Themes that emerged included the positive perceptions of lesson study as a collaborative and teacher-centered experience; the understanding that lesson study can instill a sense of professionalism to those who participate in the process; the sense that discussing student learning using objective observations from classroom is a powerful way to assess learning and uncover personal teacher beliefs; and the insight that the time commitment that lesson study requires can inhibit teachers and schools from sustaining it as a form of on-going professional development. Although these themes are consistent with the research on lesson study in Japan and elsewhere in the United States, they also extend the research on self-efficacy and science teacher professional development. In the end, this study supported some of the conclusions of the self-efficacy research as it relates to professional development while also adding that interpersonal

  5. Sirtuin and pan-class I/II deacetylase (DAC) inhibition is synergistic in preclinical models and clinical studies of lymphoma.

    PubMed

    Amengual, Jennifer E; Clark-Garvey, Sean; Kalac, Matko; Scotto, Luigi; Marchi, Enrica; Neylon, Ellen; Johannet, Paul; Wei, Ying; Zain, Jasmine; O'Connor, Owen A

    2013-09-19

    Understanding the molecular pathogenesis of lymphoma has led to paradigm-changing treatment opportunities. One example involves tailoring specific agents based on the cell of origin in aggressive lymphomas. Germinal center (GC)-derived diffuse large B-cell lymphoma (DLBCL) is known to be driven by an addiction to Bcl6, whereas the activated B-cell (ABC) subtype is driven by nuclear factor κB. In the GC subtype, there is a critical inverse relationship between Bcl6 and p53, the functional status of which is linked to each transcription factor's degree of acetylation. Deacetylation of Bcl6 is required for its transcriptional repressor effects allowing for the oncogene to drive lymphomagenesis. Conversely, acetylation of p53 is activating when class III deacetylases (DACs), or sirtuins, are inhibited by niacinamide. Treatment of DLBCL cell lines with pan-DAC inhibitors in combination with niacinamide produces synergistic cytotoxicity in GC over ABC subtypes. This correlated with acetylation of both Bcl6 and p53. This combination also produced remissions in a spontaneous aggressive B-cell lymphoma mouse model expressing Bcl6. In a phase 1 proof-of-principle clinical trial, 24% of patients with relapsed or refractory lymphoma attained a response to vorinostat and niacinamide, and 57% experienced disease stabilization. We report herein on the preclinical and clinical activity of this targeted strategy in aggressive lymphomas. This trial was registered at www.clinicaltrials.gov as #NCT00691210.

  6. SU-E-CAMPUS-I-05: Internal Dosimetric Calculations for Several Imaging Radiopharmaceuticals in Preclinical Studies and Quantitative Assessment of the Mouse Size Impact On Them. Realistic Monte Carlo Simulations Based On the 4D-MOBY Model

    SciTech Connect

    Kostou, T; Papadimitroulas, P; Kagadis, GC; Loudos, G

    2014-06-15

    Purpose: Commonly used radiopharmaceuticals were tested to define the most important dosimetric factors in preclinical studies. Dosimetric calculations were applied in two different whole-body mouse models, with varying organ size, so as to determine their impact on absorbed doses and S-values. Organ mass influence was evaluated with computational models and Monte Carlo(MC) simulations. Methods: MC simulations were executed on GATE to determine dose distribution in the 4D digital MOBY mouse phantom. Two mouse models, 28 and 34 g respectively, were constructed based on realistic preclinical exams to calculate the absorbed doses and S-values of five commonly used radionuclides in SPECT/PET studies (18F, 68Ga, 177Lu, 111In and 99mTc).Radionuclide biodistributions were obtained from literature. Realistic statistics (uncertainty lower than 4.5%) were acquired using the standard physical model in Geant4. Comparisons of the dosimetric calculations on the two different phantoms for each radiopharmaceutical are presented. Results: Dose per organ in mGy was calculated for all radiopharmaceuticals. The two models introduced a difference of 0.69% in their brain masses, while the largest differences were observed in the marrow 18.98% and in the thyroid 18.65% masses.Furthermore, S-values of the most important target-organs were calculated for each isotope. Source-organ was selected to be the whole mouse body.Differences on the S-factors were observed in the 6.0–30.0% range. Tables with all the calculations as reference dosimetric data were developed. Conclusion: Accurate dose per organ and the most appropriate S-values are derived for specific preclinical studies. The impact of the mouse model size is rather high (up to 30% for a 17.65% difference in the total mass), and thus accurate definition of the organ mass is a crucial parameter for self-absorbed S values calculation.Our goal is to extent the study for accurate estimations in small animal imaging, whereas it is known

  7. The New 3D Printed Left Atrial Appendage Closure with a Novel Holdfast Device: A Pre-Clinical Feasibility Animal Study

    PubMed Central

    Brzeziński, M.; Bury, K.; Dąbrowski, L.; Holak, P.; Sejda, A.; Pawlak, M.; Jagielak, D.; Adamiak, Z.; Rogowski, J.

    2016-01-01

    surrounding tissues. No pericarditis or macroscopic signs of inflammation at the site of the device were found. All pigs were in good condition with normal weight gain and no other clinical symptoms. Conclusion This novel 3D printed left atrial appendage closure technique with a novel holdfast device was proven to be safe and feasible in all pigs. A benign healing process without inflammation and damage to the surrounding structures or evidence of new thrombi formation was observed. Moreover, the uncomplicated survival and full LAA exclusion in all animals demonstrate the efficacy of this novel and relatively cheap device. Further clinical evaluation and implementation studies should be performed to introduce this new technology into clinical practice. PMID:27219618

  8. Developing Potential Candidates of Preclinical Preeclampsia

    PubMed Central

    Founds, Sandra; Zeng, Xuemei; Lykins, David; Roberts, James M.

    2015-01-01

    The potential for developing molecules of interest in preclinical preeclampsia from candidate genes that were discovered on gene expression microarray analysis has been challenged by limited access to additional first trimester trophoblast and decidual tissues. The question of whether these candidates encode secreted proteins that may be detected in maternal circulation early in pregnancy has been investigated using various proteomic methods. Pilot studies utilizing mass spectrometry based proteomic assays, along with enzyme linked immunosorbent assays (ELISAs), and Western immunoblotting in first trimester samples are reported. The novel targeted mass spectrometry methods led to robust multiple reaction monitoring assays. Despite detection of several candidates in early gestation, challenges persis