Sample records for preclinical efficacy studies

  1. 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

  2. Nubac Disc Arthroplasty: Preclinical Studies and Preliminary Safety and Efficacy Evaluations

    PubMed Central

    Songer, Matthew; Pimenta, Luis; Werner, Dieter; Reyes-Sanchez, Alejandro; Balsano, Massimo; Agrillo, Umberto; Coric, Domagoj; Davenport, Kenneth; Yuan, Hansen

    2007-01-01

    Background Disc arthroplasty is gaining popularity for treatment of low-back pain caused by degenerative disc disease (DDD). It can involve total disc replacement or partial disc or nucleus replacement (or augmentation). Compared with total disc replacement, nucleus replacement is less invasive, has less surgical risk, has faster postoperative recovery, and doesn't “burn bridges” should further surgery be required. However, nucleus replacement has a high risk of implant expulsion because the device is not fixed to the vertebrae. Nubac is the first polyetheretherketone (PEEK)-on-PEEK articulated disc arthroplasty device designed to optimally restore the lumbar anatomy and biomechanics. Methods ISO 10993 standards were used to evaluate the biocompatibility of the PEEK material. Chemical and thermal–mechanical tests and in vivo study assessed PEEK's biostability after exposure to high g irradiation and harsh oxidative conditions. Biomechanical tests to evaluate kinematic properties and anatomical restoration of the implanted lumbar motion segments and implant expulsion risk assessments were performed with a human cadaveric model. Because of the novelty of PEEK-on-PEEK as a self-mating articulating material, extensive wear tests were conducted with unidirectional and coupled motions. Static and fatigue strength also were tested. Animal study with a baboon model was conducted with gross, radiographic, biomechanical, and histological evaluations at 6 and 12 months postoperatively. Preliminary clinical data were collected through a prospective multicenter cohort study. Results PEEK demonstrated exceptional biocompatibility and biodurability. Nubac restored disc height and motion segment range of motion. The unique articulating design of the Nubac demonstrated low risk of implant expulsion in a human cadaveric model. Wear tests showed that the Nubac has minimal wear and compares favorably to other disc arthroplasty materials. The Nubac also had excellent static and fatigue properties for the intended application. The animal study showed that the Nubac caused no adverse local or systematic tissue reaction and there was no detectable wear debris. The preliminary clinical data showed no major intraoperative vascular and neurological complications. There was significant Visual Analog Scale and Oswestry Disability Index score improvement. Conclusions The preclinical data supported the design rationale, and the preliminary clinical data (level II evidence) on safety and efficacy were encouraging. Clinical Relevance The Nubac could be a viable first surgical option for patients with back pain caused by DDD. PMID:25802577

  3. Statistical considerations for preclinical studies.

    PubMed

    Aban, Inmaculada B; George, Brandon

    2015-08-01

    Research studies must always have proper planning, conduct, analysis and reporting in order to preserve scientific integrity. Preclinical studies, the first stage of the drug development process, are no exception to this rule. The decision to advance to clinical trials in humans relies on the results of these studies. Recent observations show that a significant number of preclinical studies lack rigor in their conduct and reporting. This paper discusses statistical aspects, such as design, sample size determination, and methods of analyses, that will help add rigor and improve the quality of preclinical studies. PMID:25725352

  4. Preclinical Efficacy Testing in Middle-Aged Rats: Nicotinamide, a Novel Neuroprotectant, Demonstrates Diminished Preclinical Efficacy after Controlled Cortical Impact

    PubMed Central

    Swan, Alicia A.; Chandrashekar, Rupa; Beare, Jason

    2011-01-01

    Abstract Age is a consistent predictor of poor outcome following traumatic brain injury (TBI). Although the elderly population has one of the highest rates of TBI-related hospitalization and death, few preclinical studies have attempted to model and treat TBI in the aged population. Recent studies have indicated that nicotinamide (NAM), a soluble B-group vitamin, improved functional recovery in experimental models of TBI in young animals. The purpose of the present study was to examine the preclinical efficacy of NAM in middle-aged rats. Groups of middle-aged (14-month-old) rats were assigned to NAM (500?mg/kg or 50?mg/kg) or saline alone (1?mL/kg) treatment conditions, and received unilateral cortical contusion injuries (CCI) and injections at 1?h and 24?h following injury. The animals were tested on a variety of tasks to assess vestibulomotor (tapered beam) and cognitive performance (reference and working memory in the Morris water maze), and were evaluated for lesion size, blood–brain barrier compromise, astrocytic activation, and edema formation. In summary, the preclinical efficacy of NAM as a treatment following CCI in middle-aged rats differs from that previously documented in younger rats; while treatment with 50?mg/kg NAM appeared to have no effect, the 500-mg/kg dose worsened performance in middle-aged animals. Histological indicators demonstrated more nuanced group differences, indicating that NAM may positively impact some of the cellular cascades following injury, but were not substantial enough to improve functional recovery. These findings emphasize the need to examine potential treatments for TBI utilizing non-standard populations, and may explain why so many treatments have failed in clinical trials. PMID:21083416

  5. 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.

  6. 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

    To develop allopregnanolone as a therapeutic for Alzheimer’s disease, we investigated multiple formulations and routes of administration in translationally relevant animal models of both sexes. Subcutaneous, topical (transdermal and intranasal), intramuscular, and intravenous allopregnanolone were bolus-administered. Pharmacokinetic analyses of intravenous allopregnanolone in rabbit and mouse indicated that peak plasma and brain levels (3-fold brain/plasma ratios) at 5min were sufficient to activate neuroregenerative responses at sub-sedative doses. Slow-release subcutaneous suspension of allopregnanolone displayed 5-fold brain/plasma ratio at Cmax at 30min. At therapeutic doses by either subcutaneous or intravenous routes, allopregnanolone mouse plasma levels ranged between 34-51ng/ml by 30min, comparable to published endogenous human level in the third trimester of pregnancy. Exposure to subcutaneous, topical, intramuscular, and intravenous allopregnanolone, at safe and tolerable doses, increased hippocampal markers of neurogenesis including BrdU and PCNA in young 3xTgAD and aged wildtype mice. Intravenous allopregnanolone transiently and robustly phosphorylated CREB within 5min and increased levels of neuronal differentiation transcription factor NeuroD within 4h. Neurogenic efficacy was achieved with allopregnanolone brain exposure of 300-500hr*ng/g. Formulations were tested to determine the no observable adverse effect level (NOAEL) and maximally tolerated doses (MTD) in male and female rats by sedation behavior time course. Sex differences were apparent, males exhibited ?40% more sedation time compared to females. Allopregnanolone formulated in sulfobutyl-ether-beta-cyclodextrin at optimized complexation ratio maximized allopregnanolone delivery and neurogenic efficacy. To establish the NOAEL and MTD for Allo-induced sedation using a once-per-week intravenous regenerative treatment regimen: In female rats the NOAEL was 0.5mg/kg and MTD 2mg/kg. The 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

  7. A preclinical study demonstrating the efficacy of nilotinib in inhibiting the growth of pediatric high-grade glioma.

    PubMed

    Au, Karolyn; Singh, Sanjay K; Burrell, Kelly; Sabha, Nesrin; Hawkins, Cynthia; Huang, Annie; Zadeh, Gelareh

    2015-05-01

    Solid tumors arising from malignant transformation of glial cells are one of the leading causes of central nervous system tumor-related death in children. Recurrence in spite of rigorous surgical and chemoradiation therapies remains a major hurdle in management of these tumors. Here, we investigate the efficacy of the second-generation receptor tyrosine kinase inhibitor nilotinib as a therapeutic option for the management of pediatric gliomas. We have utilized two independent pediatric high-grade glioma cell lines with either high platelet-derived growth factor receptor alpha (PDGFR?) or high PDGFR? expression in in vitro assays to investigate the specific downstream effects of nilotinib treatment. Using in vitro cell-based assays we show that nilotinib inhibits PDGF-BB-dependent activation of PDGFR?. We further show that nilotinib is able to decrease cell proliferation and anchorage-independent growth via suppression of AKT and ERK1/2 signaling pathways. Our results suggest that nilotinib may be effective for management of a PDGFR?-dependent group of pediatric gliomas. PMID:25732621

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

    SciTech Connect

    Owen, Richard J., E-mail: drrichardowen@tbwifi.ca [University of Alberta, Radiology and Diagnostic Imaging, Walter C. Mackenzie Health Sciences Centre (Canada); Nation, Patrick N. [University of Alberta, Laboratory Medicine and Pathology, Walter C. Mackenzie Health Sciences Centre (Canada); Polakowski, Robert [BioLipids Inc (Canada); Biliske, Jennifer A. [University of Alberta, Biological Sciences, CW405, Biological Sciences Building (Canada); Tiege, Paul B. [University of Alberta, Lipid Products Research Alberta (LiPRA), 410 Agriculture/Forestry Centre (Canada); Griffith, Irwin J. [IMBiotechnologies Ltd (Canada)

    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.

  9. [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

  10. Efficacy of Pimobendan in the Prevention of Congestive Heart Failure or Sudden Death in Doberman Pinschers with Preclinical Dilated Cardiomyopathy (The PROTECT Study)

    PubMed Central

    Summerfield, NJ; Boswood, A; O'Grady, MR; Gordon, SG; Dukes-McEwan, J; Oyama, MA; Smith, S; Patteson, M; French, AT; Culshaw, GJ; Braz-Ruivo, L; Estrada, A; O'Sullivan, ML; Loureiro, J; Willis, R; Watson, P

    2012-01-01

    Background The benefit of pimobendan in delaying the progression of preclinical dilated cardiomyopathy (DCM) in Dobermans is not reported. Hypothesis That chronic oral administration of pimobendan to Dobermans with preclinical DCM will delay the onset of CHF or sudden death and improve survival. Animals Seventy-six client-owned Dobermans recruited at 10 centers in the UK and North America. Methods The trial was a randomized, blinded, placebo-controlled, parallel group multicenter study. Dogs were allocated in a 1:1 ratio to receive pimobendan (Vetmedin capsules) or visually identical placebo. The composite primary endpoint was prospectively defined as either onset of CHF or sudden death. Time to death from all causes was a secondary endpoint. Results The proportion of dogs reaching the primary endpoint was not significantly different between groups (P = .1). The median time to the primary endpoint (onset of CHF or sudden death) was significantly longer in the pimobendan (718 days, IQR 441–1152 days) versus the placebo group (441 days, IQR 151–641 days) (log-rank P = 0.0088). The median survival time was significantly longer in the pimobendan (623 days, IQR 491–1531 days) versus the placebo group (466 days, IQR 236–710 days) (log-rank P = .034). Conclusion and Clinical Importance The administration of pimobendan to Dobermans with preclinical DCM prolongs the time to the onset of clinical signs and extends survival. Treatment of dogs in the preclinical phase of this common cardiovascular disorder with pimobendan can lead to improved outcome. PMID:23078651

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

    SciTech Connect

    Hmila, Issam [Laboratoire des Venins et Toxines, Institut Pasteur de Tunis, 13 Place Pasteur, BP-74, 1002 Tunis (Tunisia)] [Laboratoire des Venins et Toxines, Institut Pasteur de Tunis, 13 Place Pasteur, BP-74, 1002 Tunis (Tunisia); Cosyns, Bernard [Laboratory of In Vivo Cellular and Molecular Imaging, Vrije Universiteit Brussel (Belgium)] [Laboratory of In Vivo Cellular and Molecular Imaging, Vrije Universiteit Brussel (Belgium); Tounsi, Hayfa [Service d'Anatomo-Pathologie, Institut Pasteur de Tunis, 13 Place Pasteur, BP-74, 1002 Tunis (Tunisia)] [Service d'Anatomo-Pathologie, Institut Pasteur de Tunis, 13 Place Pasteur, BP-74, 1002 Tunis (Tunisia); Roosens, Bram; Caveliers, Vicky [Laboratory of In Vivo Cellular and Molecular Imaging, Vrije Universiteit Brussel (Belgium)] [Laboratory of In Vivo Cellular and Molecular Imaging, Vrije Universiteit Brussel (Belgium); Abderrazek, Rahma Ben [Laboratoire des Venins et Toxines, Institut Pasteur de Tunis, 13 Place Pasteur, BP-74, 1002 Tunis (Tunisia)] [Laboratoire des Venins et Toxines, Institut Pasteur de Tunis, 13 Place Pasteur, BP-74, 1002 Tunis (Tunisia); Boubaker, Samir [Service d'Anatomo-Pathologie, Institut Pasteur de Tunis, 13 Place Pasteur, BP-74, 1002 Tunis (Tunisia)] [Service d'Anatomo-Pathologie, Institut Pasteur de Tunis, 13 Place Pasteur, BP-74, 1002 Tunis (Tunisia); Muyldermans, Serge [Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussel (Belgium) [Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussel (Belgium); Department of Structural Biology, VIB, Brussels (Belgium); El Ayeb, Mohamed [Laboratoire des Venins et Toxines, Institut Pasteur de Tunis, 13 Place Pasteur, BP-74, 1002 Tunis (Tunisia)] [Laboratoire des Venins et Toxines, Institut Pasteur de Tunis, 13 Place Pasteur, BP-74, 1002 Tunis (Tunisia); Bouhaouala-Zahar, Balkiss, E-mail: balkiss.bouhaouala@pasteur.rns.tn [Laboratoire des Venins et Toxines, Institut Pasteur de Tunis, 13 Place Pasteur, BP-74, 1002 Tunis (Tunisia) [Laboratoire des Venins et Toxines, Institut Pasteur de Tunis, 13 Place Pasteur, BP-74, 1002 Tunis (Tunisia); Faculté de Médecine de Tunis, Université de Tunis-El Manar (Tunisia); Lahoutte, Tony [Laboratory of In Vivo Cellular and Molecular Imaging, Vrije Universiteit Brussel (Belgium)] [Laboratory of In Vivo Cellular and Molecular Imaging, Vrije Universiteit Brussel (Belgium)

    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.

  12. Preclinical Studies for Cartilage Repair

    PubMed Central

    Hurtig, Mark B.; Buschmann, Michael D.; Fortier, Lisa A.; Hoemann, Caroline D.; Hunziker, Ernst B.; Jurvelin, Jukka S.; Mainil-Varlet, Pierre; McIlwraith, C. Wayne; Sah, Robert L.; Whiteside, Robert A.

    2011-01-01

    Investigational devices for articular cartilage repair or replacement are considered to be significant risk devices by regulatory bodies. Therefore animal models are needed to provide proof of efficacy and safety prior to clinical testing. The financial commitment and regulatory steps needed to bring a new technology to clinical use can be major obstacles, so the implementation of highly predictive animal models is a pressing issue. Until recently, a reductionist approach using acute chondral defects in immature laboratory species, particularly the rabbit, was considered adequate; however, if successful and timely translation from animal models to regulatory approval and clinical use is the goal, a step-wise development using laboratory animals for screening and early development work followed by larger species such as the goat, sheep and horse for late development and pivotal studies is recommended. Such animals must have fully organized and mature cartilage. Both acute and chronic chondral defects can be used but the later are more like the lesions found in patients and may be more predictive. Quantitative and qualitative outcome measures such as macroscopic appearance, histology, biochemistry, functional imaging, and biomechanical testing of cartilage, provide reliable data to support investment decisions and subsequent applications to regulatory bodies for clinical trials. No one model or species can be considered ideal for pivotal studies, but the larger animal species are recommended for pivotal studies. Larger species such as the horse, goat and pig also allow arthroscopic delivery, and press-fit or sutured implant fixation in thick cartilage as well as second look arthroscopies and biopsy procedures.

  13. 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 ?M (NTZ was toxic above 10 ?M); 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 · ?g/ml (30 mg/kg dose) to 328 h · ?g/ml (100 mg/kg dose), the maximum concentration of the drug in serum was 20 ?g/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

  14. Preclinical Studies of Raloxifene and Related Compounds

    Microsoft Academic Search

    Robin Fuchs-Young

    \\u000a The development of raloxifene (also know as keoxifene) for clinical use was based on a series of preclinical studies that\\u000a demonstrated it has a highly desirable tissue-specific activity. Results indicated that the therapeutic effects of raloxifene\\u000a (LY138481 HCl; LY156758) mimicked some of those of estrogen in ovariectomized animals by reducing bone loss and lowering serum\\u000a cholesterol levels. Conversely, in mammary

  15. Drug-Eluting Stents in Preclinical Studies Updated Consensus Recommendations for Preclinical Evaluation

    PubMed Central

    Schwartz, Robert S.; Edelman, Elazer; Virmani, Renu; Carter, Andrew; Granada, Juan F.; Kaluza, Greg L.; Chronos, Nicolas A.F.; Robinson, Keith A.; Waksman, Ron; Weinberger, Judah; Wilson, Gregory J.; Wilensky, Robert L.

    2010-01-01

    Coronary drug-eluting stents are commonplace in clinical practice with acceptable safety and efficacy. Preclinical evaluation of novel drug-eluting stent technologies has great importance for understanding safety and possibly efficacy of these technologies, and well-defined preclinical testing methods clearly benefit multiple communities within the developmental, testing, and clinical evaluation chain. An earlier consensus publication enjoyed widespread adoption but is in need of updating. This publication is an update, presenting an integrated view for testing drug-eluting technologies in preclinical models, including novel devices such as bioabsorbable coatings, totally bioabsorbable stents, bifurcation stents, and stent-free balloon-based drug delivery. This consensus document was produced by preclinical and translational scientists and investigators engaged in interventional technology community. The United States Food and Drug Administration (USFDA) recently issued a Draft Guidance for Industry Document for Drug-Eluting Stents. This expert consensus document is consistent with the Food and Drug Administration guidance. The dynamic nature of this field mandates future modifications and additions that will be added over time. PMID:20031669

  16. Student perception about efficacy of preclinical fixed prosthodontic training to facilitate smooth transition to clinical context

    PubMed Central

    Haralur, Satheesh B.; Al-Malki, Abdullah Edrees

    2014-01-01

    Background: Studies indicate that the initial transition period between preclinical and clinical phases are the most stressful. The students have experienced the difficulty in performing clinical procedures due to the vast difference in the clinical and preclinical setup. It is better to identify the particular skill found poorly correlated, enabling educators to address the concerns. We sought the opinion and suggestion from the beneficiary student on fixed prosthodontics steps difficult to practice in clinical setup at the initial stage, their suggestion to overcome these shortcomings was also sought. Aims: To determine the fixed prosthodontics skills difficult to perform in a transition period due to poor correlation between preclinical and clinical training from our focus group study on the student's perception, and their suggestion regarding alternative methods to improve the preclinical training. Materials and Methods: Focus groups in the study were the students involved in clinical practice of fixed partial denture procedure. A well-constructed Questionnaire, designed to evaluate the difficult clinical steps in a transitional period and suggestion to improve the existing preclinical training was distributed to all focus group students. The response to the questionnaire was based on the five-point Likert scale. Statistical Analysis Used: Medians, frequencies were used to assess their perception on preclinical training and suggestion. Results: A total of 97 students participated in the study, 88% response received during the survey. The clinical steps student felt difficult during a transition period from preclinical to clinical phase were positional variations of teeth (52.6%-63.9%), fluid control (48.5-67.1%), shade selection procedure (29.9%-50.5%), subgingival cervical finish line preparation (38.1-51.5%), and gingival retraction procedure. The students felt that the inclusion of problem-based learning, preclinical patient exposure, and better simulation will alleviate the stress during the transition period. Conclusions: This study highlighted the tooth preparation steps found difficult to practice in a transition period between preclinical and clinical phases. This study also obtained suggestions from the students for innovative upgradation of the course curricula. PMID:25077166

  17. JAK2 inhibitor therapy in myeloproliferative disorders: rationale, preclinical studies and ongoing clinical trials

    Microsoft Academic Search

    A Pardanani

    2008-01-01

    The recent identification of somatic mutations such as JAK2V617F that deregulate Janus kinase (JAK)–signal transducer and activator of transcription signaling has spurred development of orally bioavailable small-molecule inhibitors that selectively target JAK2 kinase as an approach to pathogenesis-directed therapy of myeloproliferative disorders (MPD). In pre-clinical studies, these compounds inhibit JAK2V617F-mediated cell growth at nanomolar concentrations, and in vivo therapeutic efficacy

  18. 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

  19. PRECLINICAL STUDY Elevated tissue sodium concentration in malignant breast lesions

    E-print Network

    Ouwerkerk, Ronald

    Magnetic resonance imaging Á 23 Na magnetic resonance Á Sodium Á Quantification Introduction The use errors. Sodium (23 Na) MRI also yields useful information that reflects the physiological and biochemicalPRECLINICAL STUDY Elevated tissue sodium concentration in malignant breast lesions detected

  20. Humanized cobra venom factor: structure, activity, and therapeutic efficacy in preclinical disease models.

    PubMed

    Vogel, Carl-Wilhelm; Finnegan, Paul W; Fritzinger, David C

    2014-10-01

    The complement system is an integral component of both innate and adaptive immunity. However, complement is also a pathogenetic factor in many diseases. The development of agents for therapeutic complement inhibition is the topic of intense investigations by many investigators. We have developed a distinctly different therapeutic approach: complement depletion rather than inhibition. This approach is based on cobra venom factor (CVF), a C3 analog known to be able to safely deplete complement. This manuscript will briefly review the structure and activity of CVF, along with its similarities and differences to C3. Exploiting the knowledge of the structure/function relationship of CVF and C3, we created derivatives of human C3 which display the CVF-like activity of depleting complement, referred to as humanized CVF (hCVF). This review describes the structure and activity of hCVF, including the important property of not cleaving C5. The efficacy of hCVF for therapeutic complement depletion in nine preclinical models diseases with complement pathology is reviewed, including reperfusion injury, age-related macular degeneration (AMD), paroxysmal nocturnal hemoglobinuria (PNH), and immunogenicity of Factor VIII in hemophilia A. Complement depletion is characterized by the absence of toxicity, even after intra-arterial injection into the pulmonary artery of primates. No immunogenicity has been observed. PMID:25062833

  1. Preclinical and Clinical Studies of Gamma Secretase Inhibitors with Docetaxel on Human Breast Tumors

    PubMed Central

    Schott, Anne F.; Landis, Melissa D.; Dontu, Gabriela; Griffith, Kent A.; Layman, Rachel M.; Krop, Ian; Paskett, Lacey A; Wong, Helen; Dobrolecki, Lacey E.; Froehlich, Amber M.; Paranilam, Jaya; Hayes, Daniel F.; Wicha, Max S.; Chang, Jenny C.

    2013-01-01

    Purpose Accumulating evidence supports the existence of breast cancer stem cells (BCSCs), which are characterized by their capacity to self-renew and divide indefinitely, and resistance to conventional therapies. The Notch pathway is important for stem cell renewal, and is a potential target for BCSC-directed therapy. Experimental Design Using human breast tumorgraft studies, we evaluated the impact of gamma secretase inhibitors (GSI) on the BCSC population and the efficacy of combining GSI with docetaxel treatment. The mouse experimental therapy paralleled a concurrent clinical trial in advanced breast cancer patients, designed to determine the maximally tolerated dose of the GSI, MK-0752, administered sequentially with docetaxel, and to evaluate BCSC markers in serial tumor biopsies. Results Treatment with GSI reduced BCSCs in MC1 and BMC-2147 tumorgrafts by inhibition of the Notch pathway. GSI enhanced the efficacy of docetaxel in preclinical studies. In the clinical trial, 30 patients with advanced breast cancer were treated with escalating doses of MK-0752 plus docetaxel. Clinically meaningful doses of both drugs were possible, with manageable toxicity and preliminary evidence of efficacy. A decrease in CD44+/CD24?, ALDH+, and MSFE were observed in tumors of patients undergoing serial biopsies. Conclusions These preclinical data demonstrate that pharmacological inhibition of the Notch pathway can reduce BCSCs in breast tumorgraft models. The clinical trial demonstrates feasibility of combination GSI and chemotherapy, and together these results encourage further study of Notch pathway inhibitors in combination with chemotherapy in breast cancer. PMID:23340294

  2. Research progress of Hemoporfin--part one: preclinical study.

    PubMed

    Pu, Yu; Chen, Wenhui; Yu, Zhengwei

    2012-06-01

    The second generation photosensitizer Hemoporfin (7(12)-(1-methoxyethyl) -12(7)-(1-hydroxyethyl)-3,8,13,17-tetramethyl-21H,23H-porphin-2,18-dipropionic acid) is a porphyrin derivative which processes a stable structure, high singlet oxygen yield, high photoactivity, low dark toxicity and fast clearance rate. Hemoporfin, also known as hematoporphyrin monomethyl ether (HMME) has been studied and used in photodynamic therapy (PDT) in China since 1989. This series of reports will provide an overview on the preclinical and clinical studies of this PDT photosensitizer. The first part of this series will highlight the results of preclinical studies that focused on the compound's optical characteristics, mechanism of the activities, pharmacological and toxicological properties. PMID:22594989

  3. Eribulin—A review of preclinical and clinical studies

    PubMed Central

    Swami, Umang; Chaudhary, Imran; Ghalib, Mohammad H.; Goel, Sanjay

    2013-01-01

    Eribulin mesylate is a non-taxane, structurally simplified, completely synthetic, halichondrin B derivative with an end poisoning, microtubule inhibitory action. Preclinical studies have demonstrated activity in various cancer cell lines and synergistic action with gemcitabine, epirubicin, trastuzumab, cisplatin, docetaxel and vinorelbine. Eribulin has recently been approved by United States Food and Drug Administration as a third line therapy for metastatic breast cancer patients, who have previously been treated with an anthracycline and a taxane. It has also advanced to phase II trials in non-small cell lung cancer, pancreatic, prostate, bladder, head and neck cancers, sarcomas and ovarian and other gynecological tumors. Combination trials with carboplatin, gemcitabine, pemetrexed, cisplatin, and erlotinib are currently ongoing. Eribulin potentially has a low incidence of peripheral neuropathy. The predominant side effects are neutropenia and fatigue, which are manageable. This article reviews the available information on eribulin with respect to its clinical pharmacology, mechanism of action, pharmacokinetics, pharmacodynamics, metabolism, preclinical studies and clinical trials. PMID:21493087

  4. 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

  5. Confidentiality in preclinical Alzheimer disease studies

    PubMed Central

    Arias, Jalayne J.

    2014-01-01

    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 ?-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. PMID:24477112

  6. Preclinical Evaluation of Anticancer Efficacy and Pharmacological Properties of FBA-TPQ, a Novel Synthetic Makaluvamine Analog

    PubMed Central

    Zhang, Xiangrong; Xu, Hongxia; Zhang, Xu; Voruganti, Sukesh; Murugesan, Srinivasan; Nadkarni, Dwayaja H.; Velu, Sadanandan E.; Wang, Ming-Hai; Wang, Wei; Zhang, Ruiwen

    2012-01-01

    We have recently designed and synthesized a novel iminoquinone anticancer agent, 7-(4-fluorobenzylamino)-1,3,4,8-tetrahydropyrrolo[4,3,2-de]quinolin-8(1H)-one (FBA-TPQ) and initiated its preclinical development. Herein we investigated its efficacy, safety, and pharmacokinetics in in vitro and in vivo models of human pancreatic cancer. Our results demonstrated that FBA-TPQ inhibited pancreatic cancer cell growth, induced apoptosis, and caused cell cycle arrest in vitro. It inhibited the growth of xenograft tumors with minimal host toxicity. To facilitate future preclinical and clinical development of the agent, we also developed and validated a Rapid Resolution Liquid Chromatography (RRLC) method for quantitative analysis of FBA-TPQ in plasma and tissue samples. The method was found to be precise, accurate, and specific. Using this method, we carried out in vitro and in vivo evaluations of the pharmacological properties of FBA-TPQ, including stability in plasma, plasma protein binding, metabolism by S9 enzymes, plasma pharmacokinetics, and tissue distribution. Our results indicate that FBA-TPQ is a potential therapeutic agent for pancreatic cancer, providing a basis for future preclinical and clinical development. PMID:22822362

  7. Effect of soy isoflavones on the growth of human breast tumors: findings from preclinical studies

    PubMed Central

    Kwon, Youngjoo

    2014-01-01

    Breast cancer is the most common cancer among women worldwide, and many women with breast cancer live more than 5 years after their diagnosis. Breast cancer patients and survivors have a greater interest in taking soy foods and isoflavone supplements. However, the effect of isoflavones on breast cancer remains controversial. Thus, it is critical to determine if and when isoflavones are beneficial or detrimental to breast cancer patients. According to the available preclinical data, high concentrations of isoflavones inhibit the proliferation of breast cancer cells, regardless of their estrogen receptor (ER) status. In comparison, genistein, a major isoflavone, has stimulated tumor growth at low concentrations and mitigated tamoxifen efficacy in ER-positive breast cancer. Studies have indicated that the relative levels of genistein and estrogen at the target site are important to determine the genistein effect on the ER-positive tumor growth. However, studies using ovariectomized mice and subcutaneous xenograft models might not truly reflect estrogen concentrations in human breast tumors. Moreover, it may be an oversimplification that isoflavones stimulate hormone-dependent tumor growth due to their potential estrogenic effect since studies also suggest nonestrogenic anticancer effects of isoflavones and ER-independent anticancer activity of tamoxifen. Therefore, the concentrations of isoflavones and estrogen in human breast tumors should be considered better in future preclinical studies and the parameters that can estimate those levels in breast tumors are required in human clinical/epidemiological investigation. In addition, it will be important to identify the molecular mechanisms that either inhibit or promote the growth of breast cancer cells by soy isoflavones, and use those molecules to evaluate the relevance of the preclinical findings to the human disease and to predict the health effects of isoflavones in human breast tumors. PMID:25493176

  8. Experimental Design and Efficient Parameter Estimation in Preclinical Pharmacokinetic Studies

    Microsoft Academic Search

    Ene I. Ette; Catherine A. Howie; Andrew W. Kelman; Brian Whiting

    1995-01-01

    Monte Carlo simulation technique used to evaluate the effect of the arrangement of concentrations on the efficiency of estimation of population pharmacokinetic parameters in the preclinical setting is described. Although the simulations were restricted to the one compartment model with intravenous bolus input, they provide the basis of discussing some structural aspects involved in designing a destructive (“quantic”) preclinical population

  9. Preclinical studies with platelet-activating factor antagonists in models of septic shock.

    PubMed

    Dejoy, S Q; Oronsky, A L; Wick, M M; Kerwar, S S

    1993-01-01

    Since the isolation and elucidation of the structure of platelet-activating factor (PAF) in the late 1970's, several preclinical studies have suggested that PAF is a key mediator of septic shock induced in animals by either endotoxin or by Gram-negative bacteria. A number of PAF antagonists have been sythesized that protect animals from the lethal effects of endotoxin. Some of these antagonists are in early stages of clinical development. The most advanced cadidate is BN 52021, a ginkgolide, that is in Phase II/III clinical trials in patients with septic shock. Preliminary results with BN 52021 indicate that it is efficacious and significantly reduces mortality associated with Gram-negative sepsis. Pivotal trials with BN 52021 aer ongoing. The present review summarizes the biological effects of PAF and the effect of PAF antagonists in animal models of septic shock. The interrelationship of PAF and tumor necrosis factor (another key mediator of septic shock) is also discussed. PMID:18611559

  10. Bridging the Gap between Preclinical and Clinical Microbicide Trials: Blind Evaluation of Candidate Gels in Murine Models of Efficacy and Safety

    PubMed Central

    Segarra, Theodore J.; Fakioglu, Esra; Cheshenko, Natalia; Wilson, Sarah S.; Mesquita, Pedro M. M.; Doncel, Gustavo F.; Herold, Betsy C.

    2011-01-01

    Background Despite significant protection in preclinical studies, cellulose sulfate (CS) failed to protect women against HIV-1/2 and was associated with a trend toward increased HIV-1 acquisition in one of the clinical trials. These results highlight the need for preclinical tests more predictive of clinical outcomes. The objective of this study was to test coded vaginal gels, including CS, in murine models of safety and efficacy to determine the models' utility for evaluating future products. Methods Four coded formulations, including 6% CS, 2% PRO 2000 and two placebo gels, were administered intravaginally to medroxyprogesterone-treated mice and their ability to prevent genital herpes (efficacy) or to alter the susceptibility to low dose HSV challenge (safety) was determined. Nonoyxnol-9 served as a positive toxicity control. Results CS and PRO 2000 significantly protected mice from genital herpes following infection with a laboratory or clinical isolate of HSV-2 introduced in buffer (p<0.001). However, protection was reduced when virus was introduced in seminal plasma. Moreover, mice were significantly more susceptible to infection with low doses of HSV-2 when challenged 12 h after the 7th daily dose of CS or nonoxynol-9 (p<0.05). The increased susceptibility was associated with alterations in epithelial architecture. Conclusions CS prevented genital herpes when present at the time of viral challenge, but increased the rate of infection when gel was applied daily for 7 days with a vaginal wash prior to viral inoculation. The findings presumably reflect altered epithelial architecture, which may have contributed to the trend towards increased HIV observed clinically. PMID:22096611

  11. Progressive Impairment on Neuropsychological Tasks in a Longitudinal Study of Preclinical Alzheimer's Disease

    E-print Network

    Wixted, John T.

    Progressive Impairment on Neuropsychological Tasks in a Longitudinal Study of Preclinical Alzheimer. The authors report a detailed neuropsychological evaluation of 11 patients over the course of 3 years up the neuropsychological profile of 11 preclinical patients. These individuals were among a large group of older adult

  12. 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 ?m, and a negative ? 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

  13. Preclinical therapeutic efficacy of a novel pharmacological inducer of apoptosis in malignant peripheral nerve sheath tumors

    PubMed Central

    Chau, Vincent; Lim, S. Kyun; Mo, Wei; Liu, Chiachi; Patel, Amish J.; McKay, Renée M.; Wei, Shuguang; Posner, Bruce A.; De Brabander, Jef K.; Williams, Noelle S.; Parada, Luis F.; Le, Lu Q.

    2014-01-01

    Neurofibromatosis Type 1 (NF1) is an autosomal disorder that affects neural crest-derived tissues, leading to a wide spectrum of clinical presentations. Patients commonly present with plexiform neurofibromas, benign but debilitating growths that can transform into malignant peripheral nerve sheath tumors (MPNSTs), a main cause of mortality. Currently, surgery is the primary course of treatment for MPNST, but with the limitation that these tumors are highly invasive. Radiation therapy is another treatment option, but is undesirable because it can induce additional mutations. MPNST patients may also receive doxorubicin as therapy, but this DNA-intercalating agent has relatively low tumor specificity and limited efficacy. In this study, we exploited a robust genetically-engineered mouse model of MPNST that recapitulates human NF1 associated MPNST to identify a novel small chemical compound that inhibits tumor cell growth. Compound 21 (Cpd21) inhibits growth of all available in vitro models of MPNST and human MPNST cell lines, while remaining non-toxic to normally-dividing Schwann cells or mouse embryonic fibroblasts. We show that this compound delays the cell cycle and leads to cellular apoptosis. Moreover, Cpd21 can reduce MPNST burden in a mouse allograft model, underscoring the compound’s potential as a novel chemotherapeutic agent. PMID:24285727

  14. Neuraxial Analgesia In Neonates And Infants: Review of Clinical and Preclinical Strategies for the Development of Safety and Efficacy Data

    PubMed Central

    Walker, Suellen M.; Yaksh, Tony L.

    2015-01-01

    Neuraxial agents provide robust pain control, have the potential to improve outcomes, and are an important component of the perioperative care of children. Opioids or clonidine improve analgesia when added to perioperative epidural infusions; analgesia is significantly prolonged by addition of clonidine, ketamine, neostigmine or tramadol to single shot caudal injections of local anesthetic; and neonatal intrathecal anesthesia/analgesia is increasing in some centers. However, it is difficult to determine the relative risk-benefit of different techniques and drugs without detailed and sensitive data related to analgesia requirements, side-effects, and follow-up. Current data related to benefits and complications in neonates and infants are summarized, but variability in current neuraxial drug use reflects the relative lack of high quality evidence. Recent preclinical reports of adverse effects of general anesthetics on the developing brain have increased awareness of the potential benefit of neuraxial anesthesia/analgesia to avoid or reduce general anesthetic dose requirements. However, the developing spinal cord is also vulnerable to drug-related toxicity, and although there are well-established preclinical models and criteria for assessing spinal cord toxicity in adult animals, until recently there had been no systematic evaluation during early life. Therefore, the second half of this review presents preclinical data evaluating age-dependent changes in the pharmacodynamic response to different spinal analgesics, and recent studies evaluating spinal toxicity in specific developmental models. Finally, we advocate use of neuraxial agents with the widest demonstrable safety margin and suggest minimum standards for preclinical evaluation prior to adoption of new analgesics or preparations into routine clinical practice. PMID:22798528

  15. Preclinical Assessment of the Efficacy of Mycograb, a Human Recombinant Antibody against Fungal HSP90

    Microsoft Academic Search

    Ruth C. Matthews; Gordon Rigg; Samantha Hodgetts; Tracey Carter; Caroline Chapman; Carl Gregory; Chris Illidge; James Burnie

    2003-01-01

    Mycograb (NeuTec Pharma plc) is a human genetically recombinant antibody against fungal heat shock protein 90 (HSP90). Antibody to HSP90 is closely associated with recovery in patients with invasive candidiasis who are receiving amphotericin B (AMB). Using in vitro assays developed for efficacy assessment of chemo- therapeutic antifungal drugs, Mycograb showed activity against a wide range of yeast species (MICs

  16. Preclinical in vivo efficacy of two 9-dihydrotaxane analogues against human and murine tumours

    Microsoft Academic Search

    JD Alder; KP Jarvis; KC Marsh; LL Klein; JJ Clement

    1996-01-01

    Two 9-dihydrotaxane analogues were synthesised and tested for in vitro potency and in vivo efficacy against murine and human tumour xenografts in mice. The in vitro potency of 9-dihydrotaxol (9-DH-t) and 10-deacetyl-9-dihydrotaxol (10-DeAc-9-DH-t) was generally less than that of paclitaxel against human and murine tumour cells. However, both analogues were at least 20-fold more soluble than paclitaxel in water. The

  17. A preclinical study combining the DNA repair inhibitor Dbait with radiotherapy for the treatment of melanoma.

    PubMed

    Biau, Julian; Devun, Flavien; Jdey, Wael; Kotula, Ewa; Quanz, Maria; Chautard, Emmanuel; Sayarath, Mano; Sun, Jian-Sheng; Verrelle, Pierre; Dutreix, Marie

    2014-10-01

    Melanomas are highly radioresistant tumors, mainly due to efficient DNA double-strand break (DSB) repair. Dbait (which stands for DNA strand break bait) molecules mimic DSBs and trap DNA repair proteins, thereby inhibiting repair of DNA damage induced by radiation therapy (RT). First, the cytotoxic efficacy of Dbait in combination with RT was evaluated in vitro in SK28 and 501mel human melanoma cell lines. Though the extent of RT-induced damage was not increased by Dbait, it persisted for longer revealing a repair defect. Dbait enhanced RT efficacy independently of RT doses. We further assayed the capacity of DT01 (clinical form of Dbait) to enhance efficacy of "palliative" RT (10 × 3 Gy) or "radical" RT (20 × 3 Gy), in an SK28 xenografted model. Inhibition of repair of RT-induced DSB by DT01 was revealed by the significant increase of micronuclei in tumors treated with combined treatment. Mice treated with DT01 and RT combination had significantly better tumor growth control and longer survival compared to RT alone with the "palliative" protocol [tumor growth delay (TGD) by 5.7-fold; median survival: 119 vs 67 days] or the "radical" protocol (TGD by 3.2-fold; median survival: 221 vs 109 days). Only animals that received the combined treatment showed complete responses. No additional toxicity was observed in any DT01-treated groups. This preclinical study provides encouraging results for a combination of a new DNA repair inhibitor, DT01, with RT, in the absence of toxicity. A first-in-human phase I study is currently under way in the palliative management of melanoma in-transit metastases (DRIIM trial). PMID:25379020

  18. Pharmacokinetics, Trypanosoma brucei gambiense Efficacy, and Time of Drug Action of DB829, a Preclinical Candidate for Treatment of Second-Stage Human African Trypanosomiasis

    PubMed Central

    Wenzler, Tanja; Yang, Sihyung; Braissant, Olivier; Boykin, David W.; Brun, Reto

    2013-01-01

    Human African trypanosomiasis (HAT, also called sleeping sickness), a neglected tropical disease endemic to sub-Saharan Africa, is caused by the parasites Trypanosoma brucei gambiense and T. brucei rhodesiense. Current drugs against this disease have significant limitations, including toxicity, increasing resistance, and/or a complicated parenteral treatment regimen. DB829 is a novel aza-diamidine that demonstrated excellent efficacy in mice infected with T. b. rhodesiense or T. b. brucei parasites. The current study examined the pharmacokinetics, in vitro and in vivo activity against T. b. gambiense, and time of drug action of DB829 in comparison to pentamidine. DB829 showed outstanding in vivo efficacy in mice infected with parasites of T. b. gambiense strains, despite having higher in vitro 50% inhibitory concentrations (IC50s) than against T. b. rhodesiense strain STIB900. A single dose of DB829 administered intraperitoneally (5 mg/kg of body weight) cured all mice infected with different T. b. gambiense strains. No cross-resistance was observed between DB829 and pentamidine in T. b. gambiense strains isolated from melarsoprol-refractory patients. Compared to pentamidine, DB829 showed a greater systemic exposure when administered intraperitoneally, partially contributing to its improved efficacy. Isothermal microcalorimetry and in vivo time-to-kill studies revealed that DB829 is a slower-acting trypanocidal compound than pentamidine. A single dose of DB829 (20 mg/kg) administered intraperitoneally clears parasites from mouse blood within 2 to 5 days. In summary, DB829 is a promising preclinical candidate for the treatment of first- and second-stage HAT caused by both Trypanosoma brucei subspecies. PMID:23959303

  19. Dabrafenib; Preclinical Characterization, Increased Efficacy when Combined with Trametinib, while BRAF/MEK Tool Combination Reduced Skin Lesions

    PubMed Central

    King, Alastair J.; Arnone, Marc R.; Bleam, Maureen R.; Moss, Katherine G.; Yang, Jingsong; Fedorowicz, Kelly E.; Smitheman, Kimberly N.; Erhardt, Joseph A.; Hughes-Earle, Angela; Kane-Carson, Laurie S.; Sinnamon, Robert H.; Qi, Hongwei; Rheault, Tara R.; Uehling, David E.; Laquerre, Sylvie G.

    2013-01-01

    Mitogen-Activated Protein Kinase (MAPK) pathway activation has been implicated in many types of human cancer. BRAF mutations that constitutively activate MAPK signalling and bypass the need for upstream stimuli occur with high prevalence in melanoma, colorectal carcinoma, ovarian cancer, papillary thyroid carcinoma, and cholangiocarcinoma. In this report we characterize the novel, potent, and selective BRAF inhibitor, dabrafenib (GSK2118436). Cellular inhibition of BRAFV600E kinase activity by dabrafenib resulted in decreased MEK and ERK phosphorylation and inhibition of cell proliferation through an initial G1 cell cycle arrest, followed by cell death. In a BRAFV600E-containing xenograft model of human melanoma, orally administered dabrafenib inhibited ERK activation, downregulated Ki67, and upregulated p27, leading to tumor growth inhibition. However, as reported for other BRAF inhibitors, dabrafenib also induced MAPK pathway activation in wild-type BRAF cells through CRAF (RAF1) signalling, potentially explaining the squamous cell carcinomas and keratoacanthomas arising in patients treated with BRAF inhibitors. In addressing this issue, we showed that concomitant administration of BRAF and MEK inhibitors abrogated paradoxical BRAF inhibitor-induced MAPK signalling in cells, reduced the occurrence of skin lesions in rats, and enhanced the inhibition of human tumor xenograft growth in mouse models. Taken together, our findings offer preclinical proof of concept for dabrafenib as a specific and highly efficacious BRAF inhibitor and provide evidence for its potential clinical benefits when used in combination with a MEK inhibitor. PMID:23844038

  20. Bridging the Gap between Preclinical and Clinical Microbicide Trials: Blind Evaluation of Candidate Gels in Murine Models of Efficacy and Safety

    Microsoft Academic Search

    Theodore J. Segarra; Esra Fakioglu; Natalia Cheshenko; Sarah S. Wilson; Pedro M. M. Mesquita; Gustavo F. Doncel; Betsy C. Herold

    2011-01-01

    BackgroundDespite significant protection in preclinical studies, cellulose sulfate (CS) failed to protect women against HIV-1\\/2 and was associated with a trend toward increased HIV-1 acquisition in one of the clinical trials. These results highlight the need for preclinical tests more predictive of clinical outcomes. The objective of this study was to test coded vaginal gels, including CS, in murine models

  1. Preclinical assessment of the efficacy of a new antivenom (EchiTAb-Plus-ICP ®) for the treatment of viper envenoming in sub-Saharan Africa

    Microsoft Academic Search

    Álvaro Segura; Mauren Villalta; María Herrera; Guillermo León; Robert Harrison; Nandul Durfa; Abdusalami Nasidi; Juan J. Calvete; R. David G. Theakston; David A. Warrell; José María Gutiérrez

    2010-01-01

    A preclinical assessment was performed on the neutralizing efficacy of a whole IgG polyspecific antivenom (EchiTAb-Plus-ICP®), designed for the treatment of snakebite envenomings in Nigeria. It was generated by immunizing horses with the venoms of Echis ocellatus, Bitis arietans and Naja nigricollis, the most medically important species in Nigeria. Antivenom was tested against the venoms of E. ocellatus, Echis leucogaster,

  2. Use of Standardized SCID-hu Thy\\/Liv Mouse Model for Preclinical Efficacy Testing of Anti-Human Immunodeficiency Virus Type 1 Compounds

    Microsoft Academic Search

    LINDA RABIN; MARA HINCENBERGS; MARY BETH MORENO; SUZETTE WARREN; VALERIE LINQUIST; ROELF DATEMA; BRIGITTE CHARPIOT; JAN SEIFERT; HIDETO KANESHIMA; ANDJOSEPH M. MCCUNE

    measure the representation of CD41and CD81cells, 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

  3. Pre-Clinical Assays Predict Pan-African Echis Viper Efficacy for a Species-Specific Antivenom

    PubMed Central

    Casewell, Nicholas R.; Cook, Darren A. N.; Wagstaff, Simon C.; Nasidi, Abdulsalami; Durfa, Nandul; Wüster, Wolfgang; Harrison, Robert A.

    2010-01-01

    Background Snakebite is a significant cause of death and disability in subsistent farming populations of sub-Saharan Africa. Antivenom is the most effective treatment of envenoming and is manufactured from IgG of venom-immunised horses/sheep but, because of complex fiscal reasons, there is a paucity of antivenom in sub-Saharan Africa. To address the plight of thousands of snakebite victims in savannah Nigeria, the EchiTAb Study Group organised the production, testing and delivery of antivenoms designed to treat envenoming by the most medically-important snakes in the region. The Echis saw-scaled vipers have a wide African distribution and medical importance. In an effort to maximise the clinical utility of scarce antivenom resources in Africa, we aimed to ascertain, at the pre-clinical level, to what extent the E. ocellatus-specific EchiTAbG antivenom, which was designed specifically for Nigeria, neutralised the lethal activity of venom from two other African species, E. pyramidum leakeyi and E. coloratus. Methodology/Principal Findings Despite apparently quite distinctive venom protein profiles, we observed extensive cross-species similarity in the immuno-reactivity profiles of Echis species-specific antisera. Using WHO standard pre-clinical in vivo tests, we determined that the monospecific EchiTAbG antivenom was as effective at neutralising the venom-induced lethal effects of E. pyramidum leakeyi and E. coloratus as it was against E. ocellatus venom. Under the restricted conditions of this assay, the antivenom was ineffective against the lethal effects of venom from the non-African Echis species, E. carinatus sochureki. Conclusions/Significance Using WHO-recommended pre-clinical tests we have demonstrated that the new anti-E. ocellatus monospecific antivenom EchiTAbG, developed in response to the considerable snakebite-induced mortality and morbidity in Nigeria, neutralised the lethal effects of venoms from Echis species representing each taxonomic group of this genus in Africa. This suggests that this monospecific antivenom has potential to treat envenoming by most, perhaps all, African Echis species. PMID:21049058

  4. 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…

  5. 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

  6. Preclinical evaluation of efficacy and safety of an improved lentiviral vector for the treatment of ?-thalassemia and sickle cell disease.

    PubMed

    Negre, Olivier; Bartholomae, Cynthia; Beuzard, Yves; Cavazzana, Marina; Christiansen, Lauryn; Courne, Céline; Deichmann, Annette; Denaro, Maria; de Dreuzy, Edouard; Finer, Mitchell; Fronza, Raffaele; Gillet-Legrand, Béatrix; Joubert, Christophe; Kutner, Robert; Leboulch, Philippe; Maouche, Leïla; Paulard, Anaïs; Pierciey, Francis J; Rothe, Michael; Ryu, Byoung; Schmidt, Manfred; von Kalle, Christof; Payen, Emmanuel; Veres, Gabor

    2015-01-01

    A previously published clinical trial demonstrated the benefit of autologous CD34(+) cells transduced with a selfinactivating lentiviral vector (HPV569) containing an engineered ?-globin gene (?(A-T87Q)-globin) in a subject with ? thalassemia major. This vector has been modified to increase transduction efficacy without compromising safety. In vitro analyses indicated that the changes resulted in both increased vector titers (3 to 4 fold) and increased transduction efficacy (2 to 3 fold). An in vivo study in which 58 ?-thalassemic mice were transplanted with vector- or mock-transduced syngenic bone marrow cells indicated sustained therapeutic efficacy. Secondary transplantations involving 108 recipients were performed to evaluate long-term safety. The six month study showed no hematological or biochemical toxicity. Integration site (IS) profile revealed an oligo/polyclonal hematopoietic reconstitution in the primary transplants and reduced clonality in secondary transplants. Tumor cells were detected in the secondary transplant mice in all treatment groups (including the control group), without statistical differences in the tumor incidence. Immunohistochemistry and quantitative PCR demonstrated that tumor cells were not derived from transduced donor cells. This comprehensive efficacy and safety data provided the basis for initiating two clinical trials with this second generation vector (BB305) in Europe and in the USA in patients with ?-thalassemia major and sickle cell disease. PMID:25429463

  7. Preclinical efficacy of maternal embryonic leucine-zipper kinase (MELK) inhibition in acute myeloid leukemia

    PubMed Central

    Alachkar, Houda; Mutonga, Martin B.G.; Metzeler, Klaus H.; Fulton, Noreen; Malnassy, Gregory; Herold, Tobias; Spiekermann, Karsten; Bohlander, Stefan K.; Hiddemann, Wolfgang; Matsuo, Yo; Stock, Wendy; Nakamura, Yusuke

    2014-01-01

    Maternal embryonic leucine-zipper kinase (MELK), which was reported to be frequently up-regulated in various types of solid cancer, plays critical roles in formation and maintenance of cancer stem cells. However, little is known about the relevance of this kinase in hematologic malignancies. Here we report characterization of possible roles of MELK in acute myeloid leukemia (AML). MELK is expressed in AML cell lines and AML blasts with higher levels in less differentiated cells. MELK is frequently upregulated in AML with complex karyotypes and is associated with worse clinical outcome. MELK knockdown resulted in growth inhibition and apoptosis of leukemic cells. Hence, we investigated the potent anti-leukemia activity of OTS167, a small molecule MELK kinase inhibitor, in AML, and found that the compound induced cell differentiation and apoptosis as well as decreased migration of AML cells. MELK expression was positively correlated with the expression of FOXM1 as well as its downstream target genes. Furthermore, MELK inhibition resulted in downregulation of FOXM1 activity and the expression of its downstream targets. Taken together, and given that OTS167 is undergoing a phase I clinical trial in solid cancer, our study warrants clinical evaluation of this compound as a novel targeted therapy for AML patients. PMID:25365263

  8. 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 in a rat tumor model on a clinical platform, with a high accuracy achieved in the delivery of complex dose distributions. Our work demonstrates the technical feasibility of this approach and enables future investigations on the therapeutic effect of preclinical dose painting strategies using a state-of-the-art clinical platform. PMID:25897556

  9. 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. PMID:25473210

  10. Racer efficacy study

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Racer (ammonium nonanoate) is a non-selective contact herbicide that controls several weed species. Racer has been labeled by EPA in the past year for weed control in food crops and is close to receiving approval for use by organic producers. The objective of this study was to verify results from ...

  11. Pharmacokinetics, efficacy and toxicity of different pegylated liposomal doxorubicin formulations in preclinical models: is a conventional bioequivalence approach sufficient to ensure therapeutic equivalence of pegylated liposomal doxorubicin products?

    Microsoft Academic Search

    Rao N. V. S. MamidiSteve; Steve Weng; Susan Stellar; Charles Wang; Ning Yu; Tony Huang; Alfred P. Tonelli; Michael F. Kelley; Anthony Angiuoli; Man-Cheong Fung

    2010-01-01

    Purpose  To examine whether a conventional bioequivalence approach is sufficient to ensure the therapeutic equivalence of liposomal\\u000a products, the pharmacokinetics, efficacy and toxicity of different formulation variants of the marketed Doxil®\\/Caelyx® product, pegylated liposomal doxorubicin (PLD), were evaluated in several preclinical models.\\u000a \\u000a \\u000a \\u000a \\u000a Methods  Six different variants of the marketed PLD formulation were prepared by incorporating minor changes in the composition and\\u000a liposome

  12. Novel therapies for FSGS: preclinical and clinical studies.

    PubMed

    Malaga-Dieguez, Laura; Bouhassira, Diana; Gipson, Debbie; Trachtman, Howard

    2015-03-01

    Focal segmental glomerulosclerosis (FSGS) is a rare but important cause of end-stage kidney disease in children and adults. Current therapy, consisting of corticosteroids and calcineurin inhibitors, fails to achieve a sustained remission in most patients. Therefore, there is a pressing need to develop new treatments for this glomerulopathy. Traditional approaches have focused on agents that modulate the immune system. In this review, we summarize preclinical and clinical data with newer agents that may ameliorate FSGS. We focus on drugs that inhibit immune injury or inflammation, such as abatacept, rituximab, adalimumab, and stem cells. The potential of agents that block the glomerular action of circulating permeability factors such as soluble urokinase receptor is reviewed. Finally, because fibrosis represents the final common pathway of glomerular damage in FSGS, the experience with a wide range of antifibrotic agents is presented. Despite extensive research on the podocyte dysfunction in the pathogenesis of FSGS, there are few agents that directly target podocyte structure or viability. We conclude that FSGS is a heterogeneous disorder and that intensified translational research is vital to improve our understanding of distinct subtypes that have a defined prognosis and predictable response to targeted therapeutic interventions. PMID:25704355

  13. 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

  14. Dicycloplatin, a novel platinum analog in chemotherapy: synthesis of chinese pre-clinical and clinical profile and emerging mechanistic studies.

    PubMed

    Yu, Jing Jie; Yang, Xuqing; Song, Qinhua; Mueller, Michael D; Remick, Scot C

    2014-01-01

    Dicycloplatin (DCP) has better solubility and stability than both cisplatin and carboplatin. Pre-clinical and phase I studies demonstrated significant antitumor activity and fewer adverse events than carboplatin. Phase II clinical trials in advanced non-small cell lung cancer found efficacy and safety of DCP-plus-paclitaxel comparable to carboplatin-plus-paclitaxel but better tolerability. This article summarizes and reviews pre-clinical and clinical data for dicycloplatin from the Chinese medical literature. We also report on new mechanistic findings in our laboratory in West Virginia, USA. Patient blood samples were collected for DCP-prototype determination by liquid chromatography mass spectrometry (LC-MS/MS). Molecular studies of ovarian cancer cells treated with DCP or cisplatin were carried out for gene-signature profiling using immunoblotting. Pharmacokinetic mass-spectrometry showed different spectrum profiles of DCP and carboplatin in plasma. Plasma concentration of DCP prototype was 17.1 ?g/ml 2h after administration, with a peak concentration of 26.9 ?g/ml at 0.5 h. Immunoblotting showed DCP-induced activation of DNA damage pathways, including double-phosphorylated checkpoint kinase 2 (CHK2) and breast cancer 1 (BRCA1) and triple-phosphorylated p53, compared to controls. Cisplatin produced a similar profile, with increased p53 protein. DCP and cisplatin activate DNA-damage response through similar pathways. DCP may be more soluble and stable, and better-tolerated. PMID:24403501

  15. Focused Ultrasound-Induced Blood–Brain Barrier Opening to Enhance Temozolomide Delivery for Glioblastoma Treatment: A Preclinical Study

    PubMed Central

    Wei, Kuo-Chen; Chu, Po-Chun; Wang, Hay-Yan Jack; Huang, Chiung-Yin; Chen, Pin-Yuan; Tsai, Hong-Chieh; Lu, Yu-Jen; Lee, Pei-Yun; Tseng, I-Chou; Feng, Li-Ying; Hsu, Peng-Wei; Yen, Tzu-Chen; Liu, Hao-Li

    2013-01-01

    The purpose of this study is to assess the preclinical therapeutic efficacy of magnetic resonance imaging (MRI)-monitored focused ultrasound (FUS)-induced blood-brain barrier (BBB) disruption to enhance Temozolomide (TMZ) delivery for improving Glioblastoma Multiforme (GBM) treatment. MRI-monitored FUS with microbubbles was used to transcranially disrupt the BBB in brains of Fisher rats implanted with 9L glioma cells. FUS-BBB opening was spectrophotometrically determined by leakage of dyes into the brain, and TMZ was quantitated in cerebrospinal fluid (CSF) and plasma by LC-MS\\MS. The effects of treatment on tumor progression (by MRI), animal survival and brain tissue histology were investigated. Results demonstrated that FUS-BBB opening increased the local accumulation of dyes in brain parenchyma by 3.8-/2.1-fold in normal/tumor tissues. Compared to TMZ alone, combined FUS treatment increased the TMZ CSF/plasma ratio from 22.7% to 38.6%, reduced the 7-day tumor progression ratio from 24.03 to 5.06, and extended the median survival from 20 to 23 days. In conclusion, this study provided preclinical evidence that FUS BBB-opening increased the local concentration of TMZ to improve the control of tumor progression and animal survival, suggesting its clinical potential for improving current brain tumor treatment. PMID:23527068

  16. Effect of currently approved carriers and adjuvants on the pre-clinical efficacy of a conjugate vaccine against oxycodone in mice and rats.

    PubMed

    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

  17. The Relationship between Risk of Bias Criteria, Research Outcomes, and Study Sponsorship in a Cohort of Preclinical Thiazolidinedione Animal Studies: A Meta-Analysis

    PubMed Central

    Abdel-Sattar, Maher; Krauth, David; Anglemyer, Andrew; Bero, Lisa

    2015-01-01

    Introduction There is little evidence regarding the influence of conflicts of interest on preclinical research. This study examines whether industry sponsorship is associated with increased risks of bias and/or effect sizes of outcomes in published preclinical thiazolidinedione (TZD) studies. Methods We identified preclinical TZD studies published between January 1, 1965 and November 14, 2012. Coders independently extracted information on study design criteria aimed at reducing bias, results for all relevant outcomes, sponsorship source, and investigator financial ties from the 112 studies meeting the inclusion criteria. The average standardized mean difference (SMD) across studies was calculated for plasma glucose (efficacy outcome) and weight gain (harm outcome). In subgroup analyses, TZD outcomes were assessed by sponsorship source and risk of bias criteria. Results Seven studies were funded by industry alone, 17 studies funded by both industry and non-industry, 49 studies funded by non-industry alone, and 39 studies had no disclosures. None of the studies used sample size calculations, intention-to-treat analyses, blinding of investigators, or concealment of allocation. Most studies reported favorable results (88 of 112) and conclusions (95 of 112) supporting TZD use. Efficacy estimates were significantly larger in 6 studies sponsored by industry alone (?3.41; 95% CI ?5.21, ?1.53; I2 = 93%) versus 42 studies sponsored by non-industry sources (?0.97; 95% CI ?1.37, ?0.56; I2 = 81%) (p value = 0.01). Harms estimates were significantly larger in 4 studies sponsored by industry alone (5.00; 95% CI 1.22, 8.77; I2 = 93%) versus 38 studies sponsored by non-industry sources (0.30; 95% CI ?0.08, 0.68; I2 = 79%) (p value = 0.02). TZD efficacy and harms did not differ by disclosure of financial COIs or risks of bias. Conclusions Industry-sponsored TZD animal studies have exaggerated efficacy and harms outcomes compared to studies funded by non-industry sources. There was poor reporting of COIs. PMID:25642330

  18. Preclinical anti-arthritic study and pharmacokinetic properties of a potent histone deacetylase inhibitor MPT0G009.

    PubMed

    Hsieh, I-N; Liou, J-P; Lee, H-Y; Lai, M-J; Li, Y-H; Yang, C-R

    2014-01-01

    The pathology of rheumatoid arthritis includes synoviocyte proliferation and inflammatory mediator expression, which may result from dysregulated epigenetic control by histone deacetylase (HDAC). Thus, HDAC inhibitors may be useful for treating inflammatory disease. This was a preclinical study of the HDAC inhibitor, MPT0G009. The IC50 values of MPT0G009 for HDAC1, 2, 3, 6 and 8 enzymatic activities were significantly lower than those for the currently marketed HDAC inhibitor suberoylanilide hydroxamic acid (SAHA; vorinostat). In addition, MPT0G009 markedly inhibited cytokine secretion and macrophage colony-stimulating factor/receptor activator of nuclear factor kappa B ligand-induced osteoclastogenesis by macrophages (50 ng/ml each). These MPT0G009 effects on cytokine secretion and osteoclast formation were reduced by the overexpression of HDAC 1 (class I HDAC) and 6 (class II HDAC) in cells, suggesting that these effects were due to the inhibition of its activity. In an in vivo rat model, oral administration of MPT0G009 (25 mg/kg) significantly inhibited paw swelling and bone destruction. Furthermore, compared with SAHA, MPT0G009 exhibited longer half-life (9.53 h for oral administration) and higher oral bioavailability (13%) in rats. These results established the preclinical anti-arthritic efficacy and pharmacokinetic parameters of MPT0G009, which may provide a new therapeutic approach for treating inflammatory arthritis. PMID:24722291

  19. 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.…

  20. Ultra-high-resolution imaging of small animals: Implications for preclinical and research studies

    Microsoft Academic Search

    David A. Weber; Marijana Ivanovic

    1999-01-01

    Higher spatial resolution is continuously sought in nuclear medicine to improve the spatial detail and image quality that can be used for preclinical and cfinical imaging studies. The greater tissue specificity and highly selective uptake of many of the new labeled monoclonal antibodies, receptor-specific molecules, peptides, and other new radiopharmaceuticals investigated for use in imaging and therapy often require higher

  1. 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 amoenum. For several of the plants studied, conclusions need to be tempered due to methodological issues such as small sample sizes, brief intervention durations and non-replication. Current evidence does not support Hypericum perforatum or Valeriana spp. for any anxiety disorder. Acute anxiolytic activity was found for Centella asiatica, Salvia spp., Melissa officinalis, Passiflora incarnata and Citrus aurantium. Bacopa monnieri has shown anxiolytic effects in people with cognitive decline. The therapeutic application of psychotropic plant-based treatments for anxiety disorders is also discussed, specifically Psychotria viridis and Banisteriopsis caarti (ayahuasca), Psilocybe spp. and cannabidiol-enriched (low tetrahydrocannabinol (?(9)-THC)) Cannabis spp. PMID:23653088

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

    SciTech Connect

    Medin, Paul M., E-mail: Paul.medin@utsouthwestern.ed [Department of Radiation Oncology, UT Southwestern Medical Center, Dallas, TX (United States); Boike, Thomas P. [Department of Radiation Oncology, UT Southwestern Medical Center, Dallas, TX (United States)

    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.

  3. 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

  4. 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

  5. Preclinical assessment of the efficacy of a new antivenom (EchiTAb-Plus-ICP) for the treatment of viper envenoming in sub-Saharan Africa.

    PubMed

    Segura, Alvaro; Villalta, Mauren; Herrera, María; León, Guillermo; Harrison, Robert; Durfa, Nandul; Nasidi, Abdusalami; Calvete, Juan J; Theakston, R David G; Warrell, David A; Gutiérrez, José María

    2010-01-01

    A preclinical assessment was performed on the neutralizing efficacy of a whole IgG polyspecific antivenom (EchiTAb-Plus-ICP), designed for the treatment of snakebite envenomings in Nigeria. It was generated by immunizing horses with the venoms of Echis ocellatus, Bitis arietans and Naja nigricollis, the most medically important species in Nigeria. Antivenom was tested against the venoms of E. ocellatus, Echis leucogaster, Echis pyramidum leakeyi, B. arietans, Bitis gabonica, Bitis rhinoceros and Bitis nasicornis. The neutralization of the venom toxins responsible for the lethal, hemorrhagic, coagulant and local necrotizing activities was assessed, since these are the most significant effects that characterize envenoming by these species. Echis sp venoms exerted lethal, hemorrhagic, coagulant and necrotizing effects, whereas the Bitis sp venoms tested induced lethality, hemorrhage and necrosis, but were devoid of coagulant activity. The antivenom was effective in the neutralization of all effects tested in all venoms. Highest neutralization was achieved against the venoms of E. ocellatus and B. arietans, and the lowest neutralizing potency was against the venom of B. nasicornis, a species that has a low clinical relevance. It is concluded that EchiTAb-Plus-ICP, whilst specifically designed for Nigeria, has a good preclinical neutralizing profile against homologous and heterologous viperid venoms from other sub-Saharan African locations. It therefore constitutes a promising therapeutic option for the treatment of snakebite envenoming in this region. PMID:19699756

  6. Curaxin CBL0137 eradicates drug resistant cancer stem cells and potentiates efficacy of gemcitabine in preclinical models of pancreatic cancer

    PubMed Central

    Burkhart, Catherine; Fleyshman, Daria; Kohrn, Rachael; Commane, Mairead; Garrigan, Jennifer; Kurbatov, Vadim; Toshkov, Ilya; Ramachandran, Rajesh; Martello, Laura; Gurova, Katerina V.

    2014-01-01

    Pancreatic ductal adenocarcinoma (PDA) continues to be one of the deadliest cancers due to the absence of effective treatment. Curaxins are a class of small molecules with anti-cancer activity demonstrated in different models of cancer in mice. The lead curaxin compound, CBL0137, recently entered Phase I clinical trials. Curaxins modulate several important signaling pathways involved in the pathogenesis of PDA through inhibition of chromatin remodeling complex FACT. FACT is overexpressed in multiple types of tumor, with one of the highest rate of overexpression in PDA (59%). In this study, the efficacy of CBL0137 alone or in combination with current standard of care, gemcitabine, was tested against different models of PDA in vitro and in mouse models. It was found that CBL0137 alone is a potent inducer of apoptosis in pancreatic cancer cell lines and is toxic not only for proliferating bulk tumor cells, but also for pancreatic cancer stem cells. In mice, CBL0137 was effective against several PDA models, including orthotopic gemcitabine resistant PANC-1 model and patient derived xenografts, in which CBL0137 anti-tumor effect correlated with overexpression of FACT. Moreover, we observed synergy of CBL0137 with gemcitabine which may be explained by the ability of CBL0137 to inhibit several transcriptional programs induced by gemcitabine, including NF-kappaB response and expression of ribonucleotide reductase, one of the targets of gemcitabine in cells. This data suggest testing of CBL0137 efficacy in Phase II trial in PDA patients alone and in combination with gemcitabine. PMID:25402820

  7. An Oral Formulation of YK-4-279: Preclinical Efficacy and Acquired Resistance Patterns in Ewing Sarcoma.

    PubMed

    Lamhamedi-Cherradi, Salah-Eddine; Menegaz, Brian A; Ramamoorthy, Vandhana; Aiyer, Ramani A; Maywald, Rebecca L; Buford, Adrianna S; Doolittle, Dannette K; Culotta, Kirk S; O'Dorisio, James E; Ludwig, Joseph A

    2015-07-01

    Ewing sarcoma is a transcription factor-mediated pediatric bone tumor caused by a chromosomal translocation of the EWSR1 gene and one of several genes in the ETS family of transcription factors, typically FLI1 or ERG. Full activity of the resulting oncogenic fusion protein occurs only after binding RNA helicase A (RHA), and novel biologically targeted small molecules designed to interfere with that interaction have shown early promise in the preclinical setting. Herein, we demonstrate marked preclinical antineoplastic activity of an orally bioavailable formulation of YK-4-279 and identify mechanisms of acquired chemotherapy resistance that may be exploited to induce collateral sensitivity. Daily enteral administration of YK-4-279 led to significant delay in Ewing sarcoma tumor growth within a murine model. In advance of anticipated early-phase human clinical trials, we investigated both de novo and acquired mechanism(s) by which Ewing sarcoma cells evade YK-4-279-mediated cell death. Drug-resistant clones, formed by chronic in vitro exposure to steadily increased levels of YK-4-279, overexpressed c-Kit, cyclin D1, pStat3(Y705), and PKC isoforms. Interestingly, cross-resistance to imatinib and enzastaurin (selective inhibitors of c-Kit and PKC-?, respectively), was observed and the use of YK-4-279 with enzastaurin in vitro led to marked drug synergy, suggesting a potential role for combination therapies in the future. By advancing an oral formulation of YK-4-279 and identifying prominent mechanisms of resistance, this preclinical research takes us one step closer to a shared goal of curing adolescents and young adults afflicted by Ewing sarcoma. Mol Cancer Ther; 14(7); 1591-604. ©2015 AACR. PMID:25964201

  8. 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

  9. Beneficial health effects of lupeol triterpene: a review of preclinical studies.

    PubMed

    Siddique, Hifzur Rahman; Saleem, Mohammad

    2011-02-14

    Since ancient times, natural products have been used as remedies to treat human diseases. Lupeol, a phytosterol and triterpene, is widely found in edible fruits, and vegetables. Extensive research over the last three decades has revealed several important pharmacological activities of lupeol. Various in vitro and preclinical animal studies suggest that lupeol has a potential to act as an anti-inflammatory, anti-microbial, anti-protozoal, anti-proliferative, anti-invasive, anti-angiogenic and cholesterol lowering agent. Employing various in vitro and in vivo models, lupeol has also been tested for its therapeutic efficiency against conditions including wound healing, diabetes, cardiovascular disease, kidney disease, and arthritis. Lupeol has been found to be pharmacologically effective in treating various diseases under preclinical settings (in animal models) irrespective of varying routes of administration viz; topical, oral, intra-peritoneal and intravenous. It is noteworthy that lupeol has been reported to selectively target diseased and unhealthy human cells, while sparing normal and healthy cells. Published studies provide evidence that lupeol modulates the expression or activity of several molecules such as cytokines IL-2, IL4, IL5, IL?, proteases, ?-glucosidase, cFLIP, Bcl-2 and NF?B. This minireview discusses in detail the preclinical studies conducted with lupeol and provides an insight into its mechanisms of action. PMID:21118697

  10. Pre-clinical efficacy of combined therapy with novel ?-catenin antagonist BC2059 and histone deacetylase inhibitor against AML cells.

    PubMed

    Fiskus, W; Sharma, S; Saha, S; Shah, B; Devaraj, S G T; Sun, B; Horrigan, S; Leveque, C; Zu, Y; Iyer, S; Bhalla, K N

    2015-06-01

    The canonical wingless-type MMTV integration site (WNT)-?-catenin pathway is essential for self-renewal, growth and survival of acute myeloid leukemia (AML) stem/blast progenitor cells (BPCs). Deregulated WNT signaling inhibits degradation of ?-catenin, causing increased nuclear translocation and co-factor activity of ?-catenin with the transcriptional regulator T-cell factor (TCF) 4/lymphoid enhancer factor 1 in AML BPCs. Here, we determined the pre-clinical anti-AML activity of the anthraquinone oxime-analog BC2059 (BC), known to attenuate ?-catenin levels. BC treatment disrupted the binding of ?-catenin with the scaffold protein transducin ?-like 1 and proteasomal degradation and decline in the nuclear levels of ?-catenin. This was associated with reduced transcriptional activity of TCF4 and expression of its target genes, cyclin D1, c-MYC and survivin. BC treatment dose-dependently induced apoptosis of cultured and primary AML BPCs. Treatment with BC also significantly improved the median survival of immune-depleted mice engrafted with either cultured or primary AML BPCs, exhibiting nuclear expression of ?-catenin. Co-treatment with the pan-histone deacetylase inhibitor panobinostat and BC synergistically induced apoptosis of cultured and primary AML BPCs, including those expressing FLT3-ITD, as well as further significantly improved the survival of immune-depleted mice engrafted with primary AML BPCs. These findings underscore the promising pre-clinical activity and warrant further testing of BC against human AML, especially those expressing FLT3-ITD. PMID:25482131

  11. PRECLINICAL STUDY Adult human mesenchymal stem cells enhance breast

    E-print Network

    McLachlan, John

    . Keywords Mesenchymal stem cells Á Breast carcinoma Á Progesterone receptor Á Stromal-derived factor 1 ÁPRECLINICAL STUDY Adult human mesenchymal stem cells enhance breast tumorigenesis and promote Adult human mesenchymal stem cells (hMSCs) have been shown to home to sites of breast cancer

  12. A Tumor-mimic Model for Evaluating the Accuracy of HIFU Preclinical Studies: An In Vivo Study

    E-print Network

    Paris-Sud XI, Université de

    A Tumor-mimic Model for Evaluating the Accuracy of HIFU Preclinical Studies: An In Vivo Study W. A of ablative technologies such as HIFU for the treatment of liver tumors in humans has been studied in animal models without tumors or in small animals like rats and rabbits with established tumors. Because

  13. 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.

  14. Intradermal inactivated poliovirus vaccine: a preclinical dose-finding study.

    PubMed

    Kouiavskaia, Diana; Mirochnitchenko, Olga; Dragunsky, Eugenia; Kochba, Efrat; Levin, Yotam; Troy, Stephanie; Chumakov, Konstantin

    2015-05-01

    Intradermal delivery of vaccines has been shown to result in dose sparing. We tested the ability of fractional doses of inactivated poliovirus vaccine (IPV) delivered intradermally to induce levels of serum poliovirus-neutralizing antibodies similar to immunization through the intramuscular route. Immunogenicity of fractional doses of IPV was studied by comparing intramuscular and intradermal immunization of Wistar rats using NanoPass MicronJet600 microneedles. Intradermal delivery of partial vaccine doses induced antibodies at titers comparable to those after immunization with full human dose delivered intramuscularly. The results suggest that intradermal delivery of IPV may lead to dose-sparing effect and reduction of the vaccination cost. PMID:25391313

  15. Preclinical and Clinical Studies for Sodium Tungstate: Application in Humans

    PubMed Central

    Bertinat, Romina; Nualart, Francisco; Li, Xuhang; Yáñez, Alejandro J.; Gomis, Ramón

    2015-01-01

    Diabetes is a complex metabolic disorder triggered by the deficient secretion of insulin by the pancreatic ?-cell or the resistance of peripheral tissues to the action of the hormone. Chronic hyperglycemia is the major consequence of this failure, and also the main cause of diabetic problems. Indeed, several clinical trials have agreed in that tight glycemic control is the best way to stop progression of the disease. Many anti-diabetic drugs for treatment of type 2 diabetes are commercially available, but no ideal normoglycemic agent has been developed yet. Moreover, weight gain is the most common side effect of many oral anti-diabetic agents and insulin, and increased weight has been shown to worsen glycemic control and increase the risk of diabetes progression. In this sense, the inorganic salt sodium tungstate (NaW) has been studied in different animal models of metabolic syndrome and diabetes, proving to have a potent effect on normalizing blood glucose levels and reducing body weight, without any hypoglycemic action. Although the liver has been studied as the main site of NaW action, positive effects have been also addressed in muscle, pancreas, brain, adipose tissue and intestine, explaining the effective anti-diabetic action of this salt. Here, we review NaW research to date in these different target organs. We believe that NaW deserves more attention, since all available anti-diabetic treatments remain suboptimal and new therapeutics are urgently needed. PMID:25995968

  16. Anticancer potential of curcumin: preclinical and clinical studies.

    PubMed

    Aggarwal, Bharat B; Kumar, Anushree; Bharti, Alok C

    2003-01-01

    Curcumin (diferuloylmethane) is a polyphenol derived from the plant Curcuma longa, commonly called turmeric. Extensive research over the last 50 years has indicated this polyphenol can both prevent and treat cancer. The anticancer potential of curcumin stems from its ability to suppress proliferation of a wide variety of tumor cells, down-regulate transcription factors NF-kappa B, AP-1 and Egr-1; down-regulate the expression of COX2, LOX, NOS, MMP-9, uPA, TNF, chemokines, cell surface adhesion molecules and cyclin D1; down-regulate growth factor receptors (such as EGFR and HER2); and inhibit the activity of c-Jun N-terminal kinase, protein tyrosine kinases and protein serine/threonine kinases. In several systems, curcumin has been described as a potent antioxidant and anti-inflammatory agent. Evidence has also been presented to suggest that curcumin can suppress tumor initiation, promotion and metastasis. Pharmacologically, curcumin has been found to be safe. Human clinical trials indicated no dose-limiting toxicity when administered at doses up to 10 g/day. All of these studies suggest that curcumin has enormous potential in the prevention and therapy of cancer. The current review describes in detail the data supporting these studies. PMID:12680238

  17. Preclinical studies of opioids and opioid antagonists on gastrointestinal function.

    PubMed

    Greenwood-Van Meerveld, B; Gardner, C J; Little, P J; Hicks, G A; Dehaven-Hudkins, D L

    2004-10-01

    Opioid receptors in the gastrointestinal (GI) tract mediate the effects of endogenous opioid peptides and exogenously administered opioid analgesics, on a variety of physiological functions associated with motility, secretion and visceral pain. The studies reviewed or reported here describe a range of in vivo activities of opioid receptor antagonists upon GI function in rodents, focusing on mu receptors. Naloxone, and the peripherally acting mu-opioid receptor antagonists alvimopan and methylnaltrexone, reverse morphine-induced inhibition of GI transit in mice and rats, and morphine- or loperamide-induced inhibition of castor oil-induced diarrhoea in mice. At doses producing maximal reversal of morphine-induced effects upon GI transit, only the central nervous system (CNS) penetrant antagonist naloxone was able to reverse morphine-induced analgesia. Both central and peripheral opioid antagonists may affect GI function and/or visceromotor sensitivity in the absence of exogenous opioid analgesics, suggesting a constitutive role for endogenous opioid peptides in the control of GI physiology. Furthermore, in contrast to naloxone, alvimopan does not produce hypersensitivity to the visceromotor response induced by nociceptive levels of colorectal distension in a rodent model of post-inflammatory colonic hypersensitivity, suggesting that in the periphery endogenous mu-opioid receptor-mediated mechanisms do not regulate colonic sensitivity. The data support the hypothesis that peripherally acting opioid antagonists may be able to selectively block opioid receptors in the GI tract, thereby preserving normal GI physiology, while not blocking the effects of endogenous opioid peptides or exogenous opioid analgesics in the CNS. These findings suggest that the primary sites of action of mu-opioid agonists with respect to inhibition of GI function are in the periphery, whereas analgesic activity resides primarily in the CNS. PMID:15357851

  18. Preclinical toxicology studies with acyclovir: genetic toxicity tests.

    PubMed

    Clive, D; Turner, N T; Hozier, J; Batson, A G; Tucker, W E

    1983-01-01

    Acyclovir (ACV), an antiviral drug active in the treatment of oral and genital Herpes infections, has been evaluated for mutagenic and carcinogenic potential in a battery of in vitro and in vivo short-term assays. Negative results were obtained in the following in vitro tests: Ames Salmonella, plate incorporation and preincubation modification assays; E. coli polA+/polA- DNA repair; yeast (S. cerevisiae D4) gene conversion; Chinese hamster ovary cells (HGPRT, APRT loci and ouabain-resistance marker); L5178Y mouse lymphoma cells (HGPRT locus and ouabain-resistance marker); and C3H/10T1/2 mouse fibroblast neoplastic transformation assay. All except the last assay were performed in the presence and absence of an exogenous metabolic activation system. ACV was positive at high concentrations X exposure times in the absence of exogenous metabolic activation in the following in vitro systems and at the indicated concentrations: BALB/c-3T3 neoplastic transformation (50 micrograms/mL, 72 h exposure); human lymphocyte cytogenetics (250-500 micrograms/mL, 48 h exposure); and L5178Y mouse lymphoma cells (TK locus, 400-2400 micrograms/mL, 4 h exposure; predominantly small colony mutants of chromosomal origin produced). No effects were seen in vivo (mouse dominant lethal assay; rat and Chinese hamster bone marrow cytogenetics) at up to maximum tolerated doses (MTD). An unusual clastogenic effect was seen in Chinese hamsters at 5 times the MTD. Overall, positive effects were seen only at either high concentrations (greater than or equal to 250 micrograms/mL in vitro or plasma levels) or prolonged exposure (72 hr in the BALB/c-3T3 neoplastic transformation assay). These studies support the view that ACV is a chromosomal mutagen, i.e., one which causes multi-locus damage but not single gene effects. The significance of these results for the genetic risk of ACV to man is discussed. PMID:6662301

  19. Analgesic and hypnotic activities of Laghupanchamula: A preclinical study

    PubMed Central

    Ghildiyal, Shivani; Gautam, Manish K.; Joshi, Vinod K.; Goel, Raj K.

    2014-01-01

    Background: In Ayurvedic classics, two types of Laghupanchamula -five plant roots (LP) have been mentioned containing four common plants viz. Kantakari, Brihati, Shalaparni, and Prinshniparni and the fifth plant is either Gokshura (LPG) or Eranda (LPE). LP has been documented to have Shothahara (anti-inflammatory), Shulanashka (analgesic), Jvarahara (antipyretic), and Rasayana (rejuvenator) activities. Aim: To evaluate the acute toxicity (in mice), analgesic and hypnotic activity (in rats) of 50% ethanolic extract of LPG (LPGE) and LPE (LPEE). Materials and Methods: LPEG and LPEE were prepared separately by using 50% ethanol following the standard procedures. A graded dose (250, 500 and 1000 mg/kg) response study for both LPEE and LPGE was carried out for analgesic activity against rat tail flick response which indicated 500 mg/kg as the optimal effective analgesic dose. Hence, 500 mg/kg dose of LPEE and LPGE was used for hot plate test and acetic acid induced writhing model in analgesic activity and for evaluation of hypnotic activity. Results: Both the extracts did not produce any acute toxicity in mice at single oral dose of 2.0 g/kg. Both LPGE and LPEE (250, 500, and 1000 mg/kg) showed dose-dependent elevation in pain threshold and peak analgesic effect at 60 min as evidenced by increased latency period in tail-flick method by 25.1-62.4% and 38.2-79.0% respectively. LPGE and LPEE (500 mg/kg) increased reaction time in hot-plate test at peak 60 min analgesic effect by 63.2 and 85.8% and reduction in the number of acetic acid-induced writhes by 55.9 and 65.8% respectively. Both potentiated pentobarbitone-induced hypnosis as indicated by increased duration of sleep in treated rats. Conclusion: The analgesic and hypnotic effects of LP formulations authenticate their uses in Ayurvedic system of Medicine for painful conditions. PMID:25364205

  20. Preclinical and Clinical Studies on 5-Aza-2?Deoxycytidine, a Potent Inhibitor of DNA Methylation, in Cancer Therapy

    Microsoft Academic Search

    Richard L. Momparler

    The preclinical and clinical investigations by the author on the antineoplastic activity of 5-Aza-2?-deoxycytidine (5AZA),\\u000a a potent inhibitor of DNA methylation are reviewed. These include studies on the molecular, cellular and animal pharmacology\\u000a of 5AZA. These preclinical studies indicated that 5AZA has enormous potential in cancer therapy. This potential is supported\\u000a by reports in the literature indicate that 5AZA can

  1. 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.

  2. Evaluation of N-desmethylclozapine as a potential antipsychotic--preclinical studies.

    PubMed

    Natesan, Sridhar; Reckless, Greg E; Barlow, Karen B L; Nobrega, José N; Kapur, Shitij

    2007-07-01

    There is growing interest in N-desmethylclozapine (NDMC), the major metabolite of clozapine, as a unique antipsychotic because it acts in vitro as a 5-HT(2) antagonist and as a partial agonist to dopamine D(2) and muscarinic receptors. To explore this, we compared NDMC to a typical (haloperidol), atypical (clozapine), and partial-agonist atypical (aripiprazole) antipsychotic in preclinical models. The comparison was carried out using: brain D(2) and 5-HT(2) receptor occupancy; animal models predictive of antipsychotic efficacy (amphetamine-induced hyperlocomotion (AIL) and conditioned avoidance response (CAR) models); measures predictive of side effects (catalepsy and prolactin elevation); and molecular markers predictive of antipsychotic action (striatal Fos induction). NDMC (10-60 mg/kg/s.c.) showed high 5-HT(2) (64-79%), but minimal D(2) occupancy (<15% at 60 mg/kg) 1 h after administration. In contrast to other antipsychotics, NDMC was not very effective in reducing AIL or CAR and showed minimal induction of Fos in the nucleus accumbens. However, like atypical antipsychotics, it showed no catalepsy, prolactin elevation, and minimal Fos in the dorsolateral striatum. It seems unlikely that NDMC would show efficacy as a stand-alone antipsychotic, however, its freedom from catalepsy and prolactin elevation, and its unique pharmacological profile (muscarinic agonism) may make it feasible to use this drug as an adjunctive treatment to existing antipsychotic regimens. PMID:17164815

  3. Accelerating drug discovery for Alzheimer's disease: best practices for preclinical animal studies

    PubMed Central

    2011-01-01

    Animal models have contributed significantly to our understanding of the underlying biological mechanisms of Alzheimer's disease (AD). As a result, over 300 interventions have been investigated and reported to mitigate pathological phenotypes or improve behavior in AD animal models or both. To date, however, very few of these findings have resulted in target validation in humans or successful translation to disease-modifying therapies. Challenges in translating preclinical studies to clinical trials include the inability of animal models to recapitulate the human disease, variations in breeding and colony maintenance, lack of standards in design, conduct and analysis of animal trials, and publication bias due to under-reporting of negative results in the scientific literature. The quality of animal model research on novel therapeutics can be improved by bringing the rigor of human clinical trials to animal studies. Research communities in several disease areas have developed recommendations for the conduct and reporting of preclinical studies in order to increase their validity, reproducibility, and predictive value. To address these issues in the AD community, the Alzheimer's Drug Discovery Foundation partnered with Charles River Discovery Services (Morrisville, NC, USA) and Cerebricon Ltd. (Kuopio, Finland) to convene an expert advisory panel of academic, industry, and government scientists to make recommendations on best practices for animal studies testing investigational AD therapies. The panel produced recommendations regarding the measurement, analysis, and reporting of relevant AD targets, th choice of animal model, quality control measures for breeding and colony maintenance, and preclinical animal study design. Major considerations to incorporate into preclinical study design include a priori hypotheses, pharmacokinetics-pharmacodynamics studies prior to proof-of-concept testing, biomarker measurements, sample size determination, and power analysis. The panel also recommended distinguishing between pilot 'exploratory' animal studies and more extensive 'therapeutic' studies to guide interpretation. Finally, the panel proposed infrastructure and resource development, such as the establishment of a public data repository in which both positive animal studies and negative ones could be reported. By promoting best practices, these recommendations can improve the methodological quality and predictive value of AD animal studies and make the translation to human clinical trials more efficient and reliable. PMID:21943025

  4. Factors influencing the approaches to studying of preclinical and clinical students and postgraduate trainees

    PubMed Central

    2011-01-01

    Background Students can be classified into three categories depending on their approaches to studying; namely, deep approach (DA), strategic approach (SA) and surface apathetic or superficial approach (SAA). The aim of this study was to identify factors affecting the approaches to studying among Sri Lankan medical undergraduates and post graduate trainees and to analyze the change in the pattern of study skills with time and experience. Method Pre-clinical and clinical students of the Faculty of Medicine, University of Colombo and postgraduate trainees in Surgery at the National Hospital of Sri Lanka were invited to complete the Approaches and Study Skills Inventory for Students (ASSIST) questionnaire. Results A total of 187 pre clinical (M: F = 96:91), 124 clinical (M: F = 61:63) and 53 post graduate trainees (M: F = 50:3) participated in the study. Approaches of male and female students were similar. SA was significantly affected by age among the preclinical students (p = 0.01), but not in other groups. Among pre-clinical students, males preferred a teacher who supported understanding (p = 0.04) but females preferred a passive transmission of information (p < 0.001). This, too, was not visible among other groups. A linear regression performed on group (batch), gender, island rank at GCE Advance Level (AL) examination, self appraisal score and the preference scores of type of teacher only managed to explain 35% or less of variance observed for each approach in individual groups. Conclusion Different factors affect the approach to studying in different groups but these explain only a small fraction of the variance observed. PMID:21599886

  5. Development of novel combined anticalcification protocols including immunologic modification for prolonged durability of cardiac xenograft: preclinical study using large-animal long-term circulatory models.

    PubMed

    Lim, Hong-Gook; Jeong, Saeromi; Shin, Jun-Seop; Park, Chung-Gyu; Kim, Yong Jin

    2015-01-01

    Cardiac xenografts are conventionally cross-linked with glutaraldehyde (GA) to impart tissue stability, reduce antigenicity, and maintain tissue sterility. However, GA-fixed xenografts are prone to calcification after long-term implantation in humans, because of phospholipids, free aldehyde groups, and residual antigenicity. We evaluated preclinical safety and efficacy using large-animal long-term circulatory models for our novel combined anticalcification protocol including immunological modification, which had been proven effective in small animal experiments. Bovine/porcine xenografts were treated with decellularization, immunological modification with ?-galactosidase, GA fixation with organic solvent, and detoxification with glycine. Valve conduits made of these xenografts were transplanted into the pulmonary root of goats, and hemodynamic, radiological, immunohistopathological, and biochemical results were obtained for 12 months after implantation. Evaluation of echocardiography and cardiac catheterization demonstrated good hemodynamic status and function of the pulmonary xenograft valves. Durability of the xenografts was well preserved without calcification by specimen radiography and immunohistopathological examination. The calcium concentrations of the explanted xenografts were lower than the control xenografts. This preclinical study using large-animal long-term circulatory models demonstrated that our synergistic and simultaneous employment of multiple anticalcification therapies and novel tissue treatments, including immunological modifications, have promising safety and efficacy and should be examined further in future clinical studies. PMID:25303800

  6. 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

  7. Comparative plasma exposure and lung distribution of two human use commercial azithromycin formulations assessed in murine model: a preclinical study.

    PubMed

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

    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

  8. 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

  9. Targeting SRC in glioblastoma tumors and brain metastases: rationale and preclinical studies.

    PubMed

    Ahluwalia, Manmeet S; de Groot, John; Liu, Wei Michael; Gladson, Candece L

    2010-12-01

    Glioblastoma (GBM) is an extremely aggressive, infiltrative tumor with a poor prognosis. The regulatory approval of bevacizumab for recurrent GBM has confirmed that molecularly targeted agents have potential for GBM treatment. Preclinical data showing that SRC and SRC-family kinases (SFKs) mediate intracellular signaling pathways controlling key biologic/oncogenic processes provide a strong rationale for investigating SRC/SFK inhibitors, e.g., dasatinib, in GBM and clinical studies are underway. The activity of these agents against solid tumors suggests that they may also be useful in treating brain metastases. This article reviews the potential for using SRC/SFK inhibitors to treat GBM and brain metastases. PMID:20947248

  10. 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 or glutamic acid decarboxylase inhibition; a range of monoaminergic effects; and potential cannabinoid receptor modulation. Future research should focus on conducting human clinical trials on the plants reviewed with promising anxiolytic activity. PMID:23436255

  11. 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. PMID:24585466

  12. 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

  13. A comprehensive review of the preclinical efficacy profile of the ErbB family blocker afatinib in cancer.

    PubMed

    Modjtahedi, Helmout; Cho, Byoung Chul; Michel, Martin C; Solca, Flavio

    2014-06-01

    Afatinib (also known as BIBW 2992) has recently been approved in several countries for the treatment of a distinct type of epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer. This manuscript comprehensively reviews the preclinical data on afatinib, an irreversible inhibitor of the tyrosine kinase activity of members of the epidermal growth factor receptor family (ErbB) including EGFR, HER2 and ErbB4. Afatinib covalently binds to cysteine 797 of the EGFR and the corresponding cysteines 805 and 803 in HER2 and ErbB4, respectively. Such covalent binding irreversibly inhibits the tyrosine kinase activity of these receptors, resulting in reduced auto- and transphosphorylation within the ErbB dimers and inhibition of important steps in the signal transduction of all ErbB receptor family members. Afatinib inhibits cellular growth and induces apoptosis in a wide range of cells representative for non-small cell lung cancer, breast cancer, pancreatic cancer, colorectal cancer, head and neck squamous cell cancer and several other cancer types exhibiting abnormalities of the ErbB network. This translates into tumour shrinkage in a variety of in vivo rodent models of such cancers. Afatinib retains inhibitory effects on signal transduction and in vitro and in vivo cancer cell growth in tumours resistant to reversible EGFR inhibitors, such as those exhibiting the T790M mutations. Several combination treatments have been explored to prevent and/or overcome development of resistance to afatinib, the most promising being those with EGFR- or HER2-targeted antibodies, other tyrosine kinase inhibitors or inhibitors of downstream signalling molecules. PMID:24643470

  14. 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. PMID:26158521

  15. Increased preclinical efficacy of irinotecan and floxuridine coencapsulated inside liposomes is associated with tumor delivery of synergistic drug ratios.

    PubMed

    Harasym, Troy O; Tardi, Paul G; Harasym, Natashia L; Harvie, Pierrot; Johnstone, Sharon A; Mayer, Lawrence D

    2007-01-01

    Whether anticancer drug combinations act synergistically or antagonistically often depends on the ratio of the agents being combined. We show here that combinations of irinotecan and floxuridine exhibit drug ratio-dependent cytotoxicity in a broad panel of tumor cell lines in vitro where a 1:1 molar ratio consistently provided synergy and avoided antagonism. In vivo delivery of irinotecan and floxuridine coencapsulated inside liposomes at the synergistic 1:1 molar ratio (referred to as CPX-1) lead to greatly enhanced efficacy compared to the two drugs administered as a saline-based cocktail in a number of human xenograft and murine tumor models. When compared to liposomal irinotecan or liposomal floxuridine, the therapeutic activity of CPX-1 in vivo was not only superior to the individual liposomal agents, but the extent of tumor growth inhibition was greater than that predicted for combining the activities of the individual agents. In contrast, liposome delivery of irinotecan:floxuridine ratios shown to be antagonistic in vitro provided antitumor activity that was actually less than that achieved with liposomal irinotecan alone, indicative of in vivo antagonism. Synergistic antitumor activity observed for CPX-1 was associated with maintenance of the 1:1 irinotecan:floxuridine molar ratio in plasma and tumor tissue over 16-24 h. In contrast, injection of the drugs combined in saline resulted in irinotecan:floxuridine ratios that changed 10-fold within 1 h in plasma and sevenfold within 4 h in tumor tissue. These results indicate that substantial improvements in the efficacy of drug combinations may be achieved by maintaining in vitro-identified synergistic drug ratios after systemic administration using drug delivery vehicles. PMID:17913044

  16. 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…

  17. Apoptosis as a determinant of tumor sensitivity to topotecan in human ovarian tumors: preclinical in vitro/in vivo studies.

    PubMed

    Caserini, C; Pratesi, G; Tortoreto, M; Bedogné, B; Carenini, N; Supino, R; Perego, P; Righetti, S C; Zunino, F

    1997-06-01

    Preclinical and clinical studies have documented the pharmacological interest in camptothecin derivatives in the treatment of resistant tumors. In particular, topotecan, a water-soluble derivative, exhibited promising activity in pretreated ovarian carcinoma. The present study investigated the pattern of tumor response in two human ovarian carcinoma xenografts and in their cisplatin-resistant sublines characterized by different mechanisms of drug resistance. In IGROV-1/Pt1 cells, cisplatin resistance has been ascribed to a reduced susceptibility to apoptosis as a consequence of p53 mutation and inactivation of its function. In the A2780 cisplatin-resistant subline, which retained the wild-type p53 gene status, the development of resistance has been possibly related to increased cell ability to repair drug-induced DNA damage. The in vivo results of the present study showed that topotecan could overcome the resistance in A2780/CP but not in IGROV-1/Pt1 tumor xenografts. The pattern of tumor response following in vivo topotecan treatment correlated with drug ability to induce apoptosis but not with its in vitro antiproliferative activity. The antitumor efficacy of topotecan in the four tumors reflected a different cell response to drug-induced DNA damage, as suggested by different perturbations of cell cycle progression. Indeed, only in the subline refractory to topotecan in vivo, IGROV-1/Pt1, did we observe a persistent arrest of the cells in the S-phase, resulting in a cytostatic and not a cytotoxic effect, since a low level of apoptosis was induced by the drug. In conclusion, the current results support that determination of drug-induced apoptosis is a useful predictor of tumor response to topotecan in ovarian carcinomas and suggest that p53 gene status may be a critical determinant of cell response to topoisomerase inhibitors. PMID:9815771

  18. Integration of preclinical and clinical knowledge to predict intravenous PK in human: bilastine case study.

    PubMed

    Vozmediano, Valvanera; Ortega, Ignacio; Lukas, John C; Gonzalo, Ana; Rodriguez, Monica; Lucero, Maria Luisa

    2014-03-01

    Modern pharmacometrics can integrate and leverage all prior proprietary and public knowledge. Such methods can be used to scale across species or comparators, perform clinical trial simulation across alternative designs, confirm hypothesis and potentially reduce development burden, time and costs. Crucial yet typically lacking in integration is the pre-clinical stage. Prediction of PK in man, using in vitro and in vivo studies in different animal species, is increasingly well theorized but could still find wider application in drug development. The aim of the present work was to explore methods for bridging pharmacokinetic knowledge from animal species (i.v. and p.o.) and man (p.o.) into i.v. in man using the antihistamine drug bilastine as example. A model, predictive of i.v. PK in man, was developed on data from two pre-clinical species (rat and dog) and p.o. in man bilastine trials performed earlier. In the knowledge application stage, two different approaches were used to predict human plasma concentration after i.v. of bilastine: allometry (several scaling methods) and a semi-physiological method. Both approaches led to successful predictions of key i.v. PK parameters of bilastine in man. The predictive i.v. PK model was validated using later data from a clinical study of i.v. bilastine. Introduction of such knowledge in development permits proper leveraging of all emergent knowledge as well as quantification-based exploration of PK scenario, e.g. in special populations (pediatrics, renal insufficiency, comedication). In addition, the methods permit reduction or elimination and certainly optimization of learning trials, particularly those concerning alternative off-label administration routes. PMID:23619917

  19. Experimental designs for detecting synergy and antagonism between two drugs in a pre-clinical study.

    PubMed

    Sperrin, Matthew; Thygesen, Helene; Su, Ting-Li; Harbron, Chris; Whitehead, Anne

    2015-05-01

    The identification of synergistic interactions between combinations of drugs is an important area within drug discovery and development. Pre-clinically, large numbers of screening studies to identify synergistic pairs of compounds can often be ran, necessitating efficient and robust experimental designs. We consider experimental designs for detecting interaction between two drugs in a pre-clinical in vitro assay in the presence of uncertainty of the monotherapy response. The monotherapies are assumed to follow the Hill equation with common lower and upper asymptotes, and a common variance. The optimality criterion used is the variance of the interaction parameter. We focus on ray designs and investigate two algorithms for selecting the optimum set of dose combinations. The first is a forward algorithm in which design points are added sequentially. This is found to give useful solutions in simple cases but can lack robustness when knowledge about the monotherapy parameters is insufficient. The second algorithm is a more pragmatic approach where the design points are constrained to be distributed log-normally along the rays and monotherapy doses. We find that the pragmatic algorithm is more stable than the forward algorithm, and even when the forward algorithm has converged, the pragmatic algorithm can still out-perform it. Practically, we find that good designs for detecting an interaction have equal numbers of points on monotherapies and combination therapies, with those points typically placed in positions where a 50% response is expected. More uncertainty in monotherapy parameters leads to an optimal design with design points that are more spread out. Copyright © 2015?John Wiley & Sons, Ltd. PMID:25810342

  20. Mid-stage intervention achieves similar efficacy as conventional early-stage treatment using gene therapy in a pre-clinical model of retinitis pigmentosa

    PubMed Central

    Wert, Katherine J.; Sancho-Pelluz, Javier; Tsang, Stephen H.

    2014-01-01

    Deficiencies in rod-specific cyclic guanosine monophosphate (cGMP) phosphodiesterase-6 (PDE6) are the third most common cause of autosomal recessive retinitis pigmentosa (RP). Previously, viral gene therapy approaches on pre-clinical models with mutations in PDE6 have demonstrated that the photoreceptor cell survival and visual function can be rescued when the gene therapy virus is delivered into the subretinal space before the onset of disease. However, no studies have currently been published that analyze rescue effects after disease onset, a time when human RP patients are diagnosed by a clinician and would receive the treatment. We utilized the AAV2/8(Y733F)-Rho-Pde6? gene therapy virus and injected it into a pre-clinical model of RP with a mutation within the alpha subunit of PDE6: Pde6?D670G. These mice were previously shown to have long-term photoreceptor cell rescue when this gene therapy virus was delivered before the onset of disease. Now, we have determined that subretinal transduction of this rod-specific transgene at post-natal day (P) 21, when approximately half of the photoreceptor cells have undergone degeneration, is more efficient in rescuing cone than rod photoreceptor function long term. Therefore, AAV2/8(Y733F)-Rho-Pde6? is an effective gene therapy treatment that can be utilized in the clinical setting, in human patients who have lost portions of their peripheral visual field and are in the mid-stage of disease when they first present to an eye-care professional. PMID:24101599

  1. Preclinical evaluation of Rh2 in PC3 human xenograft model for prostate cancer in vivo: formulation, pharmacokinetics, biodistribution and efficacy

    Microsoft Academic Search

    Alain G. Musende; Andy Eberding; Catherine Wood; Hans Adomat; Ladan Fazli; Antonio Hurtado-Coll; William Jia; Marcel B. Bally; Emma Tomlinson Guns

    2009-01-01

    Purpose  This study assesses the pharmacokinetics, biodistribution and efficacy of ginsenoside Rh2 as a single agent administered in\\u000a a novel oral dosage formulation.\\u000a \\u000a \\u000a \\u000a Methods  A novel oral dosage formulation of Rh2 has been described. Rh2 levels in blood and tissues following administration to nu\\/nu\\u000a nude mice were determined by high performance liquid chromatography tandem mass spectroscopy. Efficacy was determined in an\\u000a established

  2. Pharmacology should be at the centre of all preclinical and clinical studies on new psychoactive substances (recreational drugs).

    PubMed

    Green, A Richard; Nutt, David J

    2014-08-01

    Despite the publication of a substantial body of preclinical and clinical information on recent recreational drugs such as 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy') and cathinone compounds such as mephedrone there remains a disturbing lack of consensus as to how dangerous these compounds are to the health of the individual and to society in general. This perspective proposes that use of good pharmacological practice should be mandatory in all preclinical and clinical studies. Its use will assist both translation and reverse translation of information produced in animals and clinical subjects. We propose several basic rules to be followed in all future studies. Preclinical studies should employ pharmacokinetic-pharmacodynamic integration thereby exposing animals to known or calculable drug concentrations. This will provide results relevant to pharmacology rather than toxicology and, crucially, data relevant to human drug use. Full experimental detail should be routinely provided, to allow comparison with other similar work. In clinical studies evidence should be provided that the drug under investigation has been ingested by the subjects being examined, and details given of all other drugs being ingested. Drug-drug interactions are an unavoidable confound but studies of a size that allows reliable statistical evaluation and preferably allows sub-group analysis, particularly by using meta-analysis, should help with this problem. This may require greater collaboration between investigative groups, as routinely occurs during pharmaceutical clinical trials. Other proposals include greater integration of preclinical and clinical scientists in both preclinical and clinical studies and changes in the law regarding Good Manufacturing Process (GMP) sourcing of drug for human studies. PMID:24674814

  3. Active and passive immunization strategies based on the SDPM1 peptide demonstrate pre-clinical efficacy in the APPswePSEN1dE9 mouse model for Alzheimer’s disease

    PubMed Central

    Camboni, Marybeth; Wang, Chiou-Miin; Miranda, Carlos; Yoon, Jung Hae; Xu, Rui; Zygmunt, Deborah; Kaspar, Brian K.; Martin, Paul T.

    2013-01-01

    Recent clinical and pre-clinical studies suggest that both active and passive immunization strategies targeting A? amyloid may have clinical benefit in Alzheimer’s disease. Here, we demonstrate that vaccination of APPswePSEN1dE9 mice with SDPM1, an engineered non-native A? amyloid-specific binding peptide, lowers brain A? amyloid plaque burden and brain A?1-40 and A?1-42 peptide levels, improves cognitive learning and memory in Morris Water maze tests and increases the expression of synaptic brain proteins. This was the case in young mice immunized prior to development of significant brain amyloid burden, and in older mice, where brain amyloid was already present. Active immunization was optimized using ALUM as an adjuvant to stimulate production of anti-SDPM1 and anti-A? amyloid antibodies. Intracerebral injection of P4D6, an SDPM1 peptide-mimotope antibody, also lowered brain amyloid plaque burden in APPswePSEN1dE9 mice. Additionally, P4D6 inhibited A? amyloid-mediated toxicity in cultured neuronal cells. The protein sequence of the variable domain within the P4D6 heavy chain was found to mimic a multimer of the SDPM1 peptide motif. These data demonstrate the efficacy of active and passive vaccine strategies to target specific A? amyloid oligomers using an engineered peptide-mimotope strategy. PMID:24021662

  4. 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

  5. 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 3?-[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 ((?)-3?-(4-fluorophenyl)-tropan-2-?-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 ? 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 similar to effects of µ-agonists on µ-agonist self-administration and food prefeeding on food-reinforced responding, which implicates behavioral mechanisms for these effects and further supports development of atypical dopamine uptake inhibitors as medications for stimulant abuse. PMID:24194527

  6. 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 3?-[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 ((-)-3?-(4-fluorophenyl)-tropan-2-?-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 ? 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 similar to effects of µ-agonists on µ-agonist self-administration and food prefeeding on food-reinforced responding, which implicates behavioral mechanisms for these effects and further supports development of atypical dopamine uptake inhibitors as medications for stimulant abuse. PMID:24194527

  7. The preclinical efficacy, selectivity and pharmacologic profile of MK-5932, an insulin-sparing selective glucocorticoid receptor modulator.

    PubMed

    Brandish, Philip E; Anderson, Kenneth; Baltus, Gretchen A; Bai, Chang; Bungard, Christopher J; Bunting, Patricia; Byford, Alan; Chiu, Chi-Sung; Cicmil, Milenko; Corcoran, Halea; Euler, Danielle; Fisher, John E; Gambone, Carlo; Hasbun-Manning, Martha; Kuklin, Nelly; Landis, Elizabeth; Lifsted, Traci Q; McElwee-Witmer, Sheila; McIntosh, Ian S; Meissner, Robert S; Miao, John; Mitchell, Helen J; Musselman, Amy; Schmidt, Azriel; Shin, John; Szczerba, Peter; Thompson, Charles D; Tribouley, Catherine; Vogel, Robert L; Warrier, Sudha; Hershey, James C

    2014-02-01

    Glucocorticoids are used widely in the treatment of inflammatory diseases, but use is accompanied by a significant burden of adverse effects. It has been hypothesized that gene- and cell-specific regulation of the glucocorticoid receptor by small molecule ligands could be translated into a therapeutic with an improved risk-benefit profile. MK-5932 is a highly selective glucocorticoid receptor modulator that is anti-inflammatory in vivo with an improved profile on glucose metabolism: Bungard et al. (2011). Bioorg. Med. Chem. 19, 7374-7386. Here we describe the full biological profile of MK-5932. Cytokine production following lipopolysaccharide (LPS) challenge was blocked by MK-5932 in both rat and human whole blood. Oral administration reduced inflammatory cytokine levels in the serum of rats challenged with LPS. MK-5932 was anti-inflammatory in a rat contact dermatitis model, but was differentiated from 6-methylprednisolone by a lack of elevation of fasting insulin or glucose levels after 7 days of dosing, even at high exposure levels. In fact, animals in the vehicle group were consistently hyperglycemic at the end of the study, and MK-5932 normalized glucose levels in a dose-dependent manner. MK-5932 was also anti-inflammatory in the rat collagen-induced arthritis and adjuvant-induced arthritis models. In healthy dogs, oral administration of MK-5932 exerted acute pharmacodynamic effects with potency comparable to prednisone, but with important differences on neutrophil counts, again suggestive of a dissociated profile. Important gaps in our understanding of mechanism of action remain, but MK-5932 will be a useful tool in dissecting the mechanisms of glucose dysregulation by therapeutic glucocortiocids. PMID:24374007

  8. Creative Self-Efficacy: An Intervention Study

    ERIC Educational Resources Information Center

    Mathisen, Gro Ellen; Bronnick, Kolbjorn S.

    2009-01-01

    This study examined the effects of creativity training on creative self-efficacy. We developed a creativity course based on social cognitive theory. The course was conducted in two formats: a five-day course and a condensed one-day course. Samples consisted of students and municipality employees (five-day course), and special education teachers…

  9. JNJ-40255293, a novel adenosine A2A/A1 antagonist with efficacy in preclinical models of Parkinson's disease.

    PubMed

    Atack, John R; Shook, Brian C; Rassnick, Stefanie; Jackson, Paul F; Rhodes, Kenneth; Drinkenburg, Wilhelmus H; Ahnaou, Abdallah; Te Riele, Paula; Langlois, Xavier; Hrupka, Brian; De Haes, Patrick; Hendrickx, Herman; Aerts, Nancy; Hens, Koen; Wellens, Annemie; Vermeire, Jef; Megens, Anton A H P

    2014-10-15

    Adenosine A2A antagonists are believed to have therapeutic potential in the treatment of Parkinson's disease (PD). We have characterized the dual adenosine A2A/A1 receptor antagonist JNJ-40255293 (2-amino-8-[2-(4-morpholinyl)ethoxy]-4-phenyl-5H-indeno[1,2-d]pyrimidin-5-one). JNJ-40255293 was a high-affinity (7.5 nM) antagonist at the human A2A receptor with 7-fold in vitro selectivity versus the human A1 receptor. A similar A2A:A1 selectivity was seen in vivo (ED50's of 0.21 and 2.1 mg/kg p.o. for occupancy of rat brain A2A and A1 receptors, respectively). The plasma EC50 for occupancy of rat brain A2A receptors was 13 ng/mL. In sleep-wake encephalographic (EEG) studies, JNJ-40255293 dose-dependently enhanced a consolidated waking associated with a subsequent delayed compensatory sleep (minimum effective dose: 0.63 mg/kg p.o.). As measured by microdialysis, JNJ-40255293 did not affect dopamine and noradrenaline release in the prefrontal cortex and the striatum. However, it was able to reverse effects (catalepsy, hypolocomotion, and conditioned avoidance impairment in rats; hypolocomotion in mice) produced by the dopamine D2 antagonist haloperidol. The compound also potentiated the agitation induced by the dopamine agonist apomorphine. JNJ-40255293 also reversed hypolocomotion produced by the dopamine-depleting agent reserpine and potentiated the effects of l-dihydroxyphenylalanine (L-DOPA) in rats with unilateral 6-hydroxydopamine-induced lesions of the nigro-striatal pathway, an animal model of Parkinson's disease. Extrapolating from the rat receptor occupancy dose-response curve, the occupancy required to produce these various effects in rats was generally in the range of 60-90%. The findings support the continued research and development of A2A antagonists as potential treatments for PD. PMID:25203719

  10. 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.

  11. 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 and that it can improve clinical and neurological outcomes and reduce health care costs. Based on the current clinical evidence using a Delphi process, an expert panel recommended that early surgical intervention should be considered in all patients from 8 to 24?h following acute traumatic SCI. PMID:20001726

  12. Coil optimization for low-field MRI: a dedicated process for small animal preclinical studies.

    PubMed

    Feuillet, T; Seurin, M-J; Leveneur, O; Viguier, E; Beuf, O

    2015-04-01

    We demonstrate a method for the fast in vivo quantification of small volumes, down to 25 µL, using low-field magnetic resonance imaging (MRI) coils. The coils were designed so as to maximize the signal-to-noise ratio (SNR) in the images. For this we developed an analytical model for describing the variations of the SNR with coil design and with size/shape suited to the object under observation. Based on the conclusions drawn from the model, the coil parameters were chosen in order to reach an SNR close to the maximum. For the validation of the model, coils were finally characterized in terms of quality factor using saline phantoms. The coil design procedure is illustrated here with two examples: first, the quantification of about 200 µL of intradermal injected gel on rabbits with a single loop surface coil and second, the imaging of the intervertebral disks in rat tails using a small volume coil to detect possible lesions. Such studies would not have been feasible for the clinical low-field MRI system at our disposal using any of the commercially available medium-sized manufactured coils. As a result of this simple optimization procedure, a wide range of applications is accessible even at low magnetic fields, leading to new opportunities for low-cost, though efficient, preclinical studies. PMID:25359877

  13. 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-? peptide (A?) leading to early deposition of A? 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 A?42 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.

  14. 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.

  15. Cerebrovascular protection as a possible mechanism for the protective effects of NXY-059 in preclinical models: an in vitro study.

    PubMed

    Culot, Maxime; Mysiorek, Caroline; Renftel, Mila; Roussel, Benoit D; Hommet, Yannick; Vivien, Denis; Cecchelli, Roméo; Fenart, Laurence; Berezowski, Vincent; Dehouck, Marie-Pierre; Lundquist, Stefan

    2009-10-19

    NXY-059, a polar compound with limited transport across the blood-brain barrier, has demonstrated neuroprotection in several animal models of acute ischemic stroke but failed to confirm clinical benefit in the second phase III trial (SAINT-II). To improve the understanding of the mechanisms responsible for its neuroprotective action in preclinical models a series of experiments was carried out in an in vitro blood-brain barrier (BBB) model. A clinically attainable concentration of 250 mumol/L of NXY-059 administered at the onset or up to 4 h after oxygen glucose deprivation (OGD) produced a significant reduction in the increased BBB permeability caused by OGD. Furthermore, OGD produced a huge influx of tissue plasminogen activator across the BBB, which was substantially reduced by NXY-059. This study suggests that the neuroprotective effects of NXY-059 preclinically, may at least in part be attributed to its ability to restore functionality of the brain endothelium. PMID:19631615

  16. 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. PMID:23742054

  17. 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

  18. 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 ?? (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 ?? (RRR = 8.3), APOE ?4 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 ?4 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 ??) and unique (e.g., APOE ?4 genotype) determinants. PMID:25585532

  19. Biological basis of sex differences in drug abuse: preclinical and clinical studies

    Microsoft Academic Search

    Wendy J. Lynch; Megan E. Roth; Marilyn E. Carroll

    2002-01-01

    .   The recent focus on drug abuse in women has brought attention to numerous differences between women and men. In this review,\\u000a we discuss both preclinical and clinical findings of sex differences in drug abuse as well as mechanisms that may underlie\\u000a these differences. Recent evidence suggests that the progression to dependence and abuse may differ between women and men;

  20. Evaluation of N-Desmethylclozapine as a Potential Antipsychotic—Preclinical Studies

    Microsoft Academic Search

    Sridhar Natesan; Greg E Reckless; Karen B L Barlow; José N Nobrega; Shitij Kapur

    2007-01-01

    There is growing interest in N-desmethylclozapine (NDMC), the major metabolite of clozapine, as a unique antipsychotic because it acts in vitro as a 5-HT2 antagonist and as a partial agonist to dopamine D2 and muscarinic receptors. To explore this, we compared NDMC to a typical (haloperidol), atypical (clozapine), and partial-agonist atypical (aripiprazole) antipsychotic in preclinical models. The comparison was carried

  1. IL-2 plasmid electroporation: from preclinical studies to phase I clinical trial.

    PubMed

    Horton, Holly M; Lalor, Peggy A; Rolland, Alain P

    2008-01-01

    Electroporation (EP)-assisted intralesional delivery of Interleukin-2 (IL-2) plasmid (pDNA) has the potential to increase the local concentration of the expressed cytokine for an extended time in the injected tumors while minimizing its systemic concentration, in comparison with systemic delivery of the recombinant cytokine. Nonclinical Investigational New Drug application-enabling studies were performed in mice to evaluate the effect of intratumoral administration of murine IL-2 pDNA on local expression and systemic distribution of IL-2 transgene as well as the inhibition of established tumor growth. The safety of repeated administrations of a human IL-2 pDNA product candidate with EP was evaluated in rats. Following the nonclinical safety and efficacy studies, a human IL-2 pDNA product candidate intralesionally administered with EP to metastatic melanoma patients is currently being investigated in a phase I clinical trial. PMID:18370214

  2. 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

  3. Physiology and Endocrinology Symposium: FGF21: Insights into mechanism of action from preclinical studies.

    PubMed

    Antonellis, P J; Kharitonenkov, A; Adams, A C

    2014-02-01

    Fibroblast growth factor 21 (FGF21) is a multifaceted metabolic regulator which has several potential applications in the treatment of metabolic disease. When administered in vivo, FGF21 exhibits a plethora of actions, modulating metabolic homeostasis in a diverse manner. However, the mechanism and site of action underlying these effects were, until recently, entirely uncertain. Using mouse models lacking either FGF receptor isoform 1 (FGFR1) or ?Klotho (KLB), a transmembrane co-factor critical for FGF21 action, our group and others sought to determine the tissue on which FGF21 acts and the receptor complex responsible for mediating its in vivo efficacy. Importantly, when KLB was ablated from all tissues mice were completely refractory to FGF21 action. Therefore, to determine the precise tissue of action we utilized mice with tissue specific deletion of FGFR1 in either adipose tissue or neurons, respectively. Surprisingly, in animals with neuronal FGFR1 loss there was no change in the metabolic activity of FGF21, suggesting a lack of central FGF21 action in the pharmacologic setting. In contrast, we found dramatic attenuation of metabolic efficacy in mice with adipose-specific FGFR1 ablation following either acute or chronic dosing with recombinant FGF21. Furthermore, several recent studies have suggested that the metabolic effects of FGF21 may occur via modulation of adipokines such as adiponectin and leptin. Importantly, the action of FGF21 via adipose tissue results in alterations in both secretion as well as systemic sensitivity to these factors. Therefore, while FGF21 itself does not seem to directly act on the CNS, leptin and other endocrine mediators may serve as intermediary facilitators of FGF21's secondary central effects downstream of an initial and direct engagement of FGF21 receptor complex in adipose tissue. Further studies are required to delineate the precise mechanistic basis underlying the interplay between peripheral and central FGF21 modes of action in both the physiological and pharmacological settings. PMID:24398833

  4. Preclinical and Pilot Clinical Studies of Docetaxel Chemoradiation for Stage III Non-Small-Cell Lung Cancer

    SciTech Connect

    Chen Yuhchyau, E-mail: yuhchyau_chen@urmc.rochester.edu [Department of Radiation Oncology, University of Rochester Medical Center, Rochester, NY (United States); Pandya, Kishan J. [Department of Medical Oncology, University of Rochester Medical Center, Rochester, NY (United States); Hyrien, Ollivier [Department of Biostatistics and Computational Biology, University of Rochester Medical Center, Rochester, NY (United States); Keng, Peter C.; Smudzin, Therese; Anderson, Joy [Department of Radiation Oncology, University of Rochester Medical Center, Rochester, NY (United States); Qazi, Raman; Smith, Brian [Department of Medical Oncology, University of Rochester Medical Center, Rochester, NY (United States); Watson, Thomas J. [Division of Cardiothoracic Surgery, University of Rochester Medical Center, Rochester, NY (United States); Feins, Richard H. [Division of Cardiothoracic Surgery, University of North Carolina at Chapel Hill, Chapel Hill, NC (United States); Johnstone, David W. [Division of Cardiothoracic Surgery, Dartmouth-Hitchcock Medical Center, Lebanon, NH (Lebanon)

    2011-08-01

    Purpose: Local and distant failure rates remain high despite aggressive chemoradiation (CRT) treatment for Stage III non-small-cell lung cancer. We conducted preclinical studies of docetaxel's cytotoxic and radiosensitizing effects on lung cancer cell lines and designed a pilot study to target distant micrometastasis upfront with one-cycle induction chemotherapy, followed by low-dose radiosensitizing docetaxel CRT. Methods and Materials: A preclinical study was conducted in human lung cancer cell lines NCI 520 and A549. Cells were treated with two concentrations of docetaxel for 3 h and then irradiated immediately or after a 24-h delay. A clonogenic survival assay was conducted and analyzed for cytotoxic effects vs. radiosensitizing effects of docetaxel. A pilot clinical study was designed based on preclinical study findings. Twenty-two patients were enrolled with a median follow-up of 4 years. Induction chemotherapy consisted of 75 mg/m{sup 2} of docetaxel and 75 mg/m{sup 2} of cisplatin on Day 1 and 150 mg/m{sup 2} of recombinant human granulocyte colony-stimulating factor on Days 2 through 10. Concurrent CRT was started 3 to 6 weeks later with twice-weekly docetaxel at 10 to 12 mg/m{sup 2} and daily delayed radiation in 1.8-Gy fractions to 64.5 Gy for gross disease. Results: The preclinical study showed potent cytotoxic effects of docetaxel and subadditive radiosensitizing effects. Delaying radiation resulted in more cancer cell death. The pilot clinical study resulted in a median survival of 32.6 months for the entire cohort, with 3- and 5-year survival rates of 50% and 19%, respectively, and a distant metastasis-free survival rate of 61% for both 3 and 5 years. A pattern-of-failure analysis showed 75% chest failures and 36% all-distant failures. Therapy was well tolerated with Grade 3 esophagitis observed in 23% of patients. Conclusions: One-cycle full-dose docetaxel/cisplatin induction chemotherapy with recombinant human granulocyte colony-stimulating factor followed by pulsed low-dose docetaxel CRT is promising with regard to its antitumor activity, low rates of distant failure, and low toxicity, suggesting that this regimen deserves further investigation.

  5. Aerosol measles vaccination in macaques: Preclinical studies of immune responses and safety

    Microsoft Academic Search

    Rik L. de Swart; Thijs Kuiken; Jorge Fernandez-de Castro; Mark J. Papania; John V. Bennett; José L. Valdespino; Phil Minor; Clyde L. Witham; Selma Yüksel; Helma Vos; Geert van Amerongen; Albert D. M. E. Osterhaus

    2006-01-01

    The comparative efficacy and safety of measles vaccination via the aerosol route versus subcutaneous injection has not been fully resolved. We vaccinated cynomolgus monkeys (Macaca fascicularis) with the live-attenuated Edmonston–Zagreb measles virus (MV) vaccine and compared different routes of administration in the immunocompetent and the immunocompromised host. Immunogenicity and protective efficacy of aerosol vaccination using devices similar to those previously

  6. Preclinical Prophylactic Efficacy Testing of Sm-p80–Based Vaccine in a Nonhuman Primate Model of Schistosoma mansoni Infection and Immunoglobulin G and E Responses to Sm-p80 in Human Serum Samples From an Area Where Schistosomiasis Is Endemic

    PubMed Central

    Ahmad, Gul; Zhang, Weidong; Torben, Workineh; Ahrorov, Afzal; Damian, Raymond T.; Wolf, Roman F.; White, Gary L.; Carey, David W.; Mwinzi, Pauline N. M.; Ganley-Leal, Lisa; Kennedy, Ronald C.

    2011-01-01

    The prophylactic efficacy of a schistosome antigen (Sm-p80) was tested in a nonhuman primate model, the baboon. Using a total of 28 baboons, different vaccination strategies were used including recombinant Sm-p80 protein formulated in Toll-like receptor 7 and Toll-like receptor 9 agonists, and DNA priming followed by boosting with protein plus adjuvants. Recombinant protein approaches provided levels of prophylactic efficacy of 52%–58%, whereas prime-boost approaches conferred 38%–47% protection in baboons. An appropriately balanced pro-inflammatory (T-helper 17 [Th17] and Th1) and anti-inflammatory (Th2) type of response was generated; the Th1 and Th17 types of immune responses appear to be indicative of increased prophylactic efficacy. Production and expression of several cytokines (interleukin 2 [IL-2], interferon ?, IL-12?, IL-1?, IL-6, and IL-22) were up-regulated in vaccinated animals. Human correlate studies revealed Sm-p80 reactivity with immunoglobulin G in human serum samples from schistosome-infected individuals. In addition, a complete lack of prevailing Sm-p80–specific immunoglobulin E in a high-risk or infected population was observed, thus minimizing the risk of hypersensitivity reaction following vaccination with Sm-p80 in humans. This study provided the proof of concept to move Sm-p80 forward into further preclinical development leading to human clinical trials. PMID:21921206

  7. 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

  8. Translational reciprocity: bridging the gap between preclinical studies and clinical treatment of stress effects on the adolescent brain.

    PubMed

    Neigh, G N; Ritschel, L A; Kilpela, L S; Harrell, C S; Bourke, C H

    2013-09-26

    The genetic, biological, and environmental backgrounds of an organism fundamentally influence the balance between risk and resilience to stress. Sex, age, and environment transact with responses to trauma in ways that can mitigate or exacerbate the likelihood that post-traumatic stress disorder will develop. Translational approaches to modeling affective disorders in animals will ultimately provide novel treatments and a better understanding of the neurobiological underpinnings behind these debilitating disorders. The extant literature on trauma/stress has focused predominately on limbic and cortical structures that innervate the hypothalamic-pituitary-adrenal axis and influence glucocorticoid-mediated negative feedback. It is through these neuroendocrine pathways that a self-perpetuating fear memory can propagate the long-term effects of early life trauma. Recent work incorporating translational approaches has provided novel pathways that can be influenced by early life stress, such as the glucocorticoid receptor chaperones, including FKBP51. Animal models of stress have differing effects on behavior and endocrine pathways; however, complete models replicating clinical characteristics of risk and resilience have not been rigorously studied. This review discusses a four-factor model that considers the importance of studying both risk and resilience in understanding the developmental response to trauma/stress. Consideration of the multifactorial nature of clinical populations in the design of preclinical models and the application of preclinical findings to clinical treatment approaches comprise the core of translational reciprocity, which is discussed in the context of the four-factor model. PMID:23069751

  9. The in vivo efficacy and side effect pharmacology of GS-5759, a novel bifunctional phosphodiesterase 4 inhibitor and long-acting ?2-adrenoceptor agonist in preclinical animal species

    PubMed Central

    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

    2014-01-01

    Bronchodilators are a central therapy for symptom relief in respiratory diseases such as chronic obstructive pulmonary disease (COPD) and asthma, with inhaled ?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 ?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 ?g/kg. GS-5759 was also a potent bronchodilator with an ED50 of 0.09 ?g/kg in guinea pigs and 3.4 ?g/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 ?g/kg for bronchodilation and ED50 = 4.9 ?g/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. PMID:25505595

  10. Latent Structure and Factorial Invariance of a Neuropsychological Test Battery for the Study of Preclinical Alzheimer’s Disease

    PubMed Central

    Dowling, N. Maritza; Hermann, Bruce; La Rue, Asenath; Sager, Mark A.

    2010-01-01

    Objective To examine the latent structure of a test battery currently being used in a longitudinal study of asymptomatic middle-aged adults with a parental history of Alzheimer’s disease (AD) and test the invariance of the factor solution across subgroups defined by selected demographic variables and known genetic risk factors for AD. Method An exploratory factor analysis (EFA) and a sequence of confirmatory factor analyses (CFA) were conducted on 24 neuropsychological measures selected to provide a comprehensive estimate of cognitive abilities most likely to be affected in preclinical AD. Once the underlying latent model was defined and the structural validity established through model comparisons, a multi-group confirmatory factor analysis model was used to test for factorial invariance across groups. Results The EFA solution revealed a factor structure consisting of 5 constructs: verbal ability, visuo-spatial ability, speed & executive function, working memory, and verbal learning & memory. The CFA models provided support for the hypothesized 5-factor structure. Results indicated factorial invariance of the model across all groups examined. Conclusions Collectively, the results suggested a relatively strong psychometric basis for using the factor structure in clinical samples that match the characteristics of this cohort. This confirmed an invariant factor structure should prove useful in research aimed to detect the earliest cognitive signature of preclinical AD in similar middle aged cohorts. PMID:21038965

  11. 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. PMID:25701764

  12. Academic Warning Preclinical Y

    E-print Network

    Leistikow, Bruce N.

    Academic Warning 1st Clinical Y 3rd Preclinical Y 2nd Preclinical Y 1st Preclinical Y 1st USMLE fail Student meets with ADSA & DOSLER ---------------------- 2 Y's left Student retakes exam Pass = off --------------------- 1 Y left Student retakes exams Pass = off warning/continue ---------------------- Fail = probation

  13. Magnetic resonance imaging (MRI)-guided transurethral ultrasound therapy of the prostate: a preclinical study with radiological and pathological correlation using customised MRI-based moulds

    PubMed Central

    Partanen, Ari; Yerram, Nitin K.; Trivedi, Hari; Dreher, Matthew R.; Oila, Juha; Hoang, Anthony N.; Volkin, Dmitry; Nix, Jeffrey; Turkbey, Baris; Bernardo, Marcelino; Haines, Diana C.; Benjamin, Compton J.; Linehan, W. Marston; Choyke, Peter; Wood, Bradford J.; Ehnholm, Gösta J.; Venkatesan, Aradhana M.; Pinto, Peter A.

    2013-01-01

    Objective To characterise the feasibility and safety of a novel transurethral ultrasound (US)-therapy device combined with real-time multi-plane magnetic resonance imaging (MRI)-based temperature monitoring and temperature feedback control, to enable spatiotemporally precise regional ablation of simulated prostate gland lesions in a preclinical canine model. To correlate ablation volumes measured with intra-procedural cumulative thermal damage estimates, post-procedural MRI, and histopathology. Materials and methods Three dogs were treated with three targeted ablations each, using a prototype MRI-guided transurethral US-therapy system (Philips Healthcare, Vantaa, Finland). MRI provided images for treatment planning, guidance, real-time multi-planar thermometry, as well as post-treatment evaluation of efficacy. After treatment, specimens underwent histopathological analysis to determine the extent of necrosis and cell viability. Statistical analyses (Pearson’s correlation, Student’s t-test) were used to evaluate the correlation between ablation volumes measured with intra-procedural cumulative thermal damage estimates, post-procedural MRI, and histopathology. Results MRI combined with a transurethral US-therapy device enabled multi-planar temperature monitoring at the target as well as in surrounding tissues, allowing for safe, targeted, and controlled ablations of prescribed lesions. Ablated volumes measured by cumulative thermal dose positively correlated with volumes determined by histopathological analysis (r2 0.83, P < 0.001). Post-procedural contrast-enhanced and diffusion-weighted MRI showed a positive correlation with non-viable areas on histopathological analysis (r2 0.89, P < 0.001, and r20.91, P = 0.003, respectively). Additionally, there was a positive correlation between ablated volumes according to cumulative thermal dose and volumes identified on post-procedural contrast-enhanced MRI (r2 0.77, P < 0.01). There was no difference in mean ablation volumes assessed with the various analysis methods (P > 0.05, Student’s t-test). Conclusions MRI-guided transurethral US therapy enabled safe and targeted ablations of prescribed lesions in a preclinical canine prostate model. Ablation volumes were reliably predicted by intra- and post-procedural imaging. Clinical studies are needed to confirm the feasibility, safety, oncological control, and functional outcomes of this therapy in patients in whom focal therapy is indicated. PMID:23746198

  14. Taking Journal Clubs off Autopilot: A Case Study of Teaching Literature Evaluation Skills to Preclinical MD/PhD Students

    PubMed Central

    Currier, Rebecca L.; Schneider, Marguerite Reid; Heubi, James E.

    2014-01-01

    Researchers designed learner-directed journal clubs to develop literature evaluation skills in preclinical students. Sessions balanced student-led discussion with structured objectives and faculty support. During the pilot with preclinical MD/PhD students, self-rated mastery improved over all 17 measured objectives. Six exercises have since been incorporated into the full medical school curriculum. PMID:24634798

  15. A 2?×?2 factorial design for the combination therapy of minocycline and remote ischemic perconditioning: efficacy in a preclinical trial in murine thromboembolic stroke model

    PubMed Central

    2014-01-01

    Background After the failure of so many drugs and therapies for acute ischemic stroke, innovative approaches are needed to develop new treatments. One promising strategy is to test combinations of agents in the pre-hospital setting prior to the administration of intravenous tissue plasminogen activator (IV-tPA) and/ or the use of mechanical reperfusion devices in the hospital. Methods We performed a 2?×?2 factorial design preclinical trial where we tested minocycline (MINO), remote ischemic perconditioning (RIPerC) and their combination treatment in a thromboembolic clot model of stroke in mice, without IV-tPA or later treated with IV-tPA at 4 hours post-stroke. Cerebral blood flow (CBF) was measured by laser speckle contrast imaging (LSCI), behavioral outcomes as neurological deficit score (NDS) and adhesive tape removal test, and infarct size measurement were performed at 48 hours post-stroke. Mice within the experimental sets were randomized for the different treatments, and all outcome measures were blinded. Results RIPerC significantly improved CBF as measured by LSCI in both with and without tPA treated mice (P?pre-clinical 2 × 2 design can be easily translated into a pre-hospital clinical trial. PMID:25337387

  16. 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-? 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

  17. The Optimal Partnership of Radiation and Immunotherapy: from Preclinical Studies to Clinical Translation

    PubMed Central

    Demaria, Sandra; Pilones, Karsten A.; Vanpouille-Box, Claire; Golden, Encouse B.; Formenti, Silvia C.

    2014-01-01

    The main role of the immune system is to restore tissue homeostasis when altered by pathogenic processes, including neoplastic transformation. Immune-mediated tumor rejection has been recognized as an extrinsic tumor suppressor mechanism that tumors need to overcome to progress. By the time a tumor becomes clinically apparent it has successfully escaped immune control by establishing an immunosuppressive microenvironment. Ionizing radiation applied locally to a tumor alters these tumor-host interactions. Accumulating evidence indicates that standard therapeutic doses of radiation have the potential to recover tumor immunogenicity and convert the tumor into an in situ personalized vaccine. Radiotherapy induces an immunogenic tumor cell death promoting cross-presentation of tumor-derived antigens by dendritic cells to T cells. In addition, radiotherapy stimulates chemokine-mediated recruitment of effector T cells to the tumor, and cellular recognition and killing by T cells that is facilitated by upregulation of major histocompatibility antigens, NKG2D ligands, adhesion molecules and death receptors. Despite these effects, radiotherapy alone is only rarely capable of generating enough proinflammatory signals to sufficiently overcome suppression, as it can also activate immunosuppressive factors. However, our group and others have shown that when combined with targeted immunotherapy agents radiotherapy significantly contributes to a therapeutically effective anti-tumor immune response. To illustrate this partnership between radiation and immunotherapy we will discuss as an example our experience in preclinical models and the molecular mechanisms identified. Additionally, the clinical translation of these combinations will be discussed. PMID:24937779

  18. High Efficacy and the Preservice Reading Teacher: A Comparative Study

    ERIC Educational Resources Information Center

    Haverback, Heather Rogers; Parault, Susan J.

    2011-01-01

    The purpose of this study was to investigate the differential impact of two field experiences, tutoring and observing, on preservice teachers' reading self-efficacy and content knowledge. Participants completed an adapted, reading version of The Teacher Sense of Efficacy Scale (TSES). Results showed that both groups reported growth in reading…

  19. Ramucirumab: preclinical research and clinical development

    PubMed Central

    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. PMID:25378934

  20. (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

  1. N-Aryl Piperazine Metabotropic Glutamate Receptor 5 Positive Allosteric Modulators Possess Efficacy in Preclinical Models of NMDA Hypofunction and Cognitive Enhancement

    PubMed Central

    Gregory, K.J.; Herman, E.J.; Ramsey, A.J.; Hammond, A.S.; Byun, N.E.; Stauffer, S.R.; Manka, J.T.; Jadhav, S.; Bridges, T.M.; Weaver, C.D.; Niswender, C.M.; Steckler, T.; Drinkenburg, W.H.; Ahnaou, A.; Lavreysen, H.; Macdonald, G.J.; Bartolomé, J.M.; Mackie, C.; Hrupka, B.J.; Caron, M.G.; Daigle, T.L.; Lindsley, C.W.; Conn, P.J.

    2013-01-01

    Impaired transmission through glutamatergic circuits has been postulated to play a role in the underlying pathophysiology of schizophrenia. Furthermore, inhibition of the N-methyl-d-aspartate (NMDA) subtype of ionotropic glutamate receptors (NMDAR) induces a syndrome that recapitulates many of the symptoms observed in patients with schizophrenia. Selective activation of metabotropic glutamate receptor subtype 5 (mGlu5) may provide a novel therapeutic approach for treatment of symptoms associated with schizophrenia through facilitation of transmission through central glutamatergic circuits. Here, we describe the characterization of two novel N-aryl piperazine mGlu5 positive allosteric modulators (PAMs): 2-(4-(2-(benzyloxy)acetyl)piperazin-1-yl)benzonitrile (VU0364289) and 1-(4-(2,4-difluorophenyl)piperazin-1-yl)-2-((4-fluorobenzyl)oxy)ethanone (DPFE). VU0364289 and DPFE induced robust leftward shifts in the glutamate concentration-response curves for Ca2+ mobilization and extracellular signal-regulated kinases 1 and 2 phosphorylation. Both PAMs displayed micromolar affinity for the common mGlu5 allosteric binding site and high selectivity for mGlu5. VU0364289 and DPFE possessed suitable pharmacokinetic properties for dosing in vivo and produced robust dose-related effects in reversing amphetamine-induced hyperlocomotion, a preclinical model predictive of antipsychotic-like activity. In addition, DPFE enhanced acquisition of contextual fear conditioning in rats and reversed behavioral deficits in a mouse model of NMDAR hypofunction. In contrast, DPFE had no effect on reversing apomorphine-induced disruptions of prepulse inhibition of the acoustic startle reflex. These mGlu5 PAMs also increased monoamine levels in the prefrontal cortex, enhanced performance in a hippocampal-mediated memory task, and elicited changes in electroencephalogram dynamics commensurate with procognitive effects. Collectively, these data support and extend the role for the development of novel mGlu5 PAMs for the treatment of psychosis and cognitive deficits observed in individuals with schizophrenia. PMID:23965381

  2. Preclinical testing of three south American antivenoms against the venoms of five medically-important Peruvian snake venoms

    Microsoft Academic Search

    G. D Laing; A Yarleque; A Marcelo; E Rodriguez; D. A Warrell; R. D. G Theakston

    2004-01-01

    World Health Organization (WHO)-recommended preclinical in vivo and in vitro studies were carried out to compare the efficacy of Brazilian, Peruvian and Colombian antivenoms in neutralizing the venom toxins responsible for the lethal, haemorrhagic, necrotizing, coagulant and defibrinogenating effects of five medically-important Peruvian snake venoms. Overall, the Brazilian antivenom was found to be the most effective followed by the Peruvian

  3. Neutralization of four Peruvian Bothrops sp. snake venoms by polyvalent antivenoms produced in Perú and Costa Rica: preclinical assessment

    Microsoft Academic Search

    Ermila Rojas; Lil Quesada; Viviana Arce; Bruno Lomonte; Gustavo Rojas; José María Gutiérrez

    2005-01-01

    Envenomations after bites inflicted by snakes of the genus Bothrops constitute a public health hazard in Perú, and the intravenous administration of equine-derived antivenoms represents the only scientifically validated treatment. This study presents a preclinical assessment of the efficacy of two whole IgG antivenoms, prepared in Perú and Costa Rica, to neutralize the most relevant toxic effects induced by the

  4. Preclinical Diastolic Dysfunction

    PubMed Central

    Wan, Siu-Hin; Vogel, Mark W.; Chen, Horng H

    2014-01-01

    Preclinical Diastolic Dysfunction (PDD) has been broadly defined as subjects with left ventricular diastolic dysfunction, without the diagnosis of congestive heart failure (HF), and with normal systolic function. PDD is an entity which remains poorly understood, yet has definite clinical significance. Although few original studies have focused on PDD, it has been shown that PDD is prevalent, and that there is a clear progression from PDD to symptomatic heart failure including dyspnea, edema, and fatigue. In diabetic patients and patients with coronary artery disease or hypertension, it has been shown that patients with PDD have a significantly higher risk of progression to heart failure and death compared to patients without PDD. Because of these findings and the increasing prevalence of the heart failure epidemic, it is clear that an understanding of PDD is essential to decreasing patients’ morbidity and mortality. This review will focus on what is known concerning preclinical diastolic dysfunction, including definitions, staging, epidemiology, pathophysiology, and the natural history of the disease. In addition, given the paucity of trials focused on PDD treatment, studies targeting risk factors associated with the development of PDD and therapeutic trials for heart failure with preserved ejection fraction will be reviewed. PMID:24291270

  5. The contribution of regional gray/white matter volume in preclinical depression assessed by the Automatic Thoughts Questionnaire: a voxel-based morphometry study.

    PubMed

    Cun, Lingli; Wang, Yanqiu; Zhang, Songyan; Wei, Dongtao; Qiu, Jiang

    2014-09-10

    Negative automatic thought is a characteristic of depression that contributes toward the risk for episodes of depression. Evidence suggests that gray and white matter abnormalities are linked with depression, but little is known about the association between the negative cognitive experience and brain structure in preclinical depression. We examined the correlation between negative thought and gray (GMV)/white matter volume (WMV) in healthy individuals with preclinical depression. The participants were 309 university students with preclinical depression, as measured by their Automatic Thoughts Questionnaire (ATQ) scores. We collected brain MRIs and used voxel-based morphometry to analyze the correlation of regional GMV/WMV with the ATQ scores. The voxel-based morphometry results showed that the GMV of the right parahippocampal gyrus and fusiform gyrus and the WMV of the right superior temporal pole increased with the severity of depression. Furthermore, the corpus callosum volume decreased with the ATQ scores. This study implied that GMV increase and corpus callosum volume reduction may be associated with negative thought in nonclinical individuals, even at a preclinical depressed level. PMID:24999908

  6. Preclinical Studies of the Chinese Herbal Medicine formulation PHY906 as a Potential Adjunct to Radiation Therapy

    PubMed Central

    Rockwell, Sara; Grove, Tina A.; Liu, Yanfeng; Cheng, Yung-Chi; Higgins, Susan A; Booth, Carmen J

    2013-01-01

    Purpose/Objectives Abdominal and pelvic radiotherapy is limited by the radiosensitivity of the small and large intestine. PHY906, a state-of-the-art adaptation of a traditional Chinese medicine, decreased intestinal injury from chemotherapy in preclinical studies and is in clinical trials with chemotherapy. This project assessed whether PHY906 would also reduce intestinal injury from whole-abdomen irradiation in mice. Materials/Methods BALB/c mice received whole-abdomen irradiation (2 Gy/day) ± PHY906 by oral gavage twice daily for 4 days. Intestinal injury was assayed by physiological observations and histological studies. Effects of PHY906 on tumor radiation response were assayed in tumor growth studies. Results PHY906 decreased the toxicity of fractionated abdominal irradiation. Radiation alone produced marked blunting and loss of villi, crypt loss, crypt hyperplasia and irregular crypt morphology, which were reduced by PHY906. The radiation-induced reduction in viable crypt counts was also mitigated by PHY906. PHY906 did not alter radiation-induced weight loss, but resulted in more rapid recovery. PHY906 did not alter growth, local invasion or metastatic spread of EMT6 mouse mammary tumors or protect tumors from growth delays produced by single-dose and fractionated irradiation. Conclusion In this mouse model system, PHY906 decreased the toxicity of abdominal irradiation, without protecting tumors, thereby increasing the therapeutic ratio. PMID:22856538

  7. MR imaging-detectable metabolic alterations in attention deficit/hyperactivity disorder: from preclinical to clinical studies.

    PubMed

    Altabella, L; Zoratto, F; Adriani, W; Canese, R

    2014-06-01

    MR spectroscopy represents one of the most suitable in vivo tool to assess neurochemical dysfunction in several brain disorders, including attention deficit/hyperactivity disorder. This is the most common neuropsychiatric disorder in childhood and adolescence, which persists into adulthood (in approximately 30%-50% of cases). In past years, many studies have applied different MR spectroscopy techniques to investigate the pathogenesis and effect of conventional treatments. In this article, we review the most recent clinical and preclinical MR spectroscopy results on subjects with attention deficit/hyperactivity disorder and animal models, from childhood to adulthood. We found that the most investigated brain regions were the (pre)frontal lobes and striatum, both involved in the frontostriatal circuits and networks that are known to be impaired in this pathology. Neurometabolite alterations were detected in several regions: the NAA, choline, and glutamatergic compounds. The creatine pool was also altered when an absolute quantitative protocol was adopted. In particular, glutamate was increased in children with attention deficit/hyperactivity disorder, and this can apparently be reversed by methylphenidate treatment. The main difficulties in reviewing MR spectroscopy studies were in the nonhomogeneity of the analyzed subjects, the variety of the investigated brain regions, and also the use of different MR spectroscopy techniques. As for possible improvements in future studies, we recommend the use of standardized protocols and the analysis of other brain regions of particular interest for attention deficit hyperactivity disorder, like the hippocampus, limbic structures, thalamus, and cerebellum. PMID:24481327

  8. Common Handling Procedures Conducted in Preclinical Safety Studies Result in Minimal Hepatic Gene Expression Changes in Sprague-Dawley Rats

    PubMed Central

    Werner, Jon; Everds, Nancy; Di Palma, Chris; Chen, Yuan; Higgins-Garn, Marnie; Tran, Sandra; Afshari, Cynthia A.; Hamadeh, Hisham K.

    2014-01-01

    Gene expression profiling is a tool to gain mechanistic understanding of adverse effects in response to compound exposure. However, little is known about how the common handling procedures of experimental animals during a preclinical study alter baseline gene expression. We report gene expression changes in the livers of female Sprague-Dawley rats following common handling procedures. Baseline gene expression changes identified in this study provide insight on how these changes may affect interpretation of gene expression profiles following compound exposure. Rats were divided into three groups. One group was not subjected to handling procedures and served as controls for both handled groups. Animals in the other two groups were weighed, subjected to restraint in Broome restrainers, and administered water via oral gavage daily for 1 or 4 days with tail vein blood collections at 1, 2, 4, and 8 hours postdose on days 1 and 4. Significantly altered genes were identified in livers of animals following 1 or 4 days of handling when compared to the unhandled animals. Gene changes in animals handled for 4 days were similar to those handled for 1 day, suggesting a lack of habituation. The altered genes were primarily immune function related genes. These findings, along with a correlating increase in corticosterone levels suggest that common handling procedures may cause a minor immune system perturbance. PMID:24551150

  9. [Preclinical study of AV0012 early stage inhibitor of hepatitis C virus infection: I. In vitro ADME and pharmacokinetics].

    PubMed

    Ivashchenko, A V; Iamanushkin, P M; Mit'kin, O D; Ezhova, E V; Korzinov, O M; Shevkun, N A; Koriakova, A G; Karapetian, R N; Bychko, V V; Ivashchenko, A A; Agrba, V Z; Lapin, B A; Orlov, S V

    2014-01-01

    In vitro immunohistochemical investigations on the human hepatoma cell line (Huh7) infected with hepatitis C virus (HCV) strain JFH-1 showed that AV0012 compound blocks the early stages of viral infection. AV0012 also blocked viral infection spread in tissue culture through the secreted virus and through tight cell-to-cell contact. AV0012 is a specific inhibitor of HCV but not of related pestivirus, flaviviruses and other RNA-containing viruses such as bovine diarrhea (BVDV), Venezuelan equine encephalitis (strain TC-83), dengue type 2 (New Guinea), yellow fever (strain 17D), west Nile fever, parainfluenza (type 3) virus, RSV (strain A2), and Rhinovirus (type 2 strain HGP). It is established that human serum does not significantly affect the antiviral activity of AV0012 in vitro. The drug combination studies with AV0012 and interferon alpha 2a in vitro showed that the two inhibitors act additively, which makes possible the use of this combination in clinical tests. AV0012 is highly soluble and stable in aqueous solutions and murine blood plasma, has limited metabolic stability, low binding to human plasma proteins, high permeability through biological membranes, and only interacts with isoenzymes 2D6 and 3A4 of human cytochrome P450. In animal pharmacokinetic studies, AV0012 was rapidly absorbed into the blood stream upon oral administration, showed sufficiently long half-elimination times, and had high oral bioavailability that reached 92% in monkeys. Further preclinical development of AV0012 is in progress. PMID:25076758

  10. [Preclinical study of immunocorrection action of the sum of active substances of Coluria geoides (Pall.) Ledeb. (Rosaceae)].

    PubMed

    Dutova, S V; Karpova, M R; Myadelets, M A; Myasnaya, N V; Sherstoboev, E Yu

    2015-01-01

    A preclinical study of the immunocorrection action of the sum of active substances isolated from ethereal-oil plants Coluria geoides (Pall.) Ledeb. (Rosaceae family) with respect to experimental immunodeficiency showed that preparations relieve symptoms of immunodeficiency caused by the administration of cyclophosphan: suppressed synthesis of anti-erythrocyte antibodies (agglutinine) and proliferative processes in the spleen. Under the influence of C. geoides preparations, the absolute numbers of cariocytes and antibody forming cells in spleen significantly increased (compared to the group of animals with experimental immunodeficiency) and in some cases reached the background level. The drugs studied produced a more pronounced stimulating effect on the synthesis of specific immunoglobulins and proliferation of antibody forming cells of spleen as compared to the effect of Echinacea tincture. Preparation C-2 (extract from underground organs and grass of C. geoides obtained by percolation method with 70% ethanol) is most promising for in-depth research and the development of new effective drugs with immunocorrecting properties. PMID:26036007

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

    PubMed Central

    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.

    2014-01-01

    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. PMID:24388362

  12. Clinical chemistry and haematology historical data in control Sprague-Dawley rats from pre-clinical toxicity studies.

    PubMed

    Petterino, Claudio; Argentino-Storino, Alberta

    2006-01-01

    The purpose of this paper is to provide historical data pertaining to clinical chemistry and haematology parameters, obtained from control Sprague-Dawley rats, used in pre-clinical toxicity studies. Mean, standard deviation, minimum and maximum values for haematological and coagulative profiles, haemato-biochemistry and urine analysis data, and the differences per sex and study duration, 4 versus 13 weeks, are presented. The studies were conducted in agreement with the GLP (Good Laboratory Practice) regulations. Statistically significant differences, at the confidence level of 99%, for the red blood cell (RBC) parameters, the white blood cell (WBC) series parameters, plasmatic albumin/globulin (A/G), alanine amino-transferase (ALT), alkaline phosphatase (ALP), creatinine, globulin, glucose, sodium, total protein, tryglycerides, urea and urine volume were observed in males, when 4-week study values were compared with those obtained from 13-week studies. Female rats showed statistically significant variations, at the confidence level of 99% for RBC number and mean corpuscular haemoglobin (MCH), mean red blood cell volume (MCV), WBCs count and lymphocytes percentage, A/G, albumin, ALT, AST, ALP, creatinine, globulin, and sodium, when 4-week study values were compared to 13-week studies. Similar differences were observed comparing the female with male haematological and biochemical data for the two different times of the sample collection. These data could be useful as a reference for evaluation of background pathology in Sprague-Dawley rats, when used in studies performed to evaluate the toxicological profile of a new chemical entity (NCE) in agreement with requirements from international regulatory agencies. PMID:16343876

  13. Factors influencing the approaches to studying of preclinical and clinical students and postgraduate trainees

    Microsoft Academic Search

    Dakshitha P Wickramasinghe; Dharmabandu N Samarasekera

    2011-01-01

    Background  Students can be classified into three categories depending on their approaches to studying; namely, deep approach (DA), strategic\\u000a approach (SA) and surface apathetic or superficial approach (SAA). The aim of this study was to identify factors affecting\\u000a the approaches to studying among Sri Lankan medical undergraduates and post graduate trainees and to analyze the change in\\u000a the pattern of study

  14. Boswellic acids and glucosamine show synergistic effect in preclinical anti-inflammatory study in rats

    Microsoft Academic Search

    Surjeet Singh; Anamika Khajuria; Subhash Chandra Taneja; Ravi Kant Khajuria; Jaswant Singh; Ghulam Nabi Qazi

    2007-01-01

    The present study revealed the synergistic effect of boswellic acid mixture (BA) and glucosamine for anti-inflammatory and anti-arthritic activities in rats. Two studies were conducted, that is, acute anti-inflammatory by carrageenan edema and chronic anti-arthritic by Mycobacterium-induced developing arthritis. Five groups of animals were included in each of the study: the vehicle control, positive control (ibuprofen 100mg\\/kg), boswellic acids (250mg\\/kg),

  15. Improved bioavailability of aceclofenac from spherical agglomerates: development, in vitro and preclinical studies.

    PubMed

    Muatlik, S; Usha, A N; Reddy, M S; Ranjith, A K; Pandey, S

    2007-07-01

    The objective of present study was to improve the solubility, dissolution rate, micromeritic properties and bioavailability of aceclofenac (NSAID) by formulating its spherical agglomerates. They were prepared with different water soluble polymers (polyvinylpyrrolidone-K30, polyvinylpyrrolidone-K90 and sodium alginate) by using acetone-water-dichloromethane solvent system. The agglomerates were subjected to various physicochemical properties, DSC, IR spectroscopy, scanning electron microscopy (SEM), micromeritic properties and dissolution studies. The in vivo studies (anti-inflammatory, analgesic and pharmacokinetic studies) were conducted in Wistar rats and Swiss albino mice. SEM studies showed that agglomerates were spherical in structure and formed by cluster of small crystals. The agglomerates prepared with polyvinylpyrrolidone-K90 exhibited improved solubility, dissolution rate and micromeritic properties compared to those prepared with other polymers and pure drug. These optimized agglomerates showed rapid analgesic and anti-inflammatory activity besides exhibiting improved bioavailability of drug when compared to pure drug. PMID:17545107

  16. An evaluation of hERG current assay performance: Translating preclinical safety studies to clinical QT prolongation.

    PubMed

    Gintant, Gary

    2011-02-01

    Block of delayed rectifier current (I(Kr), Kv11.1 encoding the hERG gene) is associated with delayed cardiac repolarization (QTc prolongation), a surrogate marker of proarrhythmia. Despite its recognized role in assessing QTc prolongation risk, a quantitative analysis of the utility and limitations of the hERG current assay has not been reported. To benchmark hERG assay performance, this retrospective study compared hERG block potency with drug-induced QTc prolongation assessed during rigorous thorough QT (TQT) clinical studies for 39 drugs from multiple classes. To place block in context, hERG safety margins (IC(50) values for block/mean maximal plasma drug concentrations during TQT studies) were compared to QTc prolongation (QTc increase?5ms). Most (9/10) drugs eliciting essentially no hERG block at maximal concentrations demonstrate no QTc prolongation despite representing a wide hERG safety margin range. Based on receiver-operator characteristics, a hERG safety margin of 45 provided optimal overall performance linking safety margins to QTc prolongation (sensitivity (true positive rate)=0.64, specificity (true negative rate)=0.88); the area under the receiver-operator curve (0.72) is indicative of moderate overall concordance. Likelihood ratios calculated from multitier contingency tables suggest that QTc prolonging drugs are only 5-7 times as likely to demonstrate low safety margins (1-30 range) compared to drugs that do not prolong QTc. Paradoxically, higher safety margins demonstrate lesser confidence predicting prolongation. The overall limitations of hERG safety margins shown using these quantitative, evidence-based approaches highlight the need for additional preclinical assays and adaptive strategies throughout drug discovery to reliably mitigate QTc prolongation risk. PMID:20807552

  17. The Importance of Non-Human Primate Models for Preclinical Studies in Hematopoiesis

    Microsoft Academic Search

    Erzsebet Szilagyi; Nadim Mahmud; Amelia Bartholomew

    \\u000a Of all living experimental models, murine studies of hematopoiesis represent the greatest number. Such models can be undeniably\\u000a elegant reflecting the extensive technological tools available. While mice can be used to study specific genetic pedigrees,\\u000a specific physiologic, and gene pathways using knockouts, and a variety of immune responses using immunologically deficient\\u000a mice, murine models are limited in their applicability for

  18. Preclinical Studies Identify Non-Apoptotic Low-Level Caspase-3 as Therapeutic Target in Pemphigus Vulgaris

    PubMed Central

    Luyet, Camille; Schulze, Katja; Sayar, Beyza S.; Howald, Denise; Müller, Eliane J.; Galichet, Arnaud

    2015-01-01

    The majority of pemphigus vulgaris (PV) patients suffer from a live-threatening loss of intercellular adhesion between keratinocytes (acantholysis). The disease is caused by auto-antibodies that bind to desmosomal cadherins desmoglein (Dsg) 3 or Dsg3 and Dsg1 in mucous membranes and skin. A currently unresolved controversy in PV is whether apoptosis is involved in the pathogenic process. The objective of this study was to perform preclinical studies to investigate apoptotic pathway activation in PV pathogenesis with the goal to assess its potential for clinical therapy. For this purpose, we investigated mouse and human skin keratinocyte cultures treated with PV antibodies (the experimental Dsg3 monospecific antibody AK23 or PV patients IgG), PV mouse models (passive transfer of AK23 or PVIgG into adult and neonatal mice) as well as PV patients’ biopsies (n=6). A combination of TUNEL assay, analyses of membrane integrity, early apoptotic markers such as cleaved poly-ADP-ribose polymerase (PARP) and the collapse of actin cytoskeleton failed to provide evidence for apoptosis in PV pathogenesis. However, the in vitro and in vivo PV models, allowing to monitor progression of lesion formation, revealed an early, transient and low-level caspase-3 activation. Pharmacological inhibition confirmed the functional implication of caspase-3 in major events in PV such as shedding of Dsg3, keratin retraction, proliferation including c-Myc induction, p38MAPK activation and acantholysis. Together, these data identify low-level caspase-3 activation downstream of disrupted Dsg3 trans- or cis-adhesion as a major event in PV pathogenesis that is non-synonymous with apoptosis and represents, unlike apoptotic components, a promising target for clinical therapy. At a broader level, these results posit that an impairment of adhesive functions in concert with low-level, non-lethal caspase-3 activation can evoke profound cellular changes which may be of relevance for other diseases including cancer. PMID:25748204

  19. 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. PMID:25533740

  20. Choosing preclinical study models of diabetic retinopathy: key problems for consideration

    PubMed Central

    Mi, Xue-Song; Yuan, Ti-Fei; Ding, Yong; Zhong, Jing-Xiang; So, Kwok-Fai

    2014-01-01

    Diabetic retinopathy (DR) is the most common complication of diabetes mellitus in the eye. Although the clinical treatment for DR has already developed to a relative high level, there are still many urgent problems that need to be investigated in clinical and basic science. Currently, many in vivo animal models and in vitro culture systems have been applied to solve these problems. Many approaches have also been used to establish different DR models. However, till now, there has not been a single study model that can clearly and exactly mimic the developmental process of the human DR. Choosing the suitable model is important, not only for achieving our research goals smoothly, but also, to better match with different experimental proposals in the study. In this review, key problems for consideration in choosing study models of DR are discussed. These problems relate to clinical relevance, different approaches for establishing models, and choice of different species of animals as well as of the specific in vitro culture systems. Attending to these considerations will deepen the understanding on current study models and optimize the experimental design for the final goal of preventing DR. PMID:25429204

  1. Preclinical validation of a vaginal cream containing copaiba oil (reproductive toxicology study)

    Microsoft Academic Search

    C. S. Lima; B. J. L. de Medeiros; H. A. S. Favacho; K. C. dos Santos; B. R. de Oliveira; J. C. Taglialegna; E. V. M. da Costa; K. J. de Campos; J. C. T. Carvalho

    2011-01-01

    The aims of this study was to evaluate the effects of oil-resin of Copaiba (Copaifera duckei Dwyer), aired in vaginal cream on the reproductive performance of female rats (Rattus norvegicus). To determine the components of the C. duckei oleoresin, gas chromatography coupled with mass spectrometry (CG–MS) was used, and considering the trans-caryophyllene sesquiterpene as a phytochemical marker in the oleoresin.

  2. 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

  3. Correlating preclinical animal studies and human clinical trials of a multifunctional, polymeric nanoparticle.

    PubMed

    Eliasof, Scott; Lazarus, Douglas; Peters, Christian G; Case, Roy I; Cole, Roderic O; Hwang, Jungyeon; Schluep, Thomas; Chao, Joseph; Lin, James; Yen, Yun; Han, Han; Wiley, Devin T; Zuckerman, Jonathan E; Davis, Mark E

    2013-09-10

    Nanoparticles are currently being investigated in a number of human clinical trials. As information on how nanoparticles function in humans is difficult to obtain, animal studies that can be correlative to human behavior are needed to provide guidance for human clinical trials. Here, we report correlative studies on animals and humans for CRLX101, a 20- to 30-nm-diameter, multifunctional, polymeric nanoparticle containing camptothecin (CPT). CRLX101 is currently in phase 2 clinical trials, and human data from several of the clinical investigations are compared with results from multispecies animal studies. The pharmacokinetics of polymer-conjugated CPT (indicative of the CRLX101 nanoparticles) in mice, rats, dogs, and humans reveal that the area under the curve scales linearly with milligrams of CPT per square meter for all species. Plasma concentrations of unconjugated CPT released from CRLX101 in animals and humans are consistent with each other after accounting for differences in serum albumin binding of CPT. Urinary excretion of polymer-conjugated CPT occurs primarily within the initial 24 h after dosing in animals and humans. The urinary excretion dynamics of polymer-conjugated and unconjugated CPT appear similar between animals and humans. CRLX101 accumulates into solid tumors and releases CPT over a period of several days to give inhibition of its target in animal xenograft models of cancer and in the tumors of humans. Taken in total, the evidence provided from animal models on the CRLX101 mechanism of action suggests that the behavior of CRLX101 in animals is translatable to humans. PMID:23980155

  4. Correlating preclinical animal studies and human clinical trials of a multifunctional, polymeric nanoparticle

    PubMed Central

    Eliasof, Scott; Lazarus, Douglas; Peters, Christian G.; Case, Roy I.; Cole, Roderic O.; Hwang, Jungyeon; Schluep, Thomas; Chao, Joseph; Lin, James; Yen, Yun; Han, Han; Wiley, Devin T.; Zuckerman, Jonathan E.; Davis, Mark E.

    2013-01-01

    Nanoparticles are currently being investigated in a number of human clinical trials. As information on how nanoparticles function in humans is difficult to obtain, animal studies that can be correlative to human behavior are needed to provide guidance for human clinical trials. Here, we report correlative studies on animals and humans for CRLX101, a 20- to 30-nm-diameter, multifunctional, polymeric nanoparticle containing camptothecin (CPT). CRLX101 is currently in phase 2 clinical trials, and human data from several of the clinical investigations are compared with results from multispecies animal studies. The pharmacokinetics of polymer-conjugated CPT (indicative of the CRLX101 nanoparticles) in mice, rats, dogs, and humans reveal that the area under the curve scales linearly with milligrams of CPT per square meter for all species. Plasma concentrations of unconjugated CPT released from CRLX101 in animals and humans are consistent with each other after accounting for differences in serum albumin binding of CPT. Urinary excretion of polymer-conjugated CPT occurs primarily within the initial 24 h after dosing in animals and humans. The urinary excretion dynamics of polymer-conjugated and unconjugated CPT appear similar between animals and humans. CRLX101 accumulates into solid tumors and releases CPT over a period of several days to give inhibition of its target in animal xenograft models of cancer and in the tumors of humans. Taken in total, the evidence provided from animal models on the CRLX101 mechanism of action suggests that the behavior of CRLX101 in animals is translatable to humans. PMID:23980155

  5. 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

  6. Novel sugar esters proniosomes for transdermal delivery of vinpocetine: preclinical and clinical studies.

    PubMed

    El-Laithy, Hanan M; Shoukry, Omar; Mahran, Laila G

    2011-01-01

    Vinpocetine (Vin) existing oral formulations suffer poor bioavailability (?7%) since Vin undergoes a marked first-pass effect (?75%) and its absorption is dissolution rate-limited. In this study, a novel sustained release proniosomal system was designed using sugar esters (SEs) as non-ionic surfactants in which proniosomes were converted to niosomes upon skin water hydration following topical application under occlusive conditions. Different in vitro aspects (encapsulation efficiency, vesicle size and shape, effect of occlusion, in vitro release, skin permeation and stability) were studied leading to an optimized formula that was assessed clinically for transdermal pharmacokinetics and skin irritation. All formulae exhibited high entrapment efficiencies, regardless of the surfactant HLB. Vesicle size analysis showed that all vesicles were in the range from 0.63 ?m to 2.52 ?m which favored efficient transdermal delivery. The extent of drug permeation through the skin from the optimized formula--containing laurate SE with shorter fatty acid chain length and high HLB--was quite high (91%) after 48 h under occlusive conditions. The extent of absorption of Vin from proniosomes was larger when compared to the oral tablet with a relative bioavailability (F(rel)) of 206%. Histopathological evaluation revealed only moderate skin irritation when using SEs compared to skin inflammation when using Tween 80. Sugar esters proniosomes may be a promising carrier for vinpocetine, especially due to their simple scaling up and their ability to control drug release. PMID:21056658

  7. 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 ?-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

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

    PubMed Central

    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

    2015-01-01

    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 ?-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

  9. 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. PMID:24038106

  10. 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. PMID:19304557

  11. Preclinical studies on histone deacetylase inhibitors as therapeutic reagents for endometrial and ovarian cancers

    PubMed Central

    Singh, Brahma N; Zhou, Hongyuan; Li, Jinping; Tipton, Tracy; Wang, Bin; Shao, Guo; Gilbert, E Nickolas; Li, Qiang; Jiang, Shi-Wen

    2012-01-01

    Histone deacetylases (HDACs) remove acetyl groups from lysine residues of histones and the deacetylation allows for tighter electrostatic interactions between DNA and histones, leading to a more compact chromatin conformation with limited access for transactivators and the suppression of transcription. HDAC mRNA and protein overexpression was observed in endometrial and ovarian cancers. Numerous in vitro studies have shown that HDAC inhibitors, through their actions on histone and nonhistone proteins, are able to reactivate the tumor suppressor genes, inhibit cell cycle progression and induce cell apoptosis in endometrial and ovarian cancer cell cultures. Results from mou se xenograft models also demonstrated the potency of HDAC inhibitors as anticancer reagents when used as single agent or in combination with classical chemotherapy drugs. PMID:22112317

  12. 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

  13. The Usefulness of Systematic Reviews of Animal Experiments for the Design of Preclinical and Clinical Studies

    PubMed Central

    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. PMID:25541545

  14. High-throughput monitoring of integration site clonality in preclinical and clinical gene therapy studies

    PubMed Central

    Giordano, Frank A; Appelt, Jens-Uwe; Link, Barbara; Gerdes, Sebastian; Lehrer, Christina; Scholz, Simone; Paruzynski, Anna; Roeder, Ingo; Wenz, Frederik; Glimm, Hanno; von Kalle, Christof; Grez, Manuel; Schmidt, Manfred; Laufs, Stephanie

    2015-01-01

    Gene transfer to hematopoietic stem cells with integrating vectors not only allows sustained correction of monogenic diseases but also tracking of individual clones in vivo. Quantitative real-time PCR (qPCR) has been shown to be an accurate method to quantify individual stem cell clones, yet due to frequently limited amounts of target material (especially in clinical studies), it is not useful for large-scale analyses. To explore whether vector integration site (IS) recovery techniques may be suitable to describe clonal contributions if combined with next-generation sequencing techniques, we designed artificial ISs of different sizes which were mixed to simulate defined clonal situations in clinical settings. We subjected all mixes to either linear amplification–mediated PCR (LAM-PCR) or nonrestrictive LAM-PCR (nrLAM-PCR), both combined with 454 sequencing. We showed that nrLAM-PCR/454-detected clonality allows estimating qPCR-detected clonality in vitro. We then followed the kinetics of two clones detected in a patient enrolled in a clinical gene therapy trial using both, nrLAM-PCR/454 and qPCR and also saw nrLAM-PCR/454 to correlate to qPCR-measured clonal contributions. The method presented here displays a feasible high-throughput strategy to monitor clonality in clinical gene therapy trials is at hand. PMID:26052530

  15. 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…

  16. Development of an Adenovirus-Based Respiratory Syncytial Virus Vaccine: Preclinical Evaluation of Efficacy, Immunogenicity, and Enhanced Disease in a Cotton Rat Model

    PubMed Central

    Kim, Eun; Okada, Kaori; Beeler, Judy A.; Crim, Roberta L.; Piedra, Pedro A.; Gilbert, Brian E.

    2014-01-01

    ABSTRACT The lack of a vaccine against respiratory syncytial virus (RSV) is a challenging and serious gap in preventive medicine. Herein, we characterize the immunogenicity of an adenovirus serotype 5-based RSV vaccine encoding the fusion (F) protein (Ad5.RSV-F) and the protection provided following immunization with Ad5.RSV-F and assess its potential for producing enhanced disease in a cotton rat (CR) model. Animals were immunized intranasally (i.n.) and/or intramuscularly (i.m.) and subsequently challenged with RSV/A/Tracy (i.n.) to assess protection. Robust immune responses were seen in CRs vaccinated with Ad5.RSV-F given i.m. or i.n., and these responses correlated with reduced replication of the virus in noses and lungs after challenge. Neutralizing antibody responses following immunization with a single dose of Ad5.RSV-F at 1 × 1011 viral particles (v.p.) elicited antibody titers 64- to 256-fold greater than those seen after natural infection. CRs boosted with Ad5.RSV-F i.n. 28 days after an i.m. dose also had significant increases in neutralizing antibody titers. Antibody affinity for different F-protein antigenic sites revealed substantial differences between antibodies elicited by Ad5.RSV-F and those seen after RSV infection; differences in antibody profiles were also seen between CRs given Ad5.RSV-F i.m. and CRs given Ad5.RSV-F i.n. Ad5.RSV-F priming did not result in enhanced disease following live-virus challenge, in contrast to the histopathology seen in CRs given the formalin-inactivated RSV/A/Burnett vaccine. IMPORTANCE Respiratory syncytial virus (RSV) is the most common cause of acute lower respiratory infection in infants and young children and a serious health threat in the immunocompromised and the elderly. Infection severity increased in children in an immunization trial, hampering the over 4-decade-long quest for a successful RSV vaccine. In this study, we show that a genetically engineered RSV-F-encoding adenoviral vector provides protective immunity against RSV challenge without enhanced lung disease in cotton rats (CRs). CRs were vaccinated under a number of different regimens, and the immunity induced by the recombinant adenoviral RSV vaccine administered by use of an intramuscular prime-intranasal boost regimen may provide the best protection for young infants and children at risk of RSV infection, since this population is naive to adenoviral preformed immunity. Overall, this report describes a potential RSV vaccine candidate that merits further evaluation in a phase I clinical study in humans. PMID:24574396

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

    PubMed

    Wu, J; Polefka, T G

    2008-02-01

    Skin moisturization is not only important for maintaining skin functional properties but also has great impact on the skin's aesthetic properties. The top layer of the skin, the stratum corneum (SC), plays a key role in protecting and preventing against external aggressions as well as in regulating water flux in and out. Confocal Raman microspectroscopy is the first commercially available technique that provides a non-invasive, in vivo method to determine depth profiles of water concentration in the skin, however, in this case it was applied in an in vitro setting. As the first phase of validating the usefulness of confocal Raman microspectroscopy, we used porcine skin as a surrogate for human skin. Water concentration profiles were obtained using confocal Raman microspectroscopy from isolated pigskin SC and compared with that using the Karl Fischer titration method. The two methods correlated very well with a regression coefficient of 1.07 as well as a correlation coefficient, R(2) = 0.989, which demonstrated the consistency and accuracy of confocal Raman microspectroscopy for water concentration determination. To evaluate the instrument's response to different skin care/cleansing products, a wide range of products were tested to compare their skin moisturization ability. Among those tested were a lotion, commercial soap bar, syndet bar, traditional non-emollient shower gel (water, Sodium Laureth Ether Sulfate (SLES), cocamidopropyl betaine system) and emollient containing shower gel (water, sunflower oil, SLES, cocamidopropyl betaine, glycerin, petrolatum). The results were consistent with what was expected. The water content on skin treated with (A) lotion was significantly higher than the non-treated control; (B) syndet bar-treated skin had a significantly higher water content than soap-based bar-treated sites; (C) non-emollient shower gel washed sites were more moisturized than soap-based bar-treated samples; and (D) emollient shower gel-treated skin was 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. PMID:18377630

  18. Preclinical immunogenicity study of trivalent meningococcal AWX-OMV vaccines for the African meningitis belt.

    PubMed

    Tunheim, G; Naess, L M; Acevedo, R; Fjeldheim, Å K; Bolstad, K; García, L; Cardoso, D; Aase, A; Zayas, C; González, H; Rosenqvist, E; Norheim, G

    2014-11-20

    In the recent decade, epidemic meningitis in the African meningitis belt has mostly been caused by Neisseria meningitidis of serogroups A, W and X (MenA, MenW and MenX, respectively). There is at present no licensed vaccine available to prevent MenX meningococcal disease. To explore a trivalent MenAWX vaccine concept, we have studied the immunogenicity in mice of MenX outer membrane vesicles (X-OMV) or MenX polysaccharide (X-PS) when combined with a bivalent A-OMV and W-OMV (AW-OMV) vaccine previously shown to be highly immunogenic in mice. The vaccine antigens were produced from three representative wild type strains of MenA (ST-7), MenW (ST-11) and MenX (ST-751) isolated from patients in the African meningitis belt. Groups of mice were immunized with two doses of X-OMV or X-PS combined with the AW-OMV vaccine or as individual components. All vaccine preparations were adsorbed to Al(OH)3. Sera from immunized mice were tested by ELISA and immunoblotting. Functional antibody responses were measured as serum bactericidal activity (SBA) and opsonophagocytic activity (OPA). Immunization of mice with X-OMV, alone or in combination with AW-OMV induced high levels of anti-X OMV IgG. Moreover, X-OMV alone or in combination with the AW-OMV vaccine induced high SBA and OPA titers against the MenX target strain. X-PS alone was not immunogenic in mice; however, addition of the AW-OMV vaccine to X-PS increased the immunogenicity of X-PS. Both AWX vaccine formulations induced high levels of IgG against A- and W-OMV and high SBA titers against the MenA and MenW vaccine strains. These results suggest that a trivalent AWX vaccine, either as a combination of OMV or OMV with X-PS, could potentially prevent the majority of meningococcal disease in the meningitis belt. PMID:25305564

  19. 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

  20. Phospholipogenic pharmaceuticals are associated with a higher incidence of histological findings than nonphospholipogenic pharmaceuticals in preclinical toxicology studies.

    PubMed

    Barone, Linda R; Boyer, Scott; Damewood, James R; Fikes, James; Ciaccio, Paul J

    2012-01-01

    While phospholipidosis is thought to be an adaptive response to chemical challenge, many phospholipogenic compounds are known to display adverse effects in preclinical species and humans. To investigate the link between phospholipogenic administration and incidence of preclinical histological signals, an internal AstraZeneca in vivo toxicology report database was searched to identify phospholipogenic and nonphospholipogenic compounds. The datasets assembled comprised 46 phospholipogenic and 62 nonphospholipogenic compounds. The phospholipogenic potential of these compounds was confirmed by a pathologist's interpretation and was supported by well-validated in silico and in vitro models. The phospholipogenic dataset contained 37 bases, 4 neutral compounds, 3 zwitterions, and 1 acid, whereas the nonphospholipogenic dataset contained 9 bases, 34 neutrals, 1 zwitterion, and 18 acids. Histologic findings were tracked for adrenal gland; bone marrow; kidney; liver; lung; lymph node; spleen; thymus; and reproductive organs. On average, plasma exposures were higher in animals dosed with the nonphospholipogenics. Phospholipogenics yielded proportionally more histologic changes (exclusive of phospholipidosis itself) in all organs. Statistically significant higher frequencies of liver necrosis, alveolitis/pneumonitis, as well as lymphocytolysis in the thymus, lymph nodes, and spleen occurred in response to phospholipogenics compared to that for nonphospholipogenics. PMID:22745636

  1. Phospholipogenic Pharmaceuticals Are Associated with a Higher Incidence of Histological Findings than Nonphospholipogenic Pharmaceuticals in Preclinical Toxicology Studies

    PubMed Central

    Barone, Linda R.; Boyer, Scott; Damewood, James R.; Fikes, James; Ciaccio, Paul J.

    2012-01-01

    While phospholipidosis is thought to be an adaptive response to chemical challenge, many phospholipogenic compounds are known to display adverse effects in preclinical species and humans. To investigate the link between phospholipogenic administration and incidence of preclinical histological signals, an internal AstraZeneca in vivo toxicology report database was searched to identify phospholipogenic and nonphospholipogenic compounds. The datasets assembled comprised 46 phospholipogenic and 62 nonphospholipogenic compounds. The phospholipogenic potential of these compounds was confirmed by a pathologist's interpretation and was supported by well-validated in silico and in vitro models. The phospholipogenic dataset contained 37 bases, 4 neutral compounds, 3 zwitterions, and 1 acid, whereas the nonphospholipogenic dataset contained 9 bases, 34 neutrals, 1 zwitterion, and 18 acids. Histologic findings were tracked for adrenal gland; bone marrow; kidney; liver; lung; lymph node; spleen; thymus; and reproductive organs. On average, plasma exposures were higher in animals dosed with the nonphospholipogenics. Phospholipogenics yielded proportionally more histologic changes (exclusive of phospholipidosis itself) in all organs. Statistically significant higher frequencies of liver necrosis, alveolitis/pneumonitis, as well as lymphocytolysis in the thymus, lymph nodes, and spleen occurred in response to phospholipogenics compared to that for nonphospholipogenics. PMID:22745636

  2. Does interprofessional simulation increase self-efficacy: a comparative study

    PubMed Central

    Watters, Colm; Reedy, Gabriel; Ross, Alastair; Morgan, Nicola J; Handslip, Rhodri; Jaye, Peter

    2015-01-01

    Objectives In this work, we have compared uniprofessional and interprofessional versions of a simulation education intervention, in an attempt to understand more about whether it improves trainees’ self-efficacy. Background Interprofessionalism has been climbing the healthcare agenda for over 50?years. Simulation education attempts to create an environment for healthcare professionals to learn, without potential safety risks for patients. Integrating simulation and interprofessional education can provide benefits to individual learners. Setting The intervention took place in a high-fidelity simulation facility located on the campus of a large urban hospital. The centre provides educational activities for an Academic Health Sciences Centre. Approximately 2500 staff are trained at the centre each year. Participants One hundred and fifteen nurses and midwives along with 156 doctors, all within the early years of their postgraduate experience participated. All were included on the basis of their ongoing postgraduate education. Methods Each course was a one-day simulation course incorporating five clinical and one communication scenarios. After each a facilitated debriefing took place. A mixed methods approach utilised precourse and postcourse questionnaires measuring self-efficacy in managing emergency situations, communication, teamwork and leadership. Results Thematic analysis of qualitative data showed improvements in communication/teamwork and leadership, for doctors and nurses undergoing simulation training. These findings were confirmed by statistical analysis showing that confidence ratings improved in nurses and doctors overall (p<0.001). Improved outcomes from baseline were observed for interprofessional versus uniprofessional trained nurses (n=115; p<0.001). Postcourse ratings for doctors showed that interprofessional training was significantly associated with better final outcomes for a communication/teamwork dimension (n=156; p<0.05). Conclusions This study provides evidence that simulation training enhances participants’ self-efficacy in clinical situations. It also leads to increases in their perceived abilities relating to communication/teamwork and leadership/management of clinical scenarios. Interprofessional training showed increased positive effects on self-efficacy for nurses and doctors. PMID:25586366

  3. Efficacy of transcranial magnetic stimulation (TMS) in depression: naturalistic study.

    PubMed

    Aliño, Juan José López-Ibor; Jiménez, J L Pastrana; Flores, S Cisneros; Alcocer, M I López-Ibor

    2010-01-01

    Transcranial magnetic stimulation (TMS) is a technique is which the evidence has been confirming its efficacy. Repetitive stimulation (rTMS) of the left prefrontal dorsolateral (LPFDL) area with frequencies between 10 and 20 Hz has been shown to be effective in major depression. This article presents the prospective analysis of the treatments performed using TMS on LPFDL at 20 Hz with an intensity of 70% in a protocol of 10 sessions on 107 patients (41 male and 61 female) due to drug treatment resistant depressive symptoms in different conditions. The patients had previously undergone two psychopharmacological attempts with adequate dosage and time, who had been considered candidates for electroconvulsive therapy (ECT) if they did not respond to any conventional treatment. A total of 62.7% had mood disorder, 13.1% obsessive-compulsive disorders (OCT), 7.5% cognitive disorders, 4.7% personality disorders and 3.7% were psychiatric disorders. Mean age of the group was 49.98 years (SD = 17.09). The global results showed that the TMS provided some degree of improvement in 48.6%, although only half, that is 24.3%, maintained it beyond week 12. Efficacy by diagnoses showed a significant difference in favor of affective disorders. In the case of bipolar disorders in the depressive phase, there was improvement in 88.9%, which was maintained in 66.7% of the patients treated. No differences in efficacy were found within each one of the groups diagnosed based on gender, age or presence of personality disorders. The efficacy of the ECT was similar to the TMS in the group in which it had to be applied in comparison with the general group. New studies are proposed with the inclusion of the TMS for resistant-depression treatment protocols in a step prior to the ECT and even before all the drug treatments had been attempted, combining it with them for their potentiation. PMID:20976637

  4. Premarket Safety and Efficacy Studies for ADHD Medications in Children

    PubMed Central

    Bourgeois, Florence T.; Kim, Jeong Min; Mandl, Kenneth D.

    2014-01-01

    Background Attention-deficit hyperactivity disorder (ADHD) is a chronic condition and pharmacotherapy is the mainstay of treatment, with a variety of ADHD medications available to patients. However, it is unclear to what extent the long-term safety and efficacy of ADHD drugs have been evaluated prior to their market authorization. We aimed to quantify the number of participants studied and their length of exposure in ADHD drug trials prior to marketing. Methods We identified all ADHD medications approved by the Food and Drug Administration (FDA) and extracted data on clinical trials performed by the sponsor and used by the FDA to evaluate the drug’s clinical efficacy and safety. For each ADHD medication, we measured the total number of participants studied and the length of participant exposure and identified any FDA requests for post-marketing trials. Results A total of 32 clinical trials were conducted for the approval of 20 ADHD drugs. The median number of participants studied per drug was 75 (IQR 0, 419). Eleven drugs (55%) were approved after <100 participants were studied and 14 (70%) after <300 participants. The median trial length prior to approval was 4 weeks (IQR 2, 9), with 5 (38%) drugs approved after participants were studied <4 weeks and 10 (77%) after <6 months. Six drugs were approved with requests for specific additional post-marketing trials, of which 2 were performed. Conclusions Clinical trials conducted for the approval of many ADHD drugs have not been designed to assess rare adverse events or long-term safety and efficacy. While post-marketing studies can fill in some of the gaps, better assurance is needed that the proper trials are conducted either before or after a new medication is approved. PMID:25007171

  5. Treatment of cognitive dysfunction in major depressive disorder--a review of the preclinical evidence for efficacy of selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors and the multimodal-acting antidepressant vortioxetine.

    PubMed

    Pehrson, Alan L; Leiser, Steven C; Gulinello, Maria; Dale, Elena; Li, Yan; Waller, Jessica A; Sanchez, Connie

    2015-04-15

    Although major depressive disorder is primarily considered a mood disorder, depressed patients commonly present with clinically significant cognitive dysfunction that may add to their functional disability. This review paper summarizes the available preclinical data on the effects of antidepressants, including monoamine reuptake inhibitors and the multimodal antidepressant vortioxetine, in behavioral tests of cognition such as cognitive flexibility, attention, and memory, or in potentially cognition-relevant mechanistic assays such as electroencephalography, in vivo microdialysis, in vivo or in vitro electrophysiology, and molecular assays related to neurogenesis or synaptic sprouting. The available data are discussed in context with clinically relevant doses and their relationship to target occupancy levels, in order to evaluate the translational relevance of preclinical doses used during testing. We conclude that there is preclinical evidence suggesting that traditional treatment with monoamine reuptake inhibitors can induce improved cognitive function, for example in cognitive flexibility and memory, and that the multimodal-acting antidepressant vortioxetine may have some advantages by comparison to these treatments. However, the translational value of the reviewed preclinical data can be questioned at times, due to the use of doses outside the therapeutically-relevant range, the lack of data on target engagement or exposure, the tendency to investigate acute rather than long term antidepressant administration, and the trend towards using normal rodents rather than models with translational relevance for depression. Finally, several suggestions are made for advancing this field, including expanded use of target occupancy assessments in preclinical and clinical experiments, and the use of translationally valuable techniques such as electroencephalography. PMID:25107284

  6. HIV Vaccine Development: Strategies for Preclinical and Clinical Investigation

    PubMed Central

    2013-01-01

    Abstract This article discusses HIV vaccine discovery and candidate vaccine testing in the context of current realities of funding and clinical trial practice. Lacking perfect animal models for testing candidate HIV vaccines, clinical investigators have proposed a strategy of iterative exploratory clinical trials in the model of cancer chemotherapy development. Problems with the appropriateness of this model to HIV vaccine development are discussed. Also, the future feasibility of this strategy in the context of increasing clinical trial costs and emerging new, efficacious prevention modalities is questioned. Strategies for making better use of animal models are presented as an alternative to iterative exploratory clinical efficacy testing. Some ways in which better data from preclinical studies can refine clinical product development are described. Finally, development of an HIV vaccine under the FDA's “Animal Rule” pathway to licensure when human efficacy studies are not feasible is discussed as a fall-back approach. Not making a preventive vaccine against HIV infection is simply not an option because eradication of AIDS will require a preventive vaccine. PMID:23379343

  7. Human B-cell cancer cell lines as a preclinical model for studies of drug effect in diffuse large B-cell lymphoma and multiple myeloma.

    PubMed

    Laursen, Maria Bach; Falgreen, Steffen; Bødker, Julie Støve; Schmitz, Alexander; Kjeldsen, Malene Krag; Sørensen, Suzette; Madsen, Jakob; El-Galaly, Tarec Christoffer; Bøgsted, Martin; Dybkær, Karen; Johnsen, Hans Erik

    2014-11-01

    Drug resistance in cancer refers to recurrent or primary refractory disease following drug therapy. At the cellular level, it is a consequence of molecular functions that ultimately enable the cell to resist cell death-one of the classical hallmarks of cancer. Thus, drug resistance is a fundamental aspect of the cancer cell phenotype, in parallel with sustained proliferation, immortality, angiogenesis, invasion, and metastasis. Here we present a preclinical model of human B-cell cancer cell lines used to identify genes involved in specific drug resistance. This process includes a standardized technical setup for specific drug screening, analysis of global gene expression, and the statistical considerations required to develop resistance gene signatures. The state of the art is illustrated by the first-step classical drug screen (including the CD20 antibody rituximab, the DNA intercalating topoisomerase II inhibitor doxorubicin, the mitotic inhibitor vincristine, and the alkylating agents cyclophosphamide and melphalan) along with the generation of gene lists predicting the chemotherapeutic outcome as validated retrospectively in clinical trial datasets. This B-cell lineage-specific preclinical model will allow us to initiate a range of laboratory studies, with focus on specific gene functions involved in molecular resistance mechanisms. PMID:25072621

  8. Comparative preclinical pharmacokinetics study of 3,3?-diindolylmethane formulations: is personalized treatment and targeted chemoprevention in the horizon?

    PubMed Central

    2013-01-01

    Background 3,3?-Diindolylmethane (DIM) is known as an agent of natural origin that provides protection against different cancers due to the broad spectrum of its biological activities in vivo. However, this substance has a very poor biodistribution and absorption in animal tissues. This preclinical trial was conducted to evaluate the pharmacokinetics and bioavailability of various DIM formulations in animal model. Materials and methods The pharmacokinetic parameters of one crystalline DIM formulation and one liquid DIM formulation (oil solution) compared to non-formulated crystalline DIM (control) were tested in 200 rats. The formulations were orally administered to animals by gavage at doses of 200 mg/kg per DIM (crystalline DIM formulation and non-formulated crystalline DIM) and 0.1 mg/kg per DIM (DIM in oil solution). DIM plasma elimination was measured using HPLC method; after that, the area under the curve (AUC), relative bioavailability, and absolute bioavailability were estimated for two formulations in relation to non-formulated crystalline DIM. Results and conclusion The highest bioavailability was achieved by administering liquid DIM (oil solution), containing cod liver oil and polysorbate. The level of DIM in rat blood plasma was about fivefold higher, though the 2,000-fold lower dose was administered compared to crystalline DIM forms. The novel pharmacological DIM substance with high bioavailability may be considered as a promising targeted antitumor chemopreventive agent. It could be used to prevent breast and ovarian cancer development in patients with heterozygous inherited and sporadic BRCA1 gene mutations. Further preclinical and clinical trials are needed to prove this concept. PMID:24325835

  9. Preclinical Rheumatoid Arthritis (Autoantibodies): An Updated Review

    PubMed Central

    Deane, Kevin D.

    2014-01-01

    Multiple studies demonstrate that there is a period of development of rheumatoid arthritis (RA) during which there are elevations of disease-related biomarkers, including autoantibodies, in the absence of and prior to the development of RA; this period can be termed ‘preclinical RA’. These ‘preclinical’ autoantibodies including rheumatoid factor and antibodies to citrullinated protein antigens, and more recent studies have also identified a wider variety of autoantibodies and a wide range of inflammatory biomarkers. These findings in conjunction with established and emerging data about genetic and environmental risk factors for RA support a model of disease development where certain factors lead to an initial triggering of RA-related autoimmunity that expands over time to the point where symptomatic arthritis classifiable as RA develops. Herein will be reviewed updates in the field, as well as a discussion of current limitations of our understanding of preclinical RA, and potential future directions for study. PMID:24643396

  10. Preclinical Applications of Quantitative Imaging Cytometry to Support Drug Discovery

    Microsoft Academic Search

    David L. Krull; Richard A. Peterson

    2011-01-01

    Preclinical drug development is actively involved in testing compounds to find cures or to manage the effects of disease, such as diabetes. Animal models, such as the Zucker diabetic fatty (ZDF) rat, are used to measure efficacy of candidate drugs. This animal model was selected because of its clinical and pathological similarities to diabetic human patients. A method using immunofluorescence

  11. [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.

  12. Self-Efficacy and Mathematics Achievement: A Study of Their Relation

    Microsoft Academic Search

    Brahm Norwich

    1987-01-01

    In this study, I investigated the relation between self-efficacy and mathematics achievement when other factors, such as self-concept of math ability, prior task achievement, and prior self-efficacy were taken into account. I assessed self-efficacy over 4 trials in a repeated-measures design with 72 children, aged 9–10 years. I assessed task performance after the first and third self-efficacy assessment. Regression analysis

  13. Preclinical evaluation of gene transfer products: safety and immunological aspects

    Microsoft Academic Search

    Marielle Christ

    2002-01-01

    As any new drug in development, gene transfer products have to be tested for their potential toxicity in preclinical studies. Strategies for preclinical safety evaluation of gene transfer compounds are similar to those undertaken for biotechnology-derived pharmaceuticals with the added complexity of having to test additional components, such as the vector and genetic material. Some recommendations have been issued by

  14. 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

  15. The Economics of Reproducibility in Preclinical Research.

    PubMed

    Freedman, Leonard P; Cockburn, Iain M; Simcoe, Timothy S

    2015-06-01

    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

  16. 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

    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

  17. Novel HDAC inhibitors exhibit pre-clinical efficacy in lymphoma models and point to the importance of CDKN1A expression levels in mediating their anti-tumor response

    PubMed Central

    Mensah, Afua Adjeiwaa; Kwee, Ivo; Gaudio, Eugenio; Rinaldi, Andrea; Ponzoni, Maurilio; Cascione, Luciano; Fossati, Gianluca; Stathis, Anastasios; Zucca, Emanuele; Caprini, Gianluca; Bertoni, Francesco

    2015-01-01

    We investigated the pre-clinical activities of two novel histone deacetylase inhibitors (HDACi), ITF-A and ITF-B, in a large panel of pre-clinical lymphoma models. The two compounds showed a dose-dependent anti-proliferative activity in the majority of cell lines. Gene expression profiling (GEP) of diffuse large B-cell lymphoma (DLBCL) cells treated with the compounds showed a modulation of genes involved in chromatin structure, cell cycle progression, apoptosis, B-cell signaling, and genes encoding metallothioneins. Cell lines showed differences between the concentrations of ITF-A and ITF-B needed to cause anti-proliferative or cytotoxic activity, and cell cycle and apoptosis genes appeared implicated in determining the type of response. In particular, CDKN1A expression was higher in DLBCL cells that, to undergo apoptosis, required a much higher amount of drug than that necessary to induce only an anti-proliferative effect. In conclusion, the two novel HDACi ITF-A and ITF-B demonstrated anti-proliferative activity across different mature B-cell lymphoma cell lines. Basal CDKN1A levels appeared to be important in determining the gap between HDACi concentrations causing cell cycle arrest and those that lead to cell death. PMID:25671298

  18. Optimization of Preclinical Animal Models

    E-print Network

    Optimization of Preclinical Animal Models Steven Perrin, PhD CEO, CSO ALS Therapy Development Institute #12;Historical Issue with Pre-clinical Animal Model Development and Validation Optimized Copy Animals · Variable #3: Gender · Variable #4: Litter Effect of increasing 'n' on Noise for Each

  19. A case study: Self-efficacy beliefs of teacher candidates regarding developing educational software

    Microsoft Academic Search

    Adem Uzun; Rüçhan Özk?l?ç; Aysan ?entürk

    2010-01-01

    The purpose of this study is to analyze the self-efficacy beliefs of the teacher candidates towards developing educational software by some variables such as gender and grade and to investigate the correlation between self-efficacy beliefs and academic achievement. Sixty students participated to this study. Education Software Development Self-Efficacy Perception Scale was used as instrument. No significant difference was found between

  20. The preclinical stage of spinocerebellar ataxias.

    PubMed

    Maas, Roderick P P W M; van Gaalen, Judith; Klockgether, Thomas; van de Warrenburg, Bart P C

    2015-07-01

    The autosomal dominant spinocerebellar ataxias (SCAs) are a heterogeneous group of degenerative diseases of the cerebellum and connected regions. The discovery of various SCA genes and the subsequent possibility of predictive testing currently allow a genetic diagnosis to be established years or even decades before the actual appearance of ataxia symptoms. A growing body of evidence, however, indicates that this preclinical stage is subject to the earliest pathophysiologic changes. This review article comprehensively summarizes the studies conducted in preclinical carriers of a mutation in one of the SCA genes. From these data, it can indeed be concluded that the preclinical phase in SCA is already characterized by detectable central and peripheral nervous system changes, which are reflected by subtle abnormalities during a careful clinical examination, changes in structural and functional brain imaging, abnormal neurophysiologic measurements, and/or altered motor learning paradigms. As these may be compensated for a long time, ataxia symptoms probably only appear after a certain threshold of dysfunction or degeneration has been exceeded. Detailed knowledge of this disease stage is of particular relevance for a better understanding of the pathogenesis of SCAs, will allow us to determine the optimal point in time for interventions in future therapeutic trials, and points to objective, valid biomarkers to assess disease progression. Further studies will benefit from a consensus-based definition of the preclinical stage, from using one and the same validated ataxia rating scale with one fixed cutoff value, and from applying similar mathematical models to calculate time to predicted disease onset. PMID:26062625

  1. Pre-Clinical Models of Acquired Neonatal Seizures: Differential Effects of Injury on Function of Chloride Co-Transporters

    PubMed Central

    Kang, SK; Kadam, SD

    2014-01-01

    Hypoxic-ischemic encephalopathy [HIE] represents the most common acquired pathology associated with neonatal seizures. HIE-associated neonatal seizures are often difficult to control, due to their refractoriness to traditional anti-seizure agents. Developmentally regulated chloride gradients during early development make the neonatal brain more seizure-susceptible by depolarizing GABAAR-mediated currents, and therefore hindering inhibition by conventional anti-seizure drugs such as phenobarbital [PB] and benzodiazepines. Pharmaco-modulation of chloride co-transporters has become a current field of research in treating refractory neonatal seizures, and the basis of two clinical trials [NCT01434225; NCT00380531]. However, the recent termination of NEMO study [NCT01434225] on bumetanide, an NKCC1 antagonist, suggests that clinical utilization of bumetanide as an adjunct to treat neonatal seizures with PB may not be a viable option. Hence, re-evaluation of bumetanide as an adjunct through pre-clinical studies is warranted. Additionally, the model-specific variability in the efficacy of bumetanide in the pre-clinical models of neonatal seizures highlights the differential consequences of insults used to induce seizures in each pre-clinical model as worth exploration. Injury itself can significantly alter the function of chloride co-transporters, and therefore the efficacy of anti-seizure agents that follow. PMID:25590049

  2. Preclinical studies on targeted delivery of multiple IFN?2b 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 IFN? affect its dosing schedule and efficacy. Fusion of IFN? to a tumor-targeting mAb (mAb-IFN?) 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-IFN? comprising tetrameric IFN?2b 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-IFN? or a mixture comprising the parental mAb and IFN?. Our findings indicate that responsiveness depends on HLA-DR expression/density and sensitivity to IFN? and hL243. C2-2b-2b induced more potent and longer-lasting IFN? signaling compared with nontargeted IFN?. 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-IFN?, peginterferonalfa-2a, or a combination of hL243 and IFN?, 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

  3. 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 ?v?3 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

  4. Preclinical development of HIvax: Human survivin highly immunogenic vaccines.

    PubMed

    Hoffmann, Peter R; Panigada, Maddalena; Soprana, Elisa; Terry, Frances; Bandar, Ivo Sah; Napolitano, Andrea; Rose, Aaron H; Hoffmann, Fukun W; Ndhlovu, Lishomwa C; Belcaid, Mahdi; Moise, Lenny; De Groot, Anne S; Carbone, Michele; Gaudino, Giovanni; Matsui, Takashi; Siccardi, Antonio; Bertino, Pietro

    2015-07-01

    Our previous work involved the development of a recombinant fowlpox virus encoding survivin (FP-surv) vaccine that was evaluated for efficacy in mesothelioma mouse models. Results showed that FP-surv vaccination generated significant immune responses, which led to delayed tumor growth and improved animal survival. We have extended those previous findings in the current study, which involves the pre-clinical development of an optimized version of FP-surv designed for human immunization (HIvax). Survivin-derived peptides for the most common haplotypes in the human population were identified and their immunogenicity confirmed in co-culture experiments using dendritic cells and T cells isolated from healthy donors. Peptides confirmed to induce CD8(+) and CD4(+) T cells activation in humans were then included in 2 transgenes optimized for presentation of processed peptides on MHC-I (HIvax1) and MHC-II (HIvax2). Fowlpox vectors expressing the HIvax transgenes were then generated and their efficacy was evaluated with subsequent co-culture experiments to measure interferon-? and granzyme B secretion. In these experiments, both antigen specific CD4(+) and CD8(+) T cells were activated by HIvax vaccines with resultant cytotoxic activity against survivin-overexpressing mesothelioma cancer cells. These results provide a rationale for clinical testing of HIvax1 and HIvax2 vaccines in patients with survivin-expressing cancers. PMID:26042612

  5. A longitudinal study of teacher burnout and perceived self-efficacy in classroom management

    Microsoft Academic Search

    André Brouwers; Welko Tomic

    2000-01-01

    This study examined the direction and time-frame of relationships between perceived self-efficacy in classroom management and the three dimensions of burnout among 243 secondary school teachers. Structural equation modeling (SEM) analyses indicated that perceived self-efficacy had a longitudinal effect on depersonalization and a synchronous effect on personal accomplishment. However, the direction was reversed for the relationship between perceived self-efficacy and

  6. 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…

  7. 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.

  8. 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, E-mail: frederic.lesage@polymtl.ca [Institute of Biomedical Engineering, École Polytechnique de Montréal, Montreal, Quebec H3C 3A7 (Canada) [Institute of Biomedical Engineering, École Polytechnique de Montréal, Montreal, Quebec H3C 3A7 (Canada); Montreal Heart Institute, Montreal, Quebec H1T 1C8 (Canada)

    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.

  9. Preclinical studies of [ 99mTc]DTPA-mannosyl-dextran? ? ? Supported in part by National Cancer Institute Grant CA72751 and University of California Breast Cancer Research Program Grants 2RB0018 and 4IB0051

    Microsoft Academic Search

    Carl K Hoh; Anne M Wallace; David R Vera

    2003-01-01

    We report the preclinical testing of a synthetic receptor-binding macromolecule, [99mTc]DTPA-mannosyl-dextran (36 kDa, 8 DTPA and 55 mannosyl units per dextran, KD = 0.12 nM), for sentinel node detection. Nonclinical safety studies included cardiac pharmacology safety studies, acute toxicology and pathology studies at 50 and 500 times the scaled human dose in both rats and rabbits after foot pad administration,

  10. Pre-clinical study of drug combinations that reduce breast cancer burden due to aberrant mTOR and metabolism promoted by LKB1 loss

    PubMed Central

    Andrade-Vieira, Rafaela; Goguen, Donna; Bentley, Heidi A.; Bowen, Chris V.; Marignani, Paola A.

    2014-01-01

    Cancer therapies that simultaneously target activated mammalian target of rapamycin (mTOR) and cell metabolism are urgently needed. The goal of our study was to identify therapies that effectively inhibited both mTOR activity and cancer cell metabolism in primary tumors in vivo. Using our mouse model of spontaneous breast cancer promoted by loss of LKB1 expression in an ErbB2 activated model; referred to as LKB1?/?NIC mice, we evaluated the effect of novel therapies in vivo on primary tumors. Treatment of LKB1?/?NIC mice with AZD8055 and 2-DG mono-therapies significantly reduced mammary gland tumorigenesis by inhibiting mTOR pathways and glycolytic metabolism; however simultaneous inhibition of these pathways with AZD8055/2-DG combination was significantly more effective at reducing tumor volume and burden. At the molecular level, combination treatment inhibited mTORC1/mTORC2 activity, selectively inhibited mitochondria function and blocked MAPK pro-survival signaling responsible for the ERK-p90RSK feedback loop. Our findings suggest that loss of LKB1 expression be considered a marker for metabolic dysfunction given its role in regulating AMPK and mTOR function. Finally, the outcome of our pre-clinical study confirms therapies that simultaneously target mTORC1/mTORC2 and glycolytic metabolism in cancer produce the best therapeutic outcome for the treatment of patients harboring metabolically active HER2 positive breast cancers. PMID:25436981

  11. 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

    2014-11-26

    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 ?L, 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. Copyright © 2014 John Wiley & Sons, Ltd. PMID:25424984

  12. Collective Efficacy: A Neglected Construct in the Study of Schools and Student Achievement

    Microsoft Academic Search

    Roger D. Goddard

    2001-01-01

    A theoretical analysis is advanced that discusses social cognitive theory at the group level to explain the formation and impact of collective efficacy. The study used student- and school-level data from a sample of urban elementary schools. Consistent with social cognitive theory, mastery experience was found to be a significant predictor of differences between schools in teachers’ collective efficacy perceptions.

  13. 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…

  14. 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…

  15. Preclinical Evaluation of HIV Eradication Strategies in the Simian Immunodeficiency Virus-Infected Rhesus Macaque: A Pilot Study Testing Inhibition of Indoleamine 2,3-Dioxygenase

    PubMed Central

    Dunham, Richard M.; Gordon, Shari N.; Vaccari, Monica; Piatak, Michael; Huang, Yong; Deeks, Steven G.; Lifson, Jeffrey; Franchini, Genoveffa

    2013-01-01

    Abstract Even in the setting of maximally suppressive antiretroviral therapy (ART), HIV persists indefinitely. Several mechanisms might contribute to this persistence, including chronic inflammation and immune dysfunction. In this study, we have explored a preclinical model for the evaluation of potential interventions that might serve to eradicate or to minimize the level of persistent virus. Given data that metabolic products of the inducible enzyme indoleamine 2,3-dioxygeanse (IDO) might foster inflammation and viral persistence, chronically simian immunodeficiency virus (SIV)-infected, ART-treated rhesus macaques were treated with the IDO inhibitor 1-methyl tryptophan (1mT). Orally administered 1mT achieved targeted plasma levels, but did not impact tryptophan metabolism or decrease viral RNA or DNA in plasma or in intestinal tissues beyond levels achieved by ART alone. Animals treated with 1mT showed no difference in the levels of T cell activation or differentiation, or in the kinetics or magnitude of viral rebound following cessation of ART. Notwithstanding these negative results, our observations suggest that the chronically SIV-infected rhesus macaque on suppressive ART can serve as a tractable model in which to test and to prioritize the selection of other potential interventions designed to eradicate HIV in vivo. In addition, this model might be used to optimize the route and dose by which such interventions are administered and the methods by which their effects are monitored. PMID:22924680

  16. 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.

  17. Universal hand-held three-dimensional optoacoustic imaging probe for deep tissue human angiography and functional preclinical studies in real time.

    PubMed

    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

  18. Children's Self-Efficacy Scale: Initial Psychometric Studies

    ERIC Educational Resources Information Center

    Martinelli, Selma de Cassia; Bartholomeu, Daniel; Caliatto, Susana Gakyia; Sassi, Adriana de Grecci

    2009-01-01

    This article describes the development of a self-efficacy measure for elementary school children. A sample of 514 children, ages 8 to 11, enrolled in Grades 2 to 4 of public schools in Brazil was investigated. The scale included 78 descriptive items about academic situations, in which the child was required to respond on a 5-point scale, the…

  19. The efficacy of vaccinial immune globulin. A 15-year study.

    PubMed

    Feery, B J

    1976-01-01

    This survey reports on the use of vaccinial immune globulin in Australia over the last 15 years. Evidence is produced that vaccinial immune globulin has proven efficacious in the prophylaxis and therapy of complications following smallpox vaccination. An indication of the type and frequency of complications following vaccination is provided. PMID:1007152

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

    PubMed Central

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

    2010-01-01

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

  1. 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 smoking cessation or reduction. If e-cigarette safety will be confirmed, however, the use of e-cigarettes alone may facilitate quitters remaining so. Registration Number NCT01785537. PMID:26061661

  2. 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…

  3. Science teaching self-efficacy in a primary school: A case study

    NASA Astrophysics Data System (ADS)

    de Laat, Jenny; Watters, James J.

    1995-12-01

    Bandura's theory of self-efficacy predicts that teachers with high, self-efficacy should persist longer, provide a greater academic focus in child-centred classrooms and exhibit different types of feedback than teachers who have lower self-efficacy. This paper reports on the science teaching self-efficacy in a group of teachers at a state primary school. The research was conducted in two stages using firstly the Science Teaching Efficacy Beliefs Instrument (STEBI-A) to identify cases, and secondly, a semistructured interview coupled with classroom observations. Thirty seven teaching staff were surveyed with the STEBI-A instrument. The five highest and five lowest scoring teachers on the personal science teaching self-efficacy subscale of the STEBI-A were interviewed. The analysis of interviews and observations indicated that teachers with high personal science teaching self-efficacy have had a long interest in science and a relatively strong background of formal science studies with opportunities for exploring out of school activities. Although they may have experienced negative science experiences in their own schooling other ameliorating factors existed which maintained their interest. Their instructional strategies in science lessons were more child-centred than those reported by teachers with lower personal science teaching self-efficacy. The implications of the results for the inservice training of teachers are discussed.

  4. [Study on methodology for evaluating clinical efficacy of traditional Tibetan medicine].

    PubMed

    Luo, Hui; Zhong, Ge-Jia

    2015-01-01

    The evaluation on clinical efficacy of traditional Tibetan medicine (TTM) is an important scientific subject during the development of TTM. Firstly, the authors introduced the current situations and problems in evaluation on clinical efficacy of traditional Tibetan medicine both at home and abroad in this study. Secondly, they compared the similarities and differences between TTM and traditional Chinese medicine (TCM) in evaluation on clinical efficacy, define their differences in details but not in nature, and proposed that TTM could selectively learn TCM's experiences in clinical research and build a specific methodology system for evaluation on clinical efficacy according to its own characteristics. Thirdly, they discussed the methodological challenges in evaluation on clinical efficacy of TTM, including the pending clinical research guidelines and disease diagnosis standards according to its own characteristics. Finally, they propound some suggestions for promoting the evaluation on clinical efficacy of TTM, including the comprehensive application of multiple research methods, overall research-based evaluation on efficacy of TTM complex intervention and selection of accepted and objective outcome indexes for efficacy evaluation. PMID:25993807

  5. Discovery and preliminary confirmation of novel early detection biomarkers for triple-negative breast cancer using preclinical plasma samples from the Women’s Health Initiative observational study

    PubMed Central

    Li, Christopher I.; Mirus, Justin E.; Zhang, Yuzheng; Ramirez, Arturo B.; Ladd, Jon J.; Prentice, Ross L.; McIntosh, Martin; Hanash, Samir M.; Lampe, Paul D.

    2012-01-01

    Triple-negative breast cancer is a particularly aggressive and lethal breast cancer subtype that is more likely to be interval-detected rather than screen-detected. The purpose of this study is to discover and initially validate novel early detection biomarkers for triple-negative breast cancer using preclinical samples. Plasma samples collected up to 17 months prior to diagnosis from 28 triple-negative cases and 28 matched controls from the Women’s Health Initiative Observational Study were equally divided into a training set and a test set and interrogated using a customized antibody array. Data were available on 889 antibodies, and in the training set statistically significant differences in case vs. control signals were observed for 93 (10.5%) antibodies at p<0.05. Of these 93 candidates, 29 were confirmed in the test set at p<0.05. Areas under the curve for these candidates ranged from 0.58 to 0.79. With specificity set at 98%, sensitivity ranged from 4% to 68% with ?20 candidates having a sensitivity 20% and 6 having a sensitivity ?40%. In an analysis of KEGG gene sets, the pyrimidine metabolism gene set was upregulated in cases compared to controls (p=0.004 in the testing set) and the JAK/Stat signaling pathway gene set was downregulated (p=0.003 in the testing set). Numerous potential early detection biomarkers specific to triple-negative breast cancer in multiple pathways were identified. Further research is required to follow-up on promising candidates in larger sample sizes and to better understand their potential biological importance as our understanding of the etiology of triple-negative breast cancer continues to grow. PMID:22903690

  6. Translational research for Parkinson?s disease: The value of pre-clinical primate models.

    PubMed

    Aron Badin, Romina; Vadori, Marta; Cozzi, Emanuele; Hantraye, Philippe

    2015-07-15

    Animal models have been highly questioned for their ability to predict the efficacy of different therapeutic strategies for neurodegenerative diseases. The increasing number of phase I/II clinical trials that fail to proceed to further stages of drug development has discredited the pertinence of such investigations. However, critical analysis of the data has often revealed errors and partially explained the lack of efficacy, opening the way to a refinement in designing pre-clinical studies. In parallel, many promising methods of drug delivery to the brain such as gene therapy or cell therapy have considerably advanced thanks to the clinical failures in the past 10 years. As methodological advances appear and knowledge becomes available, scientists will be faced with the choice of how to test new strategies or re-test old ones. With the hardening of social views and legislation regarding animal experimentation, there is increasing pressure to find alternative methods of assessment that predict efficacy (such as computational based models), or to perform efficacy trials directly in patients and only safety assays in animals. In this review we will focus on Parkinson?s disease and on the impact of a body of data issued from NHP studies. We will attempt to critically examine the advantages and limitations of various approaches from the perspective of the animal model used to address specific questions. PMID:25841877

  7. The role of childhood trauma in the neurobiology of mood and anxiety disorders: preclinical and clinical studies

    Microsoft Academic Search

    Christine Heim; Charles B. Nemeroff

    2001-01-01

    Epidemiologic studies indicate that children exposed to early adverse experiences are at increased risk for the development of depression, anxiety disorders, or both. Persistent sensitization of central nervous system (CNS) circuits as a consequence of early life stress, which are integrally involved in the regulation of stress and emotion, may represent the underlying biological substrate of an increased vulnerability to

  8. Abstract--A small, hermetic, wirelessly-controlled retinal prosthesis was developed for pre-clinical studies in Yucatan

    E-print Network

    Kelly, Shawn K.

    -clinical studies in Yucatan mini-pigs. The device was implanted on the outside of the eye in the orbit, Santa Barbara, CA 93106; J. Chen and J. F. Rizzo are with the Massachusetts Eye and Ear Infirmary inserted into the subjects' eyes, resting on or just above the epi-retinal surface. An external stimulator

  9. Preclinical Safety Pharmacology Study of a Novel Protein-Based Cancer Vaccine CHP-NY-ESO-1

    Microsoft Academic Search

    NAOZUMI HARADA; KIYOTAKA HOSHIAI; YOSHIYASU TAKAHASHI; YASUE SAKAGUCHI; TAKAYOSHI KUNO; TADASHI HISHIDA; HIROSHI SHIKU

    2008-01-01

    CHP-NY-ESO-1 is a novel therapeutic cancer vaccine consisting of a recombinant protein of cancer antigen NY-ESO-1 and a polysaccharide-based delivery system, cholesteryl pullulan. A pilot clinical study of CHP-NY-ESO-1 in cancer patients was previously conducted, and the adverse events related to this drug were observed to be limited to skin reactions at injection sites. To further establish the safety of

  10. 76 FR 1174 - Drugs for Human Use; Drug Efficacy Study Implementation; Oral Prescription Drugs Offered for...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-01-07

    ...DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket Nos. FDA-1981-N-0361...5213, 6290, 6303, 6514, 8658, 11935, and 12152] Drugs for Human Use; Drug Efficacy Study Implementation; Oral Prescription...

  11. 21 CFR 201.200 - Disclosure of drug efficacy study evaluations in labeling and advertising.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    21 Food and Drugs 4 2010-04-01 2010-04-01 false Disclosure of drug efficacy study evaluations in labeling and advertising. 201.200 Section 201.200 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT...

  12. 21 CFR 201.200 - Disclosure of drug efficacy study evaluations in labeling and advertising.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    21 Food and Drugs 4 2014-04-01 2014-04-01 false Disclosure of drug efficacy study evaluations in labeling and advertising. 201.200 Section 201.200 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT...

  13. 77 FR 43337 - Drugs for Human Use; Drug Efficacy Study Implementation; Certain Prescription Drugs Offered for...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-07-24

    ...DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket Nos. FDA-1975-N-0336...Hydrocortisone Acetate and Pramoxine Hydrochloride] Drugs for Human Use; Drug Efficacy Study Implementation; Certain...

  14. 21 CFR 201.200 - Disclosure of drug efficacy study evaluations in labeling and advertising.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    21 Food and Drugs 4 2012-04-01 2012-04-01 false Disclosure of drug efficacy study evaluations in labeling and advertising. 201.200 Section 201.200 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT...

  15. 77 FR 12310 - Drugs for Human Use; Drug Efficacy Study Implementation; Prescription Drugs That Contained...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-02-29

    ...DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-1978-N-0441] (formerly 78N-0324); DESI 10392] Drugs for Human Use; Drug Efficacy Study Implementation; Prescription...

  16. 21 CFR 201.200 - Disclosure of drug efficacy study evaluations in labeling and advertising.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    21 Food and Drugs 4 2011-04-01 2011-04-01 false Disclosure of drug efficacy study evaluations in labeling and advertising. 201.200 Section 201.200 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT...

  17. 21 CFR 201.200 - Disclosure of drug efficacy study evaluations in labeling and advertising.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    21 Food and Drugs 4 2013-04-01 2013-04-01 false Disclosure of drug efficacy study evaluations in labeling and advertising. 201.200 Section 201.200 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT...

  18. 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. PMID:21834327

  19. Preclinical testing of three South American antivenoms against the venoms of five medically-important Peruvian snake venoms.

    PubMed

    Laing, G D; Yarleque, A; Marcelo, A; Rodriguez, E; Warrell, D A; Theakston, R D G

    2004-07-01

    World Health Organization (WHO)-recommended preclinical in vivo and in vitro studies were carried out to compare the efficacy of Brazilian, Peruvian and Colombian antivenoms in neutralizing the venom toxins responsible for the lethal, haemorrhagic, necrotizing, coagulant and defibrinogenating effects of five medically-important Peruvian snake venoms. Overall, the Brazilian antivenom was found to be the most effective followed by the Peruvian and Colombian antivenoms. However, it was concluded that all three antivenoms would be acceptable for use in a randomised clinical trial in envenomed humans in Peru. PMID:15225568

  20. Preclinical Study of Treatment Response in HCT-116 Cells and Xenografts with 1H-decoupled 31P MRS

    PubMed Central

    Darpolor, Moses M.; Kennealey, Peter T.; Carl Le, H; Zakian, Kristen L.; Ackerstaff, Ellen; Rizwan, Asif; Chen, Jin-Hong; Sambol, Elliot B.; Schwartz, Gary K.; Singer, Samuel; Koutcher, Jason A.

    2011-01-01

    The topoisomerase I inhibitor, irinotecan, and its active metabolite SN-38 have been shown to induce G2/M cell cycle arrest without significant cell death in human colon carcinoma cells (HCT-116). Subsequent treatment of these G2/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 (1H)-decoupled phosphorus (31P) 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% G2/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 1H-decoupled 31P MRS indirectly measures choline kinase activity. The decrease in phosphocholine may be a potential indicator of early tumor response to the sequential treatment of irinotecan followed by flavopiridol in noninvasive and/or longitudinal studies. PMID:21994185

  1. Bone-marrow biopsy needle incorporating a snare-coil specimen-capturing device: description and preclinical studies.

    PubMed

    Goldenberg, A S; Rishton, M

    1999-01-01

    A tissue biopsy needle maximizes adequate specimen retrieval and minimizes patient pain and tissue disruption. The proposed biopsy needle incorporates an internal snare-coil for capturing specimens. The snare-coil device is described along with needle durability and performance testing. Sharply cut, nonfragmented, cored specimens were retrieved from a resin-based foam. In clinical practice, the snare-coil technology may minimize post-insertion needle manipulations and patient pain. Further studies are required to determine the impact of snare-coil needles on the retrieval of adequate specimens from patients. PMID:10626043

  2. Preclinical pharmacodynamic and pharmacokinetic studies of investigational new drugs. Annual report, 1 November 1993-31 October 1994

    SciTech Connect

    Noker, P.E.

    1994-11-11

    During the past year of this contract pharmacokinetic, pharmacodynamic, bioavailability and metabolism studies have been conducted on two anti-cyanotic agents (WR242511 and p-aminohetanophenone (PAHP)) and one nerve agent antidote (HI-6) which are under consideration for clinical development by the U.S. Army. Radiolabeled formulations of WR242511, PAHP and HI-6 were used in these investigations. Information has been obtained on the half-lives of absorption and elimination of both radioactivity and the parent compound following oral and i.v. administration of these three compounds to dogs and, for PAHP, also to rats. In addition, the rates and extent of urinary and fecal elimination of the agents has been characterized; the pharmacodynamics, as assessed by the production of methemoglobin, of two compounds (WR242511 and PAHP) has been studied; and the metabolism of each compound has been investigated. Data obtained to date indicate that: WR242511 does not directly produce methemoglobinemia but a metabolite sequestered in red cells is the responsible agent; dogs appear to metabolize PAHP differently than do rats; the major urinary metabolite of HI-6 is 2-pyridine aldoxime. Further efforts to isolate and identify the metabolites of all three compounds are in progress.

  3. 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. [Univ. of Michigan Medical Center, Ann Arbor, MI (United States)

    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.

  4. 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. PMID:25602313

  5. Evaluation of efficacy of microwave irradiation in disinfecting dental gypsum casts: an ex vivo study.

    PubMed

    Kalahasti, Deepthi; Hegde, Veena; Kosaraju, Kranti; Baliga, Srikala; Reddy, N Kulasekhar; Sujatha, Bk

    2014-12-01

    The aim of this study is to assess the efficacy of microwave irradiation in disinfecting gypsum casts and also to compare its efficacy with validated method of chemical disinfection. The present study is an ex vivo study conducted on a sample of five irreversible hydrocolloid impressions in vitro and on ten patients gypsum casts in vivo following standard impression techniques to check the efficacy of microwave oven irradiation and compare its efficacy with standard chemical method of disinfection. Results were analysed using Mann-Whitney test and Wilcoxon signed rank test. Untreated gypsum casts showed cfu/ml counts with a median log value of 6, while microwave-irradiated ones had median cfu/ml counts of 0. Casts poured from chemically disinfected impressions demonstrated cfu/ml counts with a median log value of 5. Microwave irradiation was found to be effective in disinfecting gypsum casts when compared to chemical disinfectant in disinfecting dental impressions. PMID:25489162

  6. Inhibitory Effects of Platelet-Rich Plasma on Intervertebral Disc Degeneration: A Preclinical Study in a Rabbit Model

    PubMed Central

    Gui, Keke; Ren, Weimin; Yu, Yonglin; Li, Xin; Dong, Jiachun; Yin, Wangping

    2015-01-01

    Background Platelet-rich plasma (PRP) contains multiple growth hormones that may stimulate tissue repair. This study aimed to assess the effects of PRP in a rabbit model of IDD (annulus fibrosus puncture). Material/Methods Thirty-six adult New Zealand white rabbits were randomly divided into 3 groups: 0.1 mL PRP (group A), 0.1 mL phosphate-buffered saline (group B), and control (group C) (n=12/group). Annulus fibrosus puncture was performed to establish L4/5 and L5/6 IDD models. Two and 4 weeks later, 6 rabbits from each group were given an IVD injection at L4/5 and L5/6. Two or 4 weeks after injection, rabbits were scanned with X-ray and MRI before being sacrificed. IVDs were collected for hematoxylin and eosin, Masson’s trichrome, and Safranin O staining, and type II collagen immunohistochemistry. Results Over time, IVD height and disc imaging signal intensity decreased gradually in groups B and C, but only slightly in group A (baseline: 100% for all groups; A: 95.9±4.2% at 4 weeks, 90.1±8.4 at 6 weeks; B: 75.3±5.7% at 4 weeks, 70.8±6.4% at 6 weeks; C: 74.7±5.5% at 4 weeks, 69.9±6.2% at 6 weeks; all P<0.001, P<0.01 between A vs. B and C). Degenerative histological changes in IVDs in groups B and C were more severe compared with group A. Conclusions Platelet-rich plasma interventions can effectively attenuate the IDD process in rabbits. PMID:25965093

  7. Inhibition of TGF-beta2 with AP 12009 in recurrent malignant gliomas: from preclinical to phase I/II studies.

    PubMed

    Hau, Peter; Jachimczak, Piotr; Schlingensiepen, Reimar; Schulmeyer, Frank; Jauch, Tanya; Steinbrecher, Andreas; Brawanski, Alexander; Proescholdt, Martin; Schlaier, Jürgen; Buchroithner, Johanna; Pichler, Josef; Wurm, Gabriele; Mehdorn, Maximilian; Strege, Rainer; Schuierer, Gerhard; Villarrubia, Victoria; Fellner, Franz; Jansen, Olav; Straube, Thorsten; Nohria, Virinder; Goldbrunner, Michael; Kunst, Mechthild; Schmaus, Susanne; Stauder, Gerhard; Bogdahn, Ulrich; Schlingensiepen, Karl-Hermann

    2007-01-01

    Transforming growth factor-beta2 (TGF-beta2) is known to suppress the immune response to cancer cells and plays a pivotal role in tumor progression by regulating key mechanisms including proliferation, metastasis, and angiogenesis. For targeted protein suppression the TGF-beta2-specific antisense oligodeoxynucleotide AP 12009 was developed. In vitro experiments have been performed to prove specificity and efficacy of the TGF-beta2 inhibitor AP 12009 employing patient-derived malignant glioma cells as well as peripheral blood mononuclear cells (PBMCs) from patients. Clinically, the antisense compound AP 12009 was assessed in three Phase I/II-studies for the treatment of patients with recurrent or refractory malignant (high-grade) glioma WHO grade III or IV. Although the study was not primarily designed as an efficacy evaluation, prolonged survival compared to literature data and response data were observed, which are very rarely seen in this tumor indication. Two patients experienced long-lasting complete tumor remissions. These results implicate targeted TGF-beta2-suppression using AP 12009 as a promising novel approach for malignant gliomas and other highly aggressive, TGF-beta-2-overexpressing tumors. PMID:17638524

  8. 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.

  9. Preliminary study of the safety and efficacy of extended-release oxybutynin in children

    Microsoft Academic Search

    Katrin Youdim; Barry A. Kogan

    2002-01-01

    Objectives. To test the safety and efficacy of extended-release oxybutynin in children with bladder dysfunction. The efficacy of oxybutynin in children has been limited by side effects. A new extended-release formulation of oxybutynin has some benefits versus traditional oxybutynin but has never been evaluated in children.Methods. A retrospective study was performed on 25 children who had been treated with extended-release

  10. Math and Science Pursuits: A Self-Efficacy Intervention Comparison Study

    Microsoft Academic Search

    Elizabeth D. Cordero; Sarah H. Porter; Tania Israel; Michael T. Brown

    2010-01-01

    This study compared two interventions to increase math self-efficacy among undergraduate students. Ninety-nine first-year undergraduate students participated in an intervention involving performance accomplishment or an intervention combining performance accomplishment and belief-perseverance techniques in which participants constructed a rationale for their future success in math\\/science university courses. As hypothesized, participants in the combined intervention immediately demonstrated higher math self-efficacy than did

  11. 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

  12. A Cross-Sectional Study of Engineering Students' Self-Efficacy by Gender, Ethnicity, Year, and Transfer Status

    ERIC Educational Resources Information Center

    Concannon, James P.; Barrow, Lloyd H.

    2009-01-01

    This is a cross-sectional study of 519 undergraduate engineering majors' self-efficacy beliefs at a large, research extensive, Midwestern university. Engineering self-efficacy is an individual's belief in his or her ability to successfully negotiate the academic hurdles of the engineering program. Engineering self-efficacy was obtained from four…

  13. Sleep laboratory studies of hypnotic drugs: efficacy and withdrawal effects.

    PubMed

    Kales, A; Kales, J D

    1983-04-01

    Flurazepam, temazepam, and triazolam are compared in terms of initial and short term efficacy, effectiveness during intermediate and long term use, withdrawal effects, and general side effects. The usefulness of temazepam is considerably restricted since the drug is slowly absorbed; peak blood concentrations are not reached until 2 to 3 hours after ingestion. Consequently, while the majority of insomniac patients complain primarily of difficulty falling asleep, temazepam is not effective for this sleep complaint. Further, the drug has an intermediate elimination half-life and induces a significant degree of morning sleepiness (hang-over). Rebound insomnia of a moderate degree occurs with some frequency following withdrawal of temazepam. Triazolam is effective initially and with short term use both for inducing and maintaining sleep. However, much of this effectiveness is lost with continued nightly use over an intermediate period (2 weeks). The drug has a rapid elimination rate; during drug administration, sleep may worsen in the final hours of the night (early morning insomnia), and following drug withdrawal, rebound insomnia is frequent, immediate, and severe. Side effects are frequent and include some morning sleepiness (before tolerance develops) and significant memory impairment and even episodes of amnesia. Triazolam may have a narrow margin of safety in that serious behavioral symptoms have been reported even with a 1-mg dose. Flurazepam is effective both for initiating and maintaining sleep with initial and short term drug administration. Further, its efficacy is maintained not only with intermediate term use but with long term drug use (4 weeks). Flurazepam is a long elimination half-life drug, and there is significant daytime sedation during short term use; with continued use this effect diminishes. Rebound insomnia has not been noted following withdrawal of flurazepam; there is a carry-over effectiveness into the first and second nights of withdrawal, and any withdrawal sleep disturbance would be expected to be infrequent, delayed in appearance, and mild in degree. PMID:6132933

  14. Toward making the invisible visible: Studying science teaching self-efficacy beliefs

    NASA Astrophysics Data System (ADS)

    Perkins, Catherine J.

    This dissertation consists of two articles to be submitted for publication. The first, a literature review, makes visible common influences on science teaching self-efficacy beliefs and also points to potentially invisible validation concerns regarding the instrument used. The second investigates the participants' invisible science teaching self-efficacy beliefs and, through the use of a more focused interview, makes those beliefs visible. Science teaching self-efficacy beliefs are science teachers' perceptions of their abilities to teach science effectively. The construct "teaching self-efficacy" originated in social cognitive theory (Bandura, 1977). The first article reviews the mixed results from teaching self-efficacy research in science contexts. The review focuses upon factors that facilitate or inhibit the development of self-efficacy beliefs among science teachers across stages of their careers. Although many studies of science teaching self-efficacy beliefs have utilized the Science Teaching Efficacy Belief Instrument - STEBI (Enochs & Riggs, 1990; Riggs & Enochs, 1990), this review also includes non-STEBI studies in order to represent diverse lines of research methodology. The review's findings indicate that antecedent factors such as science activities in and out of school, teacher preparation, science teaching experiences and supportive job contexts are significant influences on the development of science teaching self-efficacy beliefs. The review also indicates that the majority of these studies are short term and rely on a single STEBI administration with the collection of antecedent/demographic and/or interview data. The second article documents a study that responded to the above literature review findings. This study utilized multiple STEBI administrations during the preservice and beginning year of teaching for two science teachers. Rather than general questions, these participants were asked item specific, yet open-ended, questions to determine what events or experiences the participants felt influenced their survey answers. This methodological approach was chosen to add clarity to the STEBI scores and to add another layer in the ongoing process of instrument validation. Unlike some studies in science teaching self-efficacy, both participants' STEBI scores continued to increase as they transitioned from preservice to beginning teachers. The participant responses to the focused interview probes also validated their STEBI scores 77% of the time.

  15. The Role of Grape Seed Extract in the Treatment of Chemo/Radiotherapy Induced Toxicity: A Systematic Review of Preclinical Studies.

    PubMed

    Olaku, Oluwadamilola O; Ojukwu, Mary O; Zia, Farah Z; White, Jeffrey D

    2015-07-01

    Grapes are one of the most consumed fruits in the world and are rich in polyphenols. Grape seed proanthocyanidins (GSP) have demonstrated chemopreventive and/or chemotherapeutic effects in various cancer cell cultures and animal models. The clinical efficacy of chemotherapy is often limited by its adverse effects. Several studies show that reactive oxygen species mediate the cardiotoxicity and neurotoxicity induced by various cancer chemotherapeutic agents. This implies that concomitant administration of antioxidants may prevent these adverse effects. The review was carried out in accordance with the PRISMA guidelines. An electronic search strategy in Medline and Embase databases was conducted. Of the 41 studies reviewed, 27 studied GSP while the remainder (14) studied grape seed or skin extracts (GSE). All the studies were published in English, except 2 in Chinese. A significant percentage (34%) of the studies we reviewed assessed the effect of GSE or GSP on cardiotoxicity induced by chemotherapy. Doxorubicin was the most common chemotherapeutic drug studied followed by cisplatin. Research studies that assessed the effect of GSE or GSP on radiation treatment accounted for 22% of the articles reviewed. GSE/GSP ameliorates some of the cytotoxic effects on normal cells/tissues induced by chemo/radiotherapy. PMID:25880972

  16. Comparative study of the neurotrophic effects elicited by VEGF-B and GDNF in preclinical in vivo models of Parkinson’s disease

    PubMed Central

    Yue, Xu; Hariri, Dana J.; Caballero, Beatrice; Zhang, Shiling; Bartlett, Mitchell J.; Kaut, Oliver; Mount, David W.; Wüllner, Ullrich; Sherman, Scott J.; Falk, Torsten

    2014-01-01

    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 ?g and 10 ?g) 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 ?g), 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 ?g 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 = 1.9 e-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 controls and Parkinson’s disease patients, in neuronal cells that show co-expression with neuromelanin. These results have demonstrated that VEGF-B has potential as a neuroprotective agent for PD therapy and should be further investigated. PMID:24291725

  17. 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

  18. Measuring the Efficacy of Code Clone Information in a Bug Localization Task: An Empirical Study

    E-print Network

    Carver, Jeffrey C.

    Measuring the Efficacy of Code Clone Information in a Bug Localization Task: An Empirical Study clone detection techniques and tools. However, there has been little human-based empirical study a study that investigates the usefulness of code clone information for performing a bug localization task

  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. The Effects on Teacher Efficacy of School Based Collaborative Activities Structured as Professional Study Groups.

    ERIC Educational Resources Information Center

    Pfaff, Margaret E.

    This study examined the influence of participation in school-based professional study group activities on both general and personal teaching efficacy. It also examined teachers' perceptions of changes that occurred in their teaching performance as a result of participation in the study group sessions. Participants were elementary teachers who…

  1. 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. PMID:8286163

  2. The Interplay between Motivation, Self-Efficacy, and Approaches to Studying

    ERIC Educational Resources Information Center

    Prat-Sala, Merce; Redford, Paul

    2010-01-01

    Background: The strategies students adopt in their study are influenced by a number of social-cognitive factors and impact upon their academic performance. Aims: The present study examined the interrelationships between motivation orientation (intrinsic and extrinsic), self-efficacy (in reading academic texts and essay writing), and approaches to…

  3. The Differential Efficacy of Pemetrexed According to NSCLC Histology: A Review of Two Phase III Studies

    Microsoft Academic Search

    GIORGIO SCAGLIOTTI; NASSER HANNA; FRANK FOSSELLA; KATHERINE SUGARMAN; JOHANNES BLATTER; PATRICK PETERSON; LORINDA SIMMS; FRANCES A. SHEPHERD

    Background. Recent studies of pemetrexed have identi- fied a predictive role for non-small cell lung cancer (NSCLC) histology. We further reviewed the differen- tial efficacy of pemetrexed according to histology in two large, phase III NSCLC trials. Methods. One study tested pemetrexed versus do- cetaxel in previously treated patients (n 571) and the other tested cisplatin plus pemetrexed versus cisplatin

  4. The Analysis of Social Studies Pre-Service Teachers' Interpersonal Self-Efficacy Beliefs

    ERIC Educational Resources Information Center

    Yazici, Kubilay

    2010-01-01

    Interpersonal self efficacy scale which is developed by Brouser and Tomic (2002) and modified for Turkish by Capri and Kan (2006) is applied to 262 pre-service teachers studying in 1st-4th grades of social studies department in the Faculty of Education at Nigde University together with a personal information form. The scale is proved highly valid…

  5. Career Development Interventions and Academic Self-Efficacy and Motivation: A Pilot Study.

    ERIC Educational Resources Information Center

    Dykeman, Cass; Wood, Chris; Ingram, Michael; Herr, Edwin L.

    The impact of career development interventions on career and technical education (CTE) students' academic self-efficacy and motivation was explored in a pilot study that elicited responses from 293 students at 20 high schools across the United States. The study included a literature review, survey of high school seniors that examined 44…

  6. Comparison of the efficacy of olopatadine and fexofenadine in chronic idiopathic urticaria patients: a crossover study.

    PubMed

    Tanizaki, Hideaki; Yamamoto, Yosuke; Nakamizo, Satoshi; Otsuka, Atsushi; Miyachi, Yoshiki; Kabashima, Kenji

    2015-01-01

    Olopatadine is one of the second-generation H1 antihistamines that were used for treating allergic disorders initially in Asia, and now also in Western countries. Whereas several trials compared the efficacy on chronic urticaria among second-generation H1 antihistamines, no study has directly compared the clinical efficacy between olopatadine and other H1 antihistamines in patients with chronic idiopathic urticaria (CIU). In this study, we address this issue for the first time and conclude that olopatadine is a good candidate for the treatment of CIU. PMID:25592003

  7. A Preclinical Assessment of Neural Stem Cells as Delivery Vehicles for Anti-Amyloid Therapeutics

    PubMed Central

    Njie, eMalick G.; Kantorovich, Svetlana; Astary, Garrett W.; Green, Cameron; Zheng, Tong; Semple-Rowland, Susan L.; Steindler, Dennis A.; Sarntinoranont, Malisa; Streit, Wolfgang J.; Borchelt, David R.

    2012-01-01

    Transplantation of neural stems cells (NSCs) could be a useful means to deliver biologic therapeutics for late-stage Alzheimer's disease (AD). In this study, we conducted a small preclinical investigation of whether NSCs could be modified to express metalloproteinase 9 (MMP9), a secreted protease reported to degrade aggregated A? peptides that are the major constituents of the senile plaques. Our findings illuminated three issues with using NSCs as delivery vehicles for this particular application. First, transplanted NSCs generally failed to migrate to amyloid plaques, instead tending to colonize white matter tracts. Second, the final destination of these cells was highly influenced by how they were delivered. We found that our injection methods led to cells largely distributing to white matter tracts, which are anisotropic conduits for fluids that facilitate rapid distribution within the CNS. Third, with regard to MMP9 as a therapeutic to remove senile plaques, we observed high concentrations of endogenous metalloproteinases around amyloid plaques in the mouse models used for these preclinical tests with no evidence that the NSC-delivered enzymes elevated these activities or had any impact. Interestingly, MMP9-expressing NSCs formed substantially larger grafts. Overall, we observed long-term survival of NSCs in the brains of mice with high amyloid burden. Therefore, we conclude that such cells may have potential in therapeutic applications in AD but improved targeting of these cells to disease-specific lesions may be required to enhance efficacy. PMID:22496779

  8. Novel anticonvulsants for reducing alcohol consumption: A review of evidence from preclinical rodent drinking models

    PubMed Central

    Griffin, WC; Lopez, MF; Becker, HC; Mulholland, PJ

    2013-01-01

    Alcohol use disorders (AUDs) are a major public health issue and have an enormous social and economic burden in developed, developing, and third-world countries. Current pharmacotherapies for treating AUDs suffer from deleterious side effects and are only effective in preventing relapse in a subset of individuals. This signifies an essential need for improved medications to reduce heavy episodic drinking and alcohol-related problems. Growing literature has provided support for the use of anticonvulsants in suppressing symptoms induced by alcohol withdrawal. Emerging clinical and preclinical evidence suggests that a number of well-tolerated anticonvulsants may also decrease alcohol drinking. This review will focus on recent evidence supporting the efficacy of novel anticonvulsants in reducing voluntary alcohol consumption in rodent models. The data demonstrate that anticonvulsants reduce drinking in standard home cage two-bottle choice paradigms, self-administration of alcohol in operant chambers, and cue- and stress-induced reinstatement of alcohol seeking behaviors in rats and mice. This review also highlights evidence that some anticonvulsants were only moderately effective in reducing drinking in select strains of rodents or models. This suggests that genetics, possible neuroadaptations, or the pharmacological target affect the ability of anticonvulsants to attenuate alcohol consumption. Nonetheless, anticonvulsants are relatively safe, have little abuse potential, and can work in combination with other drugs. The results from these preclinical and clinical studies provide compelling evidence that anticonvulsants are a promising class of medication for the treatment of AUDs. PMID:24432188

  9. 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

  10. Allopregnanolone Promotes Regeneration and Reduces ?-Amyloid Burden in a Preclinical Model of Alzheimer's Disease

    PubMed Central

    Chen, Shuhua; Wang, Jun Ming; Irwin, Ronald W.; Yao, Jia; Liu, Lifei; Brinton, Roberta Diaz

    2011-01-01

    Previously, we demonstrated that allopregnanolone (AP?) promoted proliferation of rodent and human neural progenitor cells in vitro. Further, we demonstrated that AP? promoted neurogenesis in the hippocampal subgranular zone (SGZ) and reversed learning and memory deficits in the male triple transgenic mouse model of Alzheimer's (3xTgAD). In the current study, we determined the efficacy of AP? to promote the survival of newly generated neural cells while simultaneously reducing Alzheimer's disease (AD) pathology in the 3xTgAD male mouse model. Comparative analyses between three different AP? treatment regimens indicated that AP? administered 1/week for 6 months was maximally efficacious for simultaneous promotion of neurogenesis and survival of newly generated cells and reduction of AD pathology. We further investigated the efficacy of AP? to impact A? burden. Treatment was initiated either prior to or post intraneuronal A? accumulation. Results indicated that AP? administered 1/week for 6 months significantly increased survival of newly generated neurons and simultaneously reduced A? pathology with greatest efficacy in the pre-pathology treatment group. AP? significantly reduced A? generation in hippocampus, cortex, and amygdala, which was paralleled by decreased expression of A?-binding-alcohol-dehydrogenase. In addition, AP? significantly reduced microglia activation as indicated by reduced expression of OX42 while increasing CNPase, an oligodendrocyte myelin marker. Mechanistic analyses indicated that pre-pathology treatment with AP? increased expression of liver-X-receptor, pregnane-X-receptor, and 3-hydroxy-3-methyl-glutaryl-CoA-reductase (HMG-CoA-R), three proteins that regulate cholesterol homeostasis and clearance from brain. Together these findings provide preclinical evidence for the optimal treatment regimen of AP? to achieve efficacy as a disease modifying therapeutic to promote regeneration while simultaneously decreasing the pathology associated with Alzheimer's disease. PMID:21918687

  11. Study of the efficacy of antimalarial drugs delivered inside targeted immunoliposomal nanovectors

    NASA Astrophysics Data System (ADS)

    Urbán, Patricia; Estelrich, Joan; Adeva, Alberto; Cortés, Alfred; Fernàndez-Busquets, Xavier

    2011-12-01

    Paul Ehrlich's dream of a 'magic bullet' that would specifically destroy invading microbes is now a major aspect of clinical medicine. However, a century later, the implementation of this medical holy grail continues being a challenge in three main fronts: identifying the right molecular or cellular targets for a particular disease, having a drug that is effective against it, and finding a strategy for the efficient delivery of sufficient amounts of the drug in an active state exclusively to the selected targets. In a previous work, we engineered an immunoliposomal nanovector for the targeted delivery of its contents exclusively to Plasmodium falciparum-infected red blood cells [pRBCs]. In preliminary assays, the antimalarial drug chloroquine showed improved efficacy when delivered inside immunoliposomes targeted with the pRBC-specific monoclonal antibody BM1234. Because difficulties in determining the exact concentration of the drug due to its low amounts prevented an accurate estimation of the nanovector performance, here, we have developed an HPLC-based method for the precise determination of the concentrations in the liposomal preparations of chloroquine and of a second antimalarial drug, fosmidomycin. The results obtained indicate that immunoliposome encapsulation of chloroquine and fosmidomycin improves by tenfold the efficacy of antimalarial drugs. The targeting antibody used binds preferentially to pRBCs containing late maturation stages of the parasite. In accordance with this observation, the best performing immunoliposomes are those added to Plasmodium cultures having a larger number of late form-containing pRBCs. An average of five antibody molecules per liposome significantly improves in cell cultures the performance of immunoliposomes over non-functionalized liposomes as drug delivery vessels. Increasing the number of antibodies on the liposome surface correspondingly increases performance, with a reduction of 50% parasitemia achieved with immunoliposomes encapsulating 4 nM chloroquine and bearing an estimated 250 BM1234 units. The nanovector prototype described here can be a valuable platform amenable to modification and improvement with the objective of designing a nanostructure adequate to enter the preclinical pipeline as a new antimalarial therapy.

  12. Examining motivations, efficacy and interest in graduate study among teacher participants of a summer institute

    NASA Astrophysics Data System (ADS)

    Hefty, Eunice Ann

    This study examined changes in self and general science teaching efficacy of teachers attending an environmental sciences summer institute in which they earned three hours of graduate credit. The Science Teaching Efficacy Belief Instrument Form A (STEBI A) (Riggs, 1988) was administered as a pretest and posttest at nine Texas universities during June and July of 1997. The population of 145 teachers voluntarily participated in the graduate course, Teaching Environmental Sciences (TES), co-sponsored by the state's regulatory agency, the Texas Natural Resource Conservation Commission and nine Texas universities. Demographic data and data related to teacher motivation were collected as an addendum to the STEBI A. Teacher participants' apparent motivation(s) to attend TES in the absence of state and district staff development mandates were examined. Correlations between demographic data and efficacy responses were analyzed. Qualitative data collected through telephone interviews with TES teachers examined participants' interest in entering graduate studies following this summer institute, particularly with respect to science-related advanced degrees. Generally, the data revealed an increase in science teaching efficacy on posttests, particularly with respect to positively stated STEBI items. Motivations of teachers to attend this summer institute were largely influenced by interest in the subject and an apparent interest in enhancing their skills and pedagogy. The data related to teacher participants' intent to enter graduate study was inconclusive. The information provided through interviews with professors was, however, encouraging but not conclusive with respect to this study and teachers' entering graduate studies following participation in the summer institute.

  13. Study Efficacy and the Region of Proximal Learning Framework

    ERIC Educational Resources Information Center

    Kornell, Nate; Metcalfe, Janet

    2006-01-01

    One of the most important reasons to investigate human metacognition is its role in directing how people study. However, limited evidence exists that metacognitively guided study benefits learning. Three experiments are presented that provide evidence for this link. In Experiment 1, participants' learning was enhanced when they were allowed to…

  14. A Study of Secondary Science Teacher Efficacy and Level of Constructivist Instructional Practice Implementation in West Virginia Science Classrooms

    ERIC Educational Resources Information Center

    Knapp, Amanda Kristen

    2013-01-01

    The purpose of this study was to investigate the level of use of selected constructivist instructional practices and level of teacher efficacy in West Virginia secondary science classrooms. The study next sought to determine if a relationship existed between level of use of the constructivist practices and teacher efficacy. In addition the study

  15. Evaluation of the antihypertensive efficacy with ABPM: a study with Telmisartan (T)

    Microsoft Academic Search

    Mario Bendersky; Marcelo Or??as; Mar??a Pañart; Daniel Volmaro; Fabián Ayup

    2002-01-01

    Aims of the study: To evaluate the antihypertensive efficacy and the duration of effect of T in essential hypertensives (EH) patients. 56 (34 males) untreated EH patients were included. Age 56 (42-70) years old. Their mean diastolic blood pressure (DBP) had to be > 90 and < 110 mmHg in 3 office measurements on 3 separate days.Protocol: Placebo 15 d,

  16. PRELIMINARY STUDY OF THERAPEUTIC EFFICACY OF A NEW FASCIOLICIDAL DRUG DERIVED FROMCOMMIPHORA MOLMOL(MYRRH)

    Microsoft Academic Search

    AHMED MASSOUD; SAWSAN EL SISI; OSAMA SALAMA; AFAF MASSOUD

    Myrrh (from the stem of the Commiphora molmoltree) is an oleo gum resin that may prove efficacious for the treatment of fascioliasis. We studied 7 patients who were passing Fasciola eggs in their stools and treated them with myrrh. The drug (a formulation consisting of 8 parts of resin and 3.5 parts of volatile oils, all extracted from myrrh) was

  17. Safety and antiulcer efficacy studies of Achillea millefolium L. after chronic treatment in Wistar rats

    Microsoft Academic Search

    Ana Maria Cavalcanti; Cristiane Hatsuko Baggio; Cristina Setim Freitas; Lia Rieck; Renato Silva de Sousa; José Eduardo Da Silva-Santos; Sonia Mesia-Vela; Maria Consuelo Andrade Marques

    2006-01-01

    Achillea millefolium L. (Asteraceae), popularly known as yarrow, has been used in folk medicine to treat complaints such as inflammation, pain, wounds, hemorrhages and gastrointestinal disturbances. The aim of the present study was to assess the safety and efficacy of the aqueous extract (AE) of the plant after chronic exposure. Indeed, the AE was effective in protecting the gastric mucosa

  18. Traditional-Aged College Juniors' Career Planning Self-Efficacy: A Case Study

    ERIC Educational Resources Information Center

    Sherman, Dawn C.

    2012-01-01

    The purpose of this single-site case study was to explore and describe traditional-age college juniors' reports of self-efficacy (Bandura, 1997) regarding Career Planning (Barker & Kellen, 1998). More specifically, the career planning confidence levels of college juniors enrolled in a required career development course at a private…

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

    PubMed

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

    2015-03-01

    The application of modeling and simulation techniques is increasingly common in preclinical stages of the drug discovery and development process. A survey focusing on preclinical pharmacokinetic/pharmacodynamics (PK/PD) analysis was conducted across pharmaceutical companies that are members of the International Consortium for Quality and Innovation in Pharmaceutical Development. Based on survey responses, ~68% of companies use preclinical PK/PD analysis in all therapeutic areas indicating its broad application. An important goal of preclinical PK/PD analysis in all pharmaceutical companies is for the selection/optimization of doses and/or dose regimens, including prediction of human efficacious doses. Oncology was the therapeutic area with the most PK/PD analysis support and where it showed the most impact. Consistent use of more complex systems pharmacology models and hybrid physiologically based pharmacokinetic models with PK/PD components was less common compared to traditional PK/PD models. Preclinical PK/PD analysis is increasingly being included in regulatory submissions with ~73% of companies including these data to some degree. Most companies (~86%) have seen impact of preclinical PK/PD analyses in drug development. Finally, ~59% of pharmaceutical companies have plans to expand their PK/PD modeling groups over the next 2 years indicating continued growth. The growth of preclinical PK/PD modeling groups in pharmaceutical industry is necessary to establish required resources and skills to further expand use of preclinical PK/PD modeling in a meaningful and impactful manner. PMID:25630504

  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. PMID:22866232

  1. 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

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

    PubMed

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

    2015-03-01

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

  3. 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 services to assist applicants in preparing the preclinical programs and documentation for their drugs. Increasingly, private foundations are also funding preclinical work. Close interaction with the FDA, including a meeting to prepare for submission of an Investigational New Drug application, is critical to ensure that the preclinical development package properly supports the planned phase I clinical trial. PMID:19534731

  4. Discourse-Based Language Intervention: An Efficacy Study.

    ERIC Educational Resources Information Center

    Skarakis-Doyle, Elizabeth; Murphy, Lisa

    1995-01-01

    This study of a 5-year-old girl with sensorineural hearing loss examined the effect of supplementing a pragmatically based procedure of focused stimulation with structured opportunities for verbal practice using vertical constructions. Results indicated that focused stimulation was an effective treatment procedure, especially when enhanced by the…

  5. 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

  6. Mathematics: Self-Efficacy, Identity, and Achievement among African American Males from the High School Longitudinal Study

    ERIC Educational Resources Information Center

    Briggs, Calvin

    2014-01-01

    The purpose of this study was to determine if a relationship existed between mathematics self-efficacy and mathematics identity to mathematics achievement among African American males from High School Longitudinal Study of 2009 (HSLS:09). Subsequently, the extent to which mathematics self-efficacy and mathematics identity accounted for low and…

  7. Quantitative Polygraphic Controlled Study on Efficacy and Safety of Oral Splint Devices in Tooth-grinding Subjects

    Microsoft Academic Search

    C. Dubé; P. H. Rompré; C. Manzini; F. Guitard; P. de Grandmont; G. J. Lavigne

    2010-01-01

    The efficacy of occlusal splints in diminishing muscle activity and tooth-grinding damage remains controversial. The objective of this study was to compare the efficacy and safety of an occlusal splint (OS) vs. a palatal control device (PCD). Nine subjects with sleep bruxism (SB) participated in this randomized study. Sleep laboratory recordings were made on the second night to establish baseline

  8. Quantitative Polygraphic Controlled Study on Efficacy and Safety of Oral Splint Devices in Tooth-grinding Subjects

    Microsoft Academic Search

    C. Dubé; P. H. Rompré; C. Manzini; F. Guitard; P. de Grandmont; G. J. Lavigne

    2004-01-01

    The efficacy of occlusal splints in diminishing muscle activity and tooth-grinding damage remains controversial. The objective of this study was to compare the efficacy and safety of an occlusal splint (OS) vs. a palatal control device (PCD). Nine subjects with sleep bruxism (SB) participated in this randomized study. Sleep laboratory recordings were made on the second night to establish baseline

  9. Efficacy of immunotherapy with mesenchymal stem cells in man: a systematic review.

    PubMed

    Luk, Franka; de Witte, Samantha F H; Bramer, Wichor M; Baan, Carla C; Hoogduijn, Martin J

    2015-05-01

    Mesenchymal stem cells (MSC) are widely studied for their immunomodulatory properties. Data from in vitro and pre-clinical models demonstrate that MSC suppress activated immune cells and ameliorate the severity of experimental immune disease. In complex human studies, the immunomodulatory efficacy of MSC therapy is not well established. We conducted a systematic review of clinical studies which used MSC with the purpose of immunomodulation and included at least 10 patients to investigate the efficacy of MSC therapy. Sixty-two studies comprising 10 different immune disorders were included in the analysis, of which 18 studies represented controlled trials. Although several of the studies reported an amelioration of disease severity, other studies failed to observe a beneficial effect of MSC. The low number of randomized controlled trials, small number of studies per disease category and limited immunological readout parameters made it difficult to draw a definitive conclusion on the efficacy of MSC immune therapy. PMID:25817052

  10. Preclinical dosimetry of magnetic fluid hyperthermia for bladder cancer

    NASA Astrophysics Data System (ADS)

    Oliveira, Tiago R.; Stauffer, Paul R.; Lee, Chen-Ting; Landon, Chelsea; Etienne, Wiguins; Maccarini, Paolo F.; Inman, Brant; Dewhirst, Mark W.

    2013-02-01

    Background Despite positive efficacy, thermotherapy is not widely used in clinical oncology. Difficulties associated with field penetration and controlling power deposition patterns in heterogeneous tissue have limited its use for heating deep in the body. Heat generation using iron-oxide super-paramagnetic nanoparticles excited with magnetic fields has been demonstrated to overcome some of these limitations. The objective of this preclinical study is to investigate the feasibility of treating bladder cancer with magnetic fluid hyperthermia (MFH) by analyzing the thermal dosimetry of nanoparticle heating in a rat bladder model. Methods The bladders of 25 female rats were injected with 0.4 ml of Actium Biosystems magnetite-based nanoparticles (Actium Biosystems, Boulder CO) via catheters inserted in the urethra. To assess the distribution of nanoparticles in the rat after injection we used the 7 T small animal MRI system (Bruker ClinScan, Bruker BioSpin MRI GmbH, Ettlingen, Germany). Heat treatments were performed with a small animal magnetic field applicator (Actium Biosystems, Boulder CO) with a goal of raising bladder temperature to 42°C in <10min and maintaining for 60min. Temperatures were measured throughout the rat with seven fiberoptic temperature probes (OpSens Technologies, Quebec Canada) to characterize our ability to localize heat within the bladder target. Results The MRI study confirms the effectiveness of the catheterization procedure to homogenously distribute nanoparticles throughout the bladder. Thermal dosimetry data demonstrate our ability to controllably raise temperature of rat bladder >1°C/min to a steady-state of 42°C. Conclusion Our data demonstrate that a MFH system provides well-localized heating of rat bladder with effective control of temperature in the bladder and minimal heating of surrounding tissues.

  11. Differential efficacy of endodontic obturation procedures: an ex vivo study.

    PubMed

    Ardizzoni, Andrea; Generali, Luigi; Righi, Elena; Baschieri, Maria C; Cavani, Francesco; Manca, Lidia; Lugli, Eleonora; Migliarese, Luigi; Blasi, Elisabetta; Neglia, Rachele G

    2014-07-01

    By means of a double-chamber model, different root canal filling materials and procedures were compared. Briefly, the root canals of single-rooted human teeth, extracted for periodontal reasons, were instrumented and obturated by gutta-percha/Pulp Canal Sealer EWT (PCS) or by Resilon, in association with different sealers (Real Seal, RelyX Unicem or Meta). Obturation was achieved by traditional continuous wave of condensation technique (TCWCT), a modified version of it (MCWCT), or single cone technique (SCT). The obturated roots, inserted in a double-chamber model, were sterilized by gamma irradiation. Next, Enterococcus faecalis was added to the upper chamber and the specimens were incubated at 37 °C for up to 120 days; the development of turbidity in the lower chambers' broths indicated bacterial leakage through the obturated root canals. The kinetics of leakage were analyzed in different groups by means of Kaplan-Meier statistics and compared by log-rank test. The results showed that root canals obturated with either gutta-percha/PCS using the MCWCT, Resilon/Real Seal SCT or Resilon/RelyX Unicem using the TCWCT displayed significantly better performance than the remaining groups (p < 0.01). Histological evaluation, performed to investigate microbial localization inside specimens, confirmed that this parameter varied according to the obturation procedures and materials employed. This ex vivo study indicates that gutta-percha/PCS, if used with the MCWCT, is as effective as Resilon when coupled to Real Seal with the SCT or, interestingly, to RelyX Unicem with the TCWCT. These data suggest that further improvement of the currently employed root canal filling procedures is achievable, depending on both the filling materials and the technique employed, thus encouraging clinical studies in this direction. PMID:23836051

  12. A phase 3, randomized, double-blinded, active-controlled, unblinded standard of care study assessing the efficacy and safety of intramyocardial autologous CD34+ cell administration in patients with refractory angina: design of the RENEW study.

    PubMed

    Povsic, Thomas J; Junge, Candice; Nada, Adel; Schatz, Richard A; Harrington, Robert A; Davidson, Charles J; Fortuin, F David; Kereiakes, Dean J; Mendelsohn, Farrell O; Sherman, Warren; Schaer, Gary L; White, Christopher J; Stewart, Duncan; Story, Kenneth; Losordo, Douglas W; Henry, Timothy D

    2013-06-01

    Preclinical trials indicate that CD34+ cells represent an effective angiogenic stem cell component. Early-phase clinical trials suggest that intramyocardial administration of autologous CD34+ cells may improve functional capacity and symptoms of angina. RENEW is a pivotal phase 3 trial designed to determine the efficacy of granulocyte colony-stimulating factor (G-CSF)-mobilized CD34+ stem cells for the treatment for patients with refractory angina and chronic myocardial ischemia. Patients (n = 444) receiving maximally tolerated antianginal therapies and lacking conventional revascularization options with Canadian Cardiovascular Society class III or IV angina and ischemia on stress testing will be randomized 2:1:1 to cell therapy (G-CSF-mediated stem cell mobilization, apheresis, and intramyocardial injection of 1 × 10(5) autologous CD34(+) cells/kg), active control (G-CSF-mediated stem cell mobilization, apheresis, and intramyocardial placebo injection), or open-label standard of care. The primary efficacy end point is change in exercise treadmill time in the treated vs active control patients, with 90% power to detect a 60-second difference in exercise time between cell-treated (n = 200) and active control (n = 100) patients. Key secondary end points include total number of anginal episodes per week and the incidence of independently adjudicated major adverse cardiac events and serious adverse events. RENEW will be the first adequately powered study aimed at definitively determining the efficacy of a cell therapy (intramyocardially delivered autologous CD34+ cells) for improvement of functional capacity in patients with refractory angina. PMID:23708155

  13. Potential of metabolomics in preclinical and clinical drug development.

    PubMed

    Kumar, Baldeep; Prakash, Ajay; Ruhela, Rakesh Kumar; Medhi, Bikash

    2014-12-01

    Metabolomics is an upcoming technology system which involves detailed experimental analysis of metabolic profiles. Due to its diverse applications in preclinical and clinical research, it became an useful tool for the drug discovery and drug development process. This review covers the brief outline about the instrumentation and interpretation of metabolic profiles. The applications of metabolomics have a considerable scope in the pharmaceutical industry, almost at each step from drug discovery to clinical development. These include finding drug target, potential safety and efficacy biomarkers and mechanisms of drug action, the validation of preclinical experimental models against human disease profiles, and the discovery of clinical safety and efficacy biomarkers. As we all know, nowadays the drug discovery and development process is a very expensive, and risky business. Failures at any stage of drug discovery and development process cost millions of dollars to the companies. Some of these failures or the associated risks could be prevented or minimized if there were better ways of drug screening, drug toxicity profiling and monitoring adverse drug reactions. Metabolomics potentially offers an effective route to address all the issues associated with the drug discovery and development. PMID:25443721

  14. Identification and characterization of psoralen and isopsoralen as potent CYP1A2 reversible and time-dependent inhibitors in human and rat preclinical studies.

    PubMed

    Zhuang, Xiao-Mei; Zhong, Yu-Huan; Xiao, Wei-Bin; Li, Hua; Lu, Chuang

    2013-11-01

    Naturally occurring furanocoumarin compounds psoralen (PRN) and isopsoralen (IPRN) are bioactive constituents found in herbaceous plants. They are widely used as active ingredients in several Chinese herbal medicines. In this study, the CYP1A2 inhibitory potential of PRN and IPRN was investigated in rats in vitro and in vivo as well as in human liver microsomes. Both compounds exhibited reversible and time-dependent inhibition toward rat microsomal cyp1a2. The IC(50), k(inact), and K(I) values were 10.4 ± 1.4 ?M, 0.060 ± 0.002 min(-1), and 1.13 ± 0.12 ?M for PRN, and 7.1 ± 0.6 ?M, 0.10 ± 0.01 min(-1), and 1.95 ± 0.31 ?M for IPRN, respectively. In human liver microsomal incubations, potent reversible CYP1A2 inhibition was observed for both compounds, with IC(50) values of 0.26 ± 0.01 ?M and 0.22 ± 0.03 ?M for PRN and IPRN, respectively. However, time-dependent inhibition was only observed for IPRN, with kinact and KI values of 0.050 ± 0.002 min(-1) and 0.40 ± 0.06 ?M, respectively. Coadministration with PRN or IPRN significantly inhibited cyp1a2 activity in rats, with the area under the curve (AUC) of phenacetin increasing more than 5-fold. Simcyp simulation predicted that PRN would cause 1.71- and 2.12-fold increases in the phenacetin AUC in healthy volunteers and smokers, respectively. IPRN, on the other hand, would result in 3.24- and 5.01-fold increases in phenacetin AUCs in healthy volunteers and smokers, respectively. These findings represent the first detailed report comparing the potential drug-drug interactions of PRN and IPRN, and provide useful information for balancing safe and efficacious doses of PRN and IPRN. PMID:23975028

  15. Confidence in the face of risk: the Risk Assessment and Management Self-Efficacy Study (RAMSES)

    PubMed Central

    Delgadillo, Jaime; Moreea, Omar; Outhwaite-Luke, Hannah; Dace, Toby; Nicholls, Brenda; Ramseyer, Georgina; Dale, Veronica

    2014-01-01

    Aims and method To evaluate a comprehensive risk management programme. A Risk Assessment and Management Self-Efficacy Scale (RAMSES) was used to evaluate the impact of a clinical guideline and training course. Fifty-three psychological therapists were randomly allocated to training v. waiting list in a controlled, delayed-intervention design. Differences in mean self-efficacy scores between groups were examined using analysis of covariance (ANCOVA). Results The RAMSES measure had adequate factor structure, internal consistency and construct validity. When adjusting for baseline scores and cluster design, the group exposed to training had a higher mean self-efficacy score than controls. Mean differences between groups were not significant after the control group received training, nor at 6 months’ follow-up. Clinical implications Exposure to training and clinical guidelines can improve self-efficacy in risk assessment and management. An important advance put forward by this study is the specification of areas of competence in risk assessment and management, which can be measured using a psychometrically sound tool. PMID:25237500

  16. Antidepressant efficacy of agomelatine: meta-analysis of published and unpublished studies

    PubMed Central

    2014-01-01

    Objective To systematically review published and unpublished efficacy studies of agomelatine in people with depression. Design Systematic review and meta-analysis. Data sources Literature search (Pubmed, Embase, Medline), Cochrane Central Register of Controlled Trials, European Medicines Agency (EMA) regulatory file for agomelatine, manufacturers of agomelatine (Servier). Eligibility criteria Double blind randomised placebo and comparator controlled trials of agomelatine in depression with standard depression rating scales. Data synthesis Studies were pooled by using a random effects model with DerSimonian and Laird weights for comparisons with placebo and comparator antidepressant. The primary efficacy measure (change in rating scale score) was summarised with standardised mean difference (SMD; a measure of effect size) and secondary outcome measures with relative risks. All results were presented with 95% confidence intervals. Statistical heterogeneity was explored by visual inspection of funnel plots and by the I2 statistic. Moderators of effect were explored by meta-regression. Results We identified 20 trials with 7460 participants meeting inclusion criteria (11 in the published literature, four from the European Medicines Agency file, and five from the manufacturer). Almost all studies used the 17 item Hamilton depression rating scale (score 0-50). Agomelatine was significantly more effective than placebo with an effect size (SMD) of 0.24 (95% confidence interval 0.12 to 0.35) and relative risk of response 1.25 (1.11 to 1.4). Compared with other antidepressants, agomelatine showed equal efficacy (SMD 0.00, ?0.09 to 0.10). Significant heterogeneity was uncovered in most analyses, though risk of bias was low. Published studies were more likely than unpublished studies to have results that suggested advantages for agomelatine. Conclusions Agomelatine is an effective antidepressant with similar efficacy to standard antidepressants. Published trials generally had more favourable results than unpublished studies. PMID:24647162

  17. A Cross-National Comparison Study on the Accuracy of Self-Efficacy Beliefs of Middle-School Mathematics Students

    ERIC Educational Resources Information Center

    Chen, Peggy; Zimmerman, Barry

    2007-01-01

    In this cross-national study, the authors compared mathematics self-efficacy beliefs of American (n = 107) and Taiwanese (n = 188) middle-school students for level and calibration (accuracy and bias). Taiwanese students surpassed Americans in math achievement. American students evidenced slightly higher self-efficacy levels for easy math items but…

  18. Exploring the Influence of Teacher Collaboration on Teacher Self-Efficacy: A Single Case Study of a Charter High School

    ERIC Educational Resources Information Center

    McGuire, Brian David

    2011-01-01

    Teachers who work in isolation may experience low self-efficacy. Research shows an association between high self-efficacy and positive outcomes for teachers, such as teacher longevity and higher instructional effectiveness. While some studies have suggested that a collaborative teaching environment can decrease teacher attrition and increase…

  19. Efficacy of Atomoxetine in Children with Severe Autistic Disorders and Symptoms of ADHD: An Open-Label Study

    ERIC Educational Resources Information Center

    Charnsil, Chawanun

    2011-01-01

    Objective: This study aims to examine the efficacy of atomoxetine in treating symptoms of attention deficit hyperactivity disorder (ADHD) in children with severe autistic disorder. Method: Children with severe autistic disorder who had symptoms of ADHD were given atomoxetine for 10 weeks. The efficacy of atomoxetine was evaluated by using the…

  20. An Integrative Review of Early Intervention Efficacy Studies with At-Risk Children: Implications for the Handicapped.

    ERIC Educational Resources Information Center

    White, Karl; Casto, Glendon

    1985-01-01

    Results of 162 early intervention efficacy studies with disadvantaged, at-risk, and handicapped children were analyzed to draw conclusions about efficacy of early intervention, identify variables which covary with effectiveness, and identify areas for future reseach. It is concluded that early intervention has substantial immediate benefits for…

  1. A Study of Factors That Contribute to Pre-Service Teachers' Sense of Efficacy for Literacy Instruction

    ERIC Educational Resources Information Center

    Martin, Charlene

    2012-01-01

    The three-fold purpose of this mixed methods study was to (a) analyze how preservice teachers' perceptions of teacher preparation program variables affect preservice teachers self-efficacy for literacy instruction, (b) determine how preservice teachers describe their teacher preparation program with regard to self-efficacy beliefs for…

  2. Efficacy, safety, and clinical outcomes of endoscopic mucosal resection: A study of 101 cases

    Microsoft Academic Search

    Nuzhat A. Ahmad; Michael L. Kochman; William B. Long; Emma E. Furth; Gregory G. Ginsberg

    2002-01-01

    Background: Endoscopic mucosal resection (EMR) is an alternative to surgery for removal of superficial neoplastic lesions of the GI tract. The aim of this study was to assess the safety, efficacy, and clinical outcomes of EMR. Methods: Data from consecutive EMR procedures performed by using suction cap-assisted and\\/or saline solution-assisted snare resection techniques over a 45-month period were reviewed retrospectively.

  3. Cationic liposomes as carriers for aerosolized formulations of an anionic drug: Safety and efficacy study

    Microsoft Academic Search

    Shuhua Bai; Vivek Gupta; Fakhrul Ahsan

    2009-01-01

    This study tests the hypothesis that pegylated cationic liposomes are a viable carrier for inhalable formulations of low molecular weight heparin, an anionic drug. Cationic liposomal formulations of low molecular weight heparin were prepared by the hydration method using 1,2-dioleoyl-3-trimethylammonium-propane (chloride salt), cholesterol and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol)-2000]. The formulations were characterized for particle size, entrapment efficiency, pulmonary absorption and pharmacological efficacy. For

  4. Multicriteria Optimization Model for the Study of the Efficacy of Skin Antiaging Therapy

    PubMed Central

    Cri?an, Maria; Cappare, Guido; Neam?iu, Luciana; Chiorean, Ioana; Lup?a, Liana; Cri?an, Diana; Badea, Radu

    2012-01-01

    The evolution of the cutaneous structure after topical treatment with P63 antiaging complex, assessed with high frequency ultrasound, is studied by means of multicriteria optimization model. Due to the fact that the impact of the treatment may influence the quality of life, a medical index which measures, from this point of view, the efficacy of the treatment is given, also taking into account medical and economical aspects. PMID:22481971

  5. A study on the therapeutic efficacy of Cassia alata, Linn. leaf extract against Pityriasis versicolor.

    PubMed

    Damodaran, S; Venkataraman, S

    1994-03-01

    The therapeutic efficacy of Cassia alata leaf extract against Pityriasis versicolor has been reported for the first time involving humans. For the collection of clinically effective antifungal compounds from the leaves of Cassia alata, a simple procedure has been devised. A 10-year human study indicates that the leaf extract can be reliably used as a herbal medicine to treat Pityriasis versicolor. The leaf extract has no side-effects. PMID:8046939

  6. Comparative study of the efficacy of dipyrone, diclofenac sodium and pethidine in acute renal colic

    Microsoft Academic Search

    F. Garc?a-Alonso; Direccidn General de Farmacia; Horga J. E

    1991-01-01

    A randomized, double-blind, multicentre clinical trial was designed to compared the analgesic efficacy of i.m. dipyrone 1 and 2 g, i.m. diclofenac sodium and i.m. pethidine in acute renal colic. The study was carried out in 451 patients in 13 Spanish hospitals. Ureteric colic was diagnosed by the clinical features, urinalysis, or when the presence of a ureteric calculus was

  7. Overall efficacy and safety results of sofosbuvir-based therapies in phase II and III studies.

    PubMed

    Mangia, Alessandra; Piazzolla, Valeria

    2014-12-15

    The uridine nucleotide analogue sofosbuvir is a selective hepatitis C virus NS5B polymerase inhibitor, active regardless of genotype. We analyzed data on efficacy and safety of sofosbuvir, either in combination with pegylated interferon alfa-2a and ribavirin, or in combination with ribavirin alone as part of an interferon free regimen in more than 1300 patients. Treatment with sofosbuvir for 12 weeks in combination with P/R, in naïve genotype 1 patients was mainly studied in Neutrino. The efficacy of sofosbuvir as part of an all-oral combination including ribavirin alone, was explored in 555 naïve, ineligible and previous treatment failure genotype 2/3 patients. Rates of Sustained Viral Response in genotype 1 and 2 were higher than 85%. For genotype 3 and 4, a European study, Valence, and a US study on patients of Egyptian origin showed that naïve patients are cured at high rates by the all-oral combination given for 24 weeks. The efficacy of sofosbuvir plus P/R for 12 weeks in previous treatment failure genotype 3 has also been demonstrated. Sofosbuvir-based combinations are safe and well tolerated without side effects directly related to the drug. A large body of evidence suggests that sofosbuvir marks a revolution in HCV treatment. PMID:25458780

  8. EFFICACY OF AYURVEDIC HEALTH CARE SYSTEM: A STUDY IN A COMMUNITY

    PubMed Central

    Nagaraju, V.; Sriram, P.

    1990-01-01

    This study is aimed at evaluating the efficacy of the Ayurvedic system, especially for chronic diseases. Assessment of the subjective relief feed back was done on the lines as suggested in Caraka Samhita, one of the oldest classical Ayurvedic texts. An inter-disciplinary research work involving ancient medical learning and hi-tech modern electronic data processing unit evaluate the efficacy of the Ayurvedic treatment in a closed community. 80 percent of the respondents were in the relief range of 75% to 100%, while overall relief in terms of regaining positive health in addition to attending complaint relief is over 70% in all diseases groups, as reported by the respondents in this Programme. PMID:22556503

  9. Older Adult Self-Efficacy Study of Mobile Phone Diabetes Management.

    PubMed

    Quinn, Charlene C; Khokhar, Bilal; Weed, Kelly; Barr, Erik; Gruber-Baldini, Ann L

    2015-07-01

    The purpose of this study was to evaluate participant self-efficacy and use of a mobile phone diabetes health intervention for older adults during a 4-week period. Participants included seven adults (mean age, 70.3 years) with type 2 diabetes cared for by community-based primary care physicians. Participants entered blood glucose data into a mobile phone and personalized patient Internet Web portal. Based on blood glucose values, participants received automatic messages and educational information to self-manage their diabetes. Study measures included prior mobile phone/Internet use, the Stanford Self-Efficacy for Diabetes Scale, the Stanford Energy/Fatigue Scale, the Short Form-36, the Patient Health Questionnaire-9 (depression), the Patient Reported Diabetes Symptom Scale, the Diabetes Stages of Change measure, and a summary of mobile system use. Participants had high self-efficacy and high readiness and confidence in their ability to monitor changes to control their diabetes. Participants demonstrated ability to use the mobile intervention and communicate with diabetes educators. PMID:25692373

  10. Efficacy and safety of Ascoril in the management of cough--National Study Group report.

    PubMed

    Ainapure, S S; Desai, A; Korde, K

    2001-02-01

    A total of 768 patients were recruited by 81 physicians and paediatricians all over the country in this National Study Group of 'Ascoril + Expectorant'. The results of this first large scale study of a cough formula indicates that 'Ascoril + Expectorant' is effective in controlling cough, breathlessness and decreasing the volume of sputum. No serious adverse events were noted. Ascoril was well accepted by the patients and its efficacy was rated very high by the physician. The National Study Group concludes that 'Ascoril + Expectorant' is highly effective in the management of cough associated with lower respiratory tract infection and COPDs. PMID:11482804

  11. Association of Brain-Derived Neurotrophic Factor Genetic Val66Met Polymorphism with Severity of Depression, Efficacy of Fluoxetine and Its Side Effects in Chinese Major Depressive Patients

    Microsoft Academic Search

    Yan-Feng Zou; Yu Wang; Ping Liu; Xiao-Liang Feng; Bin-Yan Wang; Tong-Hua Zang; Xin Yu; Jing Wei; Zhong-Chun Liu; Ying Liu; Ming Tao; Hui-Chun Li; Ke-Qing Li; Jian Hu; Ming Li; Ke-Rang Zhang; Dong-Qing Ye; Xi-Ping Xu

    2010-01-01

    Background: Preclinical studies have shown that brain-derived neurotrophic factor (BDNF) may be involved in antidepressant action, and the BDNF gene has been suggested to be involved in the pharmacological treatment of major depressive disorder (MDD). In this study, the relationship between BDNF Val66Met polymorphism (Single Nucleotide Polymorphism Database ID: rs6265) and severity of depression, efficacy of fluoxetine and its side

  12. Serving billions: a pilot study on clinician-perceived efficacy of rehabilitative services in China.

    PubMed

    Zhao, Mei; Haley, D Rob; Nolin, JoAnn M; Dunning, Kerry; Wang, Jian; Sun, Qiangsan

    2008-01-01

    China has the world's largest number of disabled people, and this number is projected to grow. Although there is ample literature on the utilization and efficacy of Western medicine as it pertains to rehabilitation services, there is far less research on the perceived efficacy of traditional Chinese medicine (TCM). A structured questionnaire was designed for a pilot study on TCM and Western medicine used for rehabilitation services in China, their associated charges, and perceived efficacy. A sample of 33 clinicians responded to the questionnaire. The analysis found that clinicians most frequently prescribed Fenbid and Chinese herbs to treat rehabilitation morbidities, and the most common TCM treatments were acupuncture and massage therapy. The average patient charge for each visit for TCM therapy varied from 56 Yuan (dollars 7.30) for Chinese herbal medicine to 12 Yuan (dollars 1.60) for cupping therapy. The most frequently prescribed Western therapies were occupational, physical, and speech. The average charge for each visit for Western medicine varied from 111 Yuan (dollars 14.60) for physical therapy to 48 Yuan (dollars 6.30) occupational therapy. Clinicians indicated that acupuncture, Chinese herbal medicine, massage, speech, occupational, and physical therapies were "effective" or "highly effective" in treating morbidities requiring rehabilitation services. PMID:18695405

  13. An efficacy study of 3 commercially available hydroquinone 4% treatments for melasma.

    PubMed

    Grimes, Pearl E

    2007-12-01

    Melasma is a common disorder of hyperpigmentation typically characterized by relatively symmetric brown or gray-brown patches on sun-exposed facial areas. Treating melasma is challenging because of the prolonged time to response and the substantial relapse rate when therapy is discontinued. The objective of this 12-week study was to compare the clinical efficacy and tolerability of 3 hydroquinone 4%-containing creams in the treatment of melasma. The 3 creams were cream A (microencapsulated hydroquinone 4% and retinol 0.15% with antioxidants); cream B (hydroquinone 4% and retinol 0.3% with antioxidants); and cream C (fluocinolone acetonide 0.01%, hydroquinone 4%, and tretinoin 0.05%). This 2-arm, split-face, right-left bilateral, evaluator-blinded study compared cream A and cream B in treatment arm 1, and cream A and cream C in treatment arm 2. Evaluator-blinded study assessments were conducted at baseline and weeks 4, 8, and 12. Results from treatment arm 1 demonstrated that at weeks 8 and 12, treatment with cream A showed statistically significant improvements over cream B in the efficacy assessments of overall disease severity (week 8, P=.005; week 12, P=.028), lesion area (week 8, P=.005; week 12, P=.003), pigmentation intensity (week 8, P=.012; week 12, P=.012), and Melasma Area and Severity Index (MASI) score (week 8, P= .002; week 12, P= .012). Results from treatment arm 2 demonstrated that at weeks 4 and 8, treatment with cream A was similar to cream C in the efficacy assessments of overall disease severity, lesion area, pigmentation intensity, MASI score, and global evaluation of response to treatment. At week 12, cream A continued to demonstrate sustained improvements in each of the above efficacy assessments; however, cream C showed a decrease in improvement of these efficacy assessments because subjects were switched to placebo for the last 4 weeks of treatment. All 3 treatments were well-tolerated. These data confirm previous findings that the unique delivery system of microencapsulated hydroquinone 4% and retinol 0.15% with antioxidants is safe and effective for use in treating melasma, and the data show that this novel nonsteroidal product should be considered when weighing long-term treatment options. PMID:18246882

  14. Influence from genetic variability on opioid use for cancer pain: A European genetic association study of 2294 cancer pain patients

    Microsoft Academic Search

    P. Klepstad; T. Fladvad; F. Skorpen; K. Bjordal; A. Caraceni; O. Dale; A. Davies; M. Kloke; S. Lundström; M. Maltoni; L. Radbruch; R. Sabatowski; V. Sigurdardottir; F. Strasser; P. M. Fayers; S. Kaasa

    2011-01-01

    Cancer pain patients need variable opioid doses. Preclinical and clinical studies suggest that opioid efficacy is related to genetic variability. However, the studies have small samples, findings are not replicated, and several candidate genes have not been studied. Therefore, a study of genetic variability with opioid doses in a large population using a confirmatory validation population was warranted. We recruited

  15. TOPIRAMATE IN THE NEW GENERATION OF DRUGS: EFFICACY IN THE TREATMENT OF ALCOHOLIC PATIENTS

    PubMed Central

    Johnson, Bankole A.; Ait-Daoud, Nassima

    2011-01-01

    Predicated upon a neuropharmacological conceptual model, there is now solid clinical evidence to support the efficacy of topiramate for the treatment of alcohol dependence. Topiramate treatment can be initiated whilst the alcohol-dependent individual is still drinking — just when crisis intervention is most likely to be needed by a patient with or without his or her family asking the health practitioner for assistance. Because topiramate can be paired with a brief intervention, there is now the exciting possibility of treating most alcohol-dependent individuals in office-based practice or generic treatment settings. Topiramate's additional effects on other impulse-dyscontrol disorders make it a particularly interesting compound for the treatment of other comorbid drug or psychiatric disorders. Additionally, future studies should explore whether topiramate can be combined with other putative therapeutic agents to increase its efficacy. One notable clinical challenge in the development of topiramate as a pharmacotherapy to treat alcohol dependence is the determination of the smallest dose that can result in efficacy, thereby achieving the optimum balance between therapeutic benefit and adverse event profile. Animal data do provide support for topiramate's general anti-drinking effects but also indicate that its mechanisms of action might rely on several complex pharmacobehavioral changes. Additional preclinical studies are needed to elucidate more clearly the basic mechanistic processes that underlie topiramate's efficacy as a treatment for alcohol dependence. Preclinical information that topiramate may have differential effects based on genetic vulnerability opens up the possibility of future methods to optimize treatment. PMID:20482511

  16. Photoacoustic tomography of vascular therapy in a preclinical mouse model of colorectal carcinoma

    NASA Astrophysics Data System (ADS)

    Johnson, S. P.; Ogunlade, O.; Zhang, E.; Laufer, J.; Rajkumar, V.; Pedley, R. B.; Beard, P.

    2014-03-01

    Vascular therapy in oncology exploits the differences between normal blood vessels and abnormal tumour neoangiogenesis to selectively target cancer. For optimal treatment efficacy, and translation of novel compounds, the response of the tumour vasculature needs to be assessed. Photoacoustic tomography (PAT) is capable of this as it provides highly spatially resolved 3D images of vascular networks in biological tissue to cm depths. In preclinical models of cancer this is sufficient to encompass entire subcutaneous tumours, and can therefore be used to evaluate pharmacological intervention directed at the vasculature. In this study the vascular disrupting agent OXi4503 was used to treat subcutaneous tumour mouse models of two human colorectal carcinoma tumour types (SW1222, LS174T) at a range of concentrations (40mg/kg, 10mg/kg, 1mg/kg and sham dose control). The characteristic destruction of tumour vasculature caused by OXi4503 was observed by PAT and confirmed ex vivo via histology. Differences observed between the two tumour types assessed demonstrate the importance of tumour microenvironment and pathophysiology on response to therapy. Differential response to different doses of OXi4503 was observed, with outward tumour growth only seen once entire tumour viability had been re-established; this demonstrates the potential of PAT to act as a biomarker of response for the translation of novel anti-vascular compounds and also within the clinic. This study shows clearly that PAT can accurately assess the time course of drug action and relapse of pharmacodynamic effect in preclinical models of cancer and the important translational prospects for vascular targeted tumour therapies.

  17. Towards combinatorial targeted therapy in melanoma: From pre-clinical evidence to clinical application (Review)

    PubMed Central

    GRAZIA, GIULIA; PENNA, ILARIA; PEROTTI, VALENTINA; ANICHINI, ANDREA; TASSI, ELENA

    2014-01-01

    Over the last few years, clinical trials with BRAF and mitogen-activated protein/extracellular signal-regulated kinase (MEK) inhibitors have shown significant clinical activity in melanoma, but only a fraction of patients respond to these therapies, and development of resistance is frequent. This has prompted a large set of preclinical studies looking at several new combinatorial approaches of pathway- or target-specific inhibitors. At least five main drug association strategies have been verified in vitro and in preclinical models. The most promising include: i) vertical targeting of either MEK or phosphoinositide-3 kinase (PI3K)/mammalian target of rapamycin (mTOR) pathways, or their combined blockade; ii) association of receptor tyrosine kinases (RTKs) inhibitors with other pro-apoptotic strategies; iii) engagement of death receptors in combination with MEK-, mTOR/PI3K-, histone deacetylase (HDAC)-inhibitors, or with anti-apoptotic molecules modulators; iv) strategies aimed at blocking anti-apoptotic proteins belonging to B-cell lymphoma (Bcl-2) or inhibitors of apoptosis (IAP) families associated with MEK/BRAF/p38 inhibition; v) co-inhibition of other molecules important for survival [proteasome, HDAC and Signal transducers and activators of transcription (Stat)3] and the major pathways activated in melanoma; vi) simultaneous targeting of multiple anti-apoptotic molecules. Here we review the anti-melanoma efficacy and mechanism of action of the above-mentioned combinatorial strategies, together with the potential clinical application of the most promising studies that may eventually lead to therapeutic benefit. PMID:24920406

  18. 21 CFR 310.6 - Applicability of “new drug” or safety or effectiveness findings in drug efficacy study...

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    21 Food and Drugs 5 2011-04-01 2011-04-01...drugâ or safety or effectiveness findings in drug efficacy study implementation notices...hearing to identical, related, and similar drug products. 310.6 Section...

  19. 21 CFR 310.6 - Applicability of “new drug” or safety or effectiveness findings in drug efficacy study...

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    21 Food and Drugs 5 2012-04-01 2012-04-01...drugâ or safety or effectiveness findings in drug efficacy study implementation notices...hearing to identical, related, and similar drug products. 310.6 Section...

  20. 21 CFR 310.6 - Applicability of “new drug” or safety or effectiveness findings in drug efficacy study...

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    21 Food and Drugs 5 2010-04-01 2010-04-01...drugâ or safety or effectiveness findings in drug efficacy study implementation notices...hearing to identical, related, and similar drug products. 310.6 Section...

  1. 21 CFR 310.6 - Applicability of “new drug” or safety or effectiveness findings in drug efficacy study...

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    21 Food and Drugs 5 2014-04-01 2014-04-01...drugâ or safety or effectiveness findings in drug efficacy study implementation notices...hearing to identical, related, and similar drug products. 310.6 Section...

  2. 21 CFR 310.6 - Applicability of “new drug” or safety or effectiveness findings in drug efficacy study...

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    21 Food and Drugs 5 2013-04-01 2013-04-01...drugâ or safety or effectiveness findings in drug efficacy study implementation notices...hearing to identical, related, and similar drug products. 310.6 Section...

  3. Self-Efficacy Beliefs and Self-Regulated Learning Strategies in Learning English as a Second Language: Four Case Studies

    Microsoft Academic Search

    CHUANG WANG; STEPHEN J. PAPE

    2004-01-01

    n These case studies provide a description of 4 fifth-graders' self- efficacy beliefs and use of self-regulated learning strategies related to studying English as a second language. Structured interviews with the children and their parents were conducted to investigate the family context of learning English and to elicit children's self- reported self-efficacy beliefs and self-regulated learning (SRL) strategies. In addition,

  4. Protective Vaccination against Papillomavirus-Induced Skin Tumors under Immunocompetent and Immunosuppressive Conditions: A Preclinical Study Using a Natural Outbred Animal Model

    PubMed Central

    Vinzón, Sabrina E.; Braspenning-Wesch, Ilona; Müller, Martin; Geissler, Edward K.; Nindl, Ingo; Gröne, Hermann-Josef

    2014-01-01

    Certain cutaneous human papillomaviruses (HPVs), which are ubiquitous and acquired early during childhood, can cause a variety of skin tumors and are likely involved in the development of non-melanoma skin cancer, especially in immunosuppressed patients. Hence, the burden of these clinical manifestations demands for a prophylactic approach. To evaluate whether protective efficacy of a vaccine is potentially translatable to patients, we used the rodent Mastomys coucha that is naturally infected with Mastomys natalensis papillomavirus (MnPV). This skin type papillomavirus induces not only benign skin tumours, such as papillomas and keratoacanthomas, but also squamous cell carcinomas, thereby allowing a straightforward read-out for successful vaccination in a small immunocompetent laboratory animal. Here, we examined the efficacy of a virus-like particle (VLP)-based vaccine on either previously or newly established infections. VLPs raise a strong and long-lasting neutralizing antibody response that confers protection even under systemic long-term cyclosporine A treatment. Remarkably, the vaccine completely prevents the appearance of benign as well as malignant skin tumors. Protection involves the maintenance of a low viral load in the skin by an antibody-dependent prevention of virus spread. Our results provide first evidence that VLPs elicit an effective immune response in the skin under immunocompetent and immunosuppressed conditions in an outbred animal model, irrespective of the infection status at the time of vaccination. These findings provide the basis for the clinical development of potent vaccination strategies against cutaneous HPV infections and HPV-induced tumors, especially in patients awaiting organ transplantation. PMID:24586150

  5. Immunobiology of human mucin 1 in a preclinical ovarian tumor model

    PubMed Central

    Budiu, RA; Elishaev, E; Brozick, J; Lee, M; Edwards, RP; Kalinski, P; Vlad, AM

    2014-01-01

    Epithelial ovarian cancer is an aggressive malignancy, with a low 5-year median survival. Continued improvement on the development of more effective therapies depends in part on the availability of adequate preclinical models for in vivo testing of treatment efficacy. Mucin 1 (MUC1) glycoprotein is a tumor-associated antigen overexpressed in ovarian cancer cells, making it a potential target for immune therapy. To create a preclinical mouse model for MUC1-positive ovarian tumors, we generated triple transgenic (Tg) mice that heterozygously express human MUC1+/? as a transgene, and carry the conditional K-rasG12D oncoallele (loxP-Stop-loxP-K-rasG12D/+) and the floxed Pten gene (Pten/loxP/loxP). Injection of Cre recombinase-encoding adenovirus (AdCre) in the ovarian bursa of triple (MUC1KrasPten) Tg mice triggers ovarian tumors that, in analogy to human ovarian cancer, express strongly elevated MUC1 levels. The tumors metastasize loco-regionally and are accompanied by high serum MUC1, closely mimicking the human disease. Compared with the KrasPten mice with tumors, the MUC1KrasPten mice show increased loco-regional metastasis and augmented accumulation of CD4+Foxp3+ immune-suppressive regulatory T cells. Vaccination of MUC1KrasPten mice with type 1 polarized dendritic cells (DC1) loaded with a MUC1 peptide (DC1–MUC1) can circumvent tumor-mediated immune suppression in the host, activate multiple immune effector genes and effectively prolong survival. Our studies report the first human MUC1-expressing, orthotopic ovarian tumor model, reveal novel MUC1 functions in ovarian cancer biology and demonstrate its suitability as a target for immune-based therapies. PMID:22964632

  6. A prospective study to assess the efficacy and patient tolerance of three bowel preparations for colonoscopy.

    PubMed

    Rapier, Roderick; Houston, Carmela

    2006-01-01

    The adherence to the required clear liquid diet and a high-volume bowel cleansing solution prior to colonoscopy often leads to poor patient compliance and inadequate exams. This study evaluated the efficacy and patient tolerance of three bowel preparation regimens prior to colonoscopy. One hundred fourteen patients were randomized to one of three preparations. Group 1 was assigned a clear liquid diet/magnesium citrate and bisacodyl prep; group 2 was assigned to receive a diet kit/magnesium citrate and bisacodyl prep; and group 3 received a diet kit/polyethylene glycol electrolyte prep. The adequacy of bowel preparation was graded by the endoscopists performing the procedures. The preparations were rated by patients for tolerance, compliance, and side effects. The three methods of preparation did not prove to be significantly different in regards to efficacy of colon cleansing or patient tolerability. There was also no difference in compliance between the three regimens. There were no reported side effects in any of the study groups. This study suggests that a low-residue diet kit, given in conjunction with polyethylene glycol electrolyte or magnesium citrate and bisacodyl, produces adequate colon cleansing and patient tolerability. PMID:16974167

  7. Methods of monitoring menstrual function in field studies: efficacy of methods.

    PubMed

    Kesner, J S; Wright, D M; Schrader, S M; Chin, N W; Krieg, E F

    1992-01-01

    Efficacy of methods for monitoring female reproductive potential under field study conditions was evaluated. Women (n = 10) were recruited to participate for two menstrual cycles on the bases, in part, of not seeking fertility assistance, working full-time but not in the medical field, and having less than one year of college education. Luteinizing hormone (LH), estrone-3-glucuronide, and pregnanediol-3-glucuronide were measured in daily morning urine and normalized to creatinine concentrations. These urinary measures were parallel to serum LH, estradiol, and progesterone profiles. Based on these urinary measures, 6 of 19 cycles were judged to be atypical. Transvaginal ultrasonography provided insights into ovarian activity during the atypical cycles. Of 13 LH surges detected by radioimmunoassay, 7 were not detected by a semiquantitative dipstick (OvuSTICK), perhaps due to that method's sensitivity to loss of LH immunoactivity caused by sample freezing. While intervals from salivary and vaginal mucous electrical resistance signals to the LH surge during typical cycles were similar to those reported previously, they were not predictive of ovulatory status during atypical cycles. Fifty-three percent of the cycles were misclassified on the basis of the basal body temperature rise. Cervical mucous color, amount, and consistency were not predictive of ovulation under these study conditions. The results from these 19 menstrual cycles provide information about the efficacy of various methods for characterizing menstrual function under field study conditions. In this regard, urinary endocrine measures are the most informative or practical. PMID:1463919

  8. A Cross-National Comparison Study on the Accuracy of Self-Efficacy Beliefs of Middle-School Mathematics Students

    Microsoft Academic Search

    Peggy Chen; Barry Zimmerman

    2007-01-01

    In this cross-national study, the authors compared mathematics self-efficacy beliefs of American (n = 107) and Taiwanese (n = 188) middle-school students for level and calibration (accuracy and bias). Taiwanese students surpassed Americans in math achievement. American students evidenced slightly higher self-efficacy levels for easy math items but a steeper decline for moderately difficult items than did Taiwanese students. Nationality

  9. Computer Self-Efficacy, Computer Anxiety, and Attitudes toward the Internet: A Study among Undergraduates in Unimas

    Microsoft Academic Search

    Hong Kian Sam; Abang Ekhsan Abang Othman; Zaimuarifuddin Shukri Nordin

    2005-01-01

    Eighty-one female and sixty-seven male undergraduates at a Malaysian university, from seven faculties and a Center for Language Studies completed a Computer Self-Efficacy Scale, Computer Anxiety Scale, and an Attitudes toward the Internet Scale and give information about their use of the Internet. This survey research investigated undergraduates' computer anxiety, computer self-efficacy, and reported use of and attitudes toward the

  10. Efficacy and safety of pitavastatin in Japanese patients with hypercholesterolemia: LIVES study and subanalysis.

    PubMed

    Yokote, Koutaro; Shimano, Hitoshi; Urashima, Mitsuyoshi; Teramoto, Tamio

    2011-05-01

    The Livalo Effectiveness and Safety (LIVES) study was an observational study to examine the efficacy and safety of pitavastatin, a newly developed drug, in approximately 20,000 Japanese patients with hypercholesterolemia. During a 2-year follow-up period, no significant problems concerning safety were observed upon treatment with pitavastatin. Pitavastatin demonstrated potent and stable lowering of the LDL-cholesterol level. The LIVES study subanalyses revealed significant and continuous elevation of HDL-cholesterol in association with pitavastatin treatment and also showed that the drug did not adversely affect glycemic control as evaluated by the glycohemoglobin A(1c) level. Moreover, pitavastatin treatment was associated with an increase in estimated glomerular filtration rate in subjects with chronic kidney disease. These results suggest the usefulness of pitavastatin in hypercholesterolemic patients from various backgrounds. The ongoing LIVES study extension is expected to provide further data on cardiovascular outcome in subjects treated with pitavastatin. PMID:21615316

  11. Pre-Service Elementary Science Teaching Self-Efficacy and Teaching Practices: A Mixed-Methods, Dual-Phase, Embedded Case Study

    ERIC Educational Resources Information Center

    Sangueza, Cheryl Ramirez

    2010-01-01

    This mixed-method, dual-phase, embedded-case study employed the Social Cognitive Theory and the construct of self-efficacy to examine the contributors to science teaching self-efficacy and science teaching practices across different levels of efficacy in six pre-service elementary teachers during their science methods course and student teaching…

  12. Antimicrobial Efficacy of Ten Commercially Available Herbal Dentifrices against Specific Oral Microflora – In Vitro Study

    PubMed Central

    Reddy, Padma; Hemalatha; Reddy, Srikanth; Doshi, Dolar; Kulkarni, Suhas; Kumar, Manoj

    2015-01-01

    Aim: To determine and compare the antimicrobial efficacy of ten commercially available herbal dentifrices against specific strains of oral microflora using a standard diffusion method at full strength and 1:1 dilution at 24 h. Materials and Methods: The standard strains of Streptococcus. mutans (ATCC 21293), Streptococcus sangius (MTCC 442), Actinomyces viscosus (ATCC 3268), Staphylococcus aureus (ATCC 2592), Streptococcus pyogenes (MTCC 442) and Candida albicans (ATCC 183) were obtained. Antimicrobial efficacy of the dentifrices was tested in triplicate, at full strength and 1:1 dilution with the sterile water using a standard diffusion method for 24 h at 37°C. The antimicrobial efficacy was tested by observing the zones of inhibition in millimeters surrounding disk containing the dentifrice. Mean standard deviation and standard error of mean of the inhibitory zones was calculated for each herbal dentifrice. p<0.05 was considered statistically significant. Results: Danth Kanthi (DK) was the most effective against all the microorganisms producing larger zones of inhibition at 24 h (F.S – 40±1.5; 1:1 dilution – 40±2.71). Amar Premium (AP) also produced larger zones of inhibition against all microorganisms except S. aureus. Of all the dentifrices, least zones of inhibitions i.e., around 5 mm was observed against S. aureus by Amar Premium (AP) and Dabur Babool (DB) at 24 h. Conclusion: Based on the results of the present study, it can be concluded that all herbal dentifrices exhibited antimicrobial activity against the selected oral microorganisms, with DK being the most effective. Hence, it can be inferred that herbal dentifrices can also be recommended like the conventional formulations. PMID:26023642

  13. A comparative study to evaluate the efficacy and safety of combination topical preparations in acne vulgaris

    PubMed Central

    Kaur, Jasleen; Sehgal, Vijay K; Gupta, Anita K; Singh, Surinder P

    2015-01-01

    Background: The combinations of topical keratolytics with anti-microbials and topical retinoids with antimicrobials are commonly prescribed in the treatment of acne. Aim: The present study was undertaken with the aim of comparing the efficacy and safety of topical benzoyl peroxide and clindamycin versus topical benzoyl peroxide and nadifloxacin versus topical tretinoin and clindamycin in patients of acne vulgaris. Materials and Methods: 100 patients between 15 and 35 years having ?2 and ?30 inflammatory and/or noninflammatory lesions with Investigator's Global Assessment (IGA) score 2/3 were randomly divided into 3 groups. Group A was prescribed benzoyl peroxide 2.5% gel and clindamycin 1% gel, Group B was prescribed benzoyl peroxide 2.5% gel and nadifloxacin 1% cream and Group C was prescribed tretinoin 0.025% and clindamycin 1% gel. Total number of lesions and adverse effects during the treatment were assessed at 0, 4, 8, 12 weeks with IGA score. Results: There was statistically significant reduction in total number of lesions with better improvement in Group A. Adverse drug reactions during the study showed a better safety profile of Group B which is found to be statistically significant also. Conclusion: These findings confirm that Group A is more efficacious and Group B is safest among the other two groups. PMID:26097817

  14. Efficacy and safety of 1% forskolin eye drops in open angle glaucoma – An open label study

    PubMed Central

    Majeed, Muhammed; Nagabhushanam, Kalyanam; Natarajan, Sankaran; Vaidyanathan, Priti; Karri, Suresh Kumar; Jose, Jyolsna Agnes

    2015-01-01

    Purpose Current treatment for glaucoma includes beta-blockers and prostaglandin analogues which have their own disadvantages. Thus a need exists for new ocular hypotensive agents that are more efficacious and have fewer side effects. Therefore, forskolin eye drops 1%, through herbal product; a clinical trial was carried out for the safety and efficacy in the treatment of open angle glaucoma. Methods Ninety adult male/female patients of 18–60 years of age, of either sex, suffering from open angle glaucoma with an intraocular pressure (IOP) of more than 24 mm Hg were enrolled in the study. Patients were advised to instill 2 drops thrice a day (8:00 h, 14:00 h and 20:00 h) and tonometric readings were recorded on baseline visit and on Visit 2, i.e. end of 1st week, Visit 3–2nd week, Visit 4–3rd week, and Visit 5–4th week. The reduction in IOP across each time point from untreated baseline visit and reduction in IOP across various study visits were measured. Results The mean (95% CI) difference in reduction in IOP was 4.5 mm Hg (P < 0.05) in the right eye and was 5.4 mm Hg (p < 0.05) in the left eye from baseline visit (Visit 1) to final visit (Visit 5). Conclusions Forskolin 1% eye drops can be a safe alternative to beta blockers in glaucoma patients having concomitant asthma. PMID:26155078

  15. Alternatives to Hazard Ratios for Comparing the Efficacy or Safety of Therapies in Noninferiority Studies.

    PubMed

    Uno, Hajime; Wittes, Janet; Fu, Haoda; Solomon, Scott D; Claggett, Brian; Tian, Lu; Cai, Tianxi; Pfeffer, Marc A; Evans, Scott R; Wei, Lee-Jen

    2015-07-21

    A noninferiority study is often used to investigate whether a treatment's efficacy or safety profile is acceptable compared with an alternative therapy regarding the time to a clinical event. The empirical quantification of the treatment difference for such a study is routinely based on the hazard ratio (HR) estimate. The HR, which is not a relative risk, may be difficult to interpret clinically, especially when the underlying proportional hazards assumption is violated. The precision of the HR estimate depends primarily on the number of observed events but not directly on exposure times or sample size of the study population. If the event rate is low, the study may require an impractically large number of events to ensure that the prespecified noninferiority criterion for the HR is attainable. This article discusses deficiencies in the current approach for the design and analysis of a noninferiority study. Alternative procedures are provided, which do not depend on any model assumption, to compare 2 treatments. For a noninferiority safety study, the patients' exposure times are more clinically important than the observed number of events. If the patients' exposure times are long enough to evaluate safety reliably, then these alternative procedures can effectively provide clinically interpretable evidence on safety, even with relatively few observed events. These procedures are illustrated with data from 2 studies. One explores the cardiovascular safety of a pain medicine; the second examines the cardiovascular safety of a new treatment for diabetes. These alternative strategies to evaluate safety or efficacy of an intervention lead to more meaningful interpretations of the analysis results than the conventional strategy that uses the HR estimate. PMID:26054047

  16. Tolerance and efficacy of sodium oxybate in childhood narcolepsy with cataplexy: a retrospective study.

    PubMed

    Lecendreux, Michel; Poli, Francesca; Oudiette, Delphine; Benazzouz, Fatima; Donjacour, Claire E H M; Franceschini, Christian; Finotti, Elena; Pizza, Fabio; Bruni, Oliviero; Plazzi, Giuseppe

    2012-05-01

    Narcolepsy with cataplexy is a sleep disorder characterized by excessive daytime sleepiness, irresistible sleep episodes, and sudden loss of muscle tone (cataplexy) mostly triggered by emotions. Narcolepsy with cataplexy is a disabling lifelong disorder frequently arising during childhood. Pediatric narcolepsy often results in severe learning and social impairment. Improving awareness about this condition increases early diagnosis and may allow patients to rapidly access adequate treatments, including pharmacotherapy and/or non-medication-based approaches. Even though children currently undergo pharmacotherapy, data about safety and efficacy in the pediatric population are scarce. Lacking international guidelines as well as drugs registered for childhood narcolepsy with cataplexy, physicians have no other alternative but to prescribe in an off-label manner medications identical to those recommended for adults. We retrospectively evaluated 27 children ranging from 6 to 16 years old, suffering from narcolepsy with cataplexy, who had been treated with off-label sodium oxybate and had been followed in a clinical setting. Throughout a semi-structured interview, we documented the good efficacy and tolerability of sodium oxybate in the majority of the patients. This study constitutes a preliminary step towards a further randomized controlled trial in childhood narcolepsy with cataplexy. PMID:22547897

  17. Comparative anti-microbial efficacy of Azadirachta indica irrigant with standard endodontic irrigants: A preliminary study

    PubMed Central

    Dutta, Arindam; Kundabala, Mala

    2014-01-01

    Objective: The anti-microbial efficacy of 2.5% sodium hypochlorite (SHC) and 0.2% chlorhexidine gluconate were compared with an experimental irrigant formulated from the Neem tree, Azadirachta indica A. Juss. Materials and Methods: A sample of 36 single rooted anterior teeth with periapical radiolucency and absence of response to vitality tests that required root canal treatment were selected for this study. The test irrigants and their combinations were assigned to five different groups and saline served as the control. Access cavities were prepared using an aseptic technique and samples collected for both anaerobic culture and Gram stained smears, followed by irrigation and sample collection again. The number of organisms were expressed in colony forming units/ml after 72 h of incubation; the smears were analyzed for their microbial loads and tissue clearance and assessed as per defined criteria. Results: Our results found the maximum reduction in microbial loads, when analyzed by culture method, with a combination of SHC and the experimental neem irrigant. Maximum tissue clearance on the Gram Stained smears was also found with the same combination. Conclusion: Neem irrigant has anti-microbial efficacy and can be considered for endodontic use. PMID:24778508

  18. Efficacy of double gloving technique in major and minor oral surgical procedures: A prospective study

    PubMed Central

    Padhye, Mukul N.; Girotra, Charu; Khosla, Aman R.; Gupta, Kavita V.

    2011-01-01

    Background: A prospective analysis was carried out over a 1-year period to assess gloves used during 100 major and 100 minor oral surgical procedures to test for efficacy of double gloving in oral surgical procedures. Purpose: The purpose of this study was to assess the efficacy of double gloving technique in preventing cross infection in both major and minor oral surgical procedures. Materials and Methods: Gloves used during 100 major and 100 minor oral surgical procedures were analyzed to check for glove perforations and skin punctures. 100 sterile gloves were tested as control. Statistical Analysis Used: Chi-square test was used to determine whether there was any difference between the expected and observed values in various categories. Results: A higher number of glove perforations was seen in minor oral surgical procedures compared with major surgeries, dominant hand compared with the nondominant, outer gloves compared with the inner, in procedures which took a longer duration of time to complete, in procedures involving wiring and in the index finger followed by the thumb and the palm. Conclusion: Double gloving technique using sterile gloves can be used as an effective means of infection control for all major and minor surgical procedures, especially high-risk procedures involving patients who maybe suffering from or carriers of blood-borne infections. PMID:23483758

  19. Study on Efficacy of Hepatitis B Immunization in Vaccinated Beta-thalassemia Children in Tehran

    PubMed Central

    Sharifi, Zohreh; Milani, Saeideh; Shooshtari, Mahmood Mahmoodian

    2010-01-01

    Objective In thalassemic children, HBV infection is common, thus immunization against HBV will reduce and prevent the rate of infection. The aim of this study was to evaluate the efficacy of HBV immunization and the prevalence of HBV infection in beta-thalassemic children in Tehran. Methods To assess the efficacy of immunization and determine the immune response of children with beta-thalassemia, sera of 99 children who had received three doses (10/20 µg) of recombinant HBV vaccine in months 0, 1, 6, were selected and tested for HBsAg, HBsAb and anti-HBc by ELISA method. Also, these sera were tested for HBV DNA using nested-PCR method. Findings In 99 beta-thalassemic children, 89 (89.9 %) were anti-HBs positive (responders) and 10 (10.1%) anti-HBs negative (non-responders). 3 (3.03%) were anti-HBc positive and 1(1.01%) was HBsAg positive. HBV DNA was not detected in any of them. Conclusion Our results have revealed that hepatitis B vaccine is highly immunogenic for thalassemic children and particularly well tolerated. PMID:23056706

  20. Contraceptive efficacy and safety studies of a novel microemulsion-based lipophilic vaginal spermicide

    Microsoft Academic Search

    Osmond J D’Cruz; Seang H Yiv; Barbara Waurzyniak; Fatih M Uckun

    2001-01-01

    Objective: To investigate the in vivo contraceptive potency and safety of a novel microemulsion-based lipophilic vaginal spermicide.Design: In vitro and in vivo spermicidal activity and safety of a submicron-particle-size, lipophilic gel–microemulsion (GM-4).Setting: Center for Advanced Preclinical Sciences at the Parker Hughes Institute.Patient(s): Nine male volunteer sperm donors.Intervention(s): Motile human sperm in semen and medium were exposed to eight GM-4 components

  1. Chloroquine efficacy studies confirm drug susceptibility of Plasmodium vivax in Chennai, India

    PubMed Central

    2014-01-01

    Background Assessing the Plasmodium vivax burden in India is complicated by the potential threat of an emerging chloroquine (CQ) resistant parasite population from neighbouring countries in Southeast Asia. Chennai, the capital of Tamil Nadu and an urban setting for P. vivax in southern India, was selected as a sentinel site for investigating CQ efficacy and sensitivity in vivax malaria. Methods CQ efficacy was evaluated with a 28-day in vivo therapeutic study, while CQ sensitivity was measured with an in vitro drug susceptibility assay. In both studies, isolates also underwent molecular genotyping to investigate correlations between parasite diversity and drug susceptibility to CQ. Molecular genotyping included sequencing a 604 base pair (bp) fragment of the P. vivax multidrug resistant gene-1 (Pvmdr1) for single nucleotide polymorphisms (SNPs) and also the amplification of eight microsatellite (MS) loci located across the genome on eight different chromosomes. Results In the 28-day in vivo study (N=125), all subjects were aparasitaemic by Day 14. Passive case surveillance continuing beyond Day 28 in 22 subjects exposed 17 recurrent infections, which ranged from 44 to 148 days post-enrollment. Pvmdr1 sequencing of these recurrent infections revealed that 93.3% had identical mutant haplotypes (958M/Y976/1076L) to their baseline Day 0 infection. MS genotyping further revealed that nine infection pairs were related with ?75% haplotype similarity (same allele at six or more loci). To test the impact of this mutation on CQ efficacy, an in vitro drug assay (N=68) was performed. No correlation between IC50 values and the percentage of ring-stage parasites prior to culture was observed (rsadj: -0.00063, p = 0.3307) and the distribution of alleles among the Pvmdr1 SNPs and MS haplotypes showed no significant associations with IC50 values. Conclusions Plasmodium vivax was found to be susceptible to CQ drug treatment in both the in vivo therapeutic drug study and the in vitro drug assay. Though the mutant 1076L of Pvmdr1 was found in a majority of isolates tested, this single mutation did not associate with CQ resistance. MS haplotypes revealed strong heterogeneity in this population, indicating a low probability of reinfection with highly related haplotypes. PMID:24685286

  2. Efficacy and safety of moxifloxacin in community acquired pneumonia: a prospective, multicenter, observational study (CAPRIVI)

    PubMed Central

    2014-01-01

    Background Community acquired pneumonia (CAP) is a major cause of morbidity, hospitalization, and mortality worldwide. Management of CAP for many patients requires rapid initiation of empirical antibiotic treatment, based on the spectrum of activity of available antimicrobial agents and evidence on local antibiotic resistance. Few data exist on the severity profile and treatment of hospitalized CAP patients in Eastern and Central Europe and the Middle East, in particular on use of moxifloxacin (Avelox®), which is approved in these regions. Methods CAPRIVI (Community Acquired Pneumonia: tReatment wIth AVelox® in hospItalized patients) was a prospective observational study in 12 countries: Croatia, France, Hungary, Kazakhstan, Jordan, Kyrgyzstan, Lebanon, Republic of Moldova, Romania, Russia, Ukraine, and Macedonia. Patients aged >18 years were treated with moxifloxacin 400 mg daily following hospitalization with a CAP diagnosis. In addition to efficacy and safety outcomes, data were collected on patient history and disease severity measured by CRB-65 score. Results 2733 patients were enrolled. A low severity index (i.e., CRB-65 score <2) was reported in 87.5% of CAP patients assessed (n?=?1847), an unexpectedly high proportion for hospitalized patients. Moxifloxacin administered for a mean of 10.0 days (range: 2.0 to 39.0 days) was highly effective: 96.7% of patients in the efficacy population (n?=?2152) improved and 93.2% were cured of infection during the study. Severity of infection changed from “moderate” or “severe” in 91.8% of patients at baseline to “no infection” or “mild” in 95.5% at last visit. In the safety population (n?=?2595), 127 (4.9%) patients had treatment-emergent adverse events (TEAEs) and 40 (1.54%) patients had serious TEAEs; none of these 40 patients died. The safety results were consistent with the known profile of moxifloxacin. Conclusions The efficacy and safety profiles of moxifloxacin at the recommended dose of 400 mg daily are characterized in this large observational study of hospitalized CAP patients from Eastern and Central Europe and the Middle East. The high response rate in this study, which included patients with a range of disease severities, suggests that treatment with broader-spectrum drugs such as moxifloxacin is appropriate for patients with CAP who are managed in hospital. Trial registration ClinicalTrials.gov identifier: NCT00987792 PMID:24975809

  3. Aminopyrazole-Phenylalanine Based GPR142 Agonists: Discovery of Tool Compound and in Vivo Efficacy Studies.

    PubMed

    Yu, Ming; Lizarzaburu, Mike; Motani, Alykhan; Fu, Zice; Du, Xiaohui; Liu, Jiwen Jim; Jiao, Xianyun; Lai, SuJen; Fan, Peter; Fu, Angela; Liu, Qingxiang; Murakoshi, Michiko; Nara, Futoshi; Oda, Kozo; Okuyama, Ryo; Reagan, Jeff D; Watanabe, Nobuaki; Yamazaki, Mami; Xiong, Yumei; Zhang, Ying; Zhuang, Run; Lin, Daniel C-H; Houze, Jonathan B; Medina, Julio C; Li, Leping

    2013-09-12

    Herein, we report the lead optimization of amrinone-phenylalanine based GPR142 agonists. Structure-activity relationship studies led to the discovery of aminopyrazole-phenylalanine carboxylic acid 22, which exhibited good agonistic activity, high target selectivity, desirable pharmacokinetic properties, and no cytochrome P450 or hERG liability. Compound 22, together with its orally bioavailable ethyl ester prodrug 23, were found to be suitable for in vivo proof-of-concept studies. Compound 23 displayed good efficacy in a mouse oral glucose tolerance test (OGTT). Compound 22 showed GPR142 dependent stimulation of insulin secretion in isolated mouse islets and demonstrated a statistically significant glucose lowering effect in a mouse model bearing transplanted human islets. PMID:24900757

  4. Aminopyrazole–Phenylalanine Based GPR142 Agonists: Discovery of Tool Compound and in Vivo Efficacy Studies

    PubMed Central

    2013-01-01

    Herein, we report the lead optimization of amrinone–phenylalanine based GPR142 agonists. Structure–activity relationship studies led to the discovery of aminopyrazole–phenylalanine carboxylic acid 22, which exhibited good agonistic activity, high target selectivity, desirable pharmacokinetic properties, and no cytochrome P450 or hERG liability. Compound 22, together with its orally bioavailable ethyl ester prodrug 23, were found to be suitable for in vivo proof-of-concept studies. Compound 23 displayed good efficacy in a mouse oral glucose tolerance test (OGTT). Compound 22 showed GPR142 dependent stimulation of insulin secretion in isolated mouse islets and demonstrated a statistically significant glucose lowering effect in a mouse model bearing transplanted human islets. PMID:24900757

  5. Molecular imaging coupled to pattern recognition distinguishes response to temozolomide in preclinical glioblastoma.

    PubMed

    Delgado-Goñi, Teresa; Julià-Sapé, Margarida; Candiota, Ana Paula; Pumarola, Martí; Arús, Carles

    2014-11-01

    Non-invasive monitoring of response to treatment of glioblastoma (GB) is nowadays carried out using MRI. MRS and MR spectroscopic imaging (MRSI) constitute promising tools for this undertaking. A temozolomide (TMZ) protocol was optimized for GL261 GB. Sixty-three mice were studied by MRI/MRS/MRSI. The spectroscopic information was used for the classification of control brain and untreated and responding GB, and validated against post-mortem immunostainings in selected animals. A classification system was developed, based on the MRSI-sampled metabolome of normal brain parenchyma, untreated and responding GB, with a 93% accuracy. Classification of an independent test set yielded a balanced error rate of 6% or less. Classifications correlated well both with tumor volume changes detected by MRI after two TMZ cycles and with the histopathological data: a significant decrease (p < 0.05) in the proliferation and mitotic rates and a 4.6-fold increase in the apoptotic rate. A surrogate response biomarker based on the linear combination of 12 spectral features has been found in the MRS/MRSI pattern of treated tumors, allowing the non-invasive classification of growing and responding GL261 GB. The methodology described can be applied to preclinical treatment efficacy studies to test new antitumoral drugs, and begets translational potential for early response detection in clinical studies. PMID:25208348

  6. Imaging technologies for preclinical models of bone and joint disorders

    PubMed Central

    2011-01-01

    Preclinical models for musculoskeletal disorders are critical for understanding the pathogenesis of bone and joint disorders in humans and the development of effective therapies. The assessment of these models primarily relies on morphological analysis which remains time consuming and costly, requiring large numbers of animals to be tested through different stages of the disease. The implementation of preclinical imaging represents a keystone in the refinement of animal models allowing longitudinal studies and enabling a powerful, non-invasive and clinically translatable way for monitoring disease progression in real time. Our aim is to highlight examples that demonstrate the advantages and limitations of different imaging modalities including magnetic resonance imaging (MRI), computed tomography (CT), positron emission tomography (PET), single-photon emission computed tomography (SPECT) and optical imaging. All of which are in current use in preclinical skeletal research. MRI can provide high resolution of soft tissue structures, but imaging requires comparatively long acquisition times; hence, animals require long-term anaesthesia. CT is extensively used in bone and joint disorders providing excellent spatial resolution and good contrast for bone imaging. Despite its excellent structural assessment of mineralized structures, CT does not provide in vivo functional information of ongoing biological processes. Nuclear medicine is a very promising tool for investigating functional and molecular processes in vivo with new tracers becoming available as biomarkers. The combined use of imaging modalities also holds significant potential for the assessment of disease pathogenesis in animal models of musculoskeletal disorders, minimising the use of conventional invasive methods and animal redundancy. PMID:22214535

  7. A long-term efficacy study of gene replacement therapy for RPGR-associated retinal degeneration.

    PubMed

    Wu, Zhijian; Hiriyanna, Suja; Qian, Haohua; Mookherjee, Suddhasil; Campos, Maria M; Gao, Chun; Fariss, Robert; Sieving, Paul A; Li, Tiansen; Colosi, Peter; Swaroop, Anand

    2015-07-15

    Mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene account for >70% of X-linked retinitis pigmentosa (XLRP) and 15-20% of all inherited retinal degeneration. Gene replacement therapy for RPGR-XLRP was hampered by the relatively slow disease progression in mouse models and by difficulties in cloning the full-length RPGR-ORF15 cDNA that includes a purine-rich 3'-coding region; however, its effectiveness has recently been demonstrated in four dogs with RPGR mutations. To advance the therapy to clinical stage, we generated new stable vectors in AAV8 or AAV9 carrying mouse and human full-length RPGR-ORF15-coding sequence and conducted a comprehensive long-term dose-efficacy study in Rpgr-knockout mice. After validating their ability to produce full-length proteins that localize to photoreceptor connecting cilia, we evaluated various vector doses in mice during a 2-year study. We demonstrate that eyes treated with a single injection of mouse or human RPGR-ORF15 vector at an optimal dose maintained the expression of RPGR-ORF15 throughout the study duration and exhibited higher electroretinogram amplitude, thicker photoreceptor layer and better targeting of opsins to outer segments compared with sham-treated eyes. Furthermore, mice that received treatment at an advanced age also showed remarkable preservation of retinal structure and function. Retinal toxicity was observed at high vector doses, highlighting the importance of careful dose optimization in future clinical experiments. Our long-term dose-efficacy study should facilitate the design of human trials with human RPGR-ORF15 vector as a clinical candidate. PMID:25877300

  8. How clinical trials of myasthenia gravis can inform pre-clinical drug development.

    PubMed

    Rostedt Punga, Anna; Kaminski, Henry J; Richman, David P; Benatar, Michael

    2015-08-01

    Pre-clinical evaluations often provide the rationale for therapeutic assessments in humans; however, in many diseases an agent found successful in animal models does not show efficacy in human subjects. Our contention is that the approach of rigorous, clinical trials can be used to inform how preclinical assessments should be performed. Clinical trials in humans are carefully designed investigations executed with consideration of critical methodological issues, such as pre-specified entrance criteria and validated, outcome measures coupled with power analysis to identify sample size. Blinding of evaluators of subjective measures and randomization of subjects are also critical aspects of trial performance. Investigative agents are also tested in subjects with active disease, rather than prior to disease induction as in some pre-clinical assessments. Application of standard procedures, including uniform reporting standards, would likely assist in reproducibility of pre-clinical experiments. Adapting methods of clinical trial performance will likely improve the success rate of therapeutics to ultimately achieve human use. PMID:25592627

  9. Continuous morphine infusion: a retrospective study of efficacy, safety, and demographic variables.

    PubMed

    Reig, Enrique; Abejón, David

    2009-04-01

    Objectives.? This study aims to assess the efficacy of intrathecal infusion in different types of pain. A number of different variables were assessed to analyze their effect on therapy and to determine in which patients intrathecal infusion is more effective. Materials and Methods.? A retrospective study was conducted with data obtained from 1983 to 2002. During this period, 292 intrathecal morphine tests were performed, with positive results in 205 cases. Eight nonprogrammable intrathecal pumps and 205 programmable pumps were implanted. One hundred and thirty-one programmable pumps were studied in which the drug used was morphine alone. Efficacy and side-effects were analyzed in the overall sample, depending on the type of pain, gender, age (20-40, 40-64, > 65), and dose of morphine used (< 2, 2-4.9, 5-14.9, > 15). Results.? All results are expressed as median and interquartile range (p25-p75) because the data had a nonnormal distribution. The patients' mean age was 61 years (range 50-70 years); there were 61 men (46.6%) and 70 women (53.4%). The most commonly reported pain types were cancer pain (64, 48.9%), neuropathic pain (51, 38.9%), and nociceptive pain (16, 12.2%). Test dose used was 0.4 mg/day (0.2-0.7), and mean number of test days was 6 days (range 4-9 days). The initial morphine dose was 0.50 mg (0.30-1.45), mean dose was 2.70 mg (1.25-6.20), and the final dose was 4 mg (0.0-47). The initial numerical rating scale score of 8 (8,9) decreased to 4 (3-8) and 2 (1-5) at the end of the study. The overall rate of complications was 35.35%. Relief was very good in 29 (50.4%), good in 66 (22.1%), fair in 20 (15.3%), and poor in 16 (12.2%) patients. Univariate analysis. (Morphine): Gender: Male 49/58 (84.48%) vs. Female 43/65 (66.15%), RR 1.27 (1.04-1.57), p = 0.02 (chi-squared). No significant differences were found in the other variables studied (age and type of pain). The multivariate analysis (logistic regression analysis) revealed a significant difference with regard to gender, with an odds ratio of 2.78 in favor of male gender. When the efficacy and safety of the infusion was compared to the dose of morphine used, no significant differences were observed, with p = 0.65 for efficacy and p = 0.69 for safety. Conclusions.? Pain relief was obtained with this technique in approximately 70% of patients, with no differences between pain types, but with a significant difference in favor of male gender. PMID:22151285

  10. REFOS study: efficacy and safety of lanthanum carbonate in clinical practice in Spain.

    PubMed

    Torregrosa, José-Vicente; González-Parra, Emilio; González, M Teresa; Cannata-Andía, Jorge

    2014-05-21

    Lanthanum carbonate is a powerful phosphate binder that has shown efficacy and safety in clinical trials for hyperphosphataemia management, although there are few data in regular clinical practice. The study's objective was to evaluate, in regular clinical practice, its efficacy and safety in patients on dialysis. We retrospectively collected data from 15 months of monitoring, corresponding to 3 months prior to the start of treatment with lanthanum carbonate until 12 months after the start. Results included values of serum calcium, phosphorus, alkaline phosphatase, iPTH, hepatic enzymes and haemogram, as well as the daily-prescribed dose of lanthanum carbonate, the concomitant medication, treatment compliance and adverse events. 647 patients were included of which 522 completed the study. Abandonment, for the most part, was due to gastrointestinal disorders (26%) and hypophosphatemia (19%). Serum phosphorus decreased from 6.4±1.7 mg/dl (start) to 4.9±1.4 mg/dl (12 months) (P<.001). At the end of the monitoring period, 47% were within the desired phosphorus range (3.5-5mg/dl). There were no significant variations in the remaining parameters. Initial dose of lanthanum carbonate: 1900 mg/day; and end dose: 2300 mg/day. The variables independently associated with phosphataemia were baseline serum phosphorus and treatment compliance. In relation to safety, we observed 238 slight or moderate adverse effects in 117 patients, with 88% linked to gastrointestinal abnormalities. In conclusion, lanthanum carbonate reduces the serum phosphorus values in patients on dialysis with a good safety profile and acceptable adherence to that profile, with gastrointestinal disorders being the most frequent adverse effect. PMID:24849057

  11. The relationship between language learning strategies, gender, proficiency and self-efficacy beliefs: a study of ELT learners in Turkey

    Microsoft Academic Search

    Cevdet Y?lmaz

    2010-01-01

    The intent of the present study is to investigate the current English language learning strategies employed by English majors enrolled at Çanakkale Onsekiz Mart University in Turkey. The study also aims at exploring the relationship between preferred language strategies, gender, proficiency, and self-efficacy beliefs. For this purpose, a questionnaire was administered to 140 participants in the department of English Language

  12. Efficacy of antivenom against the procoagulant effect of Australian brown snake ( Pseudonaja sp.) venom: In vivo and in vitro studies

    Microsoft Academic Search

    Geoffrey K. Isbister; Margaret A. O’Leary; Jennifer J. Schneider; Simon G. A. Brown; Bart J. Currie

    2007-01-01

    Snake venom induced consumption coagulopathy (VICC) is a common complication of snake bite due to prothrombin activators or thrombin-like enzymes in the venom. This study aimed to determine the efficacy and dose of antivenom for treating VICC in patients envenomed by brown snakes (Pseudonaja spp.), including in vitro coagulation studies. In serial blood samples from patients with brown snake envenoming,

  13. Comparative study of the efficacy of fluconazole versus amphotericin B\\/flucytosine in surgical patients with systemic mycoses

    Microsoft Academic Search

    P. Kujath; C. Boos; K. Lerch; P. Kochendörfer

    1993-01-01

    Summary In an open, prospective, randomized study, the efficacy of fluconazole was compared with that of the combination amphotericin B\\/flucytosine. Forty surgical patients with deep-seated mycoses were included in the study. Absolute inclusion criteria were histological finding of fungi in a tissue sample taken during surgery from e. g. peritoneum, pancreas, lungs or trachea, a positive blood culture or candida

  14. A Comparative Study of Instructional Efficacy between First and Second-Career Teachers in Secondary School Math and Science Courses

    ERIC Educational Resources Information Center

    Gardner, Royal Anthony

    2012-01-01

    Purpose: The purpose of this study was to use Dr. James Stronge's taxonomy of the qualities of effective teachers to determine whether there are significant differences in the instructional efficacy between first- and second-career teachers who teach math and science. Methodology: A causal-comparative study examined the effects of variables…

  15. Efficacy and long-term safety of dexibuprofen [S(+)-ibuprofen]: a short-term efficacy study in patients with osteoarthritis of the hip and a 1-year tolerability study in patients with rheumatic disorders.

    PubMed

    Mayrhofer, F

    2001-11-01

    The efficacy study was performed to prove the equivalent efficacy of dexibuprofen compared to the double dose of racemic ibuprofen and to show a clinical dose-response relationship of dexibuprofen. The 1-year tolerability study was carried out to investigate the tolerability of dexibuprofen. In the efficacy study 178 inpatients with osteoarthritis of the hip were assigned to 600 or 1200 mg of dexibuprofen or 2400 mg of racemic ibuprofen daily. The primary end-point was the improvement of the WOMAC OA index. A 1-year open tolerability study included 223 outpatients pooled from six studies. The main parameter was the incidence of clinical adverse events. In the efficacy study the evaluation of the improvement of the WOMAC OA index showed equivalence of dexibuprofen 400 mg t.i.d. compared to racemic ibuprofen 800 mg t.i.d., with dexibuprofen being borderline superior (P = 0.055). The comparison between the 400 mg t.i.d. and 200 mg t.i.d. doses confirmed a significant superior efficacy of dexibuprofen 400 mg (P = 0.023). In the tolerability study the overall incidence of clinical adverse events was 15.2% (GI tract 11.7%, CNS 1.3%, skin 1.3%, others 0.9%). The active enantiomer dexibuprofen proved to be an effective NSAID with a significant dose-response relationship. Compared to the double dose of racemic ibuprofen, dexibuprofen was at least equally efficient, with borderline superiority over dexibuprofen (P = 0.055). The tolerability study in 223 patients on dexibuprofen showed an incidence of clinical adverse events of 15.2% after 12 months. The results of the studies suggest that dexibuprofen is an effective NSAID with good tolerability. PMID:11771571

  16. Discovery and preclinical studies of 5-isopropyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)- N-(2-methyl-1 H-pyrrolo[2,3- b]pyridin-5-yl)pyrrolo[2,1- f][1,2,4]triazin-4-amine (BMS-645737), an in vivo active potent VEGFR-2 inhibitor

    Microsoft Academic Search

    Réjean Ruel; Carl Thibeault; Alexandre L’Heureux; Alain Martel; Zhen-Wei Cai; Donna Wei; Ligang Qian; Joel C. Barrish; Arvind Mathur; Celia D’Arienzo; John T. Hunt; Amrita Kamath; Punit Marathe; Yueping Zhang; George Derbin; Barri Wautlet; Steven Mortillo; Robert Jeyaseelan; Benjamin Henley; Ravindra Tejwani; Rajeev S. Bhide; George L. Trainor; Joseph Fargnoli; Louis J. Lombardo

    2008-01-01

    We report herein a series of substituted N-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amines as inhibitors of vascular endothelial growth factor receptor-2 tyrosine kinase. Through structure–activity relationship studies, biochemical potency, pharmacokinetics, and kinase selectivity were optimized to afford BMS-645737 (13), a compound with good preclinical in vivo activity against human tumor xenograft models.

  17. Self-Efficacy Perceptions of Prospective Social Studies Teachers in Relation to History Teaching

    ERIC Educational Resources Information Center

    Yilmaz, Ali

    2009-01-01

    Self-efficacy is one of the important concepts of the social cognitive theory, and can be defined as individual's perception of his or her own capabilities for organizing and successfully executing the courses of action required to attain designated types of performance. Teachers with high self-efficacy perception can contribute to creation of a…

  18. A Comparative Study on the Efficacy of Solifenacin Succinate in Patients with Urinary Frequency with or without Urgency

    PubMed Central

    Han, Ji-Yeon; Lee, Kyu-Sung; Park, Won Hee; Park, Choal Hee; Lee, Jeong Gu; Lee, Jeong Zoo; Kim, Duk Yoon; Na, Yong Gil; Kwon, Dong Deuk; Choo, Myung-Soo

    2014-01-01

    Objectives Patients with overactive bladder (OAB) often have trouble perceiving urgency because of difficulties in distinguishing between urgency and desire to void. Empirical antimuscarinic treatment of patients with frequency only may be reasonable if conservative management has failed. We compared the efficacy of solifenacin in patients with frequency with or without urgency. Materials and Methods This multicenter, 12-week, open-label, comparative, non-inferiority clinical trial assessed whether the solifenacin efficacy for frequency without urgency is non-inferior to its efficacy for frequency with urgency. All patients had micturition frequency ?8 voids/day with or without urgency. Primary efficacy variable: daily frequency change at 12 weeks relative to baseline. Secondary efficacy variables: change at 12 weeks relative to baseline in Patients' Perception of Bladder Condition (PPBC), OAB Symptom Score (OABSS), and Benefit, Satisfaction, Willingness to continue (BSW) questionnaire. Results Of the 286 enrolled patients, 240 (83.9%) completed the study (without urgency n?=?115; with urgency n?=?125). Full dataset analysis revealed that the groups without and with urgency exhibited significant reductions in daily micturition frequency of ?2.49±0.35 (mean ± standard error) and ?2.63±0.37, respectively. The lower limit of the 95% two-sided CI of the comparison of the two group means was ?1.14, which is smaller than the ?0.8 margin of clinical equivalence. The two groups did not differ in improvement in PPBC, OABSS, or BSW scores. Both tolerated the treatment well. Conclusions It was not possible to verify that the solifenacin efficacy for frequency alone was non-inferior to its efficacy for OAB. Nevertheless, solifenacin tended to be effective for frequency regardless of urgency. Trial Registration ClinicalTrials.gov NCT00979472 PMID:25401784

  19. A study to test the effectiveness of placebo Reiki standardization procedures developed for a planned Reiki efficacy study.

    PubMed

    Mansour, A A; Beuche, M; Laing, G; Leis, A; Nurse, J

    1999-04-01

    Reiki is one type of alternative therapy that is increasing in popularity. It is advocated by its practitioners as a precise method for connecting universal life energy with the body's innate process of healing through hands-on techniques. The claim of Reiki practitioners is that Reiki reduces a variety of physical problems and improves psychospiritual well-being. There are abundant anecdotal records that support the previous claim, and a few pioneer scientific studies are starting to emerge. Although the Reiki research in totality supports the anecdotal records, the absence of randomized and placebo-controlled trials precludes the interpretation of the outcomes as resulting from specific effects as opposed to placebo effects plus natural history. Authorities in the field indicate that researchers interested in placebo-controlled studies should have the placebo treatment look exactly like the real intervention in every respect. Because no studies could be found in the literature that tested standardization procedures for real and placebo Reiki, the decision was made to conduct one. The purpose of this study was to test the standardization procedures developed by our research team for placebo Reiki, before going ahead and conducting our planned full-scale randomized and placebo-controlled Reiki efficacy study. This study used a 4-round, crossover experimental design in which 20 blinded subjects (12 students, 4 breast cancer survivors, and 4 observers) were exposed to a combination of 2 interventions (Reiki plus Reiki, or placebo plus placebo, or Reiki plus placebo, or placebo plus Reiki); and were then asked to evaluate the interventions using a self-administered questionnaire. The blinded observers were used in round number 4. Two real Reiki practitioners in the Usui system were chosen first, then 2 placebo practitioners who closely resembled them were recruited. The placebo practitioners were trained in Reiki by the study Reiki Master and the principal investigator, but were not initiated. The belief in Reiki is that only practitioners that are initiated could give Reiki, thus making it possible to have a placebo arm in efficacy studies. The findings of the study indicate that the developed standardization procedures were successful because none of the final participants in round 4 (4 breast cancer patients and 4 observers) could differentiate between the identity of placebo and Reiki practitioners. The qualitative comments expressed by the participants further con-firmed the quantitative data. It was concluded based on these findings that it is safe to go ahead and conduct the planned randomized 3-arm Reiki efficacy clinical trial. It is recommended that scholars interested in Reiki research could incorporate our techniques to strengthen their designs by adding a placebo arm. PMID:10328637

  20. Preclinical Assessment of the Anticancer Drug Response of Plexiform Neurofibroma Tissue Using Primary Cultures

    PubMed Central

    Mautner, Victor-F.; Friedrich, Reinhard E.; Kluwe, Lan

    2015-01-01

    Background and Purpose Individualized drug testing for tumors using a strategy analogous to antibiotic tests for infectious diseases would be highly desirable for personalized and individualized cancer care. Methods Primary cultures containing tumor and nontumor stromal cells were utilized in a novel strategy to test drug responses with respect to both efficacy and specificity. The strategy tested in this pilot study was implemented using four primary cultures derived from plexiform neurofibromas. Responses to two cytotoxic drugs (nilotinib and imatinib) were measured by following dose-dependent changes in the proportions of tumor and nontumor cells, determined by staining them with cell-type-specific antibodies. The viability of the cultured cells and the cytotoxic effect of the drugs were also measured using proliferation and cytotoxicity assays. Results The total number of cells decreased after the drug treatment, in accordance with the observed reduction in proliferation and increased cytotoxic effect upon incubation with the two anticancer drugs. The proportions of Schwann cells and fibroblasts changed dose-dependently, although the patterns of change varied between the tumor samples (from different sources) and between the two drugs. The highly variable in vitro drug responses probably reflect the large variations in the responses of tumors to therapies between individual patients in vivo. Conclusions These preliminary results suggest that the concept of assessing in vitro drug responses using primary cultures is feasible, but demands the extensive further development of an application for preclinical drug selection and drug discovery. PMID:25851896

  1. Development of a sensitive LC-MS/MS method for the determination of bilobalide in rat plasma with special consideration of ex vivo bilobalide stability: application to a preclinical pharmacokinetic study.

    PubMed

    Wang, Jie; Ouyang, Jingping; Liu, Youping; Jia, Xian; You, Song; He, Xin; Di, Xin

    2014-07-01

    The ex vivo instability of bilobalide containing three ?-lactone rings has been paid less attention by researchers who developed bioanalytical methods for bilobalide. In the present study, a sensitive LC-MS/MS method for the determination of bilobalide in rat plasma was developed with special consideration of ex vivo bilobalide stability. Several important factors affecting the stability of bilobalide in sampling and handling procedures were investigated. To prevent the ex vivo degradation of bilobalide, EDTA instead of heparin was used as an anticoagulant as well as an esterase inhibitor for blood collection and the separation of plasma was performed at 4 °C. 20 ?L of plasma sample was acidified with 0.1 M hydrochloric acid, and then extracted with ethyl ether-methylene chloride (2:1, v/v). The extract was chromatographed on a Thermo Hypersil GOLD (100 mm × 2.1 mm, 5 ?m) column using acetonitrile-10mM ammonium acetate-formic acid (90:10:0.4, v/v/v) as the mobile phase. The analyte and the internal standard (ginkgolide B) were detected by selected reaction monitoring mode via negative electrospray ionization. The method was fully validated and proved to be linear over a concentration range of 5.0-5000 ng/mL. The intra- and inter-day precisions were less than 5.2% and the accuracy was within 92.5-101%. The extraction recoveries ranged from 80.7% to 86.7%. The proposed method was successfully applied to a preclinical pharmacokinetic study of bilobalide in rats after intragastric administration of a single dose of bilobalide at 7, 14 and 28 mg/kg. PMID:24704454

  2. Bone cement with reduced proportion of monomer in total hip arthroplasty: Preclinical evaluation and randomized study of 47 cases with 5 years' follow-up

    Microsoft Academic Search

    Bo Nivbrant; Johan Kärrholm; Stefan Röhrl; Helén Hassander; Bengt Wesslén

    2001-01-01

    Bone cement with reduced amount of monomer and low curing temperature may improve implant fixation due to reduced toxicity. We analyzed the mechanical, chemical and thermal properties of such a cement (Cemex Rx) using Palacos R as control. The in vivo performance of the 2 cements was also evaluated in a prospective randomized study of 47 hips, where either of

  3. A phase I clinical pharmacologic study of pralatrexate in combination with probenecid in adults with advanced solid tumors

    Microsoft Academic Search

    Matthew G. Fury; Lee M. Krug; Christopher G. Azzoli; Sunil Sharma; Nancy Kemeny; Nian Wu; Mark G. Kris; Naiyer A. Rizvi

    2006-01-01

    Purpose: The antifolate pralatrexate (10-propargyl-10-deazaaminopterin, PDX) demonstrates greater in vitro and in vivo antitumor\\u000a efficacy than methotrexate. Preclinical models indicated that the efficacy of pralatrexate may be enhanced by coadministration\\u000a with probenecid. The aim of this phase I study was to determine the maximum-tolerated dose of pralatrexate when combined with\\u000a probenecid given every 2 weeks in humans. Methods: The starting dose

  4. Preclinical assessment of CNS drug action using eye movements in mice

    PubMed Central

    Cahill, Hugh; Rattner, Amir; Nathans, Jeremy

    2011-01-01

    The drug development process for CNS indications is hampered by a paucity of preclinical tests that accurately predict drug efficacy in humans. Here, we show that a wide variety of CNS-active drugs induce characteristic alterations in visual stimulus–induced and/or spontaneous eye movements in mice. Active compounds included sedatives and antipsychotic, antidepressant, and antiseizure drugs as well as drugs of abuse, such as cocaine, morphine, and phencyclidine. The use of quantitative eye-movement analysis was demonstrated by comparing it with the commonly used rotarod test of motor coordination and by using eye movements to monitor pharmacokinetics, blood-brain barrier penetration, drug-receptor interactions, heavy metal toxicity, pharmacologic treatment in a model of schizophrenia, and degenerative CNS disease. We conclude that eye-movement analysis could complement existing animal tests to improve preclinical drug development. PMID:21821912

  5. Preclinical evaluation of MenB vaccines: prerequisites for clinical development.

    PubMed

    Sanders, Holly; Kaaijk, Patricia; van den Dobbelsteen, Germie Pjm

    2013-01-01

    Despite the widespread use of polysaccharide and conjugate vaccines against disease caused by several serogroups of Neisseria meningitidis, vaccines targeting meningococci expressing the serogroup B capsule (MenB) have focused on subcapsular antigens, due to crossreactivity of the polysaccharide with human glycoproteins. Protein vaccines composed of outer membrane vesicles have been used successfully to control epidemics of MenB disease in several countries; however, these are specific for epidemic strains. Currently, a single serogroup B vaccine, aiming to provide comprehensive coverage, has been approved for use, and several others are undergoing clinical trials. Data on potential new vaccine candidates, from discovery to initial preclinical evaluation, are regularly published. In this review, the data required to progress from preclinical to clinical development of MenB vaccines are outlined, with reference to relevant regulatory guidelines. The issues caused by a lack of reliable animal models, particularly with respect to determination of protective efficacy, are also discussed. PMID:23256737

  6. 3D laser optoacoustic ultrasonic imaging system for preclinical research

    NASA Astrophysics Data System (ADS)

    Ermilov, Sergey A.; Conjusteau, André; Hernandez, Travis; Su, Richard; Nadvoretskiy, Vyacheslav; Tsyboulski, Dmitri; Anis, Fatima; Anastasio, Mark A.; Oraevsky, Alexander A.

    2013-03-01

    In this work, we introduce a novel three-dimensional imaging system for in vivo high-resolution anatomical and functional whole-body visualization of small animal models developed for preclinical or other type of biomedical research. The system (LOUIS-3DM) combines a multi-wavelength optoacoustic and ultrawide-band laser ultrasound tomographies to obtain coregistered maps of tissue optical absorption and acoustic properties, displayed within the skin outline of the studied animal. The most promising applications of the LOUIS-3DM include 3D angiography, cancer research, and longitudinal studies of biological distribution of optoacoustic contrast agents (carbon nanotubes, metal plasmonic nanoparticles, etc.).

  7. Oxerutins (Venoruton): efficacy in chronic venous insufficiency--a double-blind, randomized, controlled study.

    PubMed

    Petruzzellis, Vincenzo; Troccoli, Teresa; Candiani, Carlo; Guarisco, Raffaella; Lospalluti, Mario; Belcaro, Gianni; Dugall, Mark

    2002-01-01

    The aim of this study was to confirm the clinical efficacy of oxerutins by evaluation of venous parietal tone and microvascular perfusion in a double-blind, randomized, placebo-controlled study. The study included 60 patients. Venous tone was evaluated by air-plethysmography (APG) in patients with venous insufficiency (CVI). Forty patients were treated with oxerutins and 20 with placebo for 4 weeks. The dose of the first 2 weeks was higher than that of the following 2 weeks. The age range was between 18 and 65 years. Randomized patients received treatment (oxerutins or placebo) according to the grade of CVI. Patients with grade I CVI received 2 g/day in the first 2 weeks of treatment and 1 g/day in the following weeks. Patients with grade II CVI received 3 g/day in the first 2 weeks and 2 g/day in the following 2 weeks. Visits were scheduled at baseline time (visit 1), at 2 weeks (visit 2) and at 4 weeks (visit 3). They were assessed with the following: (1) APG; (2) light reflection rheography (LRR); (3) capillaroscopy; (4) liquid crystals thermography. CVI signs/symptoms--heavy legs, edema, paresthesia, and cramps--were evaluated following a 4-point rating scale (0 = no symptom; 3 = severe symptoms). At visit 3 a final opinion on efficacy was provided by both patients and investigators, based on a 4-point scale (none, fairly good, good, excellent). The two groups were homogeneous for age, sex, and clinical distribution. The changes in venous capacity, were significant (p<0.01) in the oxerutins group at visits 2 and 3; values in the placebo group remained unchanged. The changes in LRR were significant in the treatment group at visits 2 (p<0.05) and 3 (p<0.01); values in the placebo group remained unchanged. Changes in temperature were significant in the oxerutins group at visits 2 (p<0.05) and 3 (p<0.01); changes in the placebo group were not significant at the end of the study. Capillaroscopy showed an improvement in patients treated with oxerutins. The results of the analysis of signs/symptoms favored active treatment. The overall effects of oxerutins were significantly better than the effects of placebo. Considering both noninvasive tests and clinical evaluation, oxerutins is effective in controlling chronic venous hypertension, without side effect, and with good tolerability. PMID:12025912

  8. Comparative studies on the efficacy of sulphachlorpyrazine and toltrazuril for the treatment of caecal coccidiosis in chickens.

    PubMed

    Laczay, P; Vörös, G; Semjén, G

    1995-06-01

    The therapeutic efficacy of sulphachlorpyrazine and toltrazuril against experimentally induced Eimeria tenella infection was compared in battery and floor pen raised broiler chickens. In the battery studies, both drugs prevented coccidiosis-related mortality and decrease of weight gain to a similar degree, but toltrazuril was more effective in reducing intestinal lesions and faecal scores, when treatments were initiated 24 h postinfection. When medication was delayed until 72 h after inoculation, the sulphonamide proved to be more effective in preventing reduction of weight gain and intestinal lesions caused by the parasites. Under simulated use conditions both drugs showed an appropriate anticoccidial efficacy without major differences between them. PMID:7657461

  9. Noninvasive Multimodality Imaging of the Tumor Microenvironment: Registered Dynamic Magnetic Resonance Imaging and Positron Emission Tomography Studies of a Preclinical Tumor Model of Tumor Hypoxia12

    PubMed Central

    Cho, HyungJoon; Ackerstaff, Ellen; Carlin, Sean; Lupu, Mihaela E; Wang, Ya; Rizwan, Asif; O'Donoghue, Joseph; Ling, C Clifton; Humm, John L; Zanzonico, Pat B; Koutcher, Jason A

    2009-01-01

    In vivo knowledge of the spatial distribution of viable, necrotic, and hypoxic areas can provide prognostic information about the risk of developing metastases and regional radiation sensitivity and may be used potentially for localized dose escalation in radiation treatment. In this study, multimodality in vivo magnetic resonance imaging (MRI) and positron emission tomography (PET) imaging using stereotactic fiduciary markers in the Dunning R3327-AT prostate tumor were performed, focusing on the relationship between dynamic contrast-enhanced (DCE) MRI using Magnevist (Gd-DTPA) and dynamic 18F-fluoromisonidazole (18F-Fmiso) PET. The noninvasive measurements were verified using tumor tissue sections stained for hematoxylin/eosin and pimonidazole. To further validate the relationship between 18F-Fmiso and pimonidazole uptake, 18F digital autoradiography was performed on a selected tumor and compared with the corresponding pimonidazole-stained slices. The comparison of Akep values (kep = rate constant of movement of Gd-DTPA between the interstitial space and plasma and A = amplitude in the two-compartment model (Hoffmann U, Brix G, Knopp MV, Hess T and Lorenz WJ (1995). Magn Reson Med 33, 506–514) derived from DCE-MRI studies and from early 18F-Fmiso uptake PET studies showed that tumor vasculature is a major determinant of early 18F-Fmiso uptake. A negative correlation between the spatial map of Akep and the slope map of late (last 1 hour of the dynamic PET scan) 18F-Fmiso uptake was observed. The relationships between DCE-MRI and hematoxylin/eosin slices and between 18F-Fmiso PET and pimonidazole slices confirm the validity of MRI/PET measurements to image the tumor microenvironment and to identify regions of tumor necrosis, hypoxia, and well-perfused tissue. PMID:19242606

  10. Noninvasive multimodality imaging of the tumor microenvironment: registered dynamic magnetic resonance imaging and positron emission tomography studies of a preclinical tumor model of tumor hypoxia.

    PubMed

    Cho, HyungJoon; Ackerstaff, Ellen; Carlin, Sean; Lupu, Mihaela E; Wang, Ya; Rizwan, Asif; O'Donoghue, Joseph; Ling, C Clifton; Humm, John L; Zanzonico, Pat B; Koutcher, Jason A

    2009-03-01

    In vivo knowledge of the spatial distribution of viable, necrotic, and hypoxic areas can provide prognostic information about the risk of developing metastases and regional radiation sensitivity and may be used potentially for localized dose escalation in radiation treatment. In this study, multimodality in vivo magnetic resonance imaging (MRI) and positron emission tomography (PET) imaging using stereotactic fiduciary markers in the Dunning R3327-AT prostate tumor were performed, focusing on the relationship between dynamic contrast-enhanced (DCE) MRI using Magnevist (Gd-DTPA) and dynamic (18)F-fluoromisonidazole ((18)F-Fmiso) PET. The noninvasive measurements were verified using tumor tissue sections stained for hematoxylin/eosin and pimonidazole. To further validate the relationship between (18)F-Fmiso and pimonidazole uptake, (18)F digital autoradiography was performed on a selected tumor and compared with the corresponding pimonidazole-stained slices. The comparison of Akep values (kep = rate constant of movement of Gd-DTPA between the interstitial space and plasma and A = amplitude in the two-compartment model (Hoffmann U, Brix G, Knopp MV, Hess T and Lorenz WJ (1995). Magn Reson Med 33, 506-514) derived from DCE-MRI studies and from early (18)F-Fmiso uptake PET studies showed that tumor vasculature is a major determinant of early (18)F-Fmiso uptake. A negative correlation between the spatial map of Akep and the slope map of late (last 1 hour of the dynamic PET scan) (18)F-Fmiso uptake was observed. The relationships between DCE-MRI and hematoxylin/eosin slices and between (18)F-Fmiso PET and pimonidazole slices confirm the validity of MRI/PET measurements to image the tumor microenvironment and to identify regions of tumor necrosis, hypoxia, and well-perfused tissue. PMID:19242606

  11. Preclinical Evaluation of the Novel, Orally Bioavailable Selective Inhibitor of Nuclear Export (SINE) KPT-335 in Spontaneous Canine Cancer: Results of a Phase I Study

    PubMed Central

    London, Cheryl A.; Bernabe, Luis Feo; Barnard, Sandra; Kisseberth, William C.; Borgatti, Antonella; Henson, Mike; Wilson, Heather; Jensen, Kiersten; Ito, Daisuke; Modiano, Jaime F.; Bear, Misty D.; Pennell, Michael L.; Saint-Martin, Jean-Richard; McCauley, Dilara; Kauffman, Michael; Shacham, Sharon

    2014-01-01

    Background The purpose of this study was to evaluate the activity of Selective Inhibitors of Nuclear Export (SINE) compounds that inhibit the function of the nuclear export protein Exportin 1 (XPO1/CRM1) against canine tumor cell lines and perform a Phase I clinical trial of KPT-335 in dogs with spontaneous cancer to provide a preliminary assessment of biologic activity and tolerability. Methods and Findings Canine tumor cell lines derived from non-Hodgkin lymphoma (NHL), mast cell tumor, melanoma and osteosarcoma exhibited growth inhibition and apoptosis in response to nanomolar concentrations of SINE compounds; NHL cells were particularly sensitive with IC50 concentrations ranging from 2–42 nM. A Phase I clinical trial of KPT-335 was performed in 17 dogs with NHL (naive or relapsed), mast cell tumor or osteosarcoma. The maximum tolerated dose was 1.75 mg/kg given orally twice/week (Monday/Thursday) although biologic activity was observed at 1 mg/kg. Clinical benefit (CB) including partial response to therapy (PR, n?=?2) and stable disease (SD, n?=?7) was observed in 9/14 dogs with NHL with a median time to progression (TTP) for responders of 66 days (range 35–256 days). A dose expansion study was performed in 6 dogs with NHL given 1.5 mg/kg KPT-335 Monday/Wednesday/Friday; CB was observed in 4/6 dogs with a median TTP for responders of 83 days (range 35–354 days). Toxicities were primarily gastrointestinal consisting of anorexia, weight loss, vomiting and diarrhea and were manageable with supportive care, dose modulation and administration of low dose prednisone; hepatotoxicity, anorexia and weight loss were the dose limiting toxicities. Conclusions This study provides evidence that the novel orally bioavailable XPO1 inhibitor KPT-335 is safe and exhibits activity in a relevant, spontaneous large animal model of cancer. Data from this study provides critical new information that lays the groundwork for evaluation of SINE compounds in human cancer. PMID:24503695

  12. Preclinical acute toxicity studies and rodent-based dosimetry estimates of the novel sigma-1 receptor radiotracer [ 18F]FPS

    Microsoft Academic Search

    Rikki N Waterhouse; Michael G Stabin; John G Page

    2003-01-01

    [18F]1-(Fluoropropyl)-4-[(4-cyanophenoxy)methyl]piperidine ([18F]FPS) is a novel high affinity (KD = 0.5 nM) sigma receptor radioligand that exhibits saturable and selective in vivo binding to sigma receptors in rats, mice and non-human primates. In order to support an IND application for the characterization of [18F]FPS through PET imaging studies in humans, single organ and whole body radiation adsorbed doses associated with [18F]FPS

  13. Feasibility, Efficacy, and Predictive Factors for the Technical Success of Endoscopic Nasogallbladder Drainage: A Prospective Study

    PubMed Central

    Yane, Kei; Maguchi, Hiroyuki; Katanuma, Akio; Takahashi, Kuniyuki; Osanai, Manabu; Kin, Toshifumi; Takaki, Ryo; Matsumoto, Kazuyuki; Gon, Katsushige; Matsumori, Tomoaki; Tomonari, Akiko; Nojima, Masanori

    2015-01-01

    Background/Aims Several studies have shown the usefulness of endoscopic nasogallbladder drainage (ENGBD) in patients with acute cholecystitis. However, the procedure is difficult, and factors that affect technical success have not yet been clarified. We conducted a prospective study to evaluate the technical feasibility, efficacy, and predictive factors for the technical success of ENGBD in patients with acute cholecystitis. Methods All patients with moderate or severe acute cholecystitis who were enrolled underwent ENGBD between April 2009 and April 2011. Patients with surgically altered anatomy or pancreatobiliary malignancies were excluded. The primary outcomes included technical success, clinical success, and complications. Factors that could affect the technical success were also examined. Results Of the 27 patients who underwent ENGBD during the study period, technical success was achieved in 21 (78%) and clinical improvement was achieved in 20 (95%). Early complications were encountered in four patients (15%). Gallbladder wall thickness (odds ratio [OR], 1.64; 95% confidence interval [CI], 1.08 to 2.47) and age (OR, 1.16; 95% CI, 1.00 to 1.35) were effective predictors of technical failure. Conclusions ENGBD was effective in resolving acute cholecystitis; however, this modality was technically challenging and had a limited success rate. Because of technical difficulties, ENGBD should be reserved for limited indications. PMID:25287172

  14. A six-week clinical study to compare the stain removal efficacy of three dentifrices.

    PubMed

    Nathoo, Salim; Petrone, Margaret E; DeVizio, William; Chaknis, Patricia; Volpe, Anthony R

    2002-01-01

    The objective of this double-blind clinical study was to compare the tooth whitening efficacy (stain removal) of a new commercially available tooth whitening dentifrice (Colgate Total Plus Whitening Toothpaste) containing 0.2% triclosan and 3.0% PVM/MA copolymer in a 0.243% sodium fluoride/high cleaning silica base, with that of two commercially available dentifrices, Crest Multi-Care Advanced Cleaning Toothpaste and Colgate Winterfresh Gel Fluoride Toothpaste. Following a baseline examination to assess extrinsic tooth stain, qualifying adult male and female subjects were randomized into three treatment groups which were balanced for gender, age and level of extrinsic tooth stain. Subjects were asked to brush their teeth twice (morning and evening) for one minute with their assigned dentifrice using a soft-bristled toothbrush. Examinations for extrinsic tooth stain were repeated after six weeks' use of the study dentifrices. One-hundred and twenty-three (123) subjects complied with the protocol and completed the study. At the six-week examination, subjects assigned to the Colgate Total Plus Whitening Toothpaste treatment group exhibited statistically significant reductions in extrinsic tooth stain area and extrinsic tooth stain intensity relative to those subjects assigned to the Crest Multi-Care Advanced Cleaning Toothpaste and the Colgate Winterfresh Gel Fluoride Toothpaste. PMID:11695214

  15. BODY-ORIENTED THERAPY IN RECOVERY FROM CHILD SEXUAL ABUSE: AN EFFICACY STUDY

    PubMed Central

    Price, Cynthia

    2007-01-01

    Context There has been little research on body therapy for women in sexual abuse recovery. This study examines body-oriented therapy—an approach focused on body awareness and involving the combination of bodywork and the emotional processing of psychotherapy. Objective To examine the efficacy and the perceived influence on abuse recovery of body-oriented therapy. Massage therapy served as a relative control condition to address the lack of touch-based comparisons in bodywork research. Design A 2-group, repeated measures design was employed, involving randomization to either body-oriented therapy or massage group, conducted in 8, hour-long sessions by 1 of 4 research clinicians. Statistical and qualitative analysis was employed to provide both empirical and experiential perspectives on the study process. Setting Participants were seen in treatment rooms of a university in the northwestern United States and in clinician’s private offices. Participants Twenty-four adult females in psychotherapy for child sexual abuse. Interventions Body-oriented therapy protocol was delivered in three stages, involving massage, body awareness exercises, and inner-body focusing process. Massage therapy protocol was stan- dardized. Both protocols were delivered over clothes. Main Outcome Measures The outcomes reflected 3 key con-structs—psychological well being, physical well-being, and body connection. Repeated measures included: Brief Symptom Inventory, Dissociative Experiences Scale, Crime-Related Post Traumatic Stress Disorder Scale, Medical Symptoms Checklist, Scale of Body Connection and Scale of Body Investment. Results were gathered at 6 time points: baseline, 2 times during intervention, post-intervention, and at 1 month and 3 months follow-up. To examine the experiential perspective of the study process, written questionnaires were administered before and after intervention and at 1 month and 3 months follow-up. Results Repeated measures analysis of variance (ANOVA) indicated significant improvement on all outcome measures for both intervention groups, providing support for the efficacy of body therapy in recovery from childhood sexual abuse. There were no statistically significant differences between groups; however, qualitative analysis of open-ended questions about participant intervention experience revealed that the groups differed on perceived experience of the intervention and its influence on therapeutic recovery. PMID:16189948

  16. The Efficacy of Influenza Vaccination in Healthcare Workers in a Tropical Setting: A Prospective Investigator Blinded Observational Study

    Microsoft Academic Search

    Si Wei Kheok; Chia Yin Chong; Grace McCarthy; Wai Yee Lim; Khean Teik Goh; Lubna Razak; Paul Ananth Tambyah

    Introduction: Influenza vaccine has been shown to be highly effective in temperate regions with well-defined seasonal influenza. Healthcare workers (HCWs) are advised to receive regular influenza vaccination to protect themselves and their patients. However, there are limited data on the efficacy of influenza vaccine in HCWs in the tropics. Materials and Methods: In this observational, investigator blinded cohort study, bi-monthly

  17. A Study of the Effects of the Length of Student-Teaching Experiences on New Teacher Efficacy

    ERIC Educational Resources Information Center

    Addison, Alan Wayne

    2010-01-01

    This study explores the relationship between the length of student-teaching experiences and new teacher efficacy. Each year thousands of prospective new teachers endure the interview processes to be hired, complete induction programs, and begin their careers only to determine that the teaching profession is not what they assumed it would be. Local…

  18. Collaborative learning in pre?service teacher education: an exploratory study on related conceptions, self?efficacy and implementation

    Microsoft Academic Search

    Ilse Ruys; Hilde Van Keer; Antonia Aelterman

    2010-01-01

    In this study, the actual position of collaborative learning (CL) in teacher education is examined. One hundred and twenty teacher educators and 369 student teachers are surveyed on general educational beliefs, mental models and conceptions related to CL. The self?efficacy and the implementation of CL are also taken under scrutiny. The results reveal that CL is highly valued as a

  19. A Descriptive Study of the Effects of Mentoring and Induction Programs on Novice Teacher Self-Efficacy Beliefs

    ERIC Educational Resources Information Center

    Ackermann, John M.

    2012-01-01

    This study examined the effects of mentoring and induction programs on the self-efficacy beliefs of novice teachers. As school districts in Pennsylvania attempt to maintain highly qualified staff in all curricular areas, supporting newly hired teachers is at the forefront of educational policy in the United States. Beyond training novice teachers,…

  20. A Comparative Study of the Self-Efficacy Beliefs of Successful Men and Women in Mathematics, Science, and Technology Careers

    ERIC Educational Resources Information Center

    Zeldin, Amy L.; Britner, Shari L.; Pajares, Frank

    2008-01-01

    The purpose of this study was to explore the personal stories of men who selected careers in science, technology, engineering, or mathematics (STEM) to better understand the ways in which their self-efficacy beliefs were created and subsequently influenced their academic and career choices. Analysis of 10 narratives revealed that mastery…

  1. A Pilot Study on the Efficacy of Melodic Based Communication Therapy for Eliciting Speech in Nonverbal Children with Autism

    ERIC Educational Resources Information Center

    Sandiford, Givona A.; Mainess, Karen J.; Daher, Noha S.

    2013-01-01

    The purpose of this study was to compare the efficacy of Melodic Based Communication Therapy (MBCT) to traditional speech and language therapy for eliciting speech in nonverbal children with autism. Participants were 12 nonverbal children with autism ages 5 through 7 randomly assigned to either treatment group. Both groups made significant…

  2. Efficacy and Safety of Valsartan, an Angiotensin II Receptor Antagonist, in Hypertension After Renal Transplantation: A Randomized Multicenter Study

    Microsoft Academic Search

    A. Andrés; E. Morales; J. M. Morales; I. Bosch; C. Campo; L. M. Ruilope

    2006-01-01

    BackgroundThe prevalence of posttransplant hypertension is high, and it appears to be a major risk factor for graft and patient survival. The aim of this study was to assess the efficacy and safety of valsartan, an angiotensin-receptor blocker (ARB), in the treatment of posttransplant hypertension.

  3. A Study of the Efficacy of Computerized Skill Building for Adolescents: Reducing Aggression and Increasing Pro-Social Behavior.

    ERIC Educational Resources Information Center

    Stern, Robin; Repa, J. Theodore

    This article describes a pilot study that evaluated the efficacy of a computer-based, behavioral skill-building program in reducing aggression and improving academic performance among middle school students. The program is Ripple Effects'"Relate for Teens," a media rich, interactive application based on combining a proprietary learning system with…

  4. The efficacy of bosentan in inoperable chronic thromboembolic pulmonary hypertension: a 1-year follow-up study

    Microsoft Academic Search

    R. J. Hughes; X. Jais; D. Bonderman; J. Suntharalingam; M. Humbert; I. Lang; G. Simonneau; J. Pepke-Zaba

    2006-01-01

    The treatment of choice for chronic thromboembolic pulmonary hypertension (CTEPH) is pulmonary endarterectomy (PEA). However, many patients develop a severe progressive small vessel pulmonary arteriopathy that is inaccessible to surgical intervention and is associated with poor survival. The purpose of the present study was to evaluate the medium-term efficacy and safety of the dual endothelin receptor antagonist, bosentan, in inoperable

  5. Effect of Contralateral Occlusion on Long-Term Efficacy of Endarterectomy in the Asymptomatic Carotid Atherosclerosis Study (ACAS)

    Microsoft Academic Search

    William H. Baker; Virginia J. Howard; George Howard; James F. Toole

    Background and Purpose—The Asymptomatic Carotid Atherosclerosis Study (ACAS) established the effectiveness of prophylactic carotid endarterectomy, for patients in good health who had stenosis $60%, if conducted by surgeons with a surgical morbidity and mortality of ,3%. This secondary analysis was performed to determine whether the presence of contralateral cervical carotid occlusion alters the efficacy of asymptomatic ipsilateral carotid endarterectomy. Methods—One

  6. Students' major choice in accounting and its effect on their self-efficacy towards generic skills : An Australian study

    Microsoft Academic Search

    Satoshi Sugahara; Kazumi Suzuki; Gregory Boland

    2010-01-01

    Purpose – The objective of this paper is to explore undergraduate students' self-efficacy of their generic skills in an attempt to identify whether a student's choice of a major in accounting develops these types of skills. Design\\/methodology\\/approach – The present paper collected its data from a survey administered in September, 2007 to undergraduate students studying at an Australian university located

  7. A Study of S&P COMPUSTAT on Finance Students' Learning Efficacy in Taiwan: A National Survey

    Microsoft Academic Search

    H. Chen

    Since S&P COMPUSTAT is a new way for finance students in Taiwan to access foreign companies' financial statements, finance students who would like to do research regarding financial analysis must be aware of this database. The motivation of this study is to present a snapshot of S&P COMPUSTAT database usage and the finance students' learning efficacy of its use in

  8. Efficacy and morbidity of water soluble and oil-based myelography. Study compares both methods in 314 patients.

    PubMed

    Dombrowski, E T; Rezaian, S M; Northcutt, C; Boyd, W; Fundell, L; Anderson, C; Malesky, E

    1986-01-01

    Retrospective studies were carried out on 314 patients who underwent oil-based or water-soluble myelography between July 1981 and July 1982 in two community hospitals. Morbidities and efficacies were compared and it was concluded that metrizamide myelography is a preferable method. PMID:3453436

  9. Computer Self-Efficacy, Computer Anxiety, and Attitudes toward the Internet: A Study among Undergraduates in Unimas

    ERIC Educational Resources Information Center

    Sam, Hong Kian; Othman, Abang Ekhsan Abang; Nordin, Zaimuarifuddin Shukri

    2005-01-01

    Eighty-one female and sixty-seven male undergraduates at a Malaysian university, from seven faculties and a Center for Language Studies completed a Computer Self-Efficacy Scale, Computer Anxiety Scale, and an Attitudes toward the Internet Scale and give information about their use of the Internet. This survey research investigated undergraduates'…

  10. Feasibility and optimal dosage of indocyanine green fluorescence for sentinel lymph node detection using robotic single-site instrumentation: preclinical study.

    PubMed

    Levinson, Kimberly L; Mahdi, Haider; Escobar, Pedro F

    2013-01-01

    The present study was performed to determine the optimal dosage of indocyanine green (ICG) to accurately differentiate the sentinel node from surrounding tissue and then to test this dosage using novel single-port robotic instrumentation. The study was performed in healthy female pigs. After induction of anesthesia, all pigs underwent exploratory laparotomy, dissection of the bladder, and colpotomy to reveal the cervical os. With use of a 21-gauge needle, 0.5 mL normal saline solution was injected at the 3- and 9-o'clock positions as control. Four concentrations of ICG were constituted for doses of 1000, 500, 250, and 175 ?g per 0.5 mL. ICG was then injected at the 3- and 9-o'clock positions on the cervix. The SPY camera was used to track ICG into the sentinel nodes and to quantify the intensity of light emitted. SPY technology uses an intensity scale of 1 to 256; this scale was used to determine the difference in intensity between the sentinel node and surrounding tissues. The optimal dosage was tested using single-port robotic instrumentation with the same injection techniques. A sentinel node was identified at all doses except 175 ?g, at which ICG stayed in the cervix and vasculature only. For both the 500- and 250-?g doses, the sentinel node was identified before reaching maximum intensity. At maximum intensity, the difference between the surrounding tissue and the node was 207 (251 vs 44) for the 500-?g dose and 159 (251 vs 92) for the 250-?g dose. Sentinel lymph node (SLN) biopsy was successfully performed using single-port robotic technology with both the 250- and 500-?g doses. For SLN detection, the dose of ICG is related to the ability to differentiate the sentinel node from the surrounding tissue. An ICG dose of 250 to 500 ?g enables identification of a SLN with more distinction from the surrounding tissues, and this procedure is feasible using single-port robotics instrumentation. PMID:24034538

  11. Preclinical Pharmacokinetic Studies of the Tritium Labelled D-Enantiomeric Peptide D3 Developed for the Treatment of Alzheimer´s Disease

    PubMed Central

    Jiang, Nan; Leithold, Leonie H. E.; Post, Julia; Ziehm, Tamar; Mauler, Jörg; Gremer, Lothar; Cremer, Markus; Schartmann, Elena; Shah, N. Jon; Kutzsche, Janine; Langen, Karl-Josef; Breitkreutz, Jörg; Willbold, Dieter; Willuweit, Antje

    2015-01-01

    Targeting toxic amyloid beta (A?) oligomers is currently a very attractive drug development strategy for treatment of Alzheimer´s disease. Using mirror-image phage display against A?1-42, we have previously identified the fully D-enantiomeric peptide D3, which is able to eliminate A? oligomers and has proven therapeutic potential in transgenic Alzheimer´s disease animal models. However, there is little information on the pharmacokinetic behaviour of D-enantiomeric peptides in general. Therefore, we conducted experiments with the tritium labelled D-peptide D3 (3H-D3) in mice with different administration routes to study its distribution in liver, kidney, brain, plasma and gastrointestinal tract, as well as its bioavailability by i.p. and p.o. administration. In addition, we investigated the metabolic stability in liver microsomes, mouse plasma, brain, liver and kidney homogenates, and estimated the plasma protein binding. Based on its high stability and long biological half-life, our pharmacokinetic results support the therapeutic potential of D-peptides in general, with D3 being a new promising drug candidate for Alzheimer´s disease treatment. PMID:26046986

  12. Pre-clinical testing of a phased array ultrasound system for MRI-guided noninvasive surgery of the brain--a primate study.

    PubMed

    Hynynen, Kullervo; McDannold, Nathan; Clement, Greg; Jolesz, Ferenc A; Zadicario, Eyal; Killiany, Ron; Moore, Tara; Rosen, Douglas

    2006-08-01

    MRI-guided and monitored focused ultrasound thermal surgery of brain through intact skull was tested in three rhesus monkeys. The aim of this study was to determine the amount of skull heating in an animal model with a head shape similar to that of a human. The ultrasound beam was generated by a 512 channel phased array system (Exablate 3000, InSightec, Haifa, Israel) that was integrated within a 1.5-T MR-scanner. The skin was pre-cooled by degassed temperature controlled water circulating between the array surface and the skin. Skull surface temperature was measured with invasive thermocouple probes. The results showed that by applying surface cooling the skin and skull surface can be protected, and that the brain surface temperature becomes the limiting factor. The MRI thermometry was shown to be useful in detecting the tissue temperature distribution next to the bone, and it should be used to monitor the brain surface temperature. The acoustic intensity values during the 20 s sonications were adequate for thermal ablation in the human brain provided that surface cooling is used. PMID:16716552

  13. Determination of pterostilbene in rat plasma by a simple HPLC-UV method and its application in pre-clinical pharmacokinetic study.

    PubMed

    Lin, Hai-Shu; Yue, Bing-De; Ho, Paul C

    2009-12-01

    A simple HPLC-UV method was developed and validated for the quantification of pterostilbene (3,5-dimethoxy-4'-hydroxy-trans-stilbene), a pharmacologically active phytoalexin in rat plasma. The assay was carried out by measuring the UV absorbance at 320 nm. Pterostilbene and the internal standard, 3,5,4'-trimethoxy-trans-stilbene eluted at 5.7 and 9.2 min, respectively. The calibration curve (20-2000 ng/mL) was linear (R(2)> 0.997). The lower limits of detection and of quantification were 6.7 and 20 ng/mL, respectively. The intra- and inter-day precisions in terms of RSD were all lower than 6%. The analytical recovery ranged from 95.5 +/- 3.7 to 103.2 +/- 0.7% while the absolute recovery ranged from 101.9 +/- 1.1 to 104.9 +/- 4.4%. This simple HPLC method was subsequently applied in a pharmacokinetic study carried out in Sprague-Dawley rats. The terminal elimination half-life and clearance of pterostilbene were 96.6 +/- 23.7 min and 37.0 +/- 2.5 mL/min/kg, respectively, while its absolute oral bioavailability was 12.5 +/- 4.7%. Pterostilbene appeared to have better pharmacokinetic characteristics than its natural occurring analog, resveratrol. PMID:19488981

  14. Hands-On Defibrillation Has the Potential to Improve the Quality of Cardiopulmonary Resuscitation and Is Safe for Rescuers—A Preclinical Study

    PubMed Central

    Neumann, Tobias; Gruenewald, Matthias; Lauenstein, Christoph; Drews, Tobias; Iden, Timo; Meybohm, Patrick

    2012-01-01

    Background Recently, it has been demonstrated that rescuers could safely provide a low, static downward force in direct contact with patients during elective cardioversion. The purpose of our experimental study was to investigate whether shock delivery during uninterrupted chest compressions may have an impact on cardiopulmonary resuscitation (CPR) quality and can be safely performed in a realistic animal model of CPR. Methods and Results Twenty anesthetized swine were subjected to 7 minutes of ventricular fibrillation followed by CPR according to the 2010 American Heart Association Guidelines. Pregelled self-adhesive defibrillation electrodes were attached onto the torso in the ventrodorsal direction and connected to a biphasic defibrillator. Animals were randomized either to (1) hands-on defibrillation, where rescuers wore 2 pairs of polyethylene gloves and shocks were delivered during ongoing chest compressions, or (2) hands-off defibrillation, where hands were taken off during defibrillation. CPR was successful in 9 out of 10 animals in the hands-on group (versus 8 out of 10 animals in the hands-off group; not significant). In the hands-on group, chest compressions were interrupted for 0.8% [0.6%; 1.4%] of the total CPR time (versus 8.2% [4.2%; 9.0%]; P=0.0003), and coronary perfusion pressure was earlier restored to its pre-interruption level (P=0.0205). Also, rescuers neither sensed any kind of electric stimulus nor did Holter ECG reveal any serious cardiac arrhythmia. Conclusions Hands-on defibrillation may improve CPR quality and could be safely performed during uninterrupted chest compressions in our standardized porcine model. PMID:23316286

  15. A follow up study on the efficacy of metadoxine in the treatment of alcohol dependence

    PubMed Central

    Guerrini, Irene; Gentili, Claudio; Nelli, Gloria; Guazzelli, Mario

    2006-01-01

    Background We carried out a three months follow-up study on the efficacy of metadoxine in a cohort of alcoholics admitted to the Alcohol misuse Long-term Treatment (ALT) Unit – University of Pisa (Italy). We analyzed the clinical data, psychometric tests and blood tests of 160 alcoholics on admission and after 3 months of treatment. We compared 58 pts treated with metadoxine (MET) with 102 pts who did not receive (NULL) any drug as an adjunct to the psycho-educational interventions provided by the ALT Unit. Results At follow-up, the patients in treatment with metadoxine showed a significant improvement in the rate of complete abstinence (44.8% vs. 21.6%; chi square: 8.45, df = 1, p < 0.0037). Furthermore, the number of drop-outs at three months of treatment was also significantly lower in the MET than in the NULL group (17% vs. 57%; chi square of 23.22, df = 1, p < 0.001). Conclusion Our findings support the use of metadoxine in the management of alcohol dependence. However, randomized clinical trials are necessary to confirm and replicate them. This study raises the importance of identifying new pharmacological compounds effective on the outcome of alcoholism in order to help patients to best adhere to treatment programs and to prevent the development of mental and physical complications due to chronic and heavy use of alcohol. PMID:17176456

  16. A pilot study: the efficacy of virgin coconut oil as ocular rewetting agent on rabbit eyes.

    PubMed

    Mutalib, Haliza Abdul; Kaur, Sharanjeet; Ghazali, Ahmad Rohi; Chinn Hooi, Ng; Safie, Nor Hasanah

    2015-01-01

    Purpose. An open-label pilot study of virgin coconut oil (VCO) was conducted to determine the safety of the agent as ocular rewetting eye drops on rabbits. Methods. Efficacy of the VCO was assessed by measuring NIBUT, anterior eye assessment, corneal staining, pH, and Schirmer value before instillation and at 30?min, 60?min, and two weeks after instillation. Friedman test was used to analyse any changes in all the measurable variables over the period of time. Results. Only conjunctival redness with instillation of saline agent showed significant difference over the period of time (P < 0.05). However, further statistical analysis had shown no significant difference at 30?min, 60?min, and two weeks compared to initial measurement (P > 0.05). There were no changes in the NIBUT, limbal redness, palpebral conjunctiva redness, corneal staining, pH, and Schirmer value over the period of time for each agent (P > 0.05). Conclusion. VCO acts as safe rewetting eye drops as it has shown no significant difference in the measurable parameter compared to commercial brand eye drops and saline. These study data suggest that VCO is safe to be used as ocular rewetting agent on human being. PMID:25802534

  17. Using the Beliefs of Self-Efficacy to Improve the Effectiveness of ITS: An Empirical Study

    Microsoft Academic Search

    Francine Bica; Regina Verdin; Rosa Vicari

    2006-01-01

    This paper presents the preliminary results of the Student Model based on beliefs of Self-Efficacy aiming to improve the effectiveness\\u000a of Intelligent Tutoring Systems. The Self-efficacy construct means the student’s belief on his own capacity of performing\\u000a a task. This belief affects his behavior, motivation, affectivity and the choices he makes. We design an e-Learning System,\\u000a called InteliWeb, this environment

  18. A clinical study to compare the anticalculus efficacy of three dentifrice formulations.

    PubMed

    Allen, Donald R; Battista, Guido W; Petrone, Dolores M; Petrone, Margaret E; DeVizio, William; Volpe, Anthony R

    2002-01-01

    The objective of this double-blind clinical study, conducted in harmony with the accepted Volpe-Manhold design for studies of dental calculus, was to compare the supragingival anticalculus efficacy of three commercially available dentifrice formulations. The test toothpastes were Colgate Total Plus Whitening Toothpaste with an added high cleaning silica base, Crest Multi-Care Advanced Cleaning Toothpaste, and Colgate Winterfresh Gel. Adult male and female subjects from the northern New Jersey area were entered into the study based on a pre-test (baseline) Volpe-Manhold Calculus Index score of 7.0 or greater, provided a full oral prophylaxis, and stratified into three treatment groups which were balanced for age, sex and baseline calculus scores. Subjects were instructed to brush their teeth twice daily (morning and evening) for one minute with their assigned dentifrice, using a soft-bristled toothbrush. Examinations for dental calculus were again performed after eight weeks' use of the study dentifrices. One hundred (100) subjects complied with the protocol and completed the entire study. At the eight-week examination, subjects using the Colgate Total Plus Whitening Toothpaste and subjects using the Crest Multi-Care Advanced Cleaning Toothpaste exhibited statistically significant (p < 0.05) reductions in mean Volpe-Manhold Calculus Index scores as compared to the negative control dentifrice group (Colgate Winterfresh Gel). There was no statistically significant difference in mean Volpe-Manhold Calculus Index scores between subjects using the Colgate Total Plus Whitening Toothpaste and subjects using the Crest Multi-Care Advanced Cleaning Toothpaste. PMID:11695209

  19. Well-being and self-efficacy in a sample of undergraduate nurse students: A small survey study.

    PubMed

    Priesack, Anneken; Alcock, John

    2015-05-01

    This paper reports findings from a survey which aimed to explore well-being and self-efficacy and test measures of those constructs with a sample of nurse students in a University setting in the United Kingdom. Evidence indicates that undergraduate nurse programmes combine academic work and clinical placement experience in a mix that can potentially lead to stress and impact on health and well-being. Self-efficacy is known to be a resource that contributes to well-being, resilience and academic achievement and therefore relevant for investigation. A cross-sectional survey approach was used to obtain data using a paper questionnaire including the BBC Well-being Scale and Generalised Self-efficacy Scale. A total of n=108 undergraduate preregistration nurse students participated in this small study from a potential population of 450. The majority of participants (86%) were female, and the majority (75%) were aged 17-35years old. Mean and subscale scores were calculated for both instruments and inferential analyses were carried out using non-parametric techniques. Exploratory factor analyses of the BBC Well-being Scale indicated a three factor structure consistent with validation study findings. Cronbach's alpha was ?=.92 for the BBC Well-being Scale and ?=.85 for the GSE suggesting that the instruments are valid and reliable measures for nurse education research. Nurse students indicated higher scores on the BBC Well-being Scale and the GSE compared with previously studied populations and a small but significant positive correlation was found between psychological well-being and self-efficacy. Cluster analysis indicated discrete student communities in this sample that varied in their Well-being and GSE scale and subscale scores. Self-efficacy and general well-being in nurse students are worthy of further study and relevant to contemporary nurse education given current interest in interventions to promote student retention and resilience post-registration. PMID:25702848

  20. An Open-Label, Randomized, Flexible-Dose, Crossover Study to Assess the Comparative Efficacy and Safety of Sildenafil Citrate and Apomorphine Hydrochloride in Men with Erectile Dysfunction

    Microsoft Academic Search

    Bruno Giammusso; Giovanni M. Colpi; Luigi Cormio; Giuseppe Ludovico; Marcello Soli; Roberto Ponchietti; Francesco Montorsi; Claudio Panzironi; Bruno Guastella

    2008-01-01

    Introduction: We report the methodology and results of a study that compared a dopaminergic agonist, apomorphine, with a phosphodiesterase type-5 inhibitor, sildenafil, in terms of efficacy, tolerability, satisfaction and patient preference. Patients and Methods: This was a 20-week open- label, randomized, flexible-dose, crossover study to assess the comparative efficacy and safety of sildenafil and apomorphine. One sequence group received treatment

  1. Protective efficacy of adenovirus/protein vaccines against SIV challenges in rhesus monkeys.

    PubMed

    Barouch, Dan H; Alter, Galit; Broge, Thomas; Linde, Caitlyn; Ackerman, Margaret E; Brown, Eric P; Borducchi, Erica N; Smith, Kaitlin M; Nkolola, Joseph P; Liu, Jinyan; Shields, Jennifer; Parenteau, Lily; Whitney, James B; Abbink, Peter; Ng'ang'a, David M; Seaman, Michael S; Lavine, Christy L; Perry, James R; Li, Wenjun; Colantonio, Arnaud D; Lewis, Mark G; Chen, Bing; Wenschuh, Holger; Reimer, Ulf; Piatak, Michael; Lifson, Jeffrey D; Handley, Scott A; Virgin, Herbert W; Koutsoukos, Marguerite; Lorin, Clarisse; Voss, Gerald; Weijtens, Mo; Pau, Maria G; Schuitemaker, Hanneke

    2015-07-17

    Preclinical studies of viral vector-based HIV-1 vaccine candidates have previously shown partial protection against neutralization-resistant virus challenges in rhesus monkeys. In this study, we evaluated the protective efficacy of adenovirus serotype 26 (Ad26) vector priming followed by purified envelope (Env) glycoprotein boosting. Rhesus monkeys primed with Ad26 vectors expressing SIVsmE543 Env, Gag, and Pol and boosted with AS01B-adjuvanted SIVmac32H Env gp140 demonstrated complete protection in 50% of vaccinated animals against a series of repeated, heterologous, intrarectal SIVmac251 challenges that infected all controls. Protective efficacy correlated with the functionality of Env-specific antibody responses. Comparable protection was also observed with a similar Ad/Env vaccine against repeated, heterologous, intrarectal SHIV-SF162P3 challenges. These data demonstrate robust protection by Ad/Env vaccines against acquisition of neutralization-resistant virus challenges in rhesus monkeys. PMID:26138104

  2. Omics meets biology: application to the design and preclinical assessment of antivenoms.

    PubMed

    Calvete, Juan J; Sanz, Libia; Pla, Davinia; Lomonte, Bruno; Gutiérrez, José María

    2014-01-01

    Snakebite envenoming represents a neglected tropical disease that has a heavy public health impact worldwide, mostly affecting poor people involved in agricultural activities in Africa, Asia, Latin America and Oceania. A key issue that complicates the treatment of snakebite envenomings is the poor availability of the only validated treatment for this disease, antivenoms. Antivenoms can be an efficacious treatment for snakebite envenoming, provided they are safe, effective, affordable, accessible and administered appropriately. The shortage of antivenoms in various regions, particularly in Sub-Saharan Africa and some parts of Asia, can be significantly alleviated by optimizing the use of current antivenoms and by the generation of novel polyspecific antivenoms having a wide spectrum of efficacy. Complementing preclinical testing of antivenom efficacy using in vivo and in vitro functional neutralization assays, developments in venomics and antivenomics are likely to revolutionize the design and preclinical assessment of antivenoms by being able to test new antivenom preparations and to predict their paraspecific neutralization to the level of species-specific toxins. PMID:25517863

  3. [Neurodevelopmental theories of schizophrenia--preclinical studies].

    PubMed

    Lehner, Ma?gorzata; Taracha, Ewa; Wis?owska, Aleksandra; Zienowicz, Ma?gorzata; Maciejak, Piotr; Skórzewska, Anna; P?a?nik, Adam

    2003-01-01

    Schizophrenia is a complex disorder of unknown origin, characterised by abnormalities in the realms of perception, thinking and the experience of emotions that onset is restricted to young adulthood. Many techniques that range from neuropathology to neuroimaging identified subtle brain abnormalities particularly in frontal, temporal cortex, hippocampus, basal ganglia and cerebellum. Neurodevelopmental models of schizophrenia test hypotheses that this disease is caused by a defect in cerebral development which results in altered neural connectivity, brain neurochemistry and aberrant behaviour observed in adult life. Recent evidence indicates that neonatal hippocampal damage may affect prefrontal neuronal integrity. The developmental lesion model appears to have predictive validity because treatment with antipsychotic drugs normalises some abnormal behaviour changes. Therefore it will be a useful paradigm in the work on new therapies and in providing new insights about pathophysiology and etiology of schizophrenia. PMID:14560492

  4. Efficacy and safety of remifentanil and sulfentanyl in painless gastroscopic examination: a prospective study.

    PubMed

    Zhao, Yin-Jie; Liu, Su; Mao, Qing-Xiang; Ge, Heng-Jiang; Wang, Yao; Huang, Bing-Qiang; Wang, Wu-Chao; Xie, Jun-Ran

    2015-04-01

    We aim to assess efficacy and safety of remifentanil or sulfentanyl combined with propofol during painless gastroscopic examination in patients. In this study, 270 patients were randomly divided into 3 groups: propofol was given only in group P; propofol and remifentanil in group PR; propofol and sulfentanyl in group PS during the gastroscopic examination. Efficiency of group P was significantly lower than that of group PR and PS (P<0.01). Efficiency of group PR was lower than that of group PS (P<0.05). Incidence of chest wall rigidity and oxygen desaturation in group PR were higher than group P and PS (P<0.05), whereas there was no difference between groups P and PS (P>0.05). Propofol combined with remifentanil could provide satisfying anesthesia and more respiratory depression, whereas sulfentanyl at equivalent dose combined with propofol could also provide with satisfying anesthesia and less respiratory depression. Combined sufentanyl with propofol would be an effective anesthesia technique in the daytime procedure. PMID:24910942

  5. Evidence of agomelatine's antidepressant efficacy: the key points.

    PubMed

    Eser, Daniela; Baghai, Thomas C; Möller, Hans-Jürgen

    2007-10-01

    Depressive disorders are of the highest socioeconomic and health-economic importance, as they are the psychiatric disorders that most frequently cause psychosocial disability. Despite the progress that has been made, currently available pharmacotherapies for depression still have a limited antidepressant efficacy with a delayed onset of several weeks, and still cause side effects; these unmet needs represent important reasons to continue to search for novel treatment options. A disorganization of circadian rhythms has been suggested to play an important role in the pathophysiology of major depression, and complaints regarding disturbed sleep are frequent in depressed patients. As endogenous melatonin secretion underlies the regulation of circadian rhythms, compounds with activity at melatonergic receptors have been proposed as potential novel therapeutics. Agomelatine (S-20098), a compound with agonistic properties at MT1 and MT2 receptors and antagonistic properties at the 5-HT2C receptor, has been shown preclinically to exhibit robust antidepressant effects in several experimental paradigms. Clinical trials, including phase III studies, have now demonstrated the superior efficacy of agomelatine in comparison with placebo, and a similar efficacy in comparison with active comparators, for the treatment of major depression. Agomelatine was even effective in severely depressed patients. In all studies published so far, agomelatine was found to be safe and its overall tolerability profile was superior to that of selective serotonin reuptake inhibitors and selective serotonin and noradrenaline reuptake inhibitors. PMID:17917562

  6. Preclinical molecular imaging using PET and MRI.

    PubMed

    Wolf, Gunter; Abolmaali, Nasreddin

    2013-01-01

    Molecular imaging fundamentally changes the way we look at cancer. Imaging paradigms are now shifting away from classical morphological measures towards the assessment of functional, metabolic, cellular, and molecular information in vivo. Interdisciplinary driven developments of imaging methodology and probe molecules utilizing animal models of human cancers have enhanced our ability to non-invasively characterize neoplastic tissue and follow anti-cancer treatments. Preclinical molecular imaging offers a whole palette of excellent methodology to choose from. We will focus on positron emission tomography (PET) and magnetic resonance imaging (MRI) techniques, since they provide excellent and complementary molecular imaging capabilities and bear high potential for clinical translation. Prerequisites and consequences of using animal models as surrogates of human cancers in preclinical molecular imaging are outlined. We present physical principles, values and limitations of PET and MRI as molecular imaging modalities and comment on their high potential to non-invasively assess information on hypoxia, angiogenesis, apoptosis, gene expression, metabolism, and cell trafficking in preclinical cancer research. PMID:23179885

  7. [Cathepsin K antagonists: preclinical and clinical data].

    PubMed

    Gamsjäger, Marion; Resch, Heinrich

    2015-02-01

    Cathepsin K, a cysteine protease, is an essential enzyme in degradation of collagen type I. Since cathepsin K is relatively specific to osteoclasts, it represents a promising candidate for drug development. In the past decades, efforts have been made in developing highly potent, selective and orally applicable cathepsin K inhibitors. In contrast to balicatib and relacatib, whose drug development programmes were stopped due to cutaneous side-effects related to limited drug specificity, the more specific cathepsin K inhibitors odanacatib (ODN) and ONO-5334 have entered clinical trials. Odanacatib progressively increases bone mineral density (BMD) and decreases bone resorption markers in postmenopausal women with low BMD. Its clinical efficacy and safety was confirmed by several clinical studies but indicates that odanacatib is characterized by a resolution-of-effect with increases in bone resorption and rapid decreases in BMD following treatment discontinuation. A phase III fracture prevention study in postmenopausal women with osteoporosis is currently in the final phase. PMID:25572547

  8. Mapping preclinical compensation in Parkinson's disease: an imaging genomics approach.

    PubMed

    van Nuenen, Bart F L; van Eimeren, Thilo; van der Vegt, Joyce P M; Buhmann, Carsten; Klein, Christine; Bloem, Bastiaan R; Siebner, Hartwig R

    2009-01-01

    Mutations in the Parkin (PARK2) and PINK1 gene (PARK 6) can cause recessively inherited Parkinson's disease (PD). The presence of a single Parkin or PINK1 mutation is associated with a dopaminergic nigrostriatal dysfunction and conveys an increased risk to develop PD throughout lifetime. Therefore neuroimaging of non-manifesting individuals with a mutant Parkin or PINK1 allele opens up a window for the investigation of preclinical and very early phases of PD in vivo. Here we review how functional magnetic resonance imaging (fMRI) can be used to identify compensatory mechanisms that help to prevent development of overt disease. In two separate experiments, Parkin mutation carriers displayed stronger activation of rostral supplementary motor area (SMA) and right dorsal premotor cortex (PMd) during a simple motor sequence task and anterior cingulate motor area and left rostral PMd during internal movement selection as opposed to externally cued movements. The additional recruitment of the rostral SMA and right rostral PMd during the finger sequence task was also observed in a separate group of nonmanifesting mutation carriers with a single heterozygous PINK1 mutation. Because mutation carriers were not impaired at performing the task, the additional recruitment of motor cortical areas indicates a compensatory mechanism that effectively counteracts the nigrostriatal dysfunction. These first results warrant further studies that use these imaging genomics approach to tap into preclinical compensation of PD. Extensions of this line of research involve fMRI paradigms probing nonmotor brain functions. Additionally, the same fMRI paradigms should be applied to nonmanifesting mutation carriers in genes linked to autosomal dominant PD. This will help to determine how "generically" the human brain compensates for a preclinical dopaminergic dysfunction. PMID:19877238

  9. [Chromatography-efficacy relation study between HPLC fingerprints and allelopathic effect of Salvia miltiorrhiza aqueous solution on radish].

    PubMed

    Niu, Min; Liu, Hong-Yan; Li, Jia; Zhang, Yong-qing

    2015-03-01

    To explore the effective components represented by fingerprint contributed to allelopathic effect of different Salvia miltiorrhiza aqueous concentration on seeds and seedlings of radish, grey relational analysis was used to establish the chromatography-efficacy relation. The results show that 15 peaks devote high allelopathic contribution to radish seeds and seedlings. The study will provide a new concept for allelochemicals screening and study. PMID:26087550

  10. MidTerm Efficacy of Beraprost, an Oral Prostacyclin Analog, in the Treatment of Distal CTEPH: A Case Control Study

    Microsoft Academic Search

    Carmine Dario Vizza; Roberto Badagliacca; Susanna Sciomer; Roberto Poscia; Alessandro Battagliese; Mauro Schina; Luciano Agati; Francesco Fedele

    2006-01-01

    Background: Prostanoids are a well-established therapy for pulmonary arterial hypertension (PAH), and observational studies suggest their efficacy even in chronic thromboembolic pulmonary hypertension (CTEPH) patients. Objective: To compare the effects of 6 months of treatment with beraprost, an orally-active prostacyclin analog, in patients with distal CTEPH and PAH. Design: Case-control study. Population: Sixteen patients with severe pulmonary hypertension (NYHA II–IV),

  11. Breastfeeding Self-Efficacy and the Use of Prescription Medication: A Pilot Study

    PubMed Central

    Mannion, Cynthia; Mansell, Deborah

    2012-01-01

    Objective. To examine the association of self-efficacy, perception of milk production, and lactating women's use of medication prescribed to increase breast milk in a cohort of 18–40-year-old mothers over six months. Methods. Mothers (n = 76) attending community clinics completed the Breastfeeding Self-Efficacy Scale and the Humenick/Hill Lactation Scale, a measure of perceived milk production, three times. Results. Domperidone, a dopamine antagonist, was used by 28% of participants. On average, those using domperidone had lower self-efficacy scores than those not using it (P < 0.05) and were more likely to have used formula (Pearson chi-square test statistic? = 6.87, df = 1, P < 0.05). Breastfeeding self efficacy and perception of milk production were positively correlated. Conclusion. Breastfeeding assessment conducted prior to prescription of galactogogues is recommended for mothers and healthy term babies. Following Baby-Friendly hospital protocols and increasing self-efficacy for lactating women may be most effective in sustaining breastfeeding. Risks and benefits of various galactogogues are discussed. PMID:22220176

  12. Peripapillary Retinal Nerve Fiber Layer Changes in Preclinical Diabetic Retinopathy: A Meta-Analysis

    PubMed Central

    Chen, Xiaofei; Nie, Chuang; Gong, Yan; Zhang, Ying; Jin, Xin; Wei, Shihui; Zhang, Maonian

    2015-01-01

    Background Diabetic retinopathy is a microvascular neurodegenerative disorder in diabetic patients. Peripapillary retinal nerve fiber layer changes have been described in patients with preclinical diabetic retinopathy, but study results have been inconsistent. Objective To assess changes in peripapillary retinal nerve fiber layer thickness in diabetic patients with preclinical diabetic retinopathy. Methods A literature search was conducted through PubMed, EMBASE, Web of Science and Cochrane Library. Case-control studies on RNFL thickness in preclinical diabetic retinopathy patients and healthy controls were retrieved. A meta-analysis of weighted mean difference and a sensitivity analysis were performed using RevMan 5.2 software. Results Thirteen case-control studies containing 668 diabetic patients and 556 healthy controls were selected. Peripapillary RNFL thickness was significantly reduced in patients with preclinical diabetic retinopathy compared to healthy controls in studies applying Optical Coherence Tomography (-2.88?m, 95%CI: -4.44 to -1.32, P = 0.0003) and in studies applying Scanning Laser Polarimeter (-4.21?m, 95%CI: -6.45 to -1.97, P = 0.0002). Reduction of RNFL thickness was significant in the superior quadrant (-3.79?m, 95%CI: -7.08 to -0.50, P = 0.02), the inferior quadrant (-2.99?m, 95%CI: -5.44 to -0.54, P = 0.02) and the nasal quadrant (-2.88?m, 95%CI: -4.93 to -0.82, P = 0.006), but was not significant in the temporal quadrant (-1.22?m, 95%CI: -3.21 to 0.76, P = 0.23), in diabetic patients. Conclusion Peripapillary RNFL thickness was significantly decreased in preclinical diabetic retinopathy patients compared to healthy control. Neurodegenerative changes due to preclinical diabetic retinopathy need more attention. PMID:25965421

  13. A comparative study of the anticancer efficacy of doxorubicin carrying microspheres and liposomes using a rat liver tumour model.

    PubMed

    Codde, J P; Lumsden, A J; Napoli, S; Burton, M A; Gray, B N

    1993-01-01

    Due to low efficacy of chemotherapy in the treatment of liver cancer, several methods of drug targeting have been investigated. Liposomes designed to carry cytotoxic drugs to the liver are currently under clinical evaluation. While experimental evidence shows promise, this method of drug delivery has several disadvantages that include short shelf life and poor drug delivery into tumour tissue. An alternative strategy for targeted drug delivery involving use of ion exchange microspheres may overcome these limitations while still reducing systemic toxicity and maintaining therapeutic efficacy. The purpose of this study was to determine the relative antitumour efficacy of these two drugs carrying systems in the treatment of liver cancer. Compared to controls, DOX treatment with free drug, liposomes or microspheres significantly reduced tumour growth by 56% (P < 0.001), 51% (P < 0.01) and 79% (P < 0.001) respectively. Furthermore, the DOX-microsphere treatment was significantly better than either of the other DOX treatments (53%, P < 0.05) or the sham-microsphere treated group (64%, P < 0.05). Thus, drug microspheres can increase the anti-tumour efficacy compared to either free or liposomal drug while simultaneously reducing systemic toxicity. PMID:8517669

  14. PHARMACOKINETICS AND METABOLISM OF A SELECTIVE ANDROGEN RECEPTOR MODULATOR IN RATS: IMPLICATION OF MOLECULAR PROPERTIES AND INTENSIVE METABOLIC PROFILE TO INVESTIGATE IDEAL PHARMACOKINETIC CHARACTERISTICS OF A PROPANAMIDE IN PRECLINICAL STUDY

    PubMed Central

    Wu, Di; Wu, Zengru; Yang, Jun; Nair, Vipin A.; Miller, Duane D.; Dalton, James T.

    2007-01-01

    S-1 [3-(4-fluorophenoxy)-2-hydroxy-2-methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]-propanamide] is one member of a series of potent selective androgen receptor modulators (SARMs) that are being explored and developed for androgen-dependent diseases. Recent studies showed that S-1 holds great promise as a novel therapeutic agent for benign hyperplasia [W. Gao, J. D. Kearbey, V. A. Nair, K. Chung, A. F. Parlow, D. D. Miller, and J. T. Dalton (2004) Endocrinology 145:5420–5428]. We examined the pharmacokinetics and metabolism of S-1 in rats as a component of our preclinical development of this compound and continued interest in structure-activation relationships for SARM action. Forty male Sprague-Dawley rats were randomly assigned to treatment groups and received either an i.v. or a p.o. dose of S-1 at a dose level of 0.1, 1, 10, or 30 mg/kg. S-1 demonstrated a low clearance (range, 3.6–5.2 ml/min/kg), a moderate volume of distribution (range, 1460–1560 ml/kg), and a terminal half-life ranging from 3.6 to 5.2 h after i.v. doses. The oral bioavailability of S-1 ranged from 55% to 60%. Forty phase I and phase II metabolites of S-1 were identified in the urine and feces of male Sprague-Dawley rats dosed at 50 mg/kg via the i.v. route. The two major urinary metabolites of S-1 were a carboxylic acid and a sulfate-conjugate of 4-nitro-3-trifluoromethylphenylamine. Phase I metabolites arising from A-ring nitro reduction to an aromatic amine and B-ring hydroxylation were also identified in the urinary and fecal samples of rats. Furthermore, a variety of phase II metabolites through sulfation, glucuronidation, and methylation were also found. These studies demonstrate that S-1 is rapidly absorbed, slowly cleared, moderately distributed, and extensively metabolized in rats. PMID:16381665

  15. A pre-clinical pharmacokinetic study in rats of three naturally occurring iridoid glycosides, Picroside-I, II and III, using a validated simultaneous HPLC-MS/MS assay.

    PubMed

    Zhu, Jianwei; Xue, Bingyang; Ma, Bo; Zhang, Qi; Liu, Ming; Liu, Lei; Yao, Di; Qi, Huanhuan; Wang, Yonglu; Ying, Hanjie; Wu, Zimei

    2015-07-01

    A selective and sensitive high-performance liquid chromatography-electro-spray ionization tandem mass spectrometry (LC-ESI-MS/MS) method was developed for the simultaneous quantitative determination of Picroside-I, II, and III in rat plasma and tissue homogenate to aid the pre-clinical studies. The chromatographic separation was performed on a Hypersil GOLD AQ C18 column using a gradient elution program with a mobile phase consisting of 2mM ammonium acetate and acetonitrile. The detection was achieved using a triple quadrupole tandem MS in negative ionization multiple reaction monitoring (MRM) mode. One-step protein precipitation was selected for plasma and tissue sample preparation while liquid-liquid extraction failed to achieve satisfactory recoveries. The calibration curves of all three analytes in either plasma or tissue homogenate showed good linearity over the concentration range of 0.5-500ng/mL with a limit of quantitation at 0.5ng/mL. Both the intra- and inter-day accuracy and precision were within ±10%. The extraction recoveries were >70%, and the relative matrix effect ranged from 80.4% to 107.4% in all the biological samples. All the analytes were stable in matrices for at least 24h at room temperature, or 21 days in frozen. Three freeze/thaw cycles did not cause degradation. The method was successfully applied for quantification of the three iridoid glycosides in the collected plasma and various tissues following intravenous administration in rats. Picroside-I, II, and III were all eliminated rapidly with large volume of distribution. Among the three glycosides, Picroside-II showed the highest liver uptake, and only Picroside-I and II were found to get across the blood brain barrier (BBB). These results were consistent with their hepatoprotective or neuroprotective effects reported clinically. With the aid of the efficient and reliable simultaneous LC-ESI-MS/MS assay this pharmacokinetic study provided insights into their therapeutic targets of these three iridoid glycosides as well as valuable experimental basis for an expansion of their clinical indications. PMID:25984965

  16. Safety and efficacy of Qurse-e-istisqua in chronic hepatitis C Infection: An exploratory study

    PubMed Central

    Rehan, Harmeet Singh; Chopra, Deepti; Yadav, Madhur; Wardhan, Neeta; Manak, Seema; Siddiqui, KM; Aslam, Mohd.

    2015-01-01

    Background: Qurse-e-istisqua (Q-e-I), an Unani medicine commonly prescribed to treat liver disorders. Objectives: To study efficacy and safety of Q-e-I in hepatitis C virus (HCV) infection. Methods: In this randomized double-blind exploratory study, 60 naive patients of HCV infection were assigned to receive either interferon?2a (IFN?2a) (3 mIU, subcutaneous, thrice weekly), ribavirin (RBV) (1000 mg, orally, twice daily in divided doses) and placebo (n = 30) or IFN?2a, RBV and Q-e-I (5 g, orally, thrice daily in divided doses) (n = 30). HCV RNA levels, serum hyaluronic acid (SHA), ultrasound image scoring for fibrosis, liver and renal function test, prothrombin time, were done at the baseline and thereafter periodically. Results: Early virologic response (EVR), end of treatment response (ETR) and sustained virologic response (SVR) were 90%, 96.6% and 90% in the control group and 86.6%, 90.0% and 83.3% in the treatment group. SHA level was lower in the treatment group at the end of the treatment as compared to the control group. Mean end of follow-up ultrasound image scoring for fibrosis in the control and the treatment group was 1.37 ± 0.07 and 1.22 ± 0.06 respectively. Aspartate aminotransferase (AST) levels were significantly lower in the treatment group than the control group at 1-month. Commonly observed adverse drug reactions included fever, hair fall, fatigue, anemia, and diarrhea. Conclusion: Q-e-I was well tolerated and showed anti-fibrotic activity. EVR, ETR and SVR suggested that Q-e-I do not have any anti-HCV activity. Early recovery in AST and inhibition of progress of fibrosis in Q-e-I group was probably due to the anti-inflammatory and antioxidant activity of its ingredients. PMID:25821315

  17. Survivin suppressor (YM155) enhances chemotherapeutic efficacy against canine histiocytic sarcoma in murine transplantation models.

    PubMed

    Yamazaki, Hiroki; Takagi, Satoshi; Hosoya, Kenji; Okumura, Masahiro

    2015-04-01

    Histiocytic sarcoma (HS) in dogs exhibits aggressive clinical and biological behavior. Currently, no effective treatments are available for dogs with HS. Survivin, a member of a family of apoptosis protein inhibitors, could serve as a potential therapeutic target in several canine cancers. Sepantronium bromide (YM155) has recently been established as a novel survivin-targeting agent. The aim of this study was to use YM155 as a tool for evaluating survivin-targeted therapies against dogs with HS, and to investigate how YM155 treatment affects antitumor and chemotherapeutic efficacies in murine xenograft models using canine HS cells. The results showed that in HS cells with lomustine (CCNU) resistance, YM155 treatment suppressed both the cell-growth potential and cell resistance to CCNU, which essentially increases the chemotherapy efficacy in the murine models. The evidence presented here supports the favorable preclinical evaluation that survivin-targeted therapies might be effective against HS in dogs. PMID:25744435

  18. The Efficacy/Effeminacy Braid: Unpicking the Performance Studies/Theatre Studies Dichotomy.

    ERIC Educational Resources Information Center

    Bottoms, Stephen J.

    2003-01-01

    Notes that in the popular imagination, theatre is still linked integrally and stereotypically with homosexuality. Discusses various critical debates of the 1960s about the linguistic and conceptual divorce of theatre and theatricality from performance and performativity. Concludes that if Theatre Studies has an enemy at all, it is in its own…

  19. Do Pre-Service Teachers Feel Ready to Teach in Inclusive Classrooms? A Four Country Study of Teaching Self-Efficacy

    ERIC Educational Resources Information Center

    Loreman, Tim; Sharma, Umesh; Forlin, Chris

    2013-01-01

    This paper reports the results of an international study examining pre-service teacher reports of teaching self-efficacy for inclusive education; principally focusing on the explanatory relationship between a scale designed to measure teaching self-efficacy in this area and key demographic variables within Canada, Australia, Hong Kong, and…

  20. A Study of the Impact of a School-Based, Job-Embedded Professional Development Program on Elementary and Middle School Teacher Efficacy for Technology Integration

    ERIC Educational Resources Information Center

    Skoretz, Yvonne M.

    2011-01-01

    The purpose of this study was to determine the impact of a school-based, job-embedded professional development program on elementary and middle school teacher efficacy for technology integration. Teacher efficacy has been identified as a strong predictor of whether the content of professional development will transfer to classroom practice…

  1. A study of the relationships of self-efficacy of self-management of asthma and asthma self-management knowledge

    E-print Network

    McCorkle, Laura Steed

    2005-11-01

    The purposes of this study are to examine the relationship of self-efficacy regarding self-management of asthma and student self-management knowledge and also examine the extent to which self-efficacy and self-management knowledge predicts student...

  2. A multicenter phase II study to evaluate the efficacy and safety of gefitinib as first-line treatment for Korean patients with advanced pulmonary adenocarcinoma harboring EGFR mutations

    Microsoft Academic Search

    Dong-Wan Kim; Se-Hoon Lee; Jong Seok Lee; Myung Ah Lee; Jin Hyoung Kang; Si Young Kim; Sang Won Shin; Hoon-Kyo Kim; Dae Seog Heo

    2011-01-01

    This study was designed to prospectively evaluate the efficacy and safety of first-line gefitinib treatment in patients with advanced pulmonary adenocarcinoma harboring epidermal growth factor receptor (EGFR) mutations and to explore the molecular factors affecting the efficacy of gefitinib. Tumor tissue, derived from either the original tumor or the metastatic or recurrent site was taken from chemo-naïve pts with advanced

  3. A study of the relationships of self-efficacy of self-management of asthma and asthma self-management knowledge 

    E-print Network

    McCorkle, Laura Steed

    2005-11-01

    The purposes of this study are to examine the relationship of self-efficacy regarding self-management of asthma and student self-management knowledge and also examine the extent to which self-efficacy and self-management knowledge predicts student...

  4. Is high pulse pressure a marker of preclinical cardiovascular disease?

    PubMed

    de Simone, Giovanni; Roman, Mary J; Alderman, Michael H; Galderisi, Maurizio; de Divitiis, Oreste; Devereux, Richard B

    2005-04-01

    This study tests the hypothesis that high brachial pulse pressure might constitute preclinical cardiovascular disease, rather than a risk factor. We studied 1250 subjects (472 nonobese normotensive [<135/80 mm Hg] and 778 untreated hypertensive). Central pulse pressure was estimated from brachial pulse pressure and age and divided by stroke volume (PP/SV). Brachial pulse pressure was considered high when >63 mm Hg, and peripheral resistance high when >90th percentile of normal distribution. Among hypertensive subjects, 34% had high resistance; among them, 33% had high brachial pulse pressure, as opposed to 147 of 516 patients (28.5%) with normal resistance (P=not significant). After adjusting for age, sex, race, body mass index, heart rate, and center, left ventricular (LV) internal dimension and mass were lower with high resistance, and higher when brachial pulse pressure was high. PP/SV was 36% higher with high resistance than with normal resistance, and higher when brachial pulse pressure was high (all P<0.0001). Factorial analysis demonstrated that associations of high brachial pulse pressure with both higher PP/SV and LV mass were independent of other pressure components. Thus, because of these associations, our hypothesis is that in hypertension, pulse pressure may be considered as a marker of preclinical cardiovascular disease, similar to LV mass and PP/SV, rather than a cardiovascular risk factor. PMID:15767471

  5. Efficacy and Safety Results of a Drug-Free Cosmetic Fluid for Perioral Dermatitis: The Toleriane Fluide Efficacy in Perioral Dermatitis (TOLPOD) Study

    PubMed Central

    Ehmann, Laura; Reinholz, Markus; Maier, Tanja; Lang, Martin

    2014-01-01

    Background Perioral dermatitis (POD) is a common inflammatory skin disease without standard therapy. Objective We sought to evaluate the clinical value of a soothing fluid for the treatment of POD. Methods We included 51 patients with POD in this 8-week clinical trial. The Toleriane Fluide Efficacy in Perioral Dermatitis (TOLPOD) study had an open-label design and involved twice-daily application of Toleriane Fluide, a soothing cosmetic fluid. Clinical assessment of POD was performed with a predefined questionnaire including the POD severity index (PODSI). Control visits were made after 4 and 8 weeks of treatment. Results The results were compared with those of a historical control group treated with a vehicle cream. Patients treated with the soothing fluid showed a continuous and significant improvement of the PODSI over time. The improvement of PODSI observed with the soothing fluid was better, but not significantly better, than that observed in the historical controls. In addition, the subjective complaints of patients such as disease burden, itching, distension of the skin, and appearance improved during treatment. Conclusion A soothing fluid could be a clinically useful treatment option for POD. PMID:25143674

  6. Yttrium-90 Radioembolization for Unresectable Standard-chemorefractory Intrahepatic Cholangiocarcinoma: Survival, Efficacy, and Safety Study

    SciTech Connect

    Rafi, Shoaib; Piduru, Sarat M. [Emory University School of Medicine, Division of Interventional Radiology and Image Guided Medicine, Department of Radiology (United States)] [Emory University School of Medicine, Division of Interventional Radiology and Image Guided Medicine, Department of Radiology (United States); El-Rayes, Bassel; Kauh, John S. [Emory University School of Medicine, Department of Hematology and Medical Oncology (United States)] [Emory University School of Medicine, Department of Hematology and Medical Oncology (United States); Kooby, David A.; Sarmiento, Juan M. [Emory University School of Medicine, Department of Surgical Oncology in Surgery (United States)] [Emory University School of Medicine, Department of Surgical Oncology in Surgery (United States); Kim, Hyun S., E-mail: kevin.kim@emory.edu [Emory University School of Medicine, Division of Interventional Radiology and Image Guided Medicine, Department of Radiology (United States)

    2013-04-15

    To assess the overall survival, efficacy, and safety of radioembolization with yttrium-90 (Y90) for unresectable standard-chemorefractory intrahepatic cholangiocarcinoma (ICC). Patients with unresectable standard-chemorefractory ICC treated with Y90 were studied. Survival was calculated from the date of first Y90 procedure. Tumor response was assessed with the Response Evaluation Criteria in Solid Tumors criteria on follow-up computed tomography or magnetic resonance imaging scans. National Cancer Institute Common Terminology Criteria (NCI CTCAE), version 3, were used for complications. Statistical analysis was performed by the Kaplan-Meier estimator by the log rank test. Nineteen patients underwent a total of 24 resin-based Y90 treatments. Median survival from the time of diagnosis and first Y90 procedure was 752 {+-} 193 [95 % confidence interval (CI) 374-1130] and 345 {+-} 128 (95 % CI 95-595) days, respectively. Median survival with Eastern Cooperative Oncology Group (ECOG) performance status 1 (n = 15) and ECOG performance status 2 (n = 4) was 450 {+-} 190 (95 % CI 78-822) and 345 {+-} 227 (95 % CI 0-790) days, respectively (p = .214). Patients with extrahepatic metastasis (n = 11) had a median survival of 404 {+-} 309 (95 % CI 0-1010) days versus 345 {+-} 117 (95 % CI 115-575) days for patients without metastasis (n = 8) (p = .491). No mortality was reported within 30 days from first Y90 radioembolization. One patient developed grade 3 thrombocytopenia as assessed by NCI CTCAE. Fatigue and transient abdominal pain were observed in 4 (21 %) and 6 (32 %) patients, respectively. Y90 radioembolization is effective for unresectable standard-chemorefractory ICC.

  7. The efficacy of negative pressure wound therapy on chemotherapeutic extravasation ulcers: An experimental study

    PubMed Central

    Isc?, Evren; Canter, Halil I.; Dadac?, Mehmet; At?lla, Pergin; Cakar, Ayse N.; Kec?k, Abdullah

    2014-01-01

    Context: The extravasation of the chemotherapeutic agents is not an unusual phenomenon. Necrosis of the skin and underlying structures has been reported, depending on the cytotoxicity of the extravasating drug. Despite the presence of some antidotes, such wounds tend to enlarge with time and are likely to resist the treatment. Aims: The objective of this study was to investigate the efficacy of negative pressure wound therapy (NPWT) on extravasation ulcers. Settings and Design: Animals were separated into two groups; conventional dressing group and NPWT group. Materials and Methods: Extravasation necrosis was established by intradermal doxorubicin injection. Following the debridement of the necrotic areas, one group of animals was treated with the conventional dressing while NPWT was applied to the other group. The wound areas were measured, and then biopsies were taken on the 3rd, 7th and 14th days after the debridement. Statistical Analysis Used: SPSS 11.5 for Windows was used. Two-way ANOVA test was used to compare wound areas between groups. Willcoxon sign test with Bonferroni correction was used to compare histological scores between groups. Chi-square test with Bonferroni correction was used to compare histological scores within the group between the days. Results: There is no significant difference in terms of inflammatory cell count, neovascularisation, granulation tissue formation between the groups. Contrary to these results wound areas at the end of the treatment were smaller in the NPWT group compared with the dressing group. Conclusion: There is the superiority of NPWT over conventional dressing in chemotherapeutic extravasation wounds as well as the wound area is concerned, but it is not proven histologically. PMID:25593426

  8. Extended Reverse Sural Artery Flap’s Safety, Success and Efficacy - A Prospective Study

    PubMed Central

    MN, Prakashkumar; M, Shankarappa

    2014-01-01

    Background: One of the challenges in reconstructive surgeries, faced by a majority of surgeons, is the soft tissue defect management around the lower-third of the leg, plantar and dorsal feet. Due to the sensitive location and other related difficulties, only limited options are available in this region. A durable flap is the preferred option for coverage of such defects. Objective: To evaluate the safety, success and efficacy of the extended reverse sural artery flap which was harvested, with extension to proximal-third of the leg. Methodology: This prospective study was conducted at Department of Plastic Surgery, on 18 consecutive patients with soft tissue defects and exposed bones, tendons and joints of distal-third of leg and foot. We harvested medium to large sized reverse sural artery flaps with extensions to the upper third of the calf, to cover the defects found in the distal tibia, ankle, heel, foot, and sole. Results: A majority of flaps provided a good coverage for defects. Two cases developed marginal necrosis of flaps in the distal border, which was treated with use of secondary skin grafts. Four flaps developed venous congestions. In other patients, minor complications such as rupture of suture inset, development of ulcer over insensate flap, since only one patient developed ulcer and another one patient developed inset rupture and graft loss occurred. In 16 cases, the final outcome was unaffected by any complications. Conclusions: Extension of reverse sural artery flap to the proximal third of the leg was safe and reliable and it was efficiently used to treat patients with large and far wounds of distal leg, foot and sole. PMID:24995209

  9. Biodistribution and Efficacy Studies of the Proteasome Inhibitor BSc2118 in a Mouse Melanoma Model.

    PubMed

    Mlynarczuk-Bialy, Izabela; Doeppner, Thorsten R; Golab, Jakub; Nowis, Dominika; Wilczynski, Grzegorz M; Parobczak, Kamil; Wigand, Moritz E; Hajdamowicz, Malgorzata; Bia?y, Lukasz P; Aniolek, Olga; Henklein, Petra; Bähr, Mathias; Schmidt, Boris; Kuckelkorn, Ulrike; Kloetzel, Peter-M

    2014-10-01

    Inhibition of the proteasome offers many therapeutic possibilities in inflammation as well as in neoplastic diseases. However, clinical use of proteasome inhibitors is limited by the development of resistance or severe side effects. In our study we characterized the anti-tumor properties of the novel proteasome inhibitor BSc2118. The sensitivity of tumor lines to BSc2118 was analyzed in comparison to bortezomib using crystal violet staining in order to assess cell viability. The In Vivo distribution of BSc2118 in mouse tissues was tracked by a fluorescent-modified form of BSc2118 (BSc2118-FL) and visualized by confocal microscopy. Inhibition of the 20S proteasome was monitored both in cultured cell lines and in mice, respectively. Finally, safety and efficacy of BSc2118 was evaluated in a mouse melanoma model. BSc2118 inhibits proliferation of different tumor cell lines with a similar potency as compared with bortezomib. Systemic administration of BSc2118 in mice is well tolerated, even when given in a dose of 60 mg/kg body weight. After systemic injection of BSc2118 or bortezomib similar proteasome inhibition patterns are observed within the murine organs. Detection of BSc2118-FL revealed correlation of distribution pattern of BSc2118 with inhibition of proteasomal activity in cells or mouse tissues. Finally, administration of BSc2118 in a mouse melanoma model shows significant local anti-tumor effects. Concluding, BSc2118 represents a novel low-toxic agent that might be alternatively used for known proteasome inhibitors in anti-cancer treatment. PMID:25389452

  10. CAR T-cell therapy: toxicity and the relevance of preclinical models.

    PubMed

    Kalaitsidou, Milena; Kueberuwa, Gray; Schütt, Antje; Gilham, David Edward

    2015-06-01

    Chimeric antigen receptor (CAR) T cells form part of a broad wave of immunotherapies that are showing promise in early phase cancer clinical trials. This clinical delivery has been based upon preclinical efficacy testing that confirmed the proof of principle of the therapy. However, CAR T-cell therapy does not exist alone as T cells are generally given in combination with patient preconditioning, most commonly in the form of chemotherapy, and may also include systemic cytokine support, both of which are associated with toxicity. Consequently, complete CAR T-cell therapy includes elements where the toxicity profile is well known, but also includes the CAR T cell itself, for which toxicity profiles are largely unknown. With recent reports of adverse events associated with CAR T-cell therapy, there is now concern that current preclinical models may not be fit for purpose with respect to CAR T-cell toxicity profiling. Here, we explore the preclinical models used to validate CAR T-cell function and examine their potential to predict CAR T-cell driven toxicities for the future. PMID:26065475

  11. A cognitive rehabilitation paradigm effective in male rats lacks efficacy in female rats.

    PubMed

    Langdon, Kristopher D; Granter-Button, Shirley; Harley, Carolyn W; Moody-Corbett, Frances; Peeling, James; Corbett, Dale

    2014-10-01

    Cognitive dysfunction, as a consequence of dementia, is a significant cause of morbidity lacking efficacious treatment. Females comprise at least half of this demographic but have been vastly underrepresented in preclinical studies. The current study addressed this gap by assessing the protective efficacy of physical exercise and cognitive activity on learning and memory outcomes in a rat model of vascular dementia. Forty ovariectomized Sprague-Dawley rats (?6 months old) were exposed to either a diet high in saturated fats and refined sugars or standard laboratory chow and underwent either chronic bilateral carotid occlusion or Sham surgery. Learning and memory abilities were evaluated using standard cognitive outcomes over the ensuing 6 months, followed by histologic analyses of hippocampal CA1 neurons. In Experiment 1, we confirmed hypoperfusion-induced cognitive dysfunction using a 2 × 2 (Surgery × Diet) experimental design, without alterations in hippocampal architecture. In Experiment 2, hypoperfused animals were either exposed to alternating days of physical (wheel running) and cognitive activity (modified Hebb-Williams maze) or sedentary housing. In contrast to males, this combination rehabilitation paradigm did not improve cognition or histopathologic outcomes in hypoperfused animals. These findings, highlighting differences between female and male animals, show the necessity of including both sexes in preclinical experimentation. PMID:25052554

  12. The Impact of Interactive, Computerized Educational Modules on Preclinical Medical Education

    ERIC Educational Resources Information Center

    Bryner, Benjamin S.; Saddawi-Konefka, Daniel; Gest, Thomas R.

    2008-01-01

    Interactive computerized modules have been linked to improved retention of material in clinical medicine. This study examined the effects of a new series of interactive learning modules for preclinical medical education, specifically in the areas of quiz performance, perceived difficulty of concepts, study time, and perceived stress level. We…

  13. Efficacy of essential oils and biopesticides on Phytophthora infestans suppression in laboratory and growth chamber studies

    Microsoft Academic Search

    O. M. Olanya; R. P. Larkin

    2006-01-01

    Control of late blight by alternative products is important for reduction of fungicide inputs and potato production costs. The efficacy of essential oils and biopesticides for inhibition of growth of Phytophthora infestans on media and suppression of late blight on potato plants in growth chambers was examined. Growth of pathogen isolates of diverse genotypes was evaluated on Rye B media

  14. Preservice Teachers' Culturally Responsive Teaching Self-Efficacy-Forming Experiences: A Mixed Methods Study

    ERIC Educational Resources Information Center

    Siwatu, Kamau Oginga

    2011-01-01

    The author used an explanatory mixed methods research design. The first phase involved the collection of quantitative data to examine the nature of preservice teachers' (N = 192) culturally responsive teaching self-efficacy beliefs. Follow-up face-to-face interviews were carried out with a subsample selected from Phase 1 participants. These…

  15. Efficacy of marine yeasts and baker's yeast as immunostimulants in Fenneropenaeus indicus: A comparative study

    Microsoft Academic Search

    P. J. Sarlin; Rosamma Philip

    2011-01-01

    Efficacy of marine yeasts Debaryomyces hansenii (S8) and Candida tropicalis (S186) as immunostimulants to Indian white prawn Fenneropenaeus indicus was estimated in comparison with Saccharomyces cerevisiae S36. Biomass of yeast strains was prepared using Malt Extract Agar and incorporated into a standard diet to prepare yeast diets of varying concentrations. F. indicus were fed these diets for a period of

  16. Statistical Considerations for the Efficacy Assessment of Clinical Studies of Vulvar and Vaginal Atrophy

    Microsoft Academic Search

    Ling Chen; Moh-Jee Ng; Theresa H. van der Vlugt; Phill H. Price; Anthony Orencia

    2010-01-01

    The US Food and Drug Administration, Center for Drug Evaluation and Research, Office of New Drugs, Division of Reproductive and Urologic Products (DRUP) released its draft “Guidance for Industry: Estrogen and Estrogen\\/Progestin Drug Products to Treat Vasomotor Symptoms and Vulvar and Vaginal Atrophy Symptoms—Recommendations for Clinical Evaluation” in 2003. The guidance references the assessment of safety and efficacy of estrogen

  17. A study evaluating the safety and efficacy of the Velasmooth™ system in the treatment of cellulite

    Microsoft Academic Search

    Neil Sadick; Cynthia Magro

    2007-01-01

    Background: Most cellulite treatments are limited in their effectiveness. A combination of radiofrequency energy, infrared light and mechanical manipulation of the skin and fat merits further examination. Objective: Subjects were treated with a device combining these energies to evaluate its safety and efficacy. Methods: Sixteen subjects with cellulite were treated twice weekly for 6 weeks with the VelaSmoothTM system. One

  18. A Study of Science Teaching Self-Efficacy and Outcome Expectancy Beliefs of Teachers in India

    ERIC Educational Resources Information Center

    Shireen Desouza, Josephine M.; Boone, William J.; Yilmaz, Ozgul

    2004-01-01

    Elementary and middle school teachers in urban schools in India provided responses to the science efficacy instrument (STEBI-A). These responses were evaluated using Rasch analysis and parametric tests. Rasch fit statistics and person-item maps were evaluated. It was found that the instrument worked well for the two groups of teachers, but the…

  19. A Pilot Study To Measure the Caring Efficacy of Baccalaureate Nursing Students.

    ERIC Educational Resources Information Center

    Sadler, Judith

    2003-01-01

    Results of the Coates Caring Efficacy Scale for 193 preentry to final-semester nursing students indicated that mean scores were higher than in Coates' sample of novice student nurses. Students were able to articulate the role of caring in nursing. Even preentry students scored well, suggesting that factors other than nursing education contribute…

  20. EFFICACY OF ESSENTIAL OILS AND BIOPESTICIDES ON PHYTOPHTHORA INFESTANS SUPPRESSION IN LABORATORY AND GROWTH CHAMBER STUDIES

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Control of late blight by alternative products is important for reduction of fungicide inputs and potato production costs. The efficacy of essential oils and biopesticides for inhibition of Phytophthora infestans on media and suppression of late blight on potato plants was examined in growth chamber...

  1. Preclinical development of a C6-ceramide NanoLiposome, a novel sphingolipid therapeutic.

    PubMed

    Kester, Mark; Bassler, Jocelyn; Fox, Todd E; Carter, Carly J; Davidson, Jeff A; Parette, Mylisa R

    2015-06-01

    Despite the therapeutic potential of sphingolipids, the ability to develop this class of compounds as active pharmaceutical ingredients has been hampered by issues of solubility and delivery. Beyond these technical hurdles, significant challenges in completing the necessary preclinical studies to support regulatory review are necessary for commercialization. This review seeks to identify the obstacles and potential solutions in the translation of a novel liposomal technology from the academic bench to investigational new drug (IND) stage by discussing the preclinical development of the Ceramide NanoLiposome (CNL), which is currently being developed as an anticancer drug for the initial indication of hepatocellular carcinoma (HCC). PMID:25838296

  2. Safety and Efficacy of a New Parenteral Lipid Emulsion (SMOFlipid) in Surgical Patients: A Randomized, Double-Blind, Multicenter Study

    Microsoft Academic Search

    Norbert Mertes; Helmut Grimm; Peter Fürst; Peter Stehle

    2006-01-01

    Background\\/Aims: A new lipid emulsion based on soybean oil, medium chain triglycerides, olive oil and fish oil (SMOFlipid) was tested for safety, tolerance, metabolic and clinical efficacy in surgical patients. Methods: In a prospective, double-blind European multicenter study, postoperative patients (elective abdominal or thoracic surgery) were randomized to receive isonitrogenous, isoenergetic (30–35 kcal\\/kg) total parenteral nutrition over 5 postoperative days

  3. [A randomized, double blind, placebo-controlled study of the efficacy and safety of tolperisone in spasticity following cerebral stroke].

    PubMed

    Stamenova, P; Koytchev, R; Kuhn, K; Hanasen, C; Horvath, F; Ramm, S; Pongratz, D

    2006-01-01

    To study the efficacy and safety of tolperisone--a centrally acting muscle relaxant with membrane stabilizing activity--in the treatment of stroke-related spasticity. This was a randomized, double-blind, placebo-controlled, multicenter study with parallel groups. Treatment lasted 12 weeks and was started with a titration period of variable length (dose range 300-900 mg tolperisone daily). The degree of spasticity determined on the Ashworth Scale in the most severely affected joint area was denned as primary target parameter. Hundred and twenty patients (43 females, 77 males) in a mean age of 63,3 +/- 10,6 years were recruited and received treatment. In the majority of patients both limbs of each side were affected by the spasticity which on average had been present for 3,3 +/- 4,4 years. A 62% of the patients were treated with a daily dose >600 mg tolperisone. Tolperisone reduced the mean Ashworth Score by a mean of 1,03 +/- 0,71 compared with a mean reduction of 0,47 +/- 0,54 in the placebo group (p<0,0001). A 78,3% of the patients on tolperisone versus 45% of the placebo patients experienced a reduction by at least 1 point on the Ashworth Scale (p<0,0001). Functional and overall assessments of efficacy confirmed superior efficacy of tolperisone. Adverse events occurred less often on active treatment (n=19) than on placebo (n=26) and were mostly of mild-to-moderate intensity. No withdrawals caused by adverse events were reported in the tolperisone group. The findings of the present study demonstrate the efficacy and excellent tolerance of tolperisone in the treatment of spastic hypertonia following cerebral stroke. Study data further suggest that an individual dose titration which may exceed the recommended maximum dose of 450 mg daily results in optimized therapeutic benefit. PMID:16457132

  4. Impact of Vicarious Learning Experiences and Goal Setting on Preservice Teachers' Self-Efficacy for Technology Integration: A Pilot Study

    Microsoft Academic Search

    Ling Wang; Peggy A. Ertmer

    Abstract This pilot study was designed to explore,how vicarious learning experiences and goal setting influence preservice teachers’ self-efficacy for integrating technology ,into the classroom. Twenty undergraduate students who were enrolled in an,introductory educational technology course at a large Mid-western university participated and were assigned into four conditions (3experimental and 1 control). Results showed ,significant treatment effects of vicarious experiences and

  5. Safety and efficacy of tamsulosin in the treatment of painful ejaculation: a randomized, double-blind, placebo-controlled study

    Microsoft Academic Search

    M R Safarinejad; Safarinejad

    2006-01-01

    We evaluate the efficacy and safety of tamsulosin a selective ?1A-receptor antagonist in patients with painful ejaculation (PE) as a sole entity. A total of 118 men with PE were included in the study. Patients were randomly assigned to receive 0.4 mg oral daily tamsulosin (group 1, n=59) or placebo (group 2, n=59), during a 6-week period for each agent.

  6. Vaginal effects of ospemifene in the ovariectomized rat preclinical model of menopause.

    PubMed

    Unkila, Mikko; Kari, Seppo; Yatkin, Emrah; Lammintausta, Risto

    2013-11-01

    Ospemifene is a unique tissue-selective estrogen agonist/antagonist (also known as a selective estrogen receptor modulator [SERM]) with demonstrated efficacy in Phase 3 studies of postmenopausal women with vulvar and vaginal atrophy (VVA). This report describes preclinical studies on the effects of ospemifene in the ovariectomized (OVX) rat model of menopause. Ospemifene (10mg/kg/day) and the SERM comparator, raloxifene (10mg/kg/day) were administered for 2 weeks and both increased vaginal weight; ospemifene was more effective than raloxifene. In addition, ospemifene had a greater effect on increasing vaginal epithelial height compared with raloxifene. The effect on uterine weight was less pronounced for both ospemifene and raloxifene. The ED50 of ospemifene on vaginal epithelial height was 0.39mg/kg/day and the magnitude was nearly the same as was seen with the positive control, 17?-ethinyl estradiol (EE2). In a histological analysis of ospemifene-treated rat vaginas, basal cells were overlaid by 2 to 3 cell layers of thickened goblet-like mucified cells apically; however, the cornification observed with EE2 was absent. Estrogenic activity of ospemifene was confirmed by upregulation of progesterone receptors in vaginal epithelium and stroma. Ospemifene showed similar affinity for estrogen receptor (ER)-? and ER-?, but an overall lower affinity than estradiol. Ospemifene antagonized estrogen response element (ERE)-mediated transactivation on MCF-7 cells, confirming its anti-estrogenic activity in breast cancer cells. The dose response for ospemifene in the rat is consistent with that observed in clinical studies of ospemifene 30 and 60mg, showing that the OVX rat is a highly predictive model of SERM activity in postmenopausal VVA. PMID:23665515

  7. Flexible peritoneal windows for quantitative fluorescence and bioluminescence preclinical imaging.

    PubMed

    Souris, Jeffrey S; Hickson, Jonathan A; Msezane, Lambda; Rinker-Schaeffer, Carrie W; Chen, Chin-Tu

    2013-01-01

    At present, there is considerable interest in the use of in vivo fluorescence and bioluminescence imaging to track the onset and progression of pathologic processes in preclinical models of human disease. Optical quantitation of such phenomena, however, is often problematic, frequently complicated by the overlying tissue's scattering and absorption of light, as well as the presence of endogenous cutaneous and subcutaneous fluorophores. To partially circumvent this information loss, we report here the development of flexible, surgically implanted, transparent windows that enhance quantitative in vivo fluorescence and bioluminescence imaging of optical reporters. These windows are metal and glass free and thus compatible with computed tomography, magnetic resonance imaging, positron emission tomography, and single-photon emission computed tomography; they also permit visualization of much larger areas with fewer impediments to animal locomotion and grooming than those previously described. To evaluate their utility in preclinical imaging, we surgically implanted these windows in the abdominal walls of female athymic nude mice and subsequently inoculated each animal with 1 × 10(4) to 1 × 10(6) bioluminescent human ovarian cancer cells (SKOV3ip.1-luc). Longitudinal imaging studies of fenestrated animals revealed up to 48-fold gains in imaging sensitivity relative to nonfenestrated animals, with relatively few complications, allowing wide-field in vivo visualization of nascent metastatic ovarian cancer colonization. PMID:23348789

  8. Artificial Neural Network Analysis in Preclinical Breast Cancer

    PubMed Central

    Motalleb, Gholamreza

    2014-01-01

    Objective: In this study, artificial neural network (ANN) analysis of virotherapy in preclinical breast cancer was investigated. Materials and Methods: In this research article, a multilayer feed-forward neural network trained with an error back-propagation algorithm was incorporated in order to develop a predictive model. The input parameters of the model were virus dose, week and tamoxifen citrate, while tumor weight was included in the output parameter. Two different training algorithms, namely quick propagation (QP) and Levenberg-Marquardt (LM), were used to train ANN. Results: The results showed that the LM algorithm, with 3-9-1 arrangement is more efficient compared to QP. Using LM algorithm, the coefficient of determination (R2) between the actual and predicted values was determined as 0.897118 for all data. Conclusion: It can be concluded that this ANN model may provide good ability to predict the biometry information of tumor in preclinical breast cancer virotherapy. The results showed that the LM algorithm employed by Neural Power software gave the better performance compared with the QP and virus dose, and it is more important factor compared to tamoxifen and time (week). PMID:24381857

  9. The Clinical Efficacy of Mometasone Furoate in Multi-Lamellar Emulsion for Eczema: A Double-blinded Crossover Study

    PubMed Central

    Kim, Duk Han; Lee, Hyun Jong; Park, Chun Wook; Kim, Kyu Han; Lee, Kwang Hoon; Ro, Byung In

    2013-01-01

    Background Topical application of corticosteroids also has an influence on skin barrier impairment. Physiological lipid mixtures, such as multi-lamellar emulsion (MLE) containing a natural lipid component leads to effective recovery of the barrier function. Objective The purpose of this study was to conduct an evaluation of the therapeutic efficacy and skin barrier protection of topical mometasone furoate in MLE. Methods A multi-center randomized, double-blind, controlled study was performed to assess the efficacy and safety of mometasone furoate cream in MLE for Korean patients with eczema. The study group included 175 patients with eczema, who applied either mometasone furoate in MLE cream or methylprednisolone aceponate cream for 2 weeks. Treatment efficacy was evaluated using the physician's global assessment of clinical response (PGA), trans-epidermal water loss (TEWL), and visual analogue scale (VAS) for pruritus. Patients were evaluated using these indices at days 4, 8, and 15. Results Comparison of PGA score, TEWL, and VAS score at baseline with those at days 4, 8, and 15 of treatment showed a significant improvement in both groups. Patients who applied mometasone furoate in MLE (74.8%) showed better results (p<0.05) than those who applied methylprednisolone aceponate (47.8%). The TEWL improvement ratio was higher in the mometasone furoate in MLE group than that in the methylprednisolone aceponate group, and VAS improvement was also better in the mometasone furoate in MLE group. Conclusion Mometasone furoate in MLE has a better therapeutic efficacy as well as less skin barrier impairment than methylprednisolone aceponate. PMID:23467551

  10. Learning Style Preferences of Preclinical Medical Students in Oman

    PubMed Central

    Panambur, Sabitha; Nambiar, Vinod; Heming, Thomas

    2014-01-01

    Objective: Our study sought to assess the learning preferences of students studying in the preclinical years of the medical degree program at Oman Medical College, Sohar.?Methods: In this descriptive, cross-sectional study, we administered a learning style questionnaire (VARK model) to 140 students to assess their preferred mode of learning, specifically the sensory modality by which they prefer to take in information.?Results: Over one third (35%) of the respondents expressed their preference for a single mode of learning, either visual (8%), auditory (9%), read/write (9%), or kinesthetic (9%). The remaining students preferred learning using a combination of either two (14%), three (19%), or four (32%) sensory modalities.?Conclusion: The results of our study provide us with useful information to develop appropriate learning approaches to reach all types of learners at the college. PMID:25584167

  11. Relationships between admissions requirements and pre-clinical and clinical performance in a distributed veterinary curriculum.

    PubMed

    Fuentealba, Carmen; Hecker, Kent G; Nelson, Phil D; Tegzes, John H; Waldhalm, Stephen J

    2011-01-01

    The purpose of this study was twofold: first, to assess the relationships between knowledge-based admission requirements and pre-clinical and clinical performance in a distributed model of veterinary education that uses problem-based learning as the main instruction method in the first two years of the curriculum; second, to compare pre-clinical and clinical performance with performance on the Program for the Assessment of Veterinary Education Equivalence (PAVE) exam. Admissions data including overall GPA, prerequisite GPA, Graduate Record Examination (GRE) score on the Analytical, Analytical Writing, Quantitative, and Verbal sections), veterinary school performance data (GPA for pre-clinical and clinical years), and performance PAVE (taken at the end of second year) were analyzed for two classes (N = 155, 85.8% women and 14.2% men). Overall GPA, prerequisite GPA, and GRE Quantitative and Analytical scores were the best predictors for pre-clinical (years 1 and 2) performance (R = 0.49, 23.5% of the variance), GRE Analytical score was the best predictor for year 3 (pre-clinical and clinical) performance (R = 0.25, 6.3% of the variance), GRE Quantitative score was the best predictor for PAVE performance (R = 0.27, 7.5% of the variance), and GRE Analytical score was the best predictor for clinical performance (year 4; R = 0.21, 4.4% of the variance). PAVE scores correlated with GRE Quantitative scores (r = 0.27, p <.01) and veterinary school performance, with higher correlations in the pre-clinical years (rs = 0.67-0.36, p < .01), providing evidence of convergent validity for the PAVE exam. PMID:21805935

  12. Enhancing the Attitudes and Self-Efficacy of Older Adults Toward Computers and the Internet: Results of a Pilot Study

    PubMed Central

    Lagana`, Luciana

    2009-01-01

    This pilot study explored whether a manualized computer and Internet training program could enhance older adults' computer self-efficacy and attitudes toward computers and the Internet. A total of 32 community-dwelling adults 65 years of age or older were randomly assigned to either an experimental or control group, with each group consisting of 8 women and 8 men. The experimental group received 6 weeks of training with 2-hour one-on-one sessions once per week. The same training was administered to the control group upon completion of the post-test, 6 weeks after the baseline assessment, to match the procedures on all counts with the exception of training administration. The results of two ANCOVAs indicated that participants within the experimental group improved significantly on both their computer self-efficacy (p < .001) and attitudinal scores (p < .001) at the post-training assessment. No improvements were found in the control group. PMID:20148185

  13. Safety and Efficacy of Polycalcium for Improving Biomarkers of Bone Metabolism: A 4-Week Open-Label Clinical Study

    PubMed Central

    Choi, Jae-Suk; Park, Mi-Yeon; Kim, Jong-Dae; Cho, Hyung Rae

    2013-01-01

    Abstract Polycalcium is a mixture of Polycan and calcium lactate–gluconate 1:9 (w/w) with demonstrated antiosteoporosis activity in vitro and in vivo studies. These studies were a 4-week open-label, single-center trial to evaluate the efficacy of oral Polycalcium on bone metabolism and safety. In total, 30 healthy women (range 40–60 years) were administered 400?mg of Polycalcium for 4 weeks. The primary efficacy parameter was urinary deoxypyridinoline (DPYR) levels, and serum osteocalcin (OSC), bone-specific alkaline phosphatase (BALP), urinary cross-linked C-telopeptide of type-1 collagen (CTx), urinary cross-linked N-telopeptide of type-1 collagen (NTx), calcium (Ca), and phosphorus (P) levels, which were evaluated for comparison before and after administration of Polycalcium. After 4 weeks of Polycalcium administration, 27 subjects completed the test plan. Three subjects withdrew their consent to participate. The values of blood OSC, BALP, serum Ca, and serum P from baseline to 4 weeks of treatment were changed by ?28.44%, 14.37%, 6.11%, and 1.42%, respectively. Biomarkers of bone resorption: urinary DPYR, serum CTx, serum NTx, urinary Ca, and urinary P, at baseline after 4 weeks of treatment were changed by ?13.40%, 6.67%, ?5.13%, ?22.43%, and ?3.04%, respectively. Additionally, when considering the subjects' adverse effects and the results of the blood and urine tests over the 4-week trial period, the dose of 400?mg Polycalcium showed efficacy for improving bone metabolism and was well tolerated and safe. Polycalcium was apparently safe and efficacious. PMID:23477624

  14. A comparative efficacy study of photic driving brainwave entrainment technology with a novel form of more direct entrainment

    NASA Astrophysics Data System (ADS)

    Knowles, Richard Thomas

    This exploratory study compared the efficacy of a novel brainwave electromagnetic (EM) entrainment technology against a more conventional technology utilizing the photic-driving technique. Both experimental conditions were also compared with a 7-minute control session that took place immediately before each stimulation session. The Schumann Resonance (SR) frequency was selected as the delivery signal and was chosen because of previous findings suggesting that entrainment to this frequency can often produce transpersonal if not paranormal, experiences in the entrainee, which sometimes resemble remote viewing or out-of-body experiences. A pilot study determined which of two novel entrainment modalities (a copper coil or a 16-solenoid headset) worked most effectively for use with the rest of the study. In the main study, an artificial SR signal at 7.8Hz was delivered during the photic-driving sessions, but a recording of the real-time SR was used to deliver the entrainment signal during sessions devoted to the electromagnetic entrainment modality. Sixteen participants were recruited from the local area, and EEG recordings were acquired via a 32-channel Deymed electroencephalography system. Comparative analyses were performed between the control and experimental portions of each session to assess for efficacy of the novel entrainment modality used, and, in the main study, between the electromagnetic and photic-driving sessions, to assess for differential entrainment efficacy between these groups. A follow-up study was additionally performed primarily to determine whether responders could replicate their entrainment effect from the main study. Results showed that EM entrainment appeared to be possible but is not nearly as robust or reliable as photic driving. Additionally, no profound transpersonal or paranormal experiences were elicited during the course of the study, and, when asked, participants were not able to determine with any degree of success, when the stimulation coil was turned on or off.

  15. Comparative Study for the Efficacy of Small Bore Catheter in the Patients with Iatrogenic Pneumothorax

    PubMed Central

    Noh, Tae Ook

    2011-01-01

    Background It has recently become most general to use the small bore catheter to perform closed thoracostomy in treating iatrogenic pneumothorax. This study was performed for analysis of the efficacy of treatment methods by using small bore catheter such as 7 F (French) central venous catheter, 10 F trocar catheter, 12 F pigtail catheter and for analysis of the appropriateness of each procedure. Materials and Methods From March 2007 to February 2010, Retrospective review of 105 patients with iatrogenic pneumothorax, who underwent closed thoracostomy by using small bore catheter, was performed. We analyzed the total success rate for all procedures as well as the individual success rate for each procedure, and analyzed the cause of failure, additional treatment method for failure, influential factors of treatment outcome, and complications. Results The most common causes of iatrogenic pneumothorax were presented as percutaneous needle aspiration(PCNA) in 48 cases (45.7%), and central venous catheterization in 26 cases (24.8%). The mean interval to thoracostomy after the procedure was measured as 5.2 hours (1~34 hours). Total success rate of thoracostomy was 78.1%. The success rate was not significantly difference by tube type, with 7 F central venous catheter as 80%, 10 F trocar catheter as 81.6%, and 12 F pigtail catheter as 71%. Twenty one out of 23 patients that had failed with small bore catheter treatment added large bore conventional thoracostomy, and another 2 patients received surgery. The causes for treatment failure were presented as continuous air leakage in 12 cases (52.2%) and tube malfunction in 7 cases (30%). The causes for failure did not present significant differences by tube type. Statistically significant factors affecting treatment performance were not discovered. Conclusion Closed thoracostomy with small bore catheter proved to be effective for iatrogenic pneumothorax. The success rate was not difference for each type. However, it is important to select the appropriate catheter by considering the patient status, pneumothorax aspect, and medical personnel in the cardiothoracic surgery department of the relevant hospital. PMID:22324027

  16. Laboratory efficacy study of six concentrations of warfarin bait for black-tailed prairie dogs

    Microsoft Academic Search

    Jeff J. Mach; Scott E. Hygnstrom; Richard M. Poché

    2002-01-01

    Six different concentrations of warfarin bait (0.0, 44.7, 89.5, 233.0, 407.0, and 777.6ppm) were fed for 15 days to black-tailed prairie dogs to determine efficacy. The resulting mortality was 0, 30, 50, 60, 100, and 80%, respectively. No difference in mortality was observed among the sexes. Differences in bait consumption were greater between the control group and all treatment groups

  17. Multimodality imaging of hypoxia in preclinical settings

    PubMed Central

    Mason, Ralph P.; Zhao, Dawen; Pacheco-Torres, Jesús; Cui, Weina; Kodibagkar, Vikram D.; Gulaka, Praveen K.; Hao, Guiyang; Thorpe, Philip; Hahn, Eric W.; Peschke, Peter

    2011-01-01

    Hypoxia has long been recognized to influence solid tumor response to therapy. Increasingly, hypoxia has also been implicated in tumor aggressiveness, including growth, development and metastatic potential. Thus, there is a fundamental, as well as a clinical interest, in assessing in situ tumor hypoxia. This review will examine diverse approaches focusing on the pre-clinical setting, particularly, in rodents. The strategies are inevitably a compromise in terms of sensitivity, precision, temporal and spatial resolution, as well as cost, feasibility, ease and robustness of implementation. We will review capabilities of multiple modalities and examine what makes them particularly suitable for investigating specific aspects of tumor pathophysiology. Current approaches range from nuclear imaging to magnetic resonance and optical, with varying degrees of invasiveness and ability to examine spatial heterogeneity, as well as dynamic response to interventions. Ideally, measurements would be non-invasive, exploiting endogenous reporters to reveal quantitatively local oxygen tension dynamics. A primary focus of this review is magnetic resonance imaging (MRI) based techniques, such as 19F MRI oximetry, which reveals not only hypoxia in vivo, but more significantly, spatial distribution of pO2 quantitatively, with a precision relevant to radiobiology. It should be noted that pre-clinical methods may have very different criteria for acceptance, as compared with potential investigations for prognostic radiology or predictive biomarkers suitable for use in patients. PMID:20639813

  18. Stability of Repeated Student Evaluations of Teaching in the Second Preclinical Year of a Medical Curriculum

    ERIC Educational Resources Information Center

    Krantz-Girod, Catherine; Bonvin, Raphael; Lanares, Jacques; Cueanot, Seagoleine; Feihl, Francois; Bosman, Fred; Waeber, Bernard

    2004-01-01

    The second preclinical year of the medical curriculum at the Medical Faculty of the University of Lausanne in Switzerland includes nine multidisciplinary organ-system-oriented modules consisting of lectures and problem-based-learning tutorials. This study reports the experience accumulated with the evaluation of lectures during the academic years…

  19. Improved Prediction, for Medical Students with Low MCATS, of Indices of Preclinical Performance.

    ERIC Educational Resources Information Center

    Bridgham, Robert G.

    The purpose of this study was to explore the value of variables beyond undergraduate grades and admission test scores in predicting success in the preclinical curriculum of the College of Human Medicine of Michigan State University (East Lansing). Subjects included about 93 students with relatively low scores on the Medical College Admissions Test…

  20. The rationale for and pre-clinical results of chondroitinase ABC in chemonucleolysis

    Microsoft Academic Search

    Mark D Brown

    2001-01-01

    This report details the results of three enzymes, chymopapain, collagenase and chondroitinase ABC (CABC), for chemonucleolysis of the spine intervertebral disc. The deleterious effects of chymopapain and collagenase have led to pre-clinical trials of chondroitinase ABC. Animal studies of chondroitinase ABC are promising with respect to less severe side effects and tissue damage than what has been observed with chymopapain

  1. The distribution of structural neuropathology in pre-clinical Huntington's disease

    Microsoft Academic Search

    M. J. Thieben; A. J. Duggins; C. D. Good; L. Gomes; N. Mahant; F. Richards; E. McCusker; R. S. J. Frackowiak

    2002-01-01

    Summary Putative neuroprotective agents in Huntington's disease may have particular application before brain pathology becomes manifest clinically. If these agents were to be tested in clinical trials, a reliable marker of the burden and rate of progression of pathological change in the pre-clinical group would be needed. The present study investigates whether the Huntington's disease genotype is associated with regional

  2. The automated bioaerosol exposure system: Preclinical platform development and a respiratory dosimetry application with nonhuman primates

    Microsoft Academic Search

    Justin M. Hartings; Chad J. Roy

    2004-01-01

    Introduction: Well-characterized inhalation exposure systems are critical for preclinical testing and pathogenesis studies. The automated bioaerosol exposure system (ABES) provides a microprocessor-driven inhalation platform that provides exquisite data acquisition and control over all aspects of inhalation exposures. Because this represents a new technology, the development and characteristics of the ABES are thoroughly discussed. In addition to control over homeostatic and

  3. A Novel Lung Explant Model for the Ex Vivo Study of Efficacy and Mechanisms of Anti-Influenza Drugs.

    PubMed

    Nicholas, Ben; Staples, Karl J; Moese, Stefan; Meldrum, Eric; Ward, Jon; Dennison, Patrick; Havelock, Tom; Hinks, Timothy S C; Amer, Khalid; Woo, Edwin; Chamberlain, Martin; Singh, Neeta; North, Malcolm; Pink, Sandy; Wilkinson, Tom M A; Djukanovi?, Ratko

    2015-06-15

    Influenza A virus causes considerable morbidity and mortality largely because of a lack of effective antiviral drugs. Viral neuraminidase inhibitors, which inhibit viral release from the infected cell, are currently the only approved drugs for influenza, but have recently been shown to be less effective than previously thought. Growing resistance to therapies that target viral proteins has led to increased urgency in the search for novel anti-influenza compounds. However, discovery and development of new drugs have been restricted because of differences in susceptibility to influenza between animal models and humans and a lack of translation between cell culture and in vivo measures of efficacy. To circumvent these limitations, we developed an experimental approach based on ex vivo infection of human bronchial tissue explants and optimized a method of flow cytometric analysis to directly quantify infection rates in bronchial epithelial tissues. This allowed testing of the effectiveness of TVB024, a vATPase inhibitor that inhibits viral replication rather than virus release, and to compare efficacy with the current frontline neuraminidase inhibitor, oseltamivir. The study showed that the vATPase inhibitor completely abrogated epithelial cell infection, virus shedding, and the associated induction of proinflammatory mediators, whereas oseltamivir was only partially effective at reducing these mediators and ineffective against innate responses. We propose, therefore, that this explant model could be used to predict the efficacy of novel anti-influenza compounds targeting diverse stages of the viral replication cycle, thereby complementing animal models and facilitating progression of new drugs into clinical trials. PMID:25934861

  4. A comparative study of efficacy of emg bio-feedback and progressive muscular relaxation in tension headache.

    PubMed

    Gada, M T

    1984-04-01

    The aim of the present study was to find out efficacy of frontalis EMG Biofeedback therapy, deep muscular relaxation therapy and compare the efficacy of both in cases of tension headache. During two week basal-data recording period all patients were taught deep muscular relaxation by Jacobson's technique. Simultaneously patients were instructed to keep headache diary. Headache diary yielded three different parameters a) number of headache-free days per week, b) peak headache intensity (or each week and c) average daily headache activity score per week. These parameters were used to find out therapeutic efficacy of each treatment. Patients were randomly divided in two groups. EMG Biofeedback group was given frontalis EMG feedback through EMG J 33 muscle trainer of Cyborg Corporation (U.S.A.). Patients in each group were given 20 sessions (two sessions per week); each session lasting 30 minutes. Patients were instructed to practice at least one 30 minute session of relaxation at home. The data were subjected to statistical calculation. The results indicate that frontalis EMG Biofeedback therapy and deep muscle relaxation therapy are significantly effective in cases of tension headache. Both treatments are equally effective. The findings are discussed in relation to Indian situation. PMID:21965970

  5. A Novel Lung Explant Model for the Ex Vivo Study of Efficacy and Mechanisms of Anti-Influenza Drugs

    PubMed Central

    Staples, Karl J.; Moese, Stefan; Meldrum, Eric; Ward, Jon; Dennison, Patrick; Havelock, Tom; Hinks, Timothy S. C.; Amer, Khalid; Woo, Edwin; Chamberlain, Martin; Singh, Neeta; North, Malcolm; Pink, Sandy; Wilkinson, Tom M. A.; Djukanovi?, Ratko

    2015-01-01

    Influenza A virus causes considerable morbidity and mortality largely because of a lack of effective antiviral drugs. Viral neuraminidase inhibitors, which inhibit viral release from the infected cell, are currently the only approved drugs for influenza, but have recently been shown to be less effective than previously thought. Growing resistance to therapies that target viral proteins has led to increased urgency in the search for novel anti-influenza compounds. However, discovery and development of new drugs have been restricted because of differences in susceptibility to influenza between animal models and humans and a lack of translation between cell culture and in vivo measures of efficacy. To circumvent these limitations, we developed an experimental approach based on ex vivo infection of human bronchial tissue explants and optimized a method of flow cytometric analysis to directly quantify infection rates in bronchial epithelial tissues. This allowed testing of the effectiveness of TVB024, a vATPase inhibitor that inhibits viral replication rather than virus release, and to compare efficacy with the current frontline neuraminidase inhibitor, oseltamivir. The study showed that the vATPase inhibitor completely abrogated epithelial cell infection, virus shedding, and the associated induction of proinflammatory mediators, whereas oseltamivir was only partially effective at reducing these mediators and ineffective against innate responses. We propose, therefore, that this explant model could be used to predict the efficacy of novel anti-influenza compounds targeting diverse stages of the viral replication cycle, thereby complementing animal models and facilitating progression of new drugs into clinical trials. PMID:25934861

  6. A comparative study of efficacy and safety of lornoxicam versus tramadol as analgesics after surgery on head and neck.

    PubMed

    Das, Sudip Kr; Banerjee, Manasi; Mondal, Shirsendu; Ghosh, Balaram; Ghosh, Bhaskar; Sen, Shubhrakanti

    2013-07-01

    To assess efficacy and safety of lornoxicam as analgesic after surgery on head and neck in comparison to tramadol. Forty five patients undergoing operations on head and neck were recruited and randomly assigned to two parallel groups-lornoxicam and tramadol, both given intramuscular on the first post-operative day followed by oral tablets for the consecutive 4 days. Treatment was given single blind. 10 cm visual analog scale (VAS) pain score and wound tenderness assessed by a 3-point ordinal scale were the primary efficacy parameters. Use of rescue medication and percentage of subjects having at least 50 % pain relief by 48 h were also compared as secondary parameters. The groups were comparable at baseline regarding age, sex and VAS score. There was steady decline in VAS pain score from baseline to study end in both the groups, indicating good analgesic efficacy with either drug. Between groups comparisons of VAS score showed no significant difference at any time point. Between groups comparisons of wound tenderness also showed no significant difference. Five patients on lornoxicam and one patient on tramadol experienced at least 50 % pain relief at 48 hours compared to baseline while five patients from the lornoxicam group and eight from the tramadol group required rescue medicine. The tolerability of lornoxicam appeared to be significantly superior to tramadol, with less number of patients experiencing adverse drug reactions. Lornoxicam is safe, effective and comparable to tramadol for relieving postoperative pain after operations on head and neck. PMID:24427628

  7. An open-label pilot study to assess the efficacy and safety of virgin coconut oil in reducing visceral adiposity.

    PubMed

    Liau, Kai Ming; Lee, Yeong Yeh; Chen, Chee Keong; Rasool, Aida Hanum G

    2011-01-01

    Introduction. This is an open-label pilot study on four weeks of virgin coconut oil (VCO) to investigate its efficacy in weight reduction and its safety of use in 20 obese but healthy Malay volunteers. Methodology. Efficacy was assessed by measuring weight and associated anthropometric parameters and lipid profile one week before and one week after VCO intake. Safety was assessed by comparing organ function tests one week before and one week after intake of VCO. Paired t-test was used to analyse any differences in all the measurable variables. Results. Only waist circumference (WC) was significantly reduced with a mean reduction of 2.86?cm or 0.97% from initial measurement (P = .02). WC reduction was only seen in males (P < .05). There was no change in the lipid profile. There was a small reduction in creatinine and alanine transferase levels. Conclusion. VCO is efficacious for WC reduction especially in males and it is safe for use in humans. PMID:22164340

  8. An Open-Label Pilot Study to Assess the Efficacy and Safety of Virgin Coconut Oil in Reducing Visceral Adiposity

    PubMed Central

    Liau, Kai Ming; Lee, Yeong Yeh; Chen, Chee Keong; Rasool, Aida Hanum G.

    2011-01-01

    Introduction. This is an open-label pilot study on four weeks of virgin coconut oil (VCO) to investigate its efficacy in weight reduction and its safety of use in 20 obese but healthy Malay volunteers. Methodology. Efficacy was assessed by measuring weight and associated anthropometric parameters and lipid profile one week before and one week after VCO intake. Safety was assessed by comparing organ function tests one week before and one week after intake of VCO. Paired t-test was used to analyse any differences in all the measurable variables. Results. Only waist circumference (WC) was significantly reduced with a mean reduction of 2.86?cm or 0.97% from initial measurement (P = .02). WC reduction was only seen in males (P < .05). There was no change in the lipid profile. There was a small reduction in creatinine and alanine transferase levels. Conclusion. VCO is efficacious for WC reduction especially in males and it is safe for use in humans. PMID:22164340

  9. Clinical efficacies of topical agents for the treatment of seborrheic dermatitis of the scalp: a comparative study.

    PubMed

    Shin, Hyoseung; Kwon, Oh Sang; Won, Chong Hyun; Kim, Beom Joon; Lee, Yang Won; Choe, Yong Beom; Ahn, Kyu Joong; Eun, Hee Chul

    2009-03-01

    Previous studies have shown that topical steroid and shampoo containing zinc pyrithione provide clinical benefits for treatment of scalp seborrheic dermatitis. But the clinical efficacy of topical tacrolimus, a newly developed calcineurin inhibitor on seborrheic dermatitis, is not well investigated yet. We wanted to compare the clinical efficacy of topical tacrolimus with that of conventional treatment (zinc pyrithione shampoo and topical betamethasone) for treatment of seborrheic dermatitis of the scalp. Patients with seborrheic dermatitis of the scalp were randomly allocated to receive topical betamethasone, topical tacrolimus or zinc pyrithione shampoo. Some patients were instructed to continue the treatments for 8 weeks and the others to discontinue the treatments at week 4. We evaluated the efficacy using a clinical severity score, dandruff score and sebum secretion at baseline, week 4 and week 8. All treatment groups showed significant improvements in clinical assessment after 4 weeks. While the patients treated by zinc pyrithione improved continuously even after cessation of the treatment, the patients treated by betamethasone lotion or tacrolimus ointment were aggravated clinically. Topical tacrolimus was as effective as topical betamethasone, and showed more prolonged remission than topical betamethasone. To treat seborrheic dermatitis of the scalp, we think that the combination therapy of topical steroid or topical tacrolimus, and zinc pyrithione is recommended. PMID:19335686

  10. Safety and efficacy of the modified peroral endoscopic myotomy with shorter myotomy for achalasia patients: a prospective study.

    PubMed

    Wang, J; Tan, N; Xiao, Y; Chen, J; Chen, B; Ma, Z; Zhang, D; Chen, M; Cui, Y

    2014-09-12

    Peroral endoscopic myotomy (POEM) has been developed as a minimally invasive endoscopic treatment for achalasia for years. However, the optimal length of submucosal tunnel and myotomy of muscle bundles during procedure of POEM has not yet been determined, so we aim to assess safety and efficacy of modified POEM with shorter myotomy of muscle bundles in achalasia patients. Consecutive achalasia patients had been performed modified POEM with shorter myotomy, and assessed by symptoms, high-resolution manometry, and barium swallow examinations before and 3 months after POEM for safety and efficacy evaluation. Modified POEM with shorter submucosal tunnel (mean length 6.8?cm) and endoscopic myotomy of muscle bundles (total mean length 5.4?cm) were completed in 46 consecutive achalasia patients. During the 3-month follow up in all cases, significant improvement of symptoms (a significant drop in the Eckardt score 8.4 ± 3.2 vs. 2.7 ± 1.9; P < 0.001), decreased lower esophageal sphincter pressure (39.4 ± 10.1 vs. 24.4 ± 9.1?mmHg; P < 0.001) and integrated relaxation pressure (38.6 ± 10.4 vs. 25.7 ± 9.6?mmHg; P < 0.01), and a drop in height of esophagus barium-contrast column (5.4 ± 3.1 vs. 2.6 ± 1.8?cm; P < 0.001) were observed. The frequencies of adverse events were lower in those under endotracheal anesthesia and CO2 insufflations compared with intravenous anesthesia and air insufflations. Only three patients were found to have gastroesophageal reflux disease on follow up. Modified POEM with shorter myotomy under endotracheal anesthesia and CO2 insufflations shows its good safety and excellent short-term efficacy in the treatment of achalasia. But further studies are warranted to assess the long-term efficacy. PMID:25214469

  11. Distinguishing between Exploratory and Confirmatory Preclinical Research Will Improve Translation

    PubMed Central

    Kimmelman, Jonathan; Mogil, Jeffrey S.; Dirnagl, Ulrich

    2014-01-01

    Preclinical researchers confront two overarching agendas related to drug development: selecting interventions amid a vast field of candidates, and producing rigorous evidence of clinical promise for a small number of interventions. We suggest that each challenge is best met by two different, complementary modes of investigation. In the first (exploratory investigation), researchers should aim at generating robust pathophysiological theories of disease. In the second (confirmatory investigation), researchers should aim at demonstrating strong and reproducible treatment effects in relevant animal models. Each mode entails different study designs, confronts different validity threats, and supports different kinds of inferences. Research policies should seek to disentangle the two modes and leverage their complementarity. In particular, policies should discourage the common use of exploratory studies to support confirmatory inferences, promote a greater volume of confirmatory investigation, and customize design and reporting guidelines for each mode. PMID:24844265

  12. Preclinical Murine Models for Lung Cancer: Clinical Trial Applications

    PubMed Central

    Kellar, Amelia; Egan, Cay; Morris, Don

    2015-01-01

    Murine models for the study of lung cancer have historically been the backbone of preliminary preclinical data to support early human clinical trials. However, the availability of multiple experimental systems leads to debate concerning which model, if any, is best suited for a particular therapeutic strategy. It is imperative that these models accurately predict clinical benefit of therapy. This review provides an overview of the current murine models used to study lung cancer and the advantages and limitations of each model, as well as a retrospective evaluation of the uses of each model with respect to accuracy in predicting clinical benefit of therapy. A better understanding of murine models and their uses, as well as their limitations may aid future research concerning the development and implementation of new targeted therapies and chemotherapeutic agents for lung cancer. PMID:26064932

  13. Evaluation of the efficacy and safety of paliperidone extended-release in the treatment of acute mania: A randomized, double-blind, dose-response study

    Microsoft Academic Search

    Joris Berwaerts; Haiyan Xu; Isaac Nuamah; Pilar Lim; David Hough

    2010-01-01

    BackgroundAtypical antipsychotics are effective in the treatment of bipolar I disorder. In this 3-week double-blind study, the efficacy and safety of paliperidone extended-release (ER) tablets were assessed in patients with acute mania.

  14. Molecular determinants of trastuzumab efficacy: What is their clinical relevance?

    PubMed

    De, Pradip; Hasmann, Max; Leyland-Jones, Brian

    2013-12-01

    Trastuzumab-containing therapy is a standard of care for human epidermal growth factor receptor-2 (HER2)-positive breast cancer. In pre-clinical models, a wide range of molecular mechanisms have been associated with reduced sensitivity to trastuzumab in vitro. These include expression of the truncated HER2 receptor fragment p95HER2, activating mutation of the gene encoding the class 1A catalytic subunit of phosphatidylinositol 3-kinase (PIK3CA), loss of phosphatase and tensin homolog (PTEN), activation of other downstream signal transducers, prevention of cell cycle arrest, increased signaling through alternative (HER or non-HER) tyrosine kinase receptors, and resistance to antibody-dependent cellular cytotoxicity. However, the clinical significance of these mechanisms as determinants of trastuzumab efficacy in vivo has been unclear. Here, we review clinical studies of potential predictive biomarkers of trastuzumab efficacy in HER2-positive breast cancer and consider whether evaluation of such markers might inform patient selection for therapy. We find that clinical evidence relating to potential predictive biomarkers is mostly limited to small, retrospective studies, many of which have yielded conflicting findings. Some trends are evident in the retrospective data and in biomarker analyses from randomized clinical trials, particularly relating to activation of the phosphatidylinositol 3-kinase pathway, but none is sufficiently strong to form a basis for patient selection. This may be explained by the fact that multiple mechanisms of action determine the clinical efficacy of trastuzumab. In the absence of novel, validated biomarkers of efficacy, trastuzumab eligibility should continue to be based on evaluation of HER2 status according to standard methods. PMID:23562214

  15. Anti-leukemic activity of lintuzumab (SGN-33) in preclinical models of acute myeloid leukemia.

    PubMed

    Sutherland, May Kung; Yu, Changpu; Lewis, Timothy S; Miyamoto, Jamie B; Morris-Tilden, Carol A; Jonas, Mechthild; Sutherland, Jennifer; Nesterova, Albina; Gerber, Hans-Peter; Sievers, Eric L; Grewal, Iqbal S; Law, Che-Leung

    2009-01-01

    Despite therapeutic advances, the long-term survival rates for acute myeloid leukemia (AML) are estimated to be 10% or less, pointing to the need for better treatment options. AML cells express the myeloid marker CD33, making it amenable to CD33-targeted therapy. Thus, the in vitro and in vivo anti-tumor activities of lintuzumab (SGN-33), a humanized monoclonal anti-CD33 antibody undergoing clinical evaluation, were investigated. In vitro assays were used to assess the ability of lintuzumab to mediate effector functions and to decrease the production of growth factors from AML cells. SCID mice models of disseminated AML with the multi-drug resistance (MDR)-negative HL60 and the MDR(+), HEL9217 and TF1-alpha, cell lines were developed and applied to examine the in vivo antitumor activity. In vitro, lintuzumab significantly reduced the production of TNFalpha-induced pro-inflammatory cytokines and chemokines by AML cells. Lintuzumab promoted tumor cell killing through antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP) activities against MDR(-) and MDR(+) AML cell lines and primary AML patient samples. At doses from 3 to 30 mg/kg, lintuzumab significantly enhanced survival and reduced tumor burden in vivo, regardless of MDR status. Survival of the mice was dependent upon the activity of resident macrophages and neutrophils. The results suggest that lintuzumab may exert its therapeutic effects by modulating the cytokine milieu in the tumor microenvironment and through effector mediated cell killing. Given that lintuzumab induced meaningful responses in a phase 1 clinical trial, the preclinical antitumor activities defined in this study may underlie its observed therapeutic efficacy in AML patients. PMID:20065652

  16. Preclinical activity of nanoliposomal irinotecan is governed by tumor deposition and intratumor prodrug conversion.

    PubMed

    Kalra, Ashish V; Kim, Jaeyeon; Klinz, Stephan G; Paz, Nancy; Cain, Jason; Drummond, Daryl C; Nielsen, Ulrik B; Fitzgerald, Jonathan B

    2014-12-01

    A major challenge in the clinical use of cytotoxic chemotherapeutics is maximizing efficacy in tumors while sparing normal tissue. Irinotecan is used for colorectal cancer treatment but the extent of its use is limited by toxic side effects. Liposomal delivery systems offer tools to modify pharmacokinetic and safety profiles of cytotoxic drugs. In this study, we defined parameters that maximize the antitumor activity of a nanoliposomal formulation of irinotecan (nal-IRI). In a mouse xenograft model of human colon carcinoma, nal-IRI dosing could achieve higher intratumoral levels of the prodrug irinotecan and its active metabolite SN-38 compared with free irinotecan. For example, nal-IRI administered at doses 5-fold lower than free irinotecan achieved similar intratumoral exposure of SN-38 but with superior antitumor activity. Tumor response and pharmacokinetic modeling identified the duration for which concentrations of SN-38 persisted above a critical intratumoral threshold of 120 nmol/L as determinant for antitumor activity. We identified tumor permeability and carboxylesterase activity needed for prodrug activation as critical factors in achieving longer duration of SN-38 in tumors. Simulations varying tumor permeability and carboxylesterase activity predicted a concave increase in tumor SN-38 duration, which was confirmed experimentally in 13 tumor xenograft models. Tumors in which higher SN-38 duration was achieved displayed more robust growth inhibition compared with tumors with lower SN-38 duration, confirming the importance of this factor in drug response. Overall, our work shows how liposomal encapsulation of irinotecan can safely improve its antitumor activity in preclinical models by enhancing accumulation of its active metabolite within the tumor microenvironment. PMID:25273092

  17. A comparative study of instructional efficacy between first and second-career teachers in secondary school math and science courses

    NASA Astrophysics Data System (ADS)

    Gardner, Royal Anthony

    Purpose: The purpose of this study was to use Dr. James Stronge’s taxonomy of the qualities of effective teachers to determine whether there are significant differences in the instructional efficacy between first- and second-career teachers who teach math and science. Methodology: A causal-comparative study examined the effects of variables that cannot be manipulated experimentally. The survey instrument was a 50-tem self-identifying questionnaire addressing the 6 research questions used to determine significance between first- and second-career teachers in their classroom efficacy. Findings: A Mann-Whitney U-test determined there was an overall significant difference [p < 0.01] between first- and second-career teachers in their classroom efficacy, with second-career teachers being more aligned with research-based best practices for efficacy. Conclusions: The existing construct for hiring teachers should be reconsidered, so that teachers identified as effective by research-based methods are employed from the outset. Adult maturation patterns suggest that early adults serving as instructors are less effective for at least the first 3 to 5 years of the teachers’ career. This could be resolved by amending the criteria for teacher entry into the classroom. Maturity of the teacher plays a significant role in their classroom efficacy. Existing research has provided a construct for identifying effective teachers. Recommendations: Require teaching graduates to gain at least 5 years of practical experience in the disciplines in which they seek a license to teach before entering the classroom. Increase the age for teachers entering the profession to at least 26 before allowing them into the classroom to allow for adult maturation processes to occur. Increase the rigor for a teaching certification to the point where only high content knowledge instructors could pass. Require all potential teachers to be certified on a regular basis so that they have to keep up with the technology and the most current information of their professions. Develop an assessment to allow the instructor to display knowledge of the research-based best practices for instruction.

  18. Assessment of the knowledge and attitudes regarding HIV/AIDS among pre-clinical medical students in Israel

    PubMed Central

    2014-01-01

    Background Today’s medical students are the future physicians of people living with HIV/AIDS (PLWHA). It is therefore essential that medical students possess the appropriate knowledge and attitudes regarding PLWHA. This study aims to evaluate knowledge and attitudes of pre-clinical Israeli medical students and to assess whether their knowledge and attitudes change throughout their pre-clinical studies. Methods A cross-sectional study was conducted among all pre-clinical medical students from the four medical schools in Israel during the academic year of 2010/2011 (a total of 1,470 students). A self-administered questionnaire was distributed. The questionnaire sought student responses pertaining to knowledge of HIV transmission and non-transmission routes, basic knowledge of HIV/AIDS treatment and attitudes towards HIV/AIDS. Results The study’s response rate was 62.24 percent. Knowledge among pre-clinical medical students was generally high and showed a statistically significant improvement as students progressed through their pre-clinical studies. However, there were some misconceptions, mostly regarding HIV transmission via breastfeeding and knowledge of HIV prevention after exposure to the virus. Students’ attitudes were found to include stigmatizing notions. Furthermore, the majority of medical students correlated HIV with shame and fear. In addition, students’ attitudes toward HIV testing and providing confidential medical information were contradictory to health laws, protocols and guidelines. Overall, no positive changes in students’ attitudes were observed during the pre-clinical years of medical school. Conclusion The knowledge of pre-clinical medical students in Israel is generally high, although there are some knowledge inadequacies that require more emphasis in the curricula of the medical schools. Contrary to HIV-related knowledge, medical students’ attitudes are unaffected by their progression through medical school. Therefore, medical schools in Israel should modify their curricula to include teaching methods aimed at improving HIV-related attitudes and adherence to medical professionalism. PMID:24650351

  19. Adalimumab clinical efficacy is associated with rheumatoid factor and anti-cyclic citrullinated peptide antibody titer reduction: a one-year prospective study

    Microsoft Academic Search

    Fabiola Atzeni; Piercarlo Sarzi-Puttini; Donata Dell' Acqua; Simona de Portu; Germana Cecchini; Carola Cruini; Mario Carrabba; Pier Luigi Meroni

    2006-01-01

    Studies on autoantibody production in patients treated with tumor necrosis factor-? (TNF-?) inhibitors reported contradictory results. We investigated in a prospective study the efficacy of a treatment with human monoclonal anti-TNF-? antibody (adalimumab) in patients with rheumatoid arthritis (RA) and we evaluated the relationship between treatment efficacy and the incidence and titers of disease-associated and non-organ-specific autoantibodies. Fifty-seven patients with

  20. Hapten-specific naïve B cells are biomarkers of vaccine efficacy against drugs of abuse.

    PubMed

    Taylor, J J; Laudenbach, M; Tucker, A M; Jenkins, M K; Pravetoni, M

    2014-03-01

    Vaccination against drugs of abuse shows efficacy in animal models, yet few subjects achieve effective serum antibody titers in clinical studies. A barrier to translation is the lack of pre-vaccination screening assays that predict the most effective conjugate vaccines or subjects amenable to vaccination. To address this obstacle, we developed a fluorescent antigen-based enrichment method paired with flow cytometry to characterize hapten-specific B cells. Using this approach, we studied naïve and activated B cells specific for structurally-related model haptens based on derivatization of the morphinan structure at the C6 position on oxycodone or at the C8 position on hydrocodone, and showing different pre-clinical efficacy against the prescription opioid oxycodone. Prior to vaccination, naïve B cells exhibited relatively higher affinity for the more effective C6-derivatized oxycodone-based hapten (6OXY) and the 6OXY-specific naïve B cell population contained a higher number of B cells with greater affinity for free oxycodone. Higher affinity of naïve B cells for hapten or oxycodone reflected greater efficacy of vaccination in blocking oxycodone distribution to brain in mice. Shortly after immunization, activated hapten-specific B cells were detected prior to oxycodone-specific serum antibodies and provided earlier evidence of vaccine failure or success. Analysis of hapten-specific naïve and activated B cells may aid rational vaccine design and provide screening tools to predict vaccine clinical efficacy against drugs of abuse or other small molecules. PMID:24462800

  1. Phospho-aspirin (MDC-22) inhibits breast cancer in preclinical animal models: an effect mediated by EGFR inhibition, p53 acetylation and oxidative stress

    PubMed Central

    2014-01-01

    Background The anticancer properties of aspirin are restricted by its gastrointestinal toxicity and its limited efficacy. Therefore, we synthesized phospho-aspirin (PA-2; MDC-22), a novel derivative of aspirin, and evaluated its chemotherapeutic and chemopreventive efficacy in preclinical models of triple negative breast cancer (TNBC). Methods Efficacy of PA-2 was evaluated in human breast cancer cells in vitro, and in orthotopic and subcutaneous TNBC xenografts in nude mice. Mechanistic studies were also carried out to elucidate the mechanism of action of PA-2. Results PA-2 inhibited the growth of TNBC cells in vitro more potently than aspirin. Treatment of established subcutaneous TNBC xenografts (MDA-MB-231 and BT-20) with PA-2 induced a strong growth inhibitory effect, resulting in tumor stasis (79% and 90% inhibition, respectively). PA-2, but not aspirin, significantly prevented the development of orthotopic MDA-MB-231 xenografts (62% inhibition). Mechanistically, PA-2: 1) inhibited the activation of epidermal growth factor receptor (EGFR) and suppressed its downstream signaling cascades, including PI3K/AKT/mTOR and STAT3; 2) induced acetylation of p53 at multiple lysine residues and enhanced its DNA binding activity, leading to cell cycle arrest; and 3) induced oxidative stress by suppressing the thioredoxin system, consequently inhibiting the activation of the redox sensitive transcription factor NF-?B. These molecular alterations were observed in vitro and in vivo, demonstrating their relevance to the anticancer effect of PA-2. Conclusions Our findings demonstrate that PA-2 possesses potent chemotherapeutic efficacy against TNBC, and is also effective in its chemoprevention, warranting further evaluation as an anticancer agent. PMID:24575839

  2. Improvement in Stress, General Self-Efficacy, and Health Related Quality of Life following Patient Education for Patients with Neuroendocrine Tumors: A Pilot Study

    PubMed Central

    Haugland, Trude; Veenstra, Marijke; Vatn, Morten H.; Wahl, Astrid K.

    2013-01-01

    The purpose of the study was to evaluate changes in general self-efficacy, health related quality of life (HRQoL), and stress among patients with neuroendocrine tumors (NET) following a multidisciplinary educational intervention. Forty-one patients were enrolled in this exploratory pilot study. A total of 37 patients completed the full 26-week intervention based on the principles of self-efficacy. General self-efficacy was measured by the General Self-Efficacy Scale, HRQoL was measured with the SF-36, and stress was measured with the Impact of Event Scale. Mixed effect models were used to evaluate changes in general self-efficacy, mental and physical components of HRQoL, and stress adjusting for demographic and clinical variables. Results showed significant improvements in patients' general self-efficacy (? = 0.71; P < 0.05), physical component scores of HRQoL (? = 3.09; P < 0.01), and stress (? = ?2.10, P = 0.008). Findings suggest that patients with NET have the capacity to improve their ability to cope with their disease, problem-solve, improve their physical status, and reduce their stress following an educational intervention based on the principles of self-efficacy. These preliminary data provide a basis for future randomized controlled trials to test interventions to improve HRQoL for patients with NET. PMID:23738063

  3. Magnetic resonance imaging of multiple sclerosis: a study of pulse-technique efficacy

    SciTech Connect

    Runge, V.M.; Price, A.C.; Kirshner, H.S.; Allen, J.H.; Partain, C.L.; James, A.E. Jr.

    1984-11-01

    Forty-two patients with the clinical diagnosis of multiple sclerosis were examined by proton magnetic resonance imaging (MRI) at 0.5 T. An extensive protocol was used to facilitate a comparison of the efficacy of different pulse techniques. Results were also compared in 39 cases with high-resolution x-ray computed tomography (CT). MRI revealed characteristic abnormalities in each case, whereas CT was positive in only 15 of 33 patients. Cerebral abnormalities were best shown with the T2-weighted spin-echo sequence: brainstem lesions were best defined on the inversion-recovery sequence.

  4. Interregional compensatory mechanisms of motor functioning in progressing preclinical neurodegeneration

    PubMed Central

    Scheller, Elisa; Abdulkadir, Ahmed; Peter, Jessica; Tabrizi, Sarah J.; Frackowiak, Richard S.J.; Klöppel, Stefan

    2013-01-01

    Understanding brain reserve in preclinical stages of neurodegenerative disorders allows determination of which brain regions contribute to normal functioning despite accelerated neuronal loss. Besides the recruitment of additional regions, a reorganisation and shift of relevance between normally engaged regions are a suggested key mechanism. Thus, network analysis methods seem critical for investigation of changes in directed causal interactions between such candidate brain regions. To identify core compensatory regions, fifteen preclinical patients carrying the genetic mutation leading to Huntington's disease and twelve controls underwent fMRI scanning. They accomplished an auditory paced finger sequence tapping task, which challenged cognitive as well as executive aspects of motor functioning by varying speed and complexity of movements. To investigate causal interactions among brain regions a single Dynamic Causal Model (DCM) was constructed and fitted to the data from each subject. The DCM parameters were analysed using statistical methods to assess group differences in connectivity, and the relationship between connectivity patterns and predicted years to clinical onset was assessed in gene carriers. In preclinical patients, we found indications for neural reserve mechanisms predominantly driven by bilateral dorsal premotor cortex, which increasingly activated superior parietal cortices the closer individuals were to estimated clinical onset. This compensatory mechanism was restricted to complex movements characterised by high cognitive demand. Additionally, we identified task-induced connectivity changes in both groups of subjects towards pre- and caudal supplementary motor areas, which were linked to either faster or more complex task conditions. Interestingly, coupling of dorsal premotor cortex and supplementary motor area was more negative in controls compared to gene mutation carriers. Furthermore, changes in the connectivity pattern of gene carriers allowed prediction of the years to estimated disease onset in individuals. Our study characterises the connectivity pattern of core cortical regions maintaining motor function in relation to varying task demand. We identified connections of bilateral dorsal premotor cortex as critical for compensation as well as task-dependent recruitment of pre- and caudal supplementary motor area. The latter finding nicely mirrors a previously published general linear model-based analysis of the same data. Such knowledge about disease specific inter-regional effective connectivity may help identify foci for interventions based on transcranial magnetic stimulation designed to stimulate functioning and also to predict their impact on other regions in motor-associated networks. PMID:23501047

  5. Fucoidan as a Marine Anticancer Agent in Preclinical Development

    PubMed Central

    Kwak, Jong-Young

    2014-01-01

    Fucoidan is a fucose-containing sulfated polysaccharide derived from brown seaweeds, crude extracts of which are commercially available as nutritional supplements. Recent studies have demonstrated antiproliferative, antiangiogenic, and anticancer properties of fucoidan in vitro. Accordingly, the anticancer effects of fucoidan have been shown to vary depending on its structure, while it can target multiple receptors or signaling molecules in various cell types, including tumor cells and immune cells. Low toxicity and the in vitro effects of fucoidan mentioned above make it a suitable agent for cancer prevention or treatment. However, preclinical development of natural marine products requires in vivo examination of purified compounds in animal tumor models. This review discusses the effects of systemic and local administration of fucoidan on tumor growth, angiogenesis, and immune reaction and whether in vivo and in vitro results are likely applicable to the development of fucoidan as a marine anticancer drug. PMID:24477286

  6. Image Informatics for Clinical and Preclinical Biomedical Analysis

    SciTech Connect

    Tobin Jr, Kenneth William [ORNL; Chaum, Edward [ORNL; Gregor, Jens [ORNL; Karnowski, Thomas Paul [ORNL; Wall, Jonathan [ORNL; Price, Jeffery R [ORNL

    2008-01-01

    Biomedical informatics refers to the study of the application of computational and statistical algorithms, data structures, and methods to improve communication, understanding and management of biomedical information. Our objective through this chapter is to describe and demonstrate our research in the use of biomedical image databases - in both preclinical and clinical settings - to classify, predict, research, diagnose, and otherwise learn from the informational content encapsulated in historical image repositories. This will be accomplished by detailing our approach of describing image content in a Bayesian probabilistic framework to achieve learning from retrieved populations of similar images. We will use specific examples from two biomedical applications to describe anatomic segmentation, statistical feature generation and indexing, efficient retrieval architectures, and predictive results.

  7. Safety and efficacy study with various doses of SS-cream in patients with premature ejaculation in a double-blind, randomized, placebo controlled clinical study

    Microsoft Academic Search

    HK Choi; ZC Xin; YD Choi; WH Lee; SY Mah; DK Kim

    1999-01-01

    Objectives: SS-cream is a topical agent made from the extracts of natural products for treating premature ejaculation (PE). To determine the optimal clinical dosage of SS-cream on PE, we investigated the safety and efficacy of SS-cream with various doses. A double blind, randomized placebo controlled clinical study was performed.Methods: Fifty patients completed the study. Mean age of the patients was

  8. Tris-biphenyl triazine, a new ultraviolet filter studied in terms of photoprotective efficacy.

    PubMed

    Couteau, C; Paparis, E; Chauvet, C; Coiffard, L

    2015-06-20

    There are relatively few authorized ultraviolet filters in Europe and this presents a certain number of problems when we want to formulate a sun protection product which both ensures a high level of protection and respects the recommendations in force in terms of broad-spectrum efficacy, with, in particular, a critical wavelength (?c) greater than or equal to 370nm. A new ultraviolet filter has just been launched on the market. Known as tris-biphenyl triazine, it is the first filter to be registered on Annexe VI of "Cosmetics Regulation" (EC) No. 1223/2009 of the European Parliament and of the Council, which gives a list of the ultraviolet filters allowed in cosmetic products, since the regulation came into force in July 2013. This filter is both very effective (as it enables 2 SPF units and 1 UVA-PF units to be obtained respectively, by percentage of use) and very photostable (since the SPF and UVA-PF do not vary after 2h of irradiation in a solar simulator). Its broad spectrum associated with its qualities in terms of efficacy and photostability make it a choice ingredient for the formulation of sun protection products. PMID:25843762

  9. Multicenter study of long-term (two-year) efficacy of lanthanum carbonate.

    PubMed

    Ando, Ryoichi; Kimura, Hitoshi; Sato, Hidehiko; Iwamoto, Shunsuke; Yoshizaki, Yuki; Chida, Yoshiko; Ishida, Yuji; Takayama, Masanobu; Yamada, Kouei; Tachibana, Ken; Ohtsuka, Masakazu; Kikuchi, Kan; Inoue, Atsushi

    2013-04-01

    Long-term efficacy of lanthanum carbonate on hyperphosphatemia was examined in multicenter dialysis patients. Outcome and efficacy after 2 years was investigated in 101 patients who had undergone lanthanum carbonate administration. Thirty-three cases dropped out by the 2-year point; patients undergoing at least 2 years of administration totaled 68. Reasons for dropping out were as follows: improvement of hyperphosphatemia, nine cases; changing hospitals, seven cases; medical complications, five cases; digestive symptoms, four cases; poor compliance, four cases; parathyroidectomy, two cases; death, two cases. The mean dosage was increased from initial daily dosage of 744?mg to 1266?mg after 1 year, and to 1246?mg after 2 years. Serum phosphate concentration decreased significantly from the initial 6.15?mg to 5.57?mg/dL after 1 year, and to 5.45?mg/dL after 2 years. Although a lowering trend was observed in corrected calcium levels, the difference was not significant. Parathyroid hormone was unchanged. Achievement rate of Japanese Society for Dialysis Therapy (JSDT) management target values for both phosphorus and calcium improved from 32.7% to 50.0% after 1 year, and to 56.5% after 2 years. Lanthanum carbonate is useful as a therapeutic tool for hyperphosphatemia over long durations. PMID:23586506

  10. Review: efficacy of alginate supplementation in relation to appetite regulation and metabolic risk factors: evidence from animal and human studies.

    PubMed

    Georg Jensen, M; Pedersen, C; Kristensen, M; Frost, G; Astrup, A

    2013-02-01

    This review provides a critical update on human and animal studies investigating the effect of alginate supplementation on appetite regulation, glycaemic and insulinemic responses, and lipid metabolism with discussion of the evidence on potential mechanisms, efficacy and tolerability. Dependent on vehicle applied for alginate supplementation, the majority of animal and human studies suggest that alginate consumption does suppress satiety and to some extent energy intake. Only one long-term intervention trial found effects on weight loss. In addition, alginates seem to exhibit beneficial influence on postprandial glucose absorption and insulin response in animals and humans. However, alginate supplementation was only found to have cholesterol-lowering properties in animals. Several mechanisms have been suggested for the positive effect observed, which involve delayed gastric emptying, increased viscosity of digesta and slowed nutrient absorption in the small intestine upon alginate gel formation. Despite reasonable efficacy and tolerability from the acute or short-term studies, we still realize there is a critical need for development of optimal alginate types and vehicles as well as studies on further long-term investigation on alginate supplementation in humans before inferring that it could be useful in the management of obesity and the metabolic syndrome. PMID:23145880

  11. The clinical efficacy of a new tooth whitening dentifrice formulation: a six-month study in adults.

    PubMed

    Singh, Surendra; Mankodi, Suru; Chaknis, Patricia; Petrone, Margaret E; DeVizio, William; Volpe, Anthony R; Proskin, Howard M

    2002-01-01

    The objective of this double-blind clinical study was to investigate the tooth whitening efficacy of a formulation variant of a commercially available dentifrice (Colgate Total Plus Whitening Toothpaste) obtained by the addition of high-cleaning silica, relative to that of its currently marketed formulation (Colgate Total Toothpaste). Following a baseline examination for extrinsic tooth stain, qualifying adult male and female subjects from New Jersey and Florida were randomized into two treatment groups which were balanced for gender, age, and level of extrinsic tooth stain. Subjects were instructed to brush their teeth twice daily (morning and evening) for one minute with their assigned dentifrice using a soft-bristled toothbrush. Examinations for extrinsic tooth stain were repeated after six-weeks', three-months' and six-months' use of the study dentifrices. Eighty-six (86) subjects complied with the protocol and completed the entire study. At the six-month examination, subjects assigned to the new dentifrice formulation group exhibited statistically significantly lower levels of extrinsic tooth stain area and extrinsic tooth stain intensity than did those subjects assigned to the Colgate Total Toothpaste group. Thus, the results of this double-blind clinical study support the conclusion that the new dentifrice formulation variant is efficacious, compared to the control dentifrice, for the removal of extrinsic tooth stain. PMID:11695213

  12. Efficacy of ibuprofen versus lornoxicam after third molar surgery: a randomized, double-blind, crossover pilot study

    Microsoft Academic Search

    Francine D. Lustenberger; Klaus W. Grätz; Till S. Mutzbauer

    2011-01-01

    Purpose  The aim of this study is to compare the analgesic efficacy and tolerability of a pre-emptive\\/post-surgery 4-day regimen of\\u000a oral ibuprofen 400 mg with that of lornoxicam 8 mg.\\u000a \\u000a \\u000a \\u000a \\u000a Methods  Sixteen patients received ibuprofen or lornoxicam, respectively, before and after surgery of impacted third molars in two\\u000a separate appointments, in a double-blind, randomized, and crossover design. The postoperative analgesic and rescue medication\\u000a consumption

  13. [Isokinetic evaluation and gait