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1

Preclinical animal efficacy studies and drug development  

E-print Network

statistics, biased reporting etc Most of these major issues are caught during peer-review. Most journals do set of standards that will fit *all* studies. Limits to journals' power: Journals rely on peerPreclinical animal efficacy studies and drug development Most basic science journals do

2

Protective efficacy of Modified Vaccinia virus Ankara in preclinical studies.  

PubMed

Modified Vaccinia virus Ankara (MVA) is a tissue culture-derived, highly attenuated strain of vaccinia virus (VACV) exhibiting characteristic defective replication in cells from mammalian hosts. In the 1960s MVA was originally generated as a candidate virus for safer vaccination against smallpox. Now, MVA is widely used in experimental vaccine development targeting important infectious diseases and cancer. Versatile technologies for genetic engineering, large-scale production, and quality control facilitate R&D of recombinant and non-recombinant MVA vaccines matching today's requirements for new biomedical products. Such vaccines are attractive candidates for delivering antigens from pathogens against which no, or no effective vaccine is available, including emerging infections caused by highly pathogenic influenza viruses, chikungunya virus, West Nile virus or zoonotic orthopoxviruses. Other directions are seeking valuable vaccines against highly complex diseases such as AIDS, malaria, and tuberculosis. Here, we highlight examples of MVA candidate vaccines against infectious diseases, and review the efforts made to assess both the efficacy of vaccination and immune correlates of protection in preclinical studies. PMID:23523402

Volz, Asisa; Sutter, Gerd

2013-09-01

3

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

PubMed Central

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

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

2011-01-01

4

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

PubMed

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

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

2014-01-01

5

Combined analysis of pharmacokinetic and efficacy data of preclinical studies with statins markedly improves translation of drug efficacy to human trials.  

PubMed

Correct prediction of human pharmacokinetics (PK) and the safety and efficacy of novel compounds based on preclinical data, is essential but often fails. In the current study, we aimed to improve the predictive value of ApoE*3Leiden (E3L) transgenic mice regarding the cholesterol-lowering efficacy of various statins in humans by combining pharmacokinetic with efficacy data. The efficacy of five currently marketed statins (atorvastatin, simvastatin, lovastatin, pravastatin, and rosuvastatin) in hypercholesterolemic patients (low-density lipoprotein ? 160 mg/dl) was ranked based on meta-analysis of published human trials. Additionally, a preclinical combined PK efficacy data set for these five statins was established in E3L mice that were fed a high-cholesterol diet for 4 weeks, followed by 6 weeks of drug intervention in which statins were supplemented to the diet. Plasma and tissue levels of the statins were determined on administration of (radiolabeled) drugs (10 mg/kg p.o.). As expected, all statins reduced plasma cholesterol in the preclinical model, but a direct correlation between cholesterol lowering efficacy of the different statins in mice and in humans did not reach statistical significance (R(2) = 0.11, P < 0.57). It is noteworthy that, when murine data were corrected for effective liver uptake of the different statins, the correlation markedly increased (R(2) = 0.89, P < 0.05). Here we show for the first time that hepatic uptake of statins is related to their cholesterol-lowering efficacy and provide evidence that combined PK and efficacy studies can substantially improve the translational value of the E3L mouse model in the case of statin treatment. This strategy may also be applicable for other classes of drugs and other preclinical models. PMID:24049060

van de Steeg, E; Kleemann, R; Jansen, H T; van Duyvenvoorde, W; Offerman, E H; Wortelboer, H M; Degroot, J

2013-12-01

6

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

PubMed Central

Purpose To assess the safety and efficacy of chronic electrical stimulation of the retina with a suprachoroidal visual prosthesis. Methods Seven normally-sighted feline subjects were implanted for 96–143 days with a suprachoroidal electrode array and six were chronically stimulated for 70–105 days at levels that activated the visual cortex. Charge balanced, biphasic, current pulses were delivered to platinum electrodes in a monopolar stimulation mode. Retinal integrity/function and the mechanical stability of the implant were assessed monthly using electroretinography (ERG), optical coherence tomography (OCT) and fundus photography. Electrode impedances were measured weekly and electrically-evoked visual cortex potentials (eEVCPs) were measured monthly to verify that chronic stimuli were suprathreshold. At the end of the chronic stimulation period, thresholds were confirmed with multi-unit recordings from the visual cortex. Randomized, blinded histological assessments were performed by two pathologists to compare the stimulated and non-stimulated retina and adjacent tissue. Results All subjects tolerated the surgical and stimulation procedure with no evidence of discomfort or unexpected adverse outcomes. After an initial post-operative settling period, electrode arrays were mechanically stable. Mean electrode impedances were stable between 11–15 k? during the implantation period. Visually-evoked ERGs & OCT were normal, and mean eEVCP thresholds did not substantially differ over time. In 81 of 84 electrode-adjacent tissue samples examined, there were no discernible histopathological differences between stimulated and unstimulated tissue. In the remaining three tissue samples there were minor focal fibroblastic and acute inflammatory responses. Conclusions Chronic suprathreshold electrical stimulation of the retina using a suprachoroidal electrode array evoked a minimal tissue response and no adverse clinical or histological findings. Moreover, thresholds and electrode impedance remained stable for stimulation durations of up to 15 weeks. This study has demonstrated the safety and efficacy of suprachoroidal stimulation with charge balanced stimulus currents. PMID:24853376

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

2014-01-01

7

An Independent Study of the Preclinical Efficacy of C2-8 in the R6/2 Transgenic Mouse Model of Huntington's Disease  

PubMed Central

Background C2-8 is a small molecule inhibitor of polyglutamine aggregation and can reduce photoreceptor neurodegeneration in a Drosophila model of Huntington's disease (HD). Further preclinical studies have shown that oral administration of C2-8 in R6/2 HD transgenic mice can penetrate into the brain, reduce mHTT-exon1 aggregation, improve motor performance and diminish striatal neuron atrophy. Objective In this independent preclinical study, we aimed to evaluate the pharmacokinetic properties and therapeutic efficacy of C2-8 intraperitoneal (IP) delivery in the R6/2 HD mouse. Methods R6/2 mice were IP injected with low dose C2-8 (10 mg/kg), high dose C2-8 (20 mg/kg), or vehicle twice daily from 3 weeks to 3 months old. Longitudinal behavioral tests (accelerating Rotarod and wire-hang) were performed to evaluate the motor deficits, and neuropathology was measured by unbiased stereology. Results We confirmed that the compound has good blood-brain-barrier penetration after acute or sub-chronic intraperitoneal delivery. Chronic treatment with C2-8 in R6/2 mice results in a significant reduction of nuclear mHTT aggregate volume in the brains, replicating a key finding of C2-8 as a polyglutamine aggregation inhibitor in vivo. However, by comparing HD mice with C2-8 treatment to those with vehicle treatment, we were unable to demonstrate significant amelioration of motor deficits using Rotarod and wire-hang tests. Moreover, we did not observe improvement in the striatal neurodegenerative pathology, as measured by brain weight, striatal volume, and striatal neuron volume in the C2-8 treated R6/2 mice. Conclusions Our study supports the practice of independent preclinical studies for novel molecules in HD therapeutic development and suggests that the use of alternative delivery strategies and full-length HD mouse models are likely needed to further assess whether the aggregate-inhibiting properties of C2-8 can be consistently translated into a preclinical benefit in HD mice. PMID:25062731

Wang, Nan; Lu, Xiao-Hong; Sandoval, Susana V.; Yang, X. William

2014-01-01

8

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

NASA Astrophysics Data System (ADS)

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.

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

2014-02-01

9

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

SciTech Connect

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.

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

10

[Preclinical toxicological study of ecorsin].  

PubMed

A new drug preparation ecorsin based on the dry aspen bark extract was studied for toxicological safety on a preclinical stage. The drug exhibited no toxicity upon a single administration to rats and mice (both male and female). The intragastric administration of ecorsin for 3 months to rats (at a daily dose of 50, 250, and 500 mg/kg) and rabbits (25 and 50 mg/kg) led to neither functional not morphological changes in hemopoietic and lymphoid organs, liver, kidney, heart, digestive system, and CNS. The long-term administration resulted in a partial atrophic modification of convoluted seminiferous tubules in impuberal male rats, while not affecting the testes of aged animals. The administration of ecorsin at 50, 250, and 500 mg/kg led to dose-dependent changes in some characteristics of the reproductive capacity in rats. Ecorsin did not modify the extent of allergic reactions and produced no immunotoxicant and mutagen effects. PMID:11022311

Karpova, G V; Fomina, T I; Vetoshkina, T V; Borovskaia, T G; Voronova, O L; Dubskaia, T Iu; Poluéktova, M E; Timina, E A; Smol'ianinov, E S; Turetskova, V F

2000-01-01

11

[Preclinical study of noopept toxicity].  

PubMed

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

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

12

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

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

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

13

[Preclinical study of maxar safety].  

PubMed

The results of preclinical safety evaluation of the new hepatoprotector maxar showed that this drug can be classified as a low-toxicity substance with respect to acute toxicity. No significant functional and structural changes in the systems and organs of experimental animals were observed after a 6-month administration in rats (in a dose of 300, 600, and 1200 mg/kg) and in dogs (500 mg/kg). Maxar exhibited no mutagen and allergen properties, produced no immunotoxicant action, and did not adversely affect the reproduction function. PMID:14743714

Saratikov, A S; Livshits, N S; Burchenkova, F I; Kadychagova, N G; Akhmedzhanov, R R; Bashirova, L V

2003-01-01

14

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

PubMed

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

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

2014-08-01

15

USHERING IN THE STUDY AND TREATMENT OF PRECLINICAL ALZHEIMER DISEASE  

PubMed Central

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

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

2014-01-01

16

Preclinical Efficacy of the Camptothecin-Polymer Conjugate IT101 in Multiple Cancer Models  

Microsoft Academic Search

Preclinical efficacy of i.v. IT-101, a nanoparticulate conjugate of 20(S)-camptothecin and a cyclo- dextrin-based polymer, was investigated in several mouse xenografts.The effects of different mul- tiple dosing schedules on tumor growth of LS174Tcolon carcinoma xenografts are elucidated. All multiple dosing schedules administered over15 to19 days resulted in enhanced efficacy compared with untreated or single-dose groups. Further improvements in antitumor efficacy

Thomas Schluep; Jungyeong Hwang; Jianjun Cheng; Jeremy D. Heidel; Derek W. Bartlett; Beth Hollister; Mark E. Davis

17

A review of preclinical animal models utilised for TB vaccine evaluation in the context of recent human efficacy data?  

PubMed Central

Summary There is an urgent need for an improved TB vaccine. Vaccine development is hindered by the lack of immune correlates and uncertain predictive value of preclinical animal models. As data become available from human efficacy trials, there is an opportunity to evaluate the predictive value of the criteria used to select candidate vaccines. Here we review the efficacy in animal models of the MVA85A candidate vaccine in light of recent human efficacy data and propose refinements to the preclinical models with the aim of increasing their predictive value for human efficacy. PMID:24369986

McShane, Helen; Williams, Ann

2014-01-01

18

[Efficacy studies].  

PubMed

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

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

2014-07-01

19

Preclinical Efficacy Testing for Stomach and Liver Cancers  

PubMed Central

Purpose Hollow fiber assays offer an early in vivo method of anticancer drug screening. The assays have been optimized for human cancers originating from the lung, breast, colon, ovary, and brain, but not from the stomach and liver. The current study focused on optimization of hollow fiber assays for gastric and hepatocellular carcinoma cell lines. Materials and Methods Gastric (SNU-16, SNU-484, SNU-668) and hepatocellular (HepG2, SK-Hep-1, Hep3B) carcinoma cell lines in hollow fibers were transplanted subcutaneously and intraperitoneally into mice, which were subsequently treated with a standard anticancer agent, paclitaxel. The hollow fiber activity of paclitaxel in each cell line was compared with the xenograft activity. Results Using optimized inoculation densities and schedules, treatment with paclitaxel was effective in gastric carcinoma cell lines, SNU-16 and SNU-484, but not in SNU-668. In the hollow fiber assays, paclitaxel was effective in hepatocellular carcinoma cell lines, HepG2 and SK-Hep-1, but not in Hep3B. Consistent with the results of the hollow fiber assay, SNU-16 and SNU-484, but not SNU-668, showed tumor regression, and HepG2 and SK-Hep-1, but not Hep3B, showed effective tumor responses following treatment with paclitaxel in xenograft models. When EW7197, a novel compound, and flavopiridol were tested in SNU-16 cells under optimized conditions, the hollow fiber activity showed good correlation with the xenograft activity of each compound. Conclusion Our protocols may be useful for screening candidate small molecules that may exhibit activity against stomach and liver cancers, both of which are common in Korea. PMID:24851111

Park, Jun Won; Baek, Nam Suk; Lee, Seok Cheol; Oh, Su Jin; Jang, Seok Hoon; Kim, In Hoo

2014-01-01

20

Preclinical studies of alcohol binge drinking  

PubMed Central

Binge drinking is prevalent and has serious biomedical consequences. In children, adolescents, and young adults, it is a prominent risk factor for later development of alcohol-use disorders. Many preclinical models have been employed to study the genetic risks for and biomedical consequences of alcohol drinking. However, these models historically did not result in blood-alcohol concentrations (BACs) exceding 80 mg%; this relatively modest level is the threshold that currently defines a binge session, according to the NIAAA and CDC. Nevertheless, in alcohol-dependent rodents, binge drinking has been well documented. Key neurobiological substrates localized to brain reward and stress systems have been identified. Studies of newer models of binge drinking without dependence are reviewed here. In these models, rodents, non-human primates, and flies will drink enough to reach high BACs. They often display observable signs of intoxication. The neurobiological consequences of these episodes of binge drinking without dependence are reviewed, preliminary evidence for roles for GABA, glutamate, opioid peptides, and corticotropin releasing factor are discussed, as is the need for more work to identify the antecedents and consequences of binge drinking in both animal models and humans. PMID:21272009

Crabbe, John C.; Harris, R. Adron; Koob, George F.

2011-01-01

21

Preclinical pharmacology, toxicology and efficacy of sphingomyelin\\/cholesterol liposomal vincristine for therapeutic treatment of cancer  

Microsoft Academic Search

Purpose: To establish the pharmacodynamic relationships between drug biodistribution and drug toxicity\\/efficacy, a comprehensive\\u000a preclinical evaluation of sphingomyelin\\/cholesterol (SM\\/chol) liposomal vincristine and unencapsulated vincristine in mice\\u000a was undertaken. Methods: Pharmaceutically acceptable formulations of unencapsulated vincristine and liposomal vincristine at drug\\/lipid ratios of\\u000a 0.05 or 0.10 (wt\\/wt) were evaluated for toxicity, antitumor activity and pharmacokinetics following intravenous administration.\\u000a Results: Mice given

Murray S. Webb; Patricia Logan; Peter M. Kanter; Ginette St.-Onge; Karen Gelmon; Troy Harasym; Lawrence D. Mayer; Marcel B. Bally

1998-01-01

22

Novel Lignan and Stilbenoid Mixture Shows Anticarcinogenic Efficacy in Preclinical PC-3M-luc2 Prostate Cancer Model  

PubMed Central

Prostate cancer is the most common cancer of men in the Western world, and novel approaches for prostate cancer risk reduction are needed. Plant-derived phenolic compounds attenuate prostate cancer growth in preclinical models by several mechanisms, which is in line with epidemiological findings suggesting that consumption of plant-based diets is associated with low risk of prostate cancer. The objective of this study was to assess the effects of a novel lignan-stilbenoid mixture in PC-3M-luc2 human prostate cancer cells in vitro and in orthotopic xenografts. Lignan and stilbenoid –rich extract was obtained from Scots pine (Pinus sylvestris) knots. Pine knot extract as well as stilbenoids (methyl pinosylvin and pinosylvin), and lignans (matairesinol and nortrachelogenin) present in pine knot extract showed antiproliferative and proapoptotic efficacy at ?40 ?M concentration in vitro. Furthermore, pine knot extract derived stilbenoids enhanced tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induced apoptosis already at ?10 ?M concentrations. In orthotopic PC-3M-luc2 xenograft bearing immunocompromized mice, three-week peroral exposure to pine knot extract (52 mg of lignans and stilbenoids per kg of body weight) was well tolerated and showed anti-tumorigenic efficacy, demonstrated by multivariate analysis combining essential markers of tumor growth (i.e. tumor volume, vascularization, and cell proliferation). Methyl pinosylvin, pinosylvin, matairesinol, nortrachelogenin, as well as resveratrol, a metabolite of pinosylvin, were detected in serum at total concentration of 7?73 ?M, confirming the bioavailability of pine knot extract derived lignans and stilbenoids. In summary, our data indicates that pine knot extract is a novel and cost-effective source of resveratrol, methyl pinosylvin and other bioactive lignans and stilbenoids. Pine knot extract shows anticarcinogenic efficacy in preclinical prostate cancer model, and our in vitro data suggests that compounds derived from the extract may have potential as novel chemosensitizers to TRAIL. These findings promote further research on health-related applications of wood biochemicals. PMID:24699425

Laajala, Teemu D.; Smeds, Annika; Eckerman, Christer; Holmbom, Bjarne; Saarinen, Niina M.; Aittokallio, Tero; Mäkelä, Sari I.

2014-01-01

23

Chemical and preclinical studies on Hedyotis diffusa with anticancer potential.  

PubMed

This paper presents the chemical and preclinical anticancer research on Hedyotis diffusa Willd. in detail, one of the most renowned herbs often prescribed in the polyherbal formulas for cancer treatment in traditional Chinese medicine. Anthraquinones, flavonoids, and terpenoids constitute the majority of the 69 compounds that have been isolated and identified from H. diffusa. The anticancer effects of the methanolic, ethanolic, and aqueous extracts in various preclinical cancer models have been described. This review also summarized the anticancer activity of constituents of the herb and the mechanisms of action. All the studies suggest that H. diffusa has enormous potential in the therapy of cancer and warrants further chemical and pharmacological investigation. PMID:23600735

Niu, Yu; Meng, Qiu-Xia

2013-01-01

24

Analgesia in Amphibians: Preclinical Studies and Clinical Applications  

PubMed Central

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

Stevens, Craig W.

2010-01-01

25

PRECLINICAL STUDY Prediction of lymph node involvement in breast cancer  

E-print Network

PRECLINICAL STUDY Prediction of lymph node involvement in breast cancer from primary tumor tissue- ther lymph node involvement in breast cancer is influenced by gene or miRNA expression of the primary tissue from a group of 96 breast cancer patients balanced for lymph node involvement using Affymetrix

26

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

PubMed

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

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

2014-10-01

27

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

PubMed Central

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

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

28

Eritoran tetrasodium (E5564) Treatment for Sepsis: Review of Preclinical and Clinical Studies  

PubMed Central

Introduction Sepsis remains a leading cause of death worldwide. Despite years of extensive research, effective drugs that inhibit the pro-inflammatory effects of lipopolysaccharide (LPS) and improve outcome when added to conventional sepsis treatments are lacking. Eritoran tetrasodium (E5564) is a promising candidate therapy for sepsis belonging to a new class of such drugs which inhibit LPS-induced inflammation by blocking toll-like receptor 4 (TLR4). Areas covered This review focuses on the rationale for the use of eritoran tetrasodium in sepsis, as well as on its pharmacokinetics, pharmacodynamics, efficacy and safety. Pre-clinical and clinical studies from a MEDLINE/PubMed literature search in August 2010 with the search terms “eritoran” and “E5564” are discussed. Expert opinion Preclinical in vitro and in vivo studies of eritoran tetrasodium indicate it can limit excessive inflammatory mediator release associated with LPS, and improve survival in sepsis models. While early clinical results are promising, its efficacy and safety for treating patients with sepsis is currently under investigation. Even if the ongoing phase III clinical trial enrolling patients with severe sepsis and increased risk of death shows benefit from eritoran, questions remain and confirmatory studies will be necessary to define its clinical usage. PMID:21323610

Barochia, Amisha; Solomon, Steven; Cui, Xizhong; Natanson, Charles; Eichacker, Peter Q

2011-01-01

29

Pharmacological Intervention Studies Using Mouse Models of the Inflammatory Bowel Diseases: Translating Preclinical Data into New Drug Therapies  

PubMed Central

Most therapeutic agents used in clinical practice today were originally developed and tested in animal models so that drug toxicity and safety, dose-responses and efficacy could be determined. Retrospective analyses of preclinical intervention studies using animal models of different diseases demonstrate that only a small percentage of the interventions reporting promising effects translate to clinical efficacy. The failure to translate therapeutic efficacy from bench to bedside may be due, in part, to shortcomings in the design of the clinical studies; however, it is becoming clear that much of the problem resides within the preclinical studies. One potential strategy for improving our ability to identify new therapeutics that may have a reasonable chance of success in well-controlled clinical trials is to identify the most relevant mouse models IBD and pharmacologic strategies that most closely mimic the clinical situation. To begin this process, we present a critical evaluation of the different mouse models and pharmacological approaches that may be used in intervention studies as well as discuss emerging issues related to study design and data interpretation of preclinical studies. PMID:21312318

Koboziev, Iurii; Karlsson, Fridrik; Zhang, Songlin; Grisham, Matthew B.

2010-01-01

30

Preclinical efficacy of growth hormone-releasing hormone antagonists for androgen-dependent and castration-resistant human prostate cancer.  

PubMed

Advanced hormone-sensitive prostate cancer responds to androgen-deprivation therapy (ADT); however, therapeutic options for recurrent castration-resistant disease are limited. Because growth hormone-releasing hormone (GHRH) and GHRH receptor (GHRH-R) are regulated in an autocrine fashion in prostate cancer, inhibition of GHRH-R represents a compelling approach to treatment. We investigated the effects of the latest series of improved, highly potent GHRH antagonists--MIA-602, MIA-606, and MIA-690--on the growth of androgen-dependent as well as castration-resistant prostate cancer (CRPC) cells in vitro and in vivo. GHRH-R and its splice variant, SV1, were present in 22Rv1, LNCaP, and VCaP human prostate cancer cell lines. Androgen-dependent LNCaP and VCaP cells expressed higher levels of GHRH-R protein compared with castration-resistant 22Rv1 cells; however, 22Rv1 expressed higher levels of SV1. In vitro, MIA-602 decreased cell proliferation of 22Rv1, LNCaP, and VCaP prostate cancer cell lines by 70%, 61%, and 20%, respectively (all P < 0.05), indicating direct effects of MIA-602. In vivo, MIA-602 was more effective than MIA-606 and MIA-690 and decreased 22Rv1 xenograft tumor volumes in mice by 63% after 3 wk (P < 0.05). No noticeable untoward effects or changes in body weight occurred. In vitro, the VCaP cell line was minimally inhibited by MIA-602, but in vivo, this line showed a substantial reduction in growth of xenografts in response to MIA-602, indicating both direct and systemic inhibitory effects. MIA-602 also further inhibited VCaP xenografts when combined with ADT. This study demonstrates the preclinical efficacy of the GHRH antagonist MIA-602 for treatment of both androgen-dependent and CRPC. PMID:24395797

Fahrenholtz, Cale D; Rick, Ferenc G; Garcia, Maria I; Zarandi, Marta; Cai, Ren-Zhi; Block, Norman L; Schally, Andrew V; Burnstein, Kerry L

2014-01-21

31

Preclinical efficacy of growth hormone-releasing hormone antagonists for androgen-dependent and castration-resistant human prostate cancer  

PubMed Central

Advanced hormone-sensitive prostate cancer responds to androgen-deprivation therapy (ADT); however, therapeutic options for recurrent castration-resistant disease are limited. Because growth hormone-releasing hormone (GHRH) and GHRH receptor (GHRH-R) are regulated in an autocrine fashion in prostate cancer, inhibition of GHRH-R represents a compelling approach to treatment. We investigated the effects of the latest series of improved, highly potent GHRH antagonists—MIA-602, MIA-606, and MIA-690—on the growth of androgen-dependent as well as castration-resistant prostate cancer (CRPC) cells in vitro and in vivo. GHRH-R and its splice variant, SV1, were present in 22Rv1, LNCaP, and VCaP human prostate cancer cell lines. Androgen-dependent LNCaP and VCaP cells expressed higher levels of GHRH-R protein compared with castration-resistant 22Rv1 cells; however, 22Rv1 expressed higher levels of SV1. In vitro, MIA-602 decreased cell proliferation of 22Rv1, LNCaP, and VCaP prostate cancer cell lines by 70%, 61%, and 20%, respectively (all P < 0.05), indicating direct effects of MIA-602. In vivo, MIA-602 was more effective than MIA-606 and MIA-690 and decreased 22Rv1 xenograft tumor volumes in mice by 63% after 3 wk (P < 0.05). No noticeable untoward effects or changes in body weight occurred. In vitro, the VCaP cell line was minimally inhibited by MIA-602, but in vivo, this line showed a substantial reduction in growth of xenografts in response to MIA-602, indicating both direct and systemic inhibitory effects. MIA-602 also further inhibited VCaP xenografts when combined with ADT. This study demonstrates the preclinical efficacy of the GHRH antagonist MIA-602 for treatment of both androgen-dependent and CRPC. PMID:24395797

Fahrenholtz, Cale D.; Rick, Ferenc G.; Garcia, Maria I.; Zarandi, Marta; Cai, Ren-Zhi; Block, Norman L.; Schally, Andrew V.; Burnstein, Kerry L.

2014-01-01

32

Resveratrol: A review of preclinical studies for human cancer prevention  

SciTech Connect

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

Athar, Mohammad; Back, Jung Ho; Tang Xiuwei [Department of Dermatology, College of Physicians and Surgeons, Columbia University, 630 West 168th Street VC15-204, New York, NY 10032 (United States); Kim, Kwang Ho [Department of Dermatology, Hallym University College of Medicine (Korea, Republic of); Kopelovich, Levy [Division of Cancer Prevention, National Cancer Institute, Bethesda, MD 20892 (United States); Bickers, David R. [Department of Dermatology, College of Physicians and Surgeons, Columbia University, 630 West 168th Street VC15-204, New York, NY 10032 (United States); Kim, Arianna L. [Department of Dermatology, College of Physicians and Surgeons, Columbia University, 630 West 168th Street VC15-204, New York, NY 10032 (United States)], E-mail: ak309@columbia.edu

2007-11-01

33

The Efficacy of the Ribonucleotide Reductase Inhibitor Didox in Preclinical Models of AML  

PubMed Central

Acute Myeloid Leukemia (AML) is an aggressive malignancy which leads to marrow failure, and ultimately death. There is a desperate need for new therapeutics for these patients. Ribonucleotide reductase (RR) is the rate limiting enzyme in DNA synthesis. Didox (3,4-Dihydroxybenzohydroxamic acid) is a novel RR inhibitor noted to be more potent than hydroxyurea. In this report we detail the activity and toxicity of Didox in preclinical models of AML. RR was present in all AML cell lines and primary patient samples tested. Didox was active against all human and murine AML lines tested with IC50 values in the low micromolar range (mean IC50 37 µM [range 25.89–52.70 µM]). It was active against primary patient samples at concentrations that did not affect normal hematopoietic stem cells (HSCs). Didox exposure resulted in DNA damage and p53 induction culminating in apoptosis. In syngeneic, therapy-resistant AML models, single agent Didox treatment resulted in a significant reduction in leukemia burden and a survival benefit. Didox was well tolerated, as marrow from treated animals was morphologically indistinguishable from controls. Didox exposure at levels that impaired leukemia growth did not inhibit normal HSC engraftment. In summary, Didox was well tolerated and effective against preclinical models of AML. PMID:25402485

Cook, Guerry J.; Caudell, David L.; Elford, Howard L.; Pardee, Timothy S.

2014-01-01

34

Pegylated liposomal doxorubicin: proof of principle using preclinical animal models and pharmacokinetic studies.  

PubMed

Encapsulation of doxorubicin in polyethylene glycol-coated liposomes (Doxil/Caelyx [PLD]), was developed to enhance the safety and efficacy of conventional doxorubicin. The liposomes alter pharmacologic and pharmacokinetic parameters of conventional doxorubicin so that drug delivery to the tumor is enhanced while toxicity normally associated with conventional doxorubicin is decreased. In animals and humans, pharmacokinetic advantages of PLD include an increased area under the plasma concentration-time curve, longer distribution half-life, smaller volume of distribution, and reduced clearance. In preclinical models, PLD produced remission and cure against many cancers including tumors of the breast, lung, ovaries, prostate, colon, bladder, and pancreas, as well as lymphoma, sarcoma, and myeloma. It was also found to be effective as adjuvant therapy. In addition, it was found to cross the blood-brain barrier and induce remission in tumors of the central nervous system. Increased potency over conventional doxorubicin was observed and, in contrast to conventional doxorubicin, PLD was equally effective against low- and high-growth fraction tumors. The combination of PLD with vincristine or trastuzumab resulted in additive effects and possible synergy. PLD appeared to overcome multidrug resistance, possibly as the result of increased intracellular concentrations and an interaction between the liposome and P-glycoprotein function. On the basis of pharmacokinetic and preclinical studies, PLD, either alone or as part of combination therapy, has potential applications to treat a variety of cancers. PMID:15717736

Vail, David M; Amantea, Michael A; Colbern, Gail T; Martin, Francis J; Hilger, Ralf A; Working, Peter K

2004-12-01

35

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

PubMed

Neurofibromatosis type I (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 (MPNST), 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. Radiotherapy is another treatment option, but is undesirable because it can induce additional mutations. Patients with MPNST 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 nontoxic 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

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

2014-01-15

36

Novel technology to prepare oral formulations for preclinical safety studies.  

PubMed

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

Niwa, Toshiyuki; Hashimoto, Naofumi

2008-02-28

37

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

Microsoft Academic Search

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

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

2003-01-01

38

A crowdsourcing model for creating preclinical medical education study tools.  

PubMed

During their preclinical course work, medical students must memorize and recall substantial amounts of information. Recent trends in medical education emphasize collaboration through team-based learning. In the technology world, the trend toward collaboration has been characterized by the crowdsourcing movement. In 2011, the authors developed an innovative approach to team-based learning that combined students' use of flashcards to master large volumes of content with a crowdsourcing model, using a simple informatics system to enable those students to share in the effort of generating concise, high-yield study materials. The authors used Google Drive and developed a simple Java software program that enabled students to simultaneously access and edit sets of questions and answers in the form of flashcards. Through this crowdsourcing model, medical students in the class of 2014 at the Johns Hopkins University School of Medicine created a database of over 16,000 questions that corresponded to the Genes to Society basic science curriculum. An analysis of exam scores revealed that students in the class of 2014 outperformed those in the class of 2013, who did not have access to the flashcard system, and a survey of students demonstrated that users were generally satisfied with the system and found it a valuable study tool. In this article, the authors describe the development and implementation of their crowdsourcing model for creating study materials, emphasize its simplicity and user-friendliness, describe its impact on students' exam performance, and discuss how students in any educational discipline could implement a similar model of collaborative learning. PMID:23619061

Bow, Hansen C; Dattilo, Jonathan R; Jonas, Andrea M; Lehmann, Christoph U

2013-06-01

39

Preclinical Studies of Signaling Pathways in a Mutant Mouse Model of Hormone-Refractory Prostate Cancer.  

National Technical Information Service (NTIS)

We have been investigating targeted therapies for the treatment of advanced prostate cancer using a genetically-engineered mouse model of the disease. Based on previous studies, we performed pre-clinical studies to examine the consequences of combinatoria...

C. Abate-Shen

2011-01-01

40

Preclinical Studies of Signaling Pathways in a Mutant Mouse Model of Hormone-Refractory Prostate Cancer.  

National Technical Information Service (NTIS)

We have been investigating targeted therapies for the treatment of advanced prostate cancer using a genetically engineered mouse model of the disease. Based on previous studies, we performed pre-clinical studies to examine the consequences of combinatoria...

C. Abate-Shen

2009-01-01

41

Preclinical safety studies on autologous cultured human skin fibroblast transplantation.  

PubMed

Recently, FDA approved the clinical use of autologous fibroblasts (LAVIV™) for the improvement of nasolabial fold wrinkles in adults. The use of autologous fibroblasts for the augmentation of dermal and subcutaneous defects represents a potentially exciting natural alternative to the use of other filler materials for its long-term corrective ability and absence of allergic adverse effects proved by clinical application. However, compared to the clinical evidence, preclinical studies are far from enough. In this study, human skin-derived fibroblasts were cultured and expanded for both in vitro and in vivo observations. In vitro, the subcultured fibroblasts were divided into two groups. One set of cells underwent cell cycle and karyotype analysis at passages 5 and 10. The second group of cells was cocultured in medium with different concentrations of human skin extract D for the measurement of collagen concentration and cell count. In vivo, the subcultured fibroblasts were injected into nude mice subcutaneously. Biopsies were taken for morphology observation and specific collagen staining at 1, 2, and 3 months after injection. The results in vitro showed no significant differences in cell cycle distribution between passages 5 and 10. Cell proliferation and secretion were inhibited as the concentration of extract D increased. In vivo, the fibroblasts were remarkably denser on the experimental side with no dysplastic cells. Mitotic cells were easily observed at the end of the first month but were rare at the end of the third month. Type III collagen was detected at the end of the first month, while collagen type I was positive at the end of the second month. The content of both collagens increased as time passed. The above results indicated that the use of the autologous fibroblasts was safe, providing a basic support for clinical use of fibroblasts. PMID:23211390

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

2014-01-01

42

Preclinical safety studies of the combination moexipril hydrochloride/hydrochlorothiazide.  

PubMed

The general pharmacological properties of a combination of the angiotensin converting enzyme (ACE) inhibitor moexipril hydrochloride (CAS 82586-52-5) and the thiazide diuretic hydrochlorothiazide (CAS 58-93-5, HCTZ), ratio 7.5 + 12.5, were studied in generally accepted models in vitro and in vivo. In vitro, the combination showed neither agonistic nor antagonistic activities on the isolated guinea pig trachea in concentrations up to 2 x 10(-4) g/ml. In mice, there was no effect on intestinal motility or the thiopental-induced sleeping time up to 1000 mg/kg. The only activity observed in mice was an inhibition of spontaneous motility after oral dosing with 300 and 1000 mg/kg, respectively. Both HCTZ (1-10 mg/kg) alone and the combination moexipril/HCTZ (1.6 or 4.8 mg/kg) produced dose-related increases in diuresis and electrolyte excretion in rats, however, without any potentiating effects for the drug combination. On the cardiovascular system of anaesthetised dogs, the effects observed were as expected, e.g. dose-related decrease in blood pressure. Repeated dose toxicity studies in rats and dogs revealed the kidney as target organ. This effect, based on highly exaggerated pharmacological activity, is well-known for other ACE inhibitors. No potential for teratogenic effects could be observed for the drug combination. In summary, the preclinical data indicate that the combination of moexipril and HCTZ (ratio 7.5 + 12.5) represents a safe drug without relevant side effects or gross toxicity. PMID:9608878

Gietl, R; Friehe, H; Ney, P

1998-04-01

43

Mouse Model for the Preclinical Study of Metastatic Disease  

Cancer.gov

The successful development of new cancer therapeutics requires reliable preclinical data that are obtained from mouse models for cancer. Human tumor xenografts, which require transplantation of human tumor cells into an immune compromised mouse, represent the current standard mouse model for cancer. Since the immune system plays an important role in tumor growth, progression and metastasis, the current standard mouse model is not ideal for accurate prediction of therapeutic effectiveness in patients.

44

Preclinical efficacy of the synthetic retinoid ST1926 for treating adult T-cell leukemia/lymphoma.  

PubMed

Adult T-cell leukemia/lymphoma (ATL) is an aggressive neoplasm caused by human T-cell leukemia virus type 1 (HTLV-1). The HTLV-1 oncoprotein Tax plays an important role in ATL pathogenesis. ATL carries a poor prognosis due to chemotherapy resistance, stressing the need for alternative therapies. Here, we investigate the preclinical efficacy of the synthetic retinoid ST1926 in ATL and peripheral T-cell lymphomas. Clinically achievable concentrations of ST1926 induced a dramatic inhibition of cell proliferation in malignant T-cell lines and primary ATL cells with minimal effect on resting or activated normal lymphocytes. ST1926 induced apoptosis, DNA damage, and upregulation of p53 proteins in malignant T cells, whereas it caused an early downregulation of Tax proteins in HTLV-1-positive cells. In murine ATL, oral treatment with ST1926 prolonged survival and reduced leukemia cell infiltration, white blood cell counts, and spleen mass. In spleens of ST1926-treated animals, p53 and p21 proteins were upregulated, poly (ADP-ribose) polymerase was cleaved, and Tax transcripts were reduced. These results highlight the promising use of ST1926 as a targeted therapy for ATL. PMID:25035162

El Hajj, Hiba; Khalil, Bariaa; Ghandour, Botheina; Nasr, Rihab; Shahine, Sharif; Ghantous, Akram; Abdel-Samad, Rana; Sinjab, Ansam; Hasegawa, Hideki; Jabbour, Mark; Hall, William W; Zaatari, Ghazi; Dbaibo, Ghassan; Pisano, Claudio; Bazarbachi, Ali; Darwiche, Nadine

2014-09-25

45

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

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

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

2013-01-01

46

Standardization of the filovirus plaque assay for use in preclinical studies.  

PubMed

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

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

2012-12-01

47

Standardization of the Filovirus Plaque Assay for Use in Preclinical Studies  

PubMed Central

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

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

2012-01-01

48

Natural substances and Alzheimer's disease: from preclinical studies to evidence based medicine.  

PubMed

Over the last 10 years, the potential therapeutic effects of nutraceuticals to prevent or delay Alzheimer's disease were proposed. Among dietary antioxidants curcumin, Ginkgo biloba and carnitines were extensively studied for their neuroprotective effects. The rationale for this alternative therapeutic approach was based on several preclinical studies which suggested the neuroprotective effects for curcumin, Ginkgo biloba and acetyl-l-carnitine due to either a free radical scavenging activity or the inhibition of pro-inflammatory pathways or the potentiation of the cell stress response. However, although these are interesting premises, clinical studies were not able to demonstrate significant beneficial effects of curcumin, Ginkgo biloba and acetyl-l-carnitine in improving cognitive functions in Alzheimer's disease patients. The aim of this review is to summarize the main pharmacologic features of curcumin, Ginkgo biloba and carnitines as well as to underlie the main outcomes reached by clinical studies designed to demonstrate the efficacy of these natural substances in Alzheimer's disease patients. This article is part of a Special Issue entitled: Antioxidants and Antioxidant Treatment in Disease. PMID:21939756

Mancuso, Cesare; Siciliano, Raffaella; Barone, Eugenio; Preziosi, Paolo

2012-05-01

49

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

ERIC Educational Resources Information Center

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…

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

2013-01-01

50

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

PubMed Central

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

2014-01-01

51

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

ERIC Educational Resources Information Center

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.…

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

2014-01-01

52

Recommendations for the use of preclinical models in the study and treatment of osteoarthritis1  

E-print Network

Recommendations for the use of preclinical models in the study and treatment of osteoarthritis1 R. McDougall zz, K. Pritzker xx, K. Rudolphi kk, W. van den Berg {{, T. Yaksh ## y Canadian Arthritis # Université de Montreal, Montreal, Canada yy Consumer Advisory Council, Canadian Arthritis Network, Canada zz

Buschmann, Michael

53

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

PubMed Central

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

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

2014-01-01

54

Human ESC-Derived Dopamine Neurons Show Similar Preclinical Efficacy and Potency to Fetal Neurons when Grafted in a Rat Model of Parkinson’s Disease  

PubMed Central

Summary Considerable progress has been made in generating fully functional and transplantable dopamine neurons from human embryonic stem cells (hESCs). Before these cells can be used for cell replacement therapy in Parkinson’s disease (PD), it is important to verify their functional properties and efficacy in animal models. Here we provide a comprehensive preclinical assessment of hESC-derived midbrain dopamine neurons in a rat model of PD. We show long-term survival and functionality using clinically relevant MRI and PET imaging techniques and demonstrate efficacy in restoration of motor function with a potency comparable to that seen with human fetal dopamine neurons. Furthermore, we show that hESC-derived dopamine neurons can project sufficiently long distances for use in humans, fully regenerate midbrain-to-forebrain projections, and innervate correct target structures. This provides strong preclinical support for clinical translation of hESC-derived dopamine neurons using approaches similar to those established with fetal cells for the treatment of Parkinson’s disease.

Grealish, Shane; Diguet, Elsa; Kirkeby, Agnete; Mattsson, Bengt; Heuer, Andreas; Bramoulle, Yann; Van Camp, Nadja; Perrier, Anselme L.; Hantraye, Philippe; Björklund, Anders; Parmar, Malin

2014-01-01

55

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

PubMed

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

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

2013-04-01

56

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

SciTech Connect

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.

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

57

Spinal Cord Tolerance in the Age of Spinal Radiosurgery: Lessons from Pre-clinical Studies  

PubMed Central

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 1970’s. 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 pre-clinical 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. Pre-clinical 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 is 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. PMID:21183290

Medin, Paul M.; Boike, Thomas P.

2010-01-01

58

Preclinical studies of N3-O-toluyl-fluorouracil-loaded lipid-based nanosuspensions in H22-bearing mice  

PubMed Central

Purpose N3-O-toluyl-fluorouracil (TFU) is a potential antitumor prodrug of 5-fluorouracil (5-FU), but its poor solubility has limited its use in clinic. This study aimed to improve the bioavailability of TFU by preparing TFU-loaded lipid-based nanosuspensions (TFU-LNS) and perform a preclinical evaluation. Methods TFU-LNS were prepared through high-pressure homogenization and were lyophilized afterwards. For in vitro test, the physicochemical properties and cytotoxicity against HegG2 cells were conducted. For in vivo evaluation, the pharmacokinetics, tissue distribution, and antitumor efficacy were investigated in H22-bearing Kunming mice. Results TFU showed different degradability in four media; in particular, nearly all of it converted to an equimolar amount of 5-FU in blank plasma of Wistar rats. The lyophilized TFU-LNS had a mean particle size of 180.03±3.11 nm and zeta potential of ?8.02±1.43 mV and showed no discernible changes after storage at 4°C for 3 months. In the in vivo antitumor study, the antitumor efficacy of TFU-LNS was consistent with that of 5-FU injection. Furthermore, TFU-LNS released a lower concentration of 5-FU in heart and kidney throughout the tissue distribution studies. Conclusion TFU-LNS exhibited convincing antitumor activity and easy scale-up opportunity, which suggests that TFU-LNS might be a promising drug delivery system for cancer therapy. PMID:24920908

Zhang, Juan; Li, Min; Liu, Zhihong; Wang, Lili; Liu, Yongjun; Zhang, Na

2014-01-01

59

Porcine Heterotopic Composite Tissue Allograft Transplantation using A Large Animal Model for Preclinical Studies  

Microsoft Academic Search

Background: Composite tissue allograft (CTA) transplantation is currently limited by the risks of side effects resulting from long-term high-dose immunosuppression. Therefore, preclinical animal models are essential to help CTA transplanta- tion advance into clinical reality. Evidence has shown that small-animal model (rodents) immunotherapy protocols cannot be directly applied to humans. This study investigated whether a miniature porcine model is repro-

Yur-Ren Kuo; Justin M Sacks; W. P. Andrew Lee; Wen-Sheng Wu; Nai-Siong Kueh; Sheng-Fa Yao; Yuan-Cheng Chiang

60

Preclinical efficacy of sodium narcistatin to reduce inflammation and joint destruction in rats with adjuvant-induced arthritis.  

PubMed

Current therapies for the treatment of rheumatoid arthritis (RA) do not work for all patients, can lose efficacy over time, and can have significant side effects. The discovery of new, effective therapies for RA remains an unmet medical need. The Amaryllidaceae isocarbostyril narciclasine was previously shown to prophylactically reduce paw swelling in rats with adjuvant-induced arthritis (AA). In this study, the efficacy of sodium narcistatin (SNS), a water-soluble cyclic phosphate pro-drug of narciclasine, was assessed in AA rats for anti-inflammatory and bone-sparing properties after disease onset. AA rats were given daily intraperitoneal injections of SNS (1.75, 3.5, or 5 mg/kg/day, in 500 ?l sterile endotoxin-free saline) or saline from disease onset through severe disease stages. Footpad widths and radiographic scoring were used as indicators of inflammation and joint destruction, respectively. Ex vivo cytokine production by peripheral blood mononuclear cells (PMBC), splenocytes, and draining lymph node (DLN) cells were determined using ELISAs. SNS treatment dose-dependently reduced joint inflammation (~70%) and bone loss (~50%) compared with AA controls. SNS treatment also reduced spleen weight (without affecting body weight), pro-inflammatory cytokine production by PMBC, splenocytes, and DLN cells, and site-dependently altered T-helper (Th)1-/Th2-type and anti-inflammatory cytokine profiles. SNS dramatically reduces inflammation and has bone-sparing properties, possibly by reducing immune cell pro-inflammatory cytokine production. Our findings support the development of SNS as a therapeutic for RA. PMID:22159913

Lubahn, Cheri; Schaller, Jill A; Shewmacker, Eric; Wood, Carlo; Bellinger, Denise L; Byron, Donna; Melody, Noeleen; Pettit, George R; Lorton, Dianne

2012-12-01

61

Students' perceptions about the transition to the clinical phase of a medical curriculum with preclinical patient contacts; a focus group study  

Microsoft Academic Search

BACKGROUND: Studies have shown that medical students experience the transition between preclinical and clinical training as a stressful period. They are generally frustrated by their inability to apply their knowledge to solve clinical problems in practice. Preclinical patient contacts may offer a solution to this 'shock of practice.' We studied how students who have had preclinical patient contacts perceive the

Merijn B. Godefrooij; Agnes D. Diemers; Albert J. J. A. Scherpbier

2010-01-01

62

Reporting of preclinical tumor-graft cancer therapeutic studies  

PubMed Central

Purpose: Characterize the parameters of reporting tumor-graft experiments for oncologic drug development. Experimental Design: Using Institute of Scientific Information impact factors, we identified the most-cited medical and oncology journals with tumor-graft experiments in murine models. For each article, the characteristics of the experimental design, outcome measurements, and statistical analysis were examined. Results: We examined 145 articles describing tumor-graft experiments from October through December 2008. The articles spanned a range of disease types, animal models, treatments and delivery methods. One hundred (69%) articles were missing information needed to replicate the experiments. Outcome measurements included: tumor size (83%), biological changes (57%), and survival or cure-rate outcomes (28%). Thirty-three percent did not specify how tumor size was measured and 30% were missing the formula for evaluating volume. Only 14% utilized appropriate statistical methods. Ninety-one percent of studies were reported as positive and 7% reported with mixed positive-negative results; only 2% of studies were reported negative or inconclusive. Twenty-two articles from 2012 showed improvement in the utilization of statistical methods (35% optimal, p = 0.05) but had a similar fraction with experimental design issues (82%; p = 0.32) limiting reproducibility and 91% had positive results. Conclusions: Tumor-graft studies are reported without a set standard, often without the methodological information necessary to reproduce the experiments. The high percentage of positive trials suggests possible publication bias. Considering the widespread use of such experiments for oncologic drug development, scientists and publishers should develop experimental and publication guidelines for such experiments to ensure continued improvements in reporting. PMID:22895077

Sugar, Elizabeth; Pascoe, Adam J.; Azad, Nilofer

2012-01-01

63

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

PubMed

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

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

2014-09-01

64

Analgesic and hypnotic activities of Laghupanchamula: A preclinical study  

PubMed Central

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

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

2014-01-01

65

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

E-print Network

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

Paris-Sud XI, Université de

66

Neuraxial analgesia in neonates and infants: a review of clinical and preclinical strategies for the development of safety and efficacy data.  

PubMed

Neuraxial drugs provide robust pain control, have the potential to improve outcomes, and are an important component of the perioperative care of children. Opioids or clonidine improves analgesia when added to perioperative epidural infusions; analgesia is significantly prolonged by the 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, in the second half of this review, we present 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 drugs with the widest demonstrable safety margin and suggest minimum standards for preclinical evaluation before adoption of new analgesics or preparations into routine clinical practice. PMID:22798528

Walker, Suellen M; Yaksh, Tony L

2012-09-01

67

A Preclinical Study Combining the DNA Repair Inhibitor Dbait with Radiotherapy for the Treatment of Melanoma1  

PubMed Central

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

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

2014-01-01

68

Preclinical Predictors of Anticancer Drug Efficacy: Critical Assessment with Emphasis on Whether Nanomolar Potency Should Be Required of Candidate Agents  

PubMed Central

In the current paradigm of anticancer drug development, candidate compounds are evaluated by testing their in vitro potency against molecular targets relevant to carcinogenesis, their effect on cultured cancer cells, and their ability to inhibit cancer growth in animal models. We discuss the key assumptions inherent in these approaches. In recent years, great emphasis has been placed on selecting for development compounds with nanomolar in vitro potency, expecting that they will be efficacious and safer based on the assumption that they can be used at lower doses (“the nanomolar rule”). However, this rule ignores critical parameters affecting efficacy and toxicity such as physiochemical and absorption, distribution, metabolism and excretion properties, off-target effects, and multitargeting activities. Thus, uncritical application of the nanomolar rule may reject efficacious compounds or select ineffective or toxic compounds. We present examples of efficacious chemotherapeutic (alkylating agents, hormonal agents, antimetabolites, thalidomide, and valproic acid) and chemopreventive (aspirin and sulindac) agents having millimolar potency and compounds with nanomolar potency (cyclooxygenase-2 inhibitors) that, nevertheless, failed or proved to be unsafe. The effect of candidate drugs on animal models of cancer is a better predictor of human drug efficacy; particularly useful are tumor xenografts. Given the cost of failure at clinical stages, it is imperative to keep in mind the limitations of the nanomolar rule and use relevant in vivo models early in drug discovery to prioritize candidates. Although in vivo models will continue having a major role in cancer drug development, more robust approaches that combine high predictive ability with simplicity and low cost should be developed. PMID:22448039

Wong, C. C.; Cheng, Ka-Wing

2012-01-01

69

Preclinical studies at UNC use specialized ultrasound to detect presence of cancer  

Cancer.gov

In the body, tracing the twists and turns of blood vessels is difficult, but important. Vessel “bendiness” can indicate the presence and progression of cancer. This principle led UNC Lineberger Comprehensive Cancer Center scientists to a new method of using a high-resolution ultrasound to identify early tumors in preclinical studies. The method, based on vessel bendiness or “tortuosity,” potentially offers an inexpensive, non-invasive and fast method to detect cancer that could someday help doctors identify cancers when tumors are less than a centimeter in size. Their findings were published in the July 6, 2012 online issue of the journal Radiology.

70

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

PubMed

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

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

2014-03-01

71

Preclinical and clinical phase I studies of a new recombinant Filgrastim (BK0023) in comparison with Neupogen®  

PubMed Central

Background Filgrastim or methionyl-granulocyte colony-stimulating factor (Met-G-CSF), is a recombinant therapeutic protein widely used to treat severe neutropenia caused by myelosuppressive drugs in patients with nonmyeloid malignancies. In addition to its role in the regulation of granulopoiesis, treatment with G-CSF is considered the standard approach to mobilize CD34 positive (CD34+) mononuclear cells for reconstituting hemopoietic ability for bone marrow transplantation. An intended biosimilar filgrastim (coded BK0023) was produced in GMP conditions by E.coli fermentation according to an original recombinant process and showed physico-chemical properties and purity profile similar to Neupogen®, a commercial preparation of filgrastim. The aim of the present study was to demonstrate the comparability of BK0023 to Neupogen® in terms of both in vitro biological activities and in vivo toxicology, pharmacokinetics and pharmacodynamics. Methods Cell proliferation and radioligand binding assays were conducted in NFS-60 cells to compare the biological activity and functional interaction with the G-CSF receptor in vitro, while preclinical in vivo studies, including pharmacokinetics and pharmacodynamics after repeated dose were performed in normal and neutropenic rats. A phase I study was carried out in healthy male volunteers treated by multiple-dose subcutaneous administration of BK0023 and Neupogen® to evaluate their pharmacodynamic effects as well as their pharmacokinetic and safety profile and to demonstrate their pharmacodynamic equivalence and pharmacokinetic bioequivalence. Results The results reported in this work demonstrate that BK0023 is comparable in terms of biological activity, efficacy and safety to Neupogen®. Conclusions BK0023 has the same pharmacokinetic profile, efficacy and safety as the reference commercial filgrastim Neupogen® and therefore could be further developed to become a convenient option to treat neutropenia in oncological patients. Trial registration Trial registration number (TRN): NCT01933971. Date of registration: Sept 6th 2013. PMID:24555723

2014-01-01

72

Preclinical Assessment of Carboplatin Treatment Efficacy in Lung Cancer by 18F-ICMT-11-Positron Emission Tomography  

PubMed Central

Tumour response to therapy is assessed primarily in the clinic by monitoring reductions in tumour size. However, this approach lacks sensitivity since in many cases several weeks may elapse before there is evidence of tumour shrinkage. There is therefore a need to develop non-invasive imaging techniques for monitoring tumour treatment response in the clinic. Here, we assessed the pre-clinical utility of 18F-ICMT-11 positron emission tomography - a method for detecting caspase 3/7 activation - in non-small cell lung cancer (NSCLC). 18F-ICMT-11 uptake was compared to molecular biochemical measures of cell death in PC9 and A549 NSCLC cells following treatment with carboplatin in vitro and in vivo. Carboplatin-induced apoptosis in the ERCC1 low/mutant EGFR PC9 cells was characterised by time and dose-related increased caspase-3/7 activation, poly-ADP-ribose polymerase cleavage and Annexin V staining. 18F-ICMT-11 uptake was consequently increased up to 14-fold at 200 µM carboplatin compared to vehicle treated cells (P<0.01). In contrast, necrosis was the predominant death mechanism in ERCC1 high/wt EGFR A549 cells and no change in 18F-ICMT-11 uptake was detected. In vivo, histological analysis of PC9 tumour xenografts indicated high pre-therapy necrosis. A 4.6-fold increase in cleaved caspase-3/7 was measured in non-necrotic regions of PC9 tumours at 48h post carboplatin therapy. Average PET-derived tumour 18F-ICMT-11 uptake was insensitive to changes in apoptosis in the presence of substantial pre-existing necrosis. PET-based voxel intensity sorting however, identified intra-tumoural regions of high 18F-ICMT-11 uptake, enabling accurate assessment of apoptosis and therefore therapy response. In A549 tumours that lacked high pre-therapy necrosis, carboplatin induced growth inhibition that was only minimally associated with apoptosis and thus not detectable by 18F-ICMT-11 PET. PMID:24618809

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

2014-01-01

73

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

PubMed Central

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

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

2012-01-01

74

Executive Function Changes before Memory in Preclinical Alzheimer’s Pathology: A Prospective, Cross-Sectional, Case Control Study  

PubMed Central

Background Early treatment of Alzheimer’s disease may reduce its devastating effects. By focusing research on asymptomatic individuals with Alzheimer’s disease pathology (the preclinical stage), earlier indicators of disease may be discovered. Decreasing cerebrospinal fluid beta-amyloid42 is the first indicator of preclinical disorder, but it is not known which pathology causes the first clinical effects. Our hypothesis is that neuropsychological changes within the normal range will help to predict preclinical disease and locate early pathology. Methods and Findings We recruited adults with probable Alzheimer’s disease or asymptomatic cognitively healthy adults, classified after medical and neuropsychological examination. By logistic regression, we derived a cutoff for the cerebrospinal fluid beta amyloid42/tau ratios that correctly classified 85% of those with Alzheimer’s disease. We separated the asymptomatic group into those with (n?=?34; preclinical Alzheimer’s disease) and without (n?=?36; controls) abnormal beta amyloid42/tau ratios; these subgroups had similar distributions of age, gender, education, medications, apolipoprotein-? genotype, vascular risk factors, and magnetic resonance imaging features of small vessel disease. Multivariable analysis of neuropsychological data revealed that only Stroop Interference (response inhibition) independently predicted preclinical pathology (OR?=?0.13, 95% CI?=?0.04–0.42). Lack of longitudinal and post-mortem data, older age, and small population size are limitations of this study. Conclusions Our data suggest that clinical effects from early amyloid pathophysiology precede those from hippocampal intraneuronal neurofibrillary pathology. Altered cerebrospinal fluid beta amyloid42 with decreased executive performance before memory impairment matches the deposits of extracellular amyloid that appear in the basal isocortex first, and only later involve the hippocampus. We propose that Stroop Interference may be an additional important screen for early pathology and useful to monitor treatment of preclinical Alzheimer’s disease; measures of executive and memory functions in a longitudinal design will be necessary to more fully evaluate this approach. PMID:24260210

Harrington, Michael G.; Chiang, Jiarong; Pogoda, Janice M.; Gomez, Megan; Thomas, Kris; Marion, Sarah DeBoard; Miller, Karen J.; Siddarth, Prabha; Yi, Xinyao; Zhou, Feimeng; Lee, Sherri; Arakaki, Xianghong; Cowan, Robert P.; Tran, Thao; Charleswell, Cherise; Ross, Brian D.; Fonteh, Alfred N.

2013-01-01

75

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

ERIC Educational Resources Information Center

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…

Jones, Anne; Sheppard, Lorraine

2012-01-01

76

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

PubMed Central

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

Smith, Mark A.; Lynch, Wendy J.

2012-01-01

77

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

PubMed Central

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

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

2014-01-01

78

IGF ACTIVATION IN A MOLECULAR SUBCLASS OF HEPATOCELLULAR CARCINOMA AND PRE-CLINICAL EFFICACY OF IGF-1R BLOCKAGE  

PubMed Central

Background/Aims IGF signaling has a relevant role in a variety of human malignancies. We analyzed the underlying molecular mechanisms of IGF signaling activation in early hepatocellular carcinoma (HCC; BCLC class 0 or A) and assessed novel targeted therapies blocking this pathway Methods An integrative molecular dissection of the axis was conducted in a cohort of 104 HCCs analyzing gene and miRNA expression, structural aberrations and protein activation. The therapeutic potential of a selective IGF-1R inhibitor, the monoclonal antibody A12, was assessed in vitro and in a xenograft model of HCC Results Activation of the IGF axis was observed in 21% of early HCCs. Several molecular aberrations were identified, such as overexpression of IGF2 –resulting from reactivation of fetal promoters P3 and P4-, IGFBP3 downregulation and allelic losses of IGF2R 25% of cases). A gene signature defining IGF-1R activation was developed. Overall, activation of IGF signaling in HCC was significantly associated with mTOR signaling (p=0.035) and was clearly enriched in the Proliferation subclass of the molecular classification of HCC (p=0.001). We also found an inverse correlation between IGF activation and miR-100/miR-216 levels (FDR<0.05). In vitro studies showed that A12-induced abrogation of IGF-1R activation and downstream signaling significantly decreased cell viability and proliferation. In vivoA12 delayed tumor growth and prolonged survival, reducing proliferation rates and inducing apoptosis Conclusions Integrative genomic analysis showed enrichment of activation of IGF signaling in the Proliferation subclass of HCC. Effective blockage of IGF signaling with A12 provides the rationale for testing this therapy in clinical trials. PMID:20206398

Tovar, Victoria; Alsinet, Clara; Villanueva, Augusto; Hoshida, Yujin; Chiang, Derek Y.; Sole, Manel; Thung, Swan; Moyano, Susana; Toffanin, Sara; Minguez, Beatriz; Cabellos, Laia; Peix, Judit; Schwartz, Myron; Mazzaferro, Vincenzo; Bruix, Jordi; Llovet, Josep M.

2013-01-01

79

Pharmacology and pharmacodynamics of bevacizumab as monotherapy or in combination with cytotoxic therapy in preclinical studies.  

PubMed

Preclinical models have examined the pharmacologic and pharmacodynamic activities of an anti-vascular endothelial growth factor (VEGF) humanized, monoclonal antibody, bevacizumab, and/or its murine equivalent A4.6.1. These studies found that single-agent therapy with bevacizumab/A4.6.1 resulted in tumor growth inhibition of 20 different human tumor cell lines (13 tumor types) implanted into nude mice irrespective of the route of administration or tumor location. Several of these studies also observed significant inhibition of tumor metastases. Various studies have examined the feasibility of combining anti-VEGF therapy with cytotoxic or biological agents. Combining bevacizumab/A4.6.1 with doxorubicin, topotecan, paclitaxel, docetaxel, or radiotherapy resulted in additive or synergistic tumor growth inhibition. Changes in vascular functions were frequently reported, including decreased vessel diameter, density, and permeability in response to treatment. A reduction in interstitial fluid pressure was also observed. In some studies, these improvements resulted in an increase in intratumoral uptake of chemotherapy, implying that the most effective use of anti-VEGF therapy is in combination with chemotherapy. Alternatively, combination treatment with radiation increased tumor oxygenation and tumor growth inhibition. Interestingly, anti-VEGF therapy has also been reported to reduce the development of ascites in ovarian mouse models. Finally, safety pharmacology studies with bevacizumab in cynomolgus monkeys showed that this agent is generally well tolerated with no unexpected adverse events. PMID:15705858

Gerber, Hans-Peter; Ferrara, Napoleone

2005-02-01

80

JNJ-40255293, a Novel Adenosine A2A/A1 Antagonist with Efficacy in Preclinical Models of Parkinson's Disease.  

PubMed

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

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

81

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

NASA Astrophysics Data System (ADS)

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.

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

2011-02-01

82

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

PubMed Central

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

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

2006-01-01

83

Characterization of Activin/BMP2 chimera, AB204, formulated for preclinical studies.  

PubMed

AB204 is an Activin/BMP2 chimera, which has been found to exhibit a higher activity than Bone Morphogenetic Protein 2 (BMP2) in osteogenic activity. To prepare AB204 for its preclinical studies, AB204 has been characterized in various formulation buffers. We observed that AB204 purified by ion-exchange chromatography has low water solubility (2.0 mg/ml), whereas it has high water solubility (higher than 10.0 mg/ml) when purified by reverse-phase chromatography. Analysis of the purification procedures reveals that the buffer composition at the lyophilization step determines the solubility. Lyophilization from sodium acetate buffer at pH 4.5 resulted in formation of sodium hydroxide, which caused low solubility of AB204 by pH increase upon reconstitution in water. However, lyophilization from buffers, containing acetic acid or trifluoroacetic acid (TFA) rendered AB204 to be highly soluble. During the course of these analyses, we found a simple procedure to further reduce residual amount of TFA in the purified AB204. PMID:24555430

Ahn, Chihoon; Maslennikov, Innokentiy; Choi, Jung Youn; Oh, Hyosun; Cheong, Chaejoon; Choe, Senyon

2014-05-01

84

Dynamic Contrast-Enhanced Magnetic Resonance Imaging (DCE-MRI) in Preclinical Studies of Antivascular Treatments  

PubMed Central

Antivascular treatments can either be antiangiogenic or targeting established tumour vasculature. These treatments affect the tumour microvasculature and microenvironment but may not change clinical measures like tumour volume and growth. In research on antivascular treatments, information on the tumour vasculature is therefore essential. Preclinical research is often used for optimization of antivascular drugs alone or in combined treatments. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is an in vivo imaging method providing vascular information, which has become an important tool in both preclinical and clinical research. This review discusses common DCE-MRI imaging protocols and analysis methods and provides an overview of preclinical research on antivascular treatments utilizing DCE-MRI. PMID:24300371

Nielsen, Thomas; Wittenborn, Thomas; Horsman, Michael R.

2012-01-01

85

YLT192, a Novel, Orally Active Bioavailable Inhibitor of VEGFR2 Signaling with Potent Antiangiogenic Activity and Antitumor Efficacy in Preclinical Models  

PubMed Central

Antagonizing vascular endothelial growth factor receptor 2 (VEGFR2) to block angiogenesis has been applied toward cancer therapy for its role in promoting cancer growth and metastasis. However, most these clinical anticancer drugs have unexpected side effects. Development of novel VEGFR2 inhibitors with less toxicity remains an urgent need. In this study, we describe a novel, well-tolerated, and orally active VEGFR2 inhibitor, YLT192, which inhibits tumor angiogenesis and growth. YLT192 significantly inhibited kinase activity of VEGFR2 and suppressed proliferation, migration, invasion, and tube formation of human umbilical vascular endothelial cells (HUVEC) in vitro. In addition, it inhibited VEGF-induced phosphorylation of VEGFR2 and its downstream signaling regulator in HUVEC. Zebrafish embryonic models and alginate-encapsulated tumor cell assays indicated YLT192 also inhibited angiogenesis in vivo. Moreover, YLT192 could directly inhibit proliferation and induce apoptosis of cancer cells in vitro and in vivo. Oral administration of YLT192 at a dose of 100?mg/kg/day could markedly inhibited human tumor xenograft growth without causing obvious toxicities. It decreased microvessel densities (MVD) in tumor sections. It also shows good safety profiles in the studies with mice and rats. Taken together, these preclinical evaluations suggest that YLT192 inhibits angiogenesis and may be a promising anticancer drug candidate. PMID:25112436

Xia, Yong; Song, Xuejiao; Li, Deliang; Ye, Tinghong; Xu, Youzhi; Lin, Hongjun; Meng, Nana; Li, Guobo; Deng, Senyi; Zhang, Shuang; Liu, Li; Zhu, Yongxia; Zeng, Jun; Lei, Qian; Pan, Youli; Wei, Yuquan; Zhao, Yinglan; Yu, Luoting

2014-01-01

86

A Preclinical Study of the Effects of Seabuckthorn (Hippophae rhamnoides L.) Leaf Extract on Cutaneous Wound Healing in Albino Rats  

Microsoft Academic Search

Hippophae rhamnoides L. (family Elaeagnaceae), commonly known as seabuckthorn, is a wild shrub growing at high altitude (1200-4500 meters) in adverse climatic conditions. The aim of the present study was to evaluate healing potential of seabuckthorn leaves in a preclinical study on rats using a cutaneous excision-punch wound model. Four full-thickness excision-type wounds of 8.0 mm diameter were created on

Asheesh Gupta; Ratan Kumar; Karan Pal; Pratul K. Banerjee; Ramesh C. Sawhney

2005-01-01

87

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

PubMed Central

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

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

2011-01-01

88

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

PubMed Central

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

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

2014-01-01

89

Vitamin D analogs and bone: preclinical and clinical studies with eldecalcitol.  

PubMed

Eldecalcitol [1?,25-dihydroxy-2?-(3-hydroxypropyloxy)vitamin D3] is an analog of 1?,25-dihydroxyvitamin D3 [1,25(OH)2D3], bearing a hydroxypropyloxy residue at the 2? position. In preclinical studies, eldecalcitol suppressed bone resorption to a greater extent than alfacalcidol but had a similar effect on bone formation and Ca metabolism, resulting in a greater increase in bone mineral density (BMD) in ovariectomized (OVX) rats. Histological analysis in OVX rats immediately after ovariectomy revealed that eldecalcitol reduced osteoclast number and bone resorption parameters with a decrease in bone formation parameters. Eldecalcitol also promoted focal bone formation independent of bone resorption, a process known as bone minimodeling. In clinical studies, eldecalcitol showed stronger effects than alfacalcidol in increasing BMD and reducing bone resorption markers in osteoporotic patients under vitamin D supplementation. A 3-year randomized, double-blind, active-comparator clinical trial demonstrated that once-daily 0.75??g eldecalcitol reduced vertebral fracture incidence by 26% compared with 1.0??g alfacalcidol. Eldecalcitol also reduced the incidence of wrist fractures by 71% compared with alfacalcidol. Although this may be due to the previously reported effect of vitamin D in reducing the incidence of falls, it is not known whether eldecalcitol has a stronger effect in preventing falls than alfacalcidol. Because eldecalcitol stimulates intestinal Ca absorption and improves Ca balance in addition to its skeletal effects, combination treatment with antiresorptive agents may be able to show better effects than native vitamin D and Ca supplementation in preventing fractures in osteoporotic patients. Further studies are warranted to clarify these issues. PMID:24818005

Matsumoto, Toshio; Takano, Toshiyuki; Saito, Hitoshi; Takahashi, Fumiaki

2014-01-01

90

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

PubMed

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

Linsenbardt, David N; Boehm, Stephen L

2014-09-01

91

Creative Self-Efficacy: An Intervention Study  

ERIC Educational Resources Information Center

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…

Mathisen, Gro Ellen; Bronnick, Kolbjorn S.

2009-01-01

92

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

NASA Astrophysics Data System (ADS)

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

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

2012-11-01

93

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

Microsoft Academic Search

.   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;

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

2002-01-01

94

Temple study's pre-clinical data shows Angiocidin effective against leukemia  

Cancer.gov

Angiocidin, a novel tumor-inhibiting protein, has been shown to reduce acute myeloid leukemia (AML) cells in mice by almost two-thirds in pre-clinical experiments. A researcher from Temple University’s School of Medicine who discovered Angiocidin, presented the findings during the American Society of Hematology’s national meeting in Atlanta on Dec. 9. Temple University is home to the Fox Chase Cancer Center.

95

Long-term Safety and Efficacy of Human-Induced Pluripotent Stem Cell (iPS) Grafts in a Preclinical Model of Retinitis Pigmentosa  

PubMed Central

The U.S. Food and Drug Administration recently approved phase I/II clinical trials for embryonic stem (ES) cell–based retinal pigmented epithelium (RPE) transplantation, but this allograft transplantation requires lifelong immunosuppressive therapy. Autografts from patient-specific induced pluripotent stem (iPS) cells offer an alternative solution to this problem. However, more data are required to establish the safety and efficacy of iPS transplantation in animal models before moving iPS therapy into clinical trials. This study examines the efficacy of iPS transplantation in restoring functional vision in Rpe65rd12/Rpe65rd12 mice, a clinically relevant model of retinitis pigmentosa (RP). Human iPS cells were differentiated into morphologically and functionally RPE-like tissue. Quantitative real-time polymerase chain reaction (RT-PCR) and immunoblots confirmed RPE fate. The iPS-derived RPE cells were injected into the subretinal space of Rpe65rd12/Rpe65rd12 mice at 2 d postnatally. After transplantation, the long-term surviving iPS-derived RPE graft colocalized with the host native RPE cells and assimilated into the host retina without disruption. None of the mice receiving transplants developed tumors over their lifetimes. Furthermore, electroretinogram, a standard method for measuring efficacy in human trials, demonstrated improved visual function in recipients over the lifetime of this RP mouse model. Our study provides the first direct evidence of functional recovery in a clinically relevant model of retinal degeneration using iPS transplantation and supports the feasibility of autologous iPS cell transplantation for retinal and macular degenerations featuring significant RPE loss. PMID:22895806

Li, Yao; Tsai, Yi-Ting; Hsu, Chun-Wei; Erol, Deniz; Yang, Jin; Wu, Wen-Hsuan; Davis, Richard J; Egli, Dieter; Tsang, Stephen H

2012-01-01

96

Long-term safety and efficacy of human-induced pluripotent stem cell (iPS) grafts in a preclinical model of retinitis pigmentosa.  

PubMed

The U.S. Food and Drug Administration recently approved phase I/II clinical trials for embryonic stem (ES) cell-based retinal pigmented epithelium (RPE) transplantation, but this allograft transplantation requires lifelong immunosuppressive therapy. Autografts from patient-specific induced pluripotent stem (iPS) cells offer an alternative solution to this problem. However, more data are required to establish the safety and efficacy of iPS transplantation in animal models before moving iPS therapy into clinical trials. This study examines the efficacy of iPS transplantation in restoring functional vision in Rpe65(rd12)/Rpe65(rd12) mice, a clinically relevant model of retinitis pigmentosa (RP). Human iPS cells were differentiated into morphologically and functionally RPE-like tissue. Quantitative real-time polymerase chain reaction (RT-PCR) and immunoblots confirmed RPE fate. The iPS-derived RPE cells were injected into the subretinal space of Rpe65(rd12)/Rpe65(rd12) mice at 2 d postnatally. After transplantation, the long-term surviving iPS-derived RPE graft colocalized with the host native RPE cells and assimilated into the host retina without disruption. None of the mice receiving transplants developed tumors over their lifetimes. Furthermore, electroretinogram, a standard method for measuring efficacy in human trials, demonstrated improved visual function in recipients over the lifetime of this RP mouse model. Our study provides the first direct evidence of functional recovery in a clinically relevant model of retinal degeneration using iPS transplantation and supports the feasibility of autologous iPS cell transplantation for retinal and macular degenerations featuring significant RPE loss. PMID:22895806

Li, Yao; Tsai, Yi-Ting; Hsu, Chun-Wei; Erol, Deniz; Yang, Jin; Wu, Wen-Hsuan; Davis, Richard J; Egli, Dieter; Tsang, Stephen H

2012-01-01

97

Intra-arterial hepatic chemotherapy with pirarubicin. Preclinical and clinical studies.  

PubMed

Intra-arterial hepatic chemotherapy (IAHC) with adriamycin (ADM) has not increased its therapeutic index. For our preclinical studies, we selected pirarubicin (THP), an ADM derivative with faster cellular uptake. In rabbits with VX2 tumor in the liver we compared plasmatic and cellular pharmacokinetics of ADM and THP after i.v. and IAH therapy. For ADM, there were no differences in plasma and heart concentrations, with only a slight increase in tumoral levels after IAH compared to i.v. administration; on the other hand, with IAH THP, there was important reduction in systemic exposure with a major increase in tumoral drug distribution. In the phase I study, involving nine patients with implanted catheters, the starting dose of THP was 30 mg/m2 with a 10 mg/m2 intrapatient escalation every 3 weeks in the absence of toxicity. Pharmacokinetics were compared for i.v. and IAH administration in seven patients. The limiting toxicity was neutropenia and the maximal tolerated dose (MTD) ranged from 50 to 110 mg/m2. Moderate nausea-vomiting (grade 1-2) and alopecia (grade 1) occurred at the MTD. No arterial occlusion, gastroduodenal ulcer, hepatitis, or sclerosing cholangitis were seen. In the phase II study, in colorectal cancer patients (CRC) with metastasis confined to the liver, patients were enrolled until June 1990. THP (40 min infusion every 3 weeks) was initiated at 60 mg/m2 with 10 mg/m2 increment until grade 2 hematotoxicity. The median MTD was 85 mg/m2 (range of 60-120 mg/m2), and the median number of cycles was 7 (range of 2-11) with cumulated doses from 180 to 1,030 mg/m2. Grade 2-4 neutropenia was reached in 15 patients. Other toxicities included two arterial occlusions, one episode of gastritis, but no hepatic toxicity and no heart failure. Antitumor effect (in 18 patients) included 1 CR, 5 PR, 3 MR, 6 NC, and 3 PD. The median survival was 18+ months and 1-year survival was 73% +/- 12%. Seven patients had extrahepatic progression at this time. In conclusion, besides 5-FU or Fudr, THP is active in IAHC (probably in relation with high local extraction) on CRC liver metastases usually unresponsive to ADM. It can be given in an outpatient setting with minimal toxicity. PMID:2291452

Rougier, P; Munck, J N; Elias, D; Herait, P; Bognel, C; Gosse, C; Lasser, P

1990-01-01

98

Preclinical drug metabolism and pharmacokinetics, and prediction of human pharmacokinetics and efficacious dose of the investigational Aurora A kinase inhibitor alisertib (MLN8237).  

PubMed

Alisertib (MLN8237) is an investigational potent Aurora A kinase inhibitor currently under clinical trials for hematological and nonhematological malignancies. Nonclinical investigation showed that alisertib is a highly permeable compound with high plasma protein binding, low plasma clearance, and moderate volume of distribution in rats, dogs, monkeys and chimpanzees. Consistent with the above properties, the oral bioavailability in animals was greater than 82%. The predicted human oral pharmacokinetic (PK) profile was constructed using allometric scaling of plasma clearance and volume of distribution in the terminal phase from animals. The chimpanzee PK profiles were extremely useful to model absorption rate constant, which was assumed to be similar to that in humans, based on the fact that chimpanzees are phylogenetically closest to humans. The human plasma clearance was projected to be low of 0.12 L/hr/kg, with half-life of approximately 10 hr. For human efficacious dose estimation, the tumor growth inhibition as a measure of efficacy (E) was assessed in HCT116 xenograft mice at several oral QD or BID dose levels. Additionally, subcutaneous mini-pump infusion studies were conducted to assess mitotic index in tumor samples as a pharmacodynamic (PD) marker. PK/PD/E modeling showed that for optimal efficacy and PD in the xenograft mice maintaining a plasma concentration exceeding 1 µM for at least 8-12 hr would be required. These values in conjunction with the projected human PK profile estimated the optimal oral dose of approximately 103 mg QD or 62.4 mg BID in humans. Notably, the recommended Phase 2 dose being pursued in the clinic is close to the projected BID dose. PMID:24484538

Yang, Johnny J; Li, Yu; Chakravarty, Arijit; Lu, Chuang; Xia, Cindy Q; Chen, Susan; Pusalkar, Sandeep; Zhang, Mengkun; Ecsedy, Jeffrey; Manfredi, Mark G; Wu, Jing-Tao; Shyu, Wen Chyi; Balani, Suresh K

2014-07-01

99

Attempted and Successful Compensation in Preclinical and Early Manifest Neurodegeneration - A Review of Task fMRI Studies  

PubMed Central

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.

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

2014-01-01

100

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

SciTech Connect

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.

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

101

Novel pre-clinical methodologies for pharmacokinetic drug-drug interaction studies: spotlight on "humanized" animal models.  

PubMed

Abstract Poly-therapy is common due to co-occurrence of several ailments in patients, leading to the elevated possibility of drug-drug interactions (DDI). Pharmacokinetic DDI often accounts for severe adverse drug reactions in patients resulting in withdrawal of drug from the market. Hence, the prediction of DDI is necessary at pre-clinical stage of drug development. Several human tissue and cell line-based in vitro systems are routinely used for screening metabolic and transporter pathways of investigational drugs and for predicting their clinical DDI potentials. However, ample constraints are associated with the in vitro systems and sometimes in vitro-in vivo extrapolation (IVIVE) fail to assess the risk of DDI in clinic. In vitro-in vivo correlation model in animals combined with human in vitro studies may be helpful in better prediction of clinical outcome. Native animal models vary remarkably from humans in drug metabolizing enzymes and transporters, hence, the interpretation of results from animal DDI studies is difficult. With the advent of modern molecular biology and engineering tools, novel pre-clinical animal models, namely, knockout rat/mouse, transgenic rat/mouse with humanized drug metabolizing enzymes and/or transporters and chimeric rat/mouse with humanized liver are developed. These models nearly simulate human-like drug metabolism and help to validate the in vivo relevance of the in vitro human DDI data. This review briefly discusses the application of such novel pre-clinical models for screening various type of DDI along with their advantages and limitations. PMID:25270219

Jaiswal, Swati; Sharma, Abhisheak; Shukla, Mahendra; Vaghasiya, Kalpesh; Rangaraj, Nagarjun; Lal, Jawahar

2014-11-01

102

The Humanized NOD/SCID Mouse as a Preclinical Model to Study the Fate of Encapsulated Human Islets  

PubMed Central

Despite encouraging results in animal models, the transplantation of microencapsulated islets into humans has not yet reached the therapeutic level. Recent clinical trials using microencapsulated human islets in barium alginate showed the presence of dense fibrotic overgrowth around the microcapsules with no viable islets. The major reason for this is limited understanding of what occurs when encapsulated human islets are allografted. This warrants the need for a suitable small animal model. In this study, we investigated the usefulness of NOD/SCID mice reconstituted with human PBMCs (called humanized NOD/SCID mice) as a preclinical model. In this model, human T cell engraftment could be achieved, and CD45+ cells were observed in the spleen and peripheral blood. Though the engrafted T cells caused a small fibrotic overgrowth around the microencapsulated human islets, this failed to stop the encapsulated islets from functioning in the diabetic recipient mice. The ability of encapsulated islets to survive in this mouse model might partly be attributed to the presence of Th2 cytokines IL-4 and IL-10, which are known to induce graft tolerance. In conclusion, this study showed that the hu-NOD/SCID mouse is not a suitable preclinical model to study the allograft rejection mechanisms of encapsulated human islets. As another result, the maintained viability of transplanted islets on the NOD/SCID background emphasized a critical role of protective mechanisms in autoimmune diabetes transplanted subjects due to specific immunoregulatory effects provided by IL-4 and IL-10. PMID:20703439

Vaithilingam, Vijayaganapathy; Oberholzer, Jose; Guillemin, Gilles J.; Tuch, Bernard E.

2010-01-01

103

Preclinical studies of potential amyloid binding PET/SPECT ligands in Alzheimer's disease.  

PubMed

Visualizing the neuropathological hallmarks amyloid plaques and neurofibrillary tangles of Alzheimer's disease in vivo using positron emission tomography (PET) or single photon emission computed tomography will be of great value in diagnosing the individual patient and will also help in our understanding of the disease. The successful introduction of [(11)C]PIB as a PET tracer for the amyloid plaques less than 10 years ago started an intensive research, and numerous new compounds for use in molecular imaging of the amyloid plaques have been developed. The candidates are based on dyes like thioflavin T, Congo red and chrysamine G, but also on other types such as benzoxazoles, curcumin and stilbenes. In the present review, we present methods of the radiochemistry and preclinical evaluation as well as the main properties of some of these compounds. PMID:22226025

Svedberg, Marie M; Rahman, Obaidur; Hall, Håkan

2012-05-01

104

Therapeutic vaccination in chronic hepatitis B: preclinical studies in the woodchuck.  

PubMed

Recommended treatment of chronic hepatitis B with interferon-? and/or nucleos(t)ide analogues does not lead to a satisfactory result. Induction of HBV-specific T cells by therapeutic vaccination or immunotherapies may be an innovative strategy to overcome virus persistence. Vaccination with commercially available HBV vaccines in patients did not result in effective control of HBV infection, suggesting that new formulations of therapeutic vaccines are needed. The woodchuck (Marmota monax) is a useful preclinical model for developing the new therapeutic approaches in chronic hepadnaviral infections. Several innovative approaches combining antiviral treatments with nucleos(t)ide analogues, DNA vaccines, and protein vaccines were tested in the woodchuck model. In this paper we summarize the available data concerning therapeutic immunization and gene therapy using recombinant viral vectors approaches in woodchucks, which show encouraging results. In addition, we present potential innovations in immunomodulatory strategies to be evaluated in this animal model. PMID:21188201

Kosinska, Anna D; Zhang, Ejuan; Lu, Mengji; Roggendorf, Michael

2010-01-01

105

Evaluation of efficacy and safety of the anti-VWF Nanobody ALX-0681 in a preclinical baboon model of acquired thrombotic thrombocytopenic purpura.  

PubMed

ALX-0681 is a therapeutic Nanobody targeting the A1-domain of VWF. It inhibits the interaction between ultra-large VWF and platelet GpIb-IX-V, which plays a crucial role in the pathogenesis of thrombotic thrombocytopenic purpura (TTP). In the present study, we report the efficacy and safety profile of ALX-0681 in a baboon model of acquired TTP. In this model, acute episodes of TTP are induced by administration of an ADAMTS13-inhibiting mAb. ALX-0681 completely prevented the rapid onset of severe thrombocytopenia and schistocytic hemolytic anemia. After induction of TTP, platelet counts also rapidly recovered on administration of ALX-0681. This effect was corroborated by the full neutralization of VWF activity. The schistocytic hemolytic anemia was also halted and partially reversed by ALX-0681 treatment. Brain CT scans and post mortem analysis did not reveal any sign of bleeding, suggesting that complete neutralization of VWF by ALX-0681 under conditions of thrombocytopenia was not linked with an excessive bleeding risk. The results obtained in this study demonstrate that ALX-0681 can successfully treat and prevent the most important hallmarks of acquired TTP without evidence of a severe bleeding risk. Therefore, ALX-0681 offers an attractive new therapeutic option for acquired TTP in the clinical setting. PMID:22948047

Callewaert, Filip; Roodt, Jan; Ulrichts, Hans; Stohr, Thomas; van Rensburg, Walter Janse; Lamprecht, Seb; Rossenu, Stefaan; Priem, Sofie; Willems, Wouter; Holz, Josefin-Beate

2012-10-25

106

The oral HDAC inhibitor pracinostat (SB939) is efficacious and synergistic with the JAK2 inhibitor pacritinib (SB1518) in preclinical models of AML  

PubMed Central

Acute myeloid leukemia (AML) is currently treated with aggressive chemotherapy that is not well tolerated in many elderly patients, hence the unmet medical need for effective therapies with less toxicity and better tolerability. Inhibitors of FMS-like tyrosine kinase 3 (FLT3), JAK2 and histone deacetylase inhibitors (HDACi) have been tested in clinical studies, but showed only moderate single-agent activity. High efficacy of the HDACi pracinostat treating AML and synergy with the JAK2/FLT3 inhibitor pacritinib is demonstrated. Both compounds inhibit JAK-signal transducer and activator of transcription (STAT) signaling in AML cells with JAK2V617F mutations, but also diminish FLT3 signaling, particularly in FLT3-ITD (internal tandem duplication) cell lines. In vitro, this combination led to decreased cell proliferation and increased apoptosis. The synergy translated in vivo in two different AML models, the SET-2 megakaryoblastic AML mouse model carrying a JAK2V617F mutation, and the MOLM-13 model of FLT3-ITD-driven AML. Pracinostat and pacritinib in combination showed synergy on tumor growth, reduction of metastases and synergistically decreased JAK2 or FLT signaling, depending on the cellular context. In addition, several plasma cytokines/growth factors/chemokines triggered by the tumor growth were normalized, providing a rationale for combination therapy with an HDACi and a JAK2/FLT3 inhibitor for the treatment of AML patients, particularly those with FLT3 or JAK2 mutations. PMID:22829971

Novotny-Diermayr, V; Hart, S; Goh, K C; Cheong, A; Ong, L-C; Hentze, H; Pasha, M K; Jayaraman, R; Ethirajulu, K; Wood, J M

2012-01-01

107

Preclinical profile of cabazitaxel  

PubMed Central

First-generation taxanes have changed the treatment paradigm for a wide variety of cancers, but innate or acquired resistance frequently limits their use. Cabazitaxel is a novel second-generation taxane developed to overcome such resistance. In vitro, cabazitaxel showed similar antiproliferative activity to docetaxel in taxane-sensitive cell lines and markedly greater activity in cell lines resistant to taxanes. In vivo, cabazitaxel demonstrated excellent antitumor activity in a broad spectrum of docetaxel-sensitive tumor xenografts, including a castration-resistant prostate tumor xenograft, HID28, where cabazitaxel exhibited greater efficacy than docetaxel. Importantly, cabazitaxel was also active against tumors with innate or acquired resistance to docetaxel, suggesting therapeutic potential for patients progressing following taxane treatment and those with docetaxel-refractory tumors. In patients with tumors of the central nervous system (CNS), and in patients with pediatric tumors, therapeutic success with first-generation taxanes has been limited. Cabazitaxel demonstrated greater antitumor activity than docetaxel in xenograft models of CNS disease and pediatric tumors, suggesting potential clinical utility in these special patient populations. Based on therapeutic synergism observed in an in vivo tumor model, cabazitaxel is also being investigated clinically in combination with cisplatin. Nonclinical evaluation of the safety of cabazitaxel in a range of animal species showed largely reversible changes in the bone marrow, lymphoid system, gastrointestinal tract, and male reproductive system. Preclinical safety signals of cabazitaxel were consistent with the previously reported safety profiles of paclitaxel and docetaxel. Clinical observations with cabazitaxel were consistent with preclinical results, and cabazitaxel is indicated, in combination with prednisone, for the treatment of patients with hormone-refractory metastatic prostate cancer previously treated with docetaxel. In conclusion, the demonstrated activity of cabazitaxel in tumors with innate or acquired resistance to docetaxel, CNS tumors, and pediatric tumors made this agent a candidate for further clinical evaluation in a broader range of patient populations compared with first-generation taxanes. PMID:25378905

Vrignaud, Patricia; Semiond, Dorothée; Benning, Veronique; Beys, Eric; Bouchard, Hervé; Gupta, Sunil

2014-01-01

108

Implementing preclinical study findings to protocol design: translational studies with alloreactive CTL for gliomas  

PubMed Central

We are accruing patients to a Phase I dose escalation cellular therapy trial (www.clinicaltrials.gov, NCT01144247) involving intratumoral placement of alloreactive cytotoxic T lymphocytes (alloCTL) for recurrent gliomas. The trial is being conducted to confirm the findings of a prior pilot study that indicated this adjuvant therapy may be beneficial in extending survival of recurrent WHO grade III gliomas. To reduce costs of the cellular therapy, we tested a number of synthetic tissue culture media and found the AIM-V growth medium superior for their growth. We also moved the production of the alloCTL from artificial capillary systems to less expensive tissue culture bags. To standardize alloCTL infusates used for therapy, release criteria of ?60% CD3+ and ?60% viability were established that consistently translated to a 4 hr cytotoxicity of ?30% at a 30:1 effector to target ratio. To allow time for completion of quality control testing and transport to the infusion site, we determined that 30,000 IU of human recombinant Interleukin-2 in the cellular infusates sufficiently retained cell viability and cytotoxicity to allow a 10 hr expiration time to be placed on the infusates. We identified a cytotoxic T cell subset, CD3+/CD8+/CD69+, that demonstrated upregulated IFN-? production upon exposure to relevant target cells. The phenotypic identification of this T cell subset was indicative of robust in vitro cytotoxic function and thus will be followed to determine if it correlates with patient immune response to treatment. Finally, other therapeutic agents routinely used for glioma treatment were integrated into an analysis of alloCTL cytotoxic functionality. Temozolomide and bevacizumab do not adversely affect cytotoxic function of the alloCTL in the short-term, thus providing rationale for further investigating combinatorial chemo-immunotherapy for gliomas. PMID:22347526

Hickey, Michelle J; Malone, Colin C; Erickson, Kate E; Gomez, German G; Young, Emma L; Liau, Linda M; Prins, Robert M; Kruse, Carol A

2012-01-01

109

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

PubMed

The usage of laser correlation spectroscopy for verification of preclinical and clinical states is substantiated. Developed "semiotic" classifier for solving the problems of preclinical and clinical states is presented. The substantiation of biological algorithms as well as the mathematical support and software for the proposed classifier for the data of laser correlation spectroscopy of blood plasma are presented. PMID:9848161

Ternovo?, K S; Kryzhanovski?, G N; Musi?chuk, Iu I; Noskin, L A; Klopov, N V; Noskin, V A; Starodub, N F

1998-01-01

110

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

PubMed Central

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

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

2014-01-01

111

Reproducibility of results in preclinical studies: a perspective from the bone field.  

PubMed

The biomedical research enterprise-and the public support for it-is predicated on the belief that discoveries and the conclusions drawn from them can be trusted to build a body of knowledge which will be used to improve human health. As in all other areas of scientific inquiry, knowledge and understanding grow by layering new discoveries upon earlier ones. The process self-corrects and distills knowledge by discarding false ideas and unsubstantiated claims. Although self-correction is inexorable in the long-term, in recent years biomedical scientists and the public alike have become alarmed and deeply troubled by the fact that many published results cannot be reproduced. The chorus of concern reached a high pitch with a recent commentary from the NIH Director, Francis S. Collins, and Principal Deputy Director, Lawrence A. Tabak, and their announcement of specific plans to enhance reproducibility of preclinical research that relies on animal models. In this invited perspective, we highlight the magnitude of the problem across biomedical fields and address the relevance of these concerns to the field of bone and mineral metabolism. We also suggest how our specialty journals, our scientific organizations, and our community of bone and mineral researchers can help to overcome this troubling trend. © 2014 American Society for Bone and Mineral Research. PMID:24916175

Manolagas, Stavros C; Kronenberg, Henry M

2014-10-01

112

A 2 x 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

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

2014-01-01

113

Phase II study evaluating the efficacy and safety of sagopilone (ZK-EPO) in patients with metastatic breast cancer that has progressed following chemotherapy  

Microsoft Academic Search

Sagopilone is a novel, fully synthetic epothilone that has shown promising preclinical activity in a range of tumor models,\\u000a including platinum-resistant ovarian cancer and metastatic breast cancer (MBC). This open-label, multicenter, Phase II study\\u000a investigated the efficacy, safety, and tolerability of sagopilone administered to patients with MBC. Women with MBC whose\\u000a previous chemotherapy regimen included a taxane and an anthracycline

Phuong K. Morrow; Stephen Divers; Louise Provencher; Shiuh-Wen Luoh; Teresa M. Petrella; Marius Giurescu; Thomas Schmelter; Yao Wang; Gabriel N. Hortobagyi; Linda T. Vahdat

2010-01-01

114

Efficient vitreolysis by combining plasmin and sulfur hexafluoride injection in a preclinical study in rabbit eyes  

PubMed Central

Purpose To investigate the efficacy of plasmin and sulfur hexafluoride (SF6) on the vitreoretinal junction, as well as the long-term safety in the eye and effect on the recipient’s general health after application in the eye. Methods The study design included four groups of rabbits with three animals in each group. Group 1 received an intravitreal injection (IVI) of plasmin and SF6 in the right eye; group 2 received an IVI of plasmin in the right eye; group 3 received an IVI of SF6 in the right eye; and group 4 received an IVI of balanced salt solution in the right eye, which served as a normal control. Long-term safety (up to approximately three months) after plasmin and/or SF6 injection was evaluated morphologically by clinical examination, histology, and immunohistochemistry, and functionally by electroretinograms (ERGs). General health evaluations after intravitreal injection included the assessment of weight gain, food intake, body temperature, and complete blood count analysis. Results Plasmin plus SF6 injection resulted in complete posterior vitreous detachment (PVD), whereas plasmin or SF6 injection alone resulted in only partial PVD. Balanced salt solution did not induce PVD. Eighty days after intravitreal injection, there were no major differences among the eyes of the three groups of animals compared with the normal control animals upon clinical evaluation, or regarding retinal morphology and ERGs. The lenses examined remained clear for up to 80 days following the intravitreal injection of plasmin plus SF6, except one eye in the plasmin-treated group. ERGs decreased transiently one week after intravitreal injection in groups 1 through 3, but animals recovered fully to normal status afterward. General health was not affected after the injection of plasmin plus SF6. Conclusions Efficient vitreoretinal separation could be achieved, and an acceptable long-term safety profile was noted after plasmin plus SF6 injection in the eye. No major ocular toxicity or systemic toxicity was found after the injection of plasmin plus SF6. These results provide good support for the future clinical use of plasmin plus SF6 for treatment of a variety of vitreoretinopathies. PMID:23049236

Wu, Wei-Chi; Liu, Chi-Hsien; Chen, Chih-Chun; Wang, Nan-Kai; Chen, Kwan-Jen; Chen, Tun-Lu; Hwang, Yih-Shiou; Li, Lien-Min

2012-01-01

115

A new mathematical approach for the estimation of the AUC and its variability under different experimental designs in preclinical studies.  

PubMed

The aim of the present work was to develop a new mathematical method for estimating the area under the curve (AUC) and its variability that could be applied in different preclinical experimental designs and amenable to be implemented in standard calculation worksheets. In order to assess the usefulness of the new approach, different experimental scenarios were studied and the results were compared with those obtained with commonly used software: WinNonlin® and Phoenix WinNonlin®. The results do not show statistical differences among the AUC values obtained by both procedures, but the new method appears to be a better estimator of the AUC standard error, measured as the coverage of 95% confidence interval. In this way, the new proposed method demonstrates to be as useful as WinNonlin® software when it was applicable. PMID:21268234

Navarro-Fontestad, Carmen; González-Álvarez, Isabel; Fernández-Teruel, Carlos; Bermejo, Marival; Casabó, Vicente Germán

2012-01-01

116

Ramucirumab: preclinical research and clinical development  

PubMed Central

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

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

2014-01-01

117

Genetic engineering of murine CD8+ and CD4+ T cells for pre-clinical adoptive immunotherapy studies  

PubMed Central

T-cell-receptor (TCR) gene therapy enables for the rapid creation of antigen-specific T cells from mice of any strain and represents a valuable tool for pre-clinical immunotherapy studies. Here, we describe the superiority of gamma-retroviral vectors compared to lentiviral vectors for transduction of murine T cells and surprisingly illustrate robust gene-transfer into phenotypically naïve/memory-stem cell (CD62Lhi/CD44low) and central memory (CD62Lhi/CD44hi) CD8+ T cells using murine-stem-cell-based gamma-retroviral vectors (MSGV1). We created MSGV1 vectors for a MHC-class I restricted T-cell receptor (TCR) specific for the melanocyte-differentiation antigen, gp100 (MSGV1-pmel-1), and a MHC-class II restricted TCR specific for tyrosinase-related-protein-1 (MSGV1-TRP-1), and found that robust gene expression required codon optimization of TCR sequences for the pmel-1 TCR. To test for functionality, we adoptively transferred TCR-engineered T cells into mice bearing B16 melanomas and observed delayed growth of established tumors with pmel-1TCR engineered CD8+ T cells and significant tumor regression with TRP-1 TCR transduced CD4+ T cells. We simultaneously created lentiviral vectors encoding the pmel-1TCR, but found that these vectors mediated low TCR expression in murine T cells, but robust gene expression in other murine and human cell lines. These results indicate that preclinical murine models of adoptive immunotherapies are more practical using gamma-retroviral rather than lentiviral vectors. PMID:21499127

Kerkar, Sid P; Sanchez-Perez, Luis; Yang, Shicheng; Borman, Zachary; Muranski, Pawel; Ji, Yun; Chinnasamy, Dhanalakshmi; Kaiser, Andrew DM; Hinrichs, Christian; Klebanoff, Christopher A; Scott, Christopher; Gattinoni, Luca; Morgan, Richard A; Rosenberg, Steven A; Restifo, Nicholas P

2011-01-01

118

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

PubMed Central

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

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.; Bartolome, J.M.; Mackie, C.; Hrupka, B.J.; Caron, M.G.; Daigle, T.L.; Lindsley, C.W.; Conn, P.J.

2013-01-01

119

Self-Efficacy and Statistics Performance among Sport Studies Students  

ERIC Educational Resources Information Center

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

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

2004-01-01

120

Drug targeting of estrogen receptor signaling in the cardiovascular system: preclinical and clinical studies.  

PubMed

Atherosclerosis and associated coronary heart disease events have lower prevalence in women than in men, especially during young adult years. Although multiple lines of evidence suggest that estrogens contribute to this difference, the efficacy of hormone replacement therapy for the prevention of cardiovascular disease in postmenopausal women is controversial. The protective action of estrogen in the cardiovascular system appears to be mediated indirectly by an effect on serum lipoprotein and triglyceride profiles and on the expression of coagulant and fibrinolytic proteins, and by a direct effect on the vessel wall itself. Estrogen has both rapid effects involving alteration of membrane ionic permeability and activation of membrane-bound enzymes and increases in endothelial cell nitric oxide synthase activity, as well as longer-term effects on gene expression that are mediated, at least in part, by the ligand-activated transcription factors, estrogen receptor alpha and beta. Compounds with pure antiestrogenic activity and selective estrogen receptor modulators that regulate estrogen receptor function in a tissue-specific manner have been developed in an attempt to achieve the cardioprotective effects of estrogens while minimizing the undesirable risks associated with hormone replacement therapy (e.g., endometrial and breast cancer). In this review, we will discuss recent developments on the mechanisms of estrogen action in the cardiovascular system. The results of clinical trials testing the long-term efficacy of hormone replacement therapy for the treatment of cardiovascular disease will also be discussed. PMID:15320794

Sanz-González, Silvia M; Cano, Antonio; Valverde, M A; Hermenegildo, Carlos; Andrés, Vicente

2004-04-01

121

Sequential Therapy With JX-594, A Targeted Oncolytic Poxvirus, Followed by Sorafenib in Hepatocellular Carcinoma: Preclinical and Clinical Demonstration of Combination Efficacy  

PubMed Central

JX-594 is a targeted and granulocyte-macrophage colony stimulating factor (GM-CSF) expressing oncolytic poxvirus designed to selectively replicate in and destroy cancer cells through viral oncolysis and tumor-specific immunity. In a phase 1 trial, JX-594 injection into hepatocellular carcinoma (HCC) was well-tolerated and associated with viral replication, decreased tumor perfusion, and tumor necrosis. We hypothesized that JX-594 and sorafenib, a small molecule inhibitor of B-raf and vascular endothelial growth factor receptor (VEGFR) approved for HCC, would have clinical benefit in combination given their demonstrated efficacy in HCC patients and their complementary mechanisms-of-action. HCC cell lines were uniformly sensitive to JX-594. Anti-raf kinase effects of concurrent sorafenib inhibited JX-594 replication in vitro, whereas sequential therapy was superior to either agent alone in murine tumor models. We therefore explored pilot safety and efficacy of JX-594 followed by sorafenib in three HCC patients. In all three patients, sequential treatment was (i) well-tolerated, (ii) associated with significantly decreased tumor perfusion, and (iii) associated with objective tumor responses (Choi criteria; up to 100% necrosis). HCC historical control patients on sorafenib alone at the same institutions had no objective tumor responses (0 of 15). Treatment of HCC with JX-594 followed by sorafenib has antitumoral activity, and JX-594 may sensitize tumors to subsequent therapy with VEGF/VEGFR inhibitors. PMID:21427706

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

2011-01-01

122

The Route to Drug Development Preclinical  

E-print Network

The Route to Drug Development Preclinical Studies in rodents (and other animal species) looking pancreas after every meal, making us feel full. After pre-clinical testing on rats, the team, led by Dr John McMichael Centre on 020 8383 8082. Is this the end of obesity? First time in human trials begin

123

A gender study investigating physics self-efficacy  

NASA Astrophysics Data System (ADS)

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

Sawtelle, Vashti

124

The discovery of rivaroxaban: translating preclinical assessments into clinical practice  

PubMed Central

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

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

2013-01-01

125

Preclinical study of using multiphoton microscopy to diagnose liver cancer and differentiate benign and malignant liver lesions  

NASA Astrophysics Data System (ADS)

Recently, the miniaturized multiphoton microscopy (MPM) and multiphoton probe allow the clinical use of multiphoton endoscopy for diagnosing cancer via ``optical biopsy''. The purpose of this study was to establish MPM optical diagnostic features for liver cancer and evaluate the sensitivity, specificity, and accuracy of MPM optical diagnosis. Firstly, we performed a pilot study to establish the MPM diagnostic features by investigating 60 surgical specimens, and found that high-resolution MPM images clearly demonstrated apparent differences between benign and malignant liver lesions in terms of their tissue architecture and cell morphology. Cancer cells, characterized by irregular size and shape, enlarged nuclei, and increased nuclear-cytoplasmic ratio, were identified by MPM images, which were comparable to hematoxylin-eosin staining images. Secondly, we performed a blinded study to evaluate the sensitivity, specificity, and accuracy of MPM optical diagnosis by investigating another 164 specimens, and found that the sensitivity, specificity, and accuracy of MPM diagnosis was 96.32%, 96.43%, and 96.34%, respectively. In conclusion, it is feasible to use MPM to diagnose liver cancer and differentiate benign and malignant liver lesions. This preclinical study provides the groundwork for further using multiphoton endoscopy to perform real-time noninvasive ``optical biopsy'' for liver lesions in the near future.

Yan, Jun; Zhuo, Shuangmu; Chen, Gang; Wu, Xiufeng; Zhou, Dong; Xie, Shusen; Jiang, Jiahao; Ying, Mingang; Jia, Fan; Chen, Jianxin; Zhou, Jian

2012-02-01

126

A Case Study of Elementary Beginning Mathematics Teachers' Efficacy Development  

ERIC Educational Resources Information Center

The main purpose of this research was to explore the developmental process of and possible changes in beginning elementary mathematics teachers' efficacy. Beginning teachers with and without mathematics and science backgrounds were also compared to explore differences in their efficacy development. A multiple-case study method with a process and…

Chang, Yu-Liang

2010-01-01

127

Self-Efficacy and Collaborative Learning: An Intervention Study  

ERIC Educational Resources Information Center

Findings from empirical research suggest that both self-efficacy beliefs and collaborative learning may have an influence upon student academic performance. However, the phenomena of self-efficacy beliefs, collaborative learning, and academic achievement have not been studied in concert with one another. Using quantitative research methods, I…

Robertson, Jane

2012-01-01

128

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

SciTech Connect

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

Miller, Janine D. [Department of Dermatology, Case Western Reserve University/University Hospitals of Cleveland, Cleveland, OH 44106 (United States); Case Skin Diseases Research Center, Case Western Reserve University/University Hospitals of Cleveland, Cleveland, OH 44106 (United States); Case Comprehensive Cancer Center, Case Western Reserve University/University Hospitals of Cleveland, Cleveland, OH 44106 (United States); Baron, Elma D. [Department of Dermatology, Case Western Reserve University/University Hospitals of Cleveland, Cleveland, OH 44106 (United States); Case Skin Diseases Research Center, Case Western Reserve University/University Hospitals of Cleveland, Cleveland, OH 44106 (United States); Case Comprehensive Cancer Center, Case Western Reserve University/University Hospitals of Cleveland, Cleveland, OH 44106 (United States); Louis-Stokes VA Medical Center, 10701 East Boulevard, Cleveland, OH 44106 (United States); Scull, Heather [Department of Dermatology, Case Western Reserve University/University Hospitals of Cleveland, Cleveland, OH 44106 (United States); Case Skin Diseases Research Center, Case Western Reserve University/University Hospitals of Cleveland, Cleveland, OH 44106 (United States); Case Comprehensive Cancer Center, Case Western Reserve University/University Hospitals of Cleveland, Cleveland, OH 44106 (United States); Hsia, Andrew [Department of Dermatology, Case Western Reserve University/University Hospitals of Cleveland, Cleveland, OH 44106 (United States); Berlin, Jeffrey C. [Department of Dermatology, Case Western Reserve University/University Hospitals of Cleveland, Cleveland, OH 44106 (United States); Department of Chemistry, Case Western Reserve University/University Hospitals of Cleveland, Cleveland, OH 44106 (United States)] (and others)

2007-11-01

129

Establishment of patient-derived non-small cell lung cancer xenograft models with genetic aberrations within EGFR, KRAS and FGFR1: useful tools for preclinical studies of targeted therapies  

PubMed Central

Background Patient-derived tumor xenograft models have been established and increasingly used for preclinical studies of targeted therapies in recent years. However, patient-derived non-small cell lung cancer (NSCLC) xenograft mouse models are relatively few in number and are limited in their degree of genetic characterization and validation. In this study, we aimed to establish a variety of patient-derived NSCLC models and characterize these for common genetic aberrations to provide more informative models for preclinical drug efficacy testing. Methods NSCLC tissues from thirty-one patients were collected and implanted into immunodeficient mice. Established xenograft models were characterized for common genetic aberrations, including detection of gene mutations within EGFR and KRAS, and genetic amplification of FGFR1 and cMET. Finally, gefitinib anti-tumor efficacy was tested in these patient-derived NSCLC xenograft models. Results Ten passable patient-derived NSCLC xenograft models were established by implantation of NSCLC specimens of thirty-one patients into immunodeficient mice. Genetic aberrations were detected in six of the models, including one model with an EGFR activating mutation (Exon19 Del), one model with KRAS mutation, one model with both KRAS mutation and cMET gene amplification, and three models with FGFR1 amplification. Anti-tumor efficacy studies using gefitinib demonstrated that the EGFR activating mutation model had superior sensitivity and that the KRAS mutation models were resistant to gefitinib. The range of gefitinib responses in the patient-derived NSCLC xenograft models were consistent with the results reported from clinical trials. Furthermore, we observed that patient-derived NSCLC models with FGFR1 gene amplification were insensitive to gefitinib treatment. Conclusions Ten patient-derived NSCLC xenograft models were established containing a variety of genetic aberrations including EGFR activating mutation, KRAS mutation, and FGFR1 and cMET amplification. Gefitinib anti-tumor efficacy in these patient-derived NSCLC xenografts containing EGFR and KRAS mutation was consistent with the reported results from previous clinical trials. Thus, data from our panel of patient-derived NSCLC xenograft models confirms the utility of these models in furthering our understanding of this disease and aiding the development of personalized therapies for NSCLC patients. PMID:23842453

2013-01-01

130

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

PubMed Central

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

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

2014-01-01

131

Preclinical models of shock and sepsis: what can they tell us?  

PubMed

The goal of translational research is to transform biologic knowledge into new treatments for human disease. Although preclinical models replicate some of the features of the disease process modeled, they invariably fail to reproduce the complexity of human illness, and by their very experimental nature, they are readily manipulated to maximize evidence of efficacy. The result is that successful translation from preclinical models to clinically effective therapy is uncommon, and that clinical trials are often undertaken without a comprehensive and realistic preclinical portfolio of studies to optimize their design. The lethal and morbid human conditions of sepsis and shock are attractive targets for new therapies and enormously challenging processes to translate because they entail considerable clinical heterogeneity, require emergent effective intervention, and are shaped not only by the initial insult, but by approaches to subsequent resuscitation and support. A colloquium jointly sponsored by the Shock Society and the International Sepsis Forum in June 2004 addressed the challenges of translational research in shock and sepsis. Through a comprehensive review of a broad variety of model approaches, and vigorous debate about the merits of differing strategies, a series of common themes emerged. We concluded that there is no single ideal model of shock or sepsis, but rather a large number of complementary models that recapitulate some discrete features of the disorders while minimizing others. Consequently, successful preclinical investigation mandates the use of a panel of preclinical studies consciously designed to address specific questions of relevance to the clinical setting. A corollary of this conclusion is that preclinical studies can shape concepts of disease and can be used to refine decisions regarding optimal patient populations for therapeutic interventional trials. We further recognized that the design and reporting of preclinical studies is highly variable, thereby limiting effective data interpretation and integration between studies. Hence, greater model standardization would aid in interpreting data and in pooling results into systematic data syntheses: such efforts should be promoted and undertaken. PMID:16374365

Marshall, John C; Deitch, Edwin; Moldawer, Lyle L; Opal, Steven; Redl, Heinz; van der Poll, Tom

2005-12-01

132

Kidney Injury Molecule-1 Outperforms Traditional Biomarkers of Kidney Injury in Multi-site Preclinical Biomarker Qualification Studies  

PubMed Central

Kidney toxicity accounts for a significant percentage of morbidity and drug candidate failure. Serum creatinine (SCr) and blood urea nitrogen (BUN) have been used to monitor kidney dysfunction for over a century but these markers are insensitive and non-specific. In multi-site preclinical rat toxicology studies the diagnostic performance of urinary kidney injury molecule-1 (Kim-1) was compared to traditional biomarkers as predictors of kidney tubular histopathologic changes, currently considered the “gold standard” of nephrotoxicity. In multiple models of kidney injury, urinary Kim-1 significantly outperformed SCr and BUN. The area under the receiver operating characteristic curve for Kim-1 was between 0.91 and 0.99 as compared to 0.79 to 0.9 for BUN and 0.73 to 0.85 for SCr. Thus urinary Kim-1 is the first injury biomarker of kidney toxicity qualified by the FDA and EMEA and is expected to significantly improve kidney safety monitoring. PMID:20458318

Vaidya, Vishal S.; Ozer, Josef S.; Frank, Dieterle; Collings, Fitz B.; Ramirez, Victoria; Troth, Sean; Muniappa, Nagaraja; Thudium, Douglas; Gerhold, David; Holder, Daniel J.; Bobadilla, Norma A.; Marrer, Estelle; Perentes, Elias; Cordier, Andre; Vonderscher, Jacky; Maurer, Gerard; Goering, Peter L.; Sistare, Frank D.; Bonventre, Joseph V.

2010-01-01

133

MKT-077, a novel rhodacyanine dye in clinical trials, exhibits anticarcinoma activity in preclinical studies based on selective mitochondrial accumulation.  

PubMed

MKT-077 (formerly known as FJ-776) is a newly synthesized, highly water-soluble ( > 200 mg/ml) rhodacyanine dye that exhibits significant antitumor activity in a variety of model systems. In culture, MKT-077 inhibits the growth of five human cancer cell lines (colon carcinoma CX-1, breast carcinoma MCF-7, pancreatic carcinoma (CRL 1420, bladder transitional cell carcinoma EJ, and melanoma LOX) but not monkey kidney CV-1, an indicator cell line for normal epithelial cells. In nude mice, MKT-077 inhibits the growth of s.c. implanted human renal carcinoma A498 and human prostate carcinoma DU145 and prolongs the survival of mice bearing i.p. implanted human melanoma LOX (tumor:control = 344%). Subcellular localization indicates that MKT-077 is taken up and retained by mitochondria, and flow cytometric analysis suggests that CX-1 cells take up MKT-077 to a much greater extent than CV-1 cells. Quantitation of MKT-077 uptake by ethanol extraction shows that CX-1 cells accumulate 65-fold more MKT-077 than do CV-1 cells. MKT-077 is the first delocalized lipophilic cation with a favorable pharmacological and toxicological profile in preclinical studies. MKT-077 is now being investigated in Phase I clinical trials. PMID:8564968

Koya, K; Li, Y; Wang, H; Ukai, T; Tatsuta, N; Kawakami, M; Shishido; Chen, L B

1996-02-01

134

Preclinical to clinical translation of tofacitinib, a Janus kinase inhibitor, in rheumatoid arthritis.  

PubMed

A critical piece in the translation of preclinical studies to clinical trials is the determination of dosing regimens that allow maximum therapeutic benefit with minimum toxicity. The preclinical pharmacokinetic (PK)/pharmacodynamic (PD) profile of tofacitinib, an oral Janus kinase (JAK) inhibitor, in a mouse collagen-induced arthritis (mCIA) model was compared with clinical PK/PD data from patients with rheumatoid arthritis (RA). Preclinical evaluations included target modulation and PK/PD modeling based on continuous subcutaneous infusion or oral once- or twice-daily (BID) dosing paradigms in mice. The human PK/PD profile was obtained from pooled data from four phase 2 studies in patients with RA, and maximal effect models were used to evaluate efficacy after 12 weeks of tofacitinib treatment (1-15 mg BID). In mCIA, the main driver of efficacy was inhibition of cytokine receptor signaling mediated by JAK1 heterodimers, but not JAK2 homodimers, and continuous daily inhibition was not required to maintain efficacy. Projected efficacy could be predicted from total daily exposure irrespective of the oral dosing paradigm, with a total steady-state plasma concentration achieving 50% of the maximal response (Cave50) of ~100 nM. Tofacitinib potency (ED50) in clinical studies was ~3.5 mg BID (90% confidence interval: 2.3, 5.5) or total Cave50 of ~40 nM, derived using Disease Activity Scores from patients with RA. The collective clinical and preclinical data indicated the importance of Cave as a driver of efficacy, rather than maximum or minimum plasma concentration (Cmax or Cmin), where Cave50 values were within ~2-fold of each other. PMID:24218541

Dowty, Martin E; Jesson, Michael I; Ghosh, Sarbani; Lee, Jamie; Meyer, Debra M; Krishnaswami, Sriram; Kishore, Nandini

2014-01-01

135

Pre-Clinical Atherosclerosis due to HIV Infection: Carotid Intima-Medial Thickness Measurements from the FRAM Study  

PubMed Central

Background Cardiovascular disease (CVD) is an increasing cause of morbidity and mortality in HIV-infected patients. However, it is controversial whether HIV infection contributes to accelerated atherosclerosis independent of traditional CVD risk factors. Methods Cross-sectional study of HIV-infected and control subjects without pre-existing CVD from the study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM) and the Multi-Ethnic Study of Atherosclerosis (MESA). Pre-clinical atherosclerosis was assessed by carotid intima-medial thickness (IMT) measurements in the internal/bulb and common regions in HIV-infected and control subjects after adjusting for traditional CVD risk factors. Results For internal carotid, mean IMT was 1.17±0.50mm for HIV-infected participants and 1.06±0.58mm for controls (p<0.0001). After multivariable adjustment for demographic characteristics, the mean difference of HIV-infected vs. controls was +0.188mm (95%CI 0.113-0.263, p<0.0001). Further adjustment for traditional CVD risk factors modestly attenuated the HIV association (+0.148mm, 95%CI 0.072-0.224, p=0.0001). For the common carotid, HIV infection was independently associated with greater IMT (+0.033mm, 95%CI 0.010, 0.056, p=0.005). The association of HIV infection with IMT was similar to that of smoking which was also associated with greater IMT (internal +0.173mm, common +0.020mm). Conclusions Even after adjustment for traditional CVD risk factors, HIV infection was accompanied by more extensive atherosclerosis measured by IMT. The stronger association of HIV infection with IMT in the internal/bulb region compared to the common carotid may explain previous discrepancies in the literature. The association of HIV infection with IMT was similar to that of traditional CVD risk factors, such as smoking. PMID:19455012

Grunfeld, C.; Delaney, J.A.C.; Wanke, C.; Currier, J.S.; Scherzer, R.; Biggs, M. L.; Tien, P.; Shlipak, M.; Sidney, S.; Polak, J.F.; O'Leary, D.; Bacchetti, P.; Kronmal, R.

2010-01-01

136

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

PubMed Central

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.

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

2014-01-01

137

Novel sugar esters proniosomes for transdermal delivery of vinpocetine: Preclinical and clinical studies  

Microsoft Academic Search

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

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

2011-01-01

138

Preclinical Studies and Clinical Correlation of the Effect of Alkylating Dose1  

Microsoft Academic Search

Dose-response studies were performed with the alkylating agents (nitrogen mustard, \\/V,Ar'-bis(2-chloroethyl)-AI-nitrosourea, melphalan, cisplatin (CDDP), 4-hydroperoxycyclophosphamide (4-HC), and tri- methyleneiminethiophosphoramide) in both the MCF-7 human breast carcinoma cell line and the EMT6 and FSalIC murine tumor lines. Increasing selection pressure with the alkylating agents CDDP, mel phalan, and 4-HC In vitro produced low levels (6.5- to 9-fold) of drug resistance, despite

Emil Frei; Beverly A. Teicher; Sylvia A. Holden; Kathleen N. S. Cathcart; Yenyun Wang

1988-01-01

139

Assessment of cell sheets derived from human periodontal ligament cells: a pre-clinical study  

Microsoft Academic Search

Periodontal-ligament-derived cells (PDL cells) have stem-cell-like properties and, when implanted into periodontal defects\\u000a in vivo, can induce periodontal regeneration including the formation of new bone, cementum, and periodontal ligament. We have\\u000a previously demonstrated that PDL cell sheets, harvested from temperature-responsive cell culture dishes, have a great potential\\u000a for periodontal regeneration. The purpose of this study has been to validate the

Kaoru Washio; Takanori Iwata; Manabu Mizutani; Tomohiro Ando; Masayuki Yamato; Teruo Okano; Isao Ishikawa

2010-01-01

140

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

PubMed

Abstract 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

Nesan, Dinushan; Ng, Dominic S

2014-12-01

141

AAV-Mediated Gene Therapy for Choroideremia: Preclinical Studies in Personalized Models  

PubMed Central

Choroideremia (CHM) is an X- linked retinal degeneration that is symptomatic in the 1st or 2nd decade of life causing nyctalopia and loss of peripheral vision. The disease progresses through mid-life, when most patients become blind. CHM is a favorable target for gene augmentation therapy, as the disease is due to loss of function of a protein necessary for retinal cell health, Rab Escort Protein 1 (REP1).The CHM cDNA can be packaged in recombinant adeno-associated virus (rAAV), which has an established track record in human gene therapy studies, and, in addition, there are sensitive and quantitative assays to document REP1 activity. An animal model that accurately reflects the human condition is not available. In this study, we tested the ability to restore REP1 function in personalized in vitro models of CHM: lymphoblasts and induced pluripotent stems cells (iPSCs) from human patients. The initial step of evaluating safety of the treatment was carried out by evaluating for acute retinal histopathologic effects in normal-sighted mice and no obvious toxicity was identified. Delivery of the CHM cDNA to affected cells restores REP1 enzymatic activity and also restores proper protein trafficking. The gene transfer is efficient and the preliminary safety data are encouraging. These studies pave the way for a human clinical trial of gene therapy for CHM. PMID:23667438

Vasireddy, Vidyullatha; Kohnke, Monika; Black, Aaron D.; Alexandrov, Krill; Zhou, Shangzhen; Maguire, Albert M.; Chung, Daniel C.; Mac, Helen; Sullivan, Lisa; Gadue, Paul; Bennicelli, Jeannette L.; French, Deborah L.; Bennett, Jean

2013-01-01

142

A preclinical study of the effects of seabuckthorn (Hippophae rhamnoides L.) leaf extract on cutaneous wound healing in albino rats.  

PubMed

Hippophae rhamnoides L. (family Elaeagnaceae), commonly known as seabuckthorn, is a wild shrub growing at high altitude (1200-4500 meters) in adverse climatic conditions. The aim of the present study was to evaluate healing potential of seabuckthorn leaves in a preclinical study on rats using a cutaneous excision-punch wound model. Four full-thickness excision-type wounds of 8.0 mm diameter were created on the dorsal surface of rats under aseptic conditions. The aqueous lyophilized extract of seabuckthorn leaves, at doses of 0.5%, 1.0%, and 1.5% w/v prepared in propylene glycol, were applied topically twice daily for 7 days. Control animals received the vehicle alone in an identical manner. Wound granulation tissues were excised on eighth day postwounding, and the hydroxyproline, hexosamine, total protein content, and antioxidant levels were determined. Wound surface area was also measured on the eighth day before wound excision to determine wound contraction. Topical application of 1.0% seabuckthorn leaf extract statistically significantly augmented the healing process, as evidenced by increases in the content of hydroxyproline and protein as well as the reduction in wound area when compared with similar effects in response to treatment using povidone-iodine ointment (standard care). The reduced glutathione, vitamin C, superoxide dismutase, catalase, and glutathione peroxidase activities showed significant increases in seabuckthorn leaf extract-treated wounds as compared to controls. The lipid peroxide levels were significantly decreased in leaf extract-treated wounds. The results suggest that aqueous leaf extract of seabuckthorn promotes wound healing, which may be due to increased antioxidant levels in the granulation tissue. PMID:15911921

Gupta, Asheesh; Kumar, Ratan; Pal, Karan; Banerjee, Pratul K; Sawhney, Ramesh C

2005-06-01

143

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

PubMed Central

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

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

144

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

PubMed

The concept of natural orifice transluminal endoscopic surgery (NOTES) is an emerging experimental alternative to conventional surgery that eliminates skin incisions using an endoscope passed through a natural orifice (e.g., mouth, urethra, or anus). This study was designed to evaluate the feasibility and safety of thyroid resection via an entirely transoral tri-vestibular route using endoscopy, and to introduce NOTES to the head and neck area of medicine. We performed ten complete endoscopic thyroid lobectomies with central lymph node dissection via a tri-vestibular approach in fresh-frozen cadavers. A 5-mm endoscope with a deflectable tip was used to visualize the surgical field. Three cannulas were inserted through the midline and bilateral incision sites in the vestibule to position the instruments and endoscope. We refined and described the surgical technique in each step using video clips. We identified and preserved neighboring critical structures during surgery. We also confirmed that there were no obvious remnant thyroid tissues and no injury to the neighboring structures after exploration. The transoral tri-vestibular approach seems to provide a good view and surgical field for endoscopic thyroidectomy. However, the transoral approach for thyroidectomy remains experimental, and the detailed surgical technique should be refined via further clinical studies. PMID:24496566

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

2014-12-01

145

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

PubMed

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

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

2011-01-01

146

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

PubMed

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

Arias, Jalayne J; Karlawish, Jason

2014-02-25

147

Novel transdermal delivery of Timolol maleate using sugar esters: preclinical and clinical studies.  

PubMed

The feasibility of matrix controlled transdermal patch based on sugar fatty acid ester (SE) as penetration and absorption enhancer containing Timolol maleate (TM) was investigated. The influence of fatty acid type, chain length and hydrophile-lipophile balance (HLB) on the in vitro drug release as well as its permeation across hairless rat skin were studied and compared aiming to select a patch formula for clinical performance. Skin irritation induced by SE patch was evaluated by visual scoring, color reflectance measurements and non-invasive transepidermal water loss (TEWL) technique. The results indicated that among different SEs tried, laurate SE with shorter fatty acid chain length and higher HLB value significantly increased the amount of TM liberated from the patch (99+/-2.1%) and its permeation across rat skin (86+/-4.3%). The total drug permeation and flux values were approximately 5-fold greater compared to SE free patch. The extent of absorption of TM-SE patch expressed by AUC was 64% larger as compared to the oral solution with steady plasma concentration over 18 h and relative bioavailability (F(rel)) of 163%. The developed patch was well tolerated by all the subjects with only moderate skin irritation, which was recovered in 24h after patch removal. The results are very encouraging and offer an alternative approach to maintain higher, prolonged and controlled blood level profile of the drug over 18-24h. PMID:19126429

El-Laithy, Hanan M

2009-05-01

148

[Developing and standardizing experimental protocols using human iPS-derived cells to predict adverse drug reactions in pre-clinical safety studies].  

PubMed

In this study, we have standardized experimental protocols to evaluate the possibility of using cells differentiated from human induced pluripotent stem cells (hiPSCs) in the pre-clinical studies for the drug approval processes. Cells differentiated from hiPSC, especially cardiomyocytes, neurons and hepatocytes, are expected to be used as new pharmacological and toxicological assay tools. Current preclinical test methods have limitations for predicting clinical adverse drug reactions. This is because of the so-called 'problem of species difference'. Drug-induced arrhythmia, cognitive impairment and hepatotoxicity which can't be predicted in pre-clinical studies are major causes of the high rate attrition of new-drug candidates in clinical studies and of withdrawal of products from the market. The development of new pre-clinical test methods using cells differentiated from hiPSCs would resolve these problems, in addition to solving the issue of "the replacement, refinement and reduction (3Rs)" of animal experiments. From 2010 to 2011, we surveyed companies belonging to the Japan Pharmaceutical Manufacturers Association (JPMA) and academic researchers about the usage of differentiated cells in their laboratories. We found that studies were performed using differentiated cells from different cell lines of hiPSC with laboratory-specific differentiation methods. The cells were cultured in various conditions and their activities were measured using different methods. This resulted in a variety of pharmacological responses of the cells. It is therefore impossible to compare reproducibility and ensure reliability of experiments using these cells. To utilize the cells in the drug approval processes, we need robust, standardized test methods to accurately reproduce these methods in all laboratories. We will then be able to compare and analyze the obtained results. Based on the survey, the Ministry of Health, Labor and Welfare funded our study. In our study, we standardize pharmacological methods among several laboratories, including our laboratory, to develop robust tests, using the same lot of cells, the same culture conditions, reference compounds, experimental protocols, and analysis methodology. In conclusion, to standardize robust test methods, we need a consistent supply of high-quality differentiated cells. Further, indexes to quantify the quality of the differentiated cells will be needed for their effective usage in the pre-clinical safety studies. PMID:24340667

Sekino, Yuko; Sato, Kaoru; Kanda, Yasunari; Ishida, Seiichi

2013-01-01

149

Preclinical episodes of orofacial pain symptoms and their association with healthcare behaviors in the OPPERA prospective cohort study.  

PubMed Central

The course of preclinical pain symptoms sheds light on the etiology and prognosis of chronic pain. We aimed to quantify rates of developing initial- and recurrent-symptoms of painful temporomandibular disorder (TMD) and to evaluate associations with health behaviors. In the OPPERA prospective cohort study, 2,719 people aged 18-44 years with lifetime absence of TMD when enrolled completed 25,103 quarterly (three-monthly) questionnaires during amedian 2.3-year follow-up period. Questionnaires documented TMD symptom episodes, headache, other body pain, health care attendance and analgesic usage and. Kaplan-Meier methods for clustered data estimated symptom-free survival time. Multivariable models assessed demographic variation in TMD symptom rates and evaluated associations with healthcare and analgesic use. One third of people developed TMD symptoms and for one quarter of symptomatic episodes, pain intensity was severe. Initial TMD symptoms developed at anannual rate of 18.8 episodes per 100 people. The annual rate more than doubled for first-recurrence and doubled again for second-or-subsequent recurrence such that, one year after first recurrence, 71% of people experienced second recurrence. The overall rate increased with age and was greater in African-Americans and lower in Asians relative to Whites. The probability of TMD symptoms was strongly associated with concurrent episodes of headache and body pain and with past episodes of TMD symptoms. Episodes of TMD symptoms, headache and body pain were associated with increases of ~10% in probability of analgesic usage and healthcare attendance. Yet, even when TMD, headache and body pain occurred concurrently, 27% of people neither attended healthcare nor used analgesics. PMID:23531476

Slade, Gary D.; Sanders, Anne E.; Bair, Eric; Brownstein, Naomi; Dampier, Dawn; Knott, Charles; Fillingim, Roger; Maixner, William O.; Smith, Shad; Greenspan, Joel; Dubner, Ron; Ohrbach, Richard

2013-01-01

150

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

PubMed Central

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

Chiu, Chi-Tso; Chuang, De-Maw

2011-01-01

151

Preclinical studies and clinical correlation of the effect of alkylating dose.  

PubMed

Dose-response studies were performed with the alkylating agents [nitrogen mustard, N,N'-bis(2-chloroethyl)-N-nitrosourea, melphalan, cisplatin (CDDP), 4-hydroperoxycyclophosphamide (4-HC), and trimethyleneiminethiophosphoramide] in both the MCF-7 human breast carcinoma cell line and the EMT6 and FSaIIC murine tumor lines. Increasing selection pressure with the alkylating agents CDDP, melphalan, and 4-HC in vitro produced low levels (6.5- to 9-fold) of drug resistance, despite an intensive and prolonged treatment program. The MCF-7 sublines made resistant to CDDP and 4-HC did not exhibit cross-resistance to other alkylating agents; however, the MCF-7 subline resistant to melphalan was partially cross-resistant to nitrogen mustard, 4-HC, and CDDP. A log-linear relationship was maintained between surviving fraction of MCF-7 cells in culture and drug concentration with alkylating agents, whereas for nonalkylating agents the survival curves tended to plateau at high drug concentrations. Log-linear tumor cell kill was also obtained over a wide dosage range with several alkylating agents in murine tumors treated in vivo. Tumor cell survival assay by colony formation indicated the continuing importance of dose in the action of the drugs even at high levels of tumor cell kill. With some agents, there was a difference between the slopes of the tumor cell killing curves in vivo as compared to in vitro. Cyclophosphamide was far more potent in vitro (4-HC) than in vivo (cyclophosphamide). Trimethyleneiminethiophosphoramide and N,N'-bis(2-chloroethyl)-N-nitrosourea were both more potent in vivo than in vitro. These differences may be explained by the various metabolic patterns of these drugs. Dose of alkylating agents is clearly a crucial variable particularly where multilog tumor cell kill is the goal, and in this regard, the effect of drug dose on the tumoricidal action of the alkylating agents is substantially greater than for nonalkylating agents. PMID:3180059

Frei, E; Teicher, B A; Holden, S A; Cathcart, K N; Wang, Y Y

1988-11-15

152

Photoacoustic spectroscopy in the monitoring of breast tumor development: a pre-clinical study  

NASA Astrophysics Data System (ADS)

Breast cancer is the most frequently diagnosed cancer type and its detection at an early stage can reduce the mortality rate substantially. With the aim to detect breast cancer early, by studying tumor progression in nude mice, a pulsed laser induced photoacoustic spectroscopy set up has been designed and developed. MCF-7 cells xenografts were developed using six to eight weeks old female nude mice and tumor tissues were extracted on different days (10th, 15th and 20th Day) post injection and the corresponding photoacoustic spectra were recorded at 281nm excitation. A total of 144 time domain spectra were recorded from 36 animals belonging to the three time points (10th, 15th and 20th day post injection) and converted into frequency domains by Fast Fourier Transform (FFT) tools of the MATLAB algorithms and analyzed. The frequency patterns of the tumor masses on 10th, 15th and 20th day of tumor development showed a gradual increase in intensity at certain frequencies, 5.93 x103 Hz, 15.9 x103 Hz, 29.69 x103 Hz and 32.5 x103 Hz in the FFT patterns indicating that these frequencies were more sensitive towards tumor development. Further analysis of the data yielded a clear variation in the spectral parameters with progression of the disease suggesting that the technique may be suitable for early detection of the disease. Thus, we expect that the developed setup may be useful in assessing the different phases of tumor development which may have clinical implications.

Priya, Mallika; Rao, Bola Sadashiva Satish; Ray, Satadru; Mahato, Krishna Kishore

2014-03-01

153

Preclinical students' experiences in early clerkships after skills training partly offered in primary health care centers: a qualitative study from Indonesia  

PubMed Central

Background Students may encounter difficulties when they have to apply clinical skills trained in their pre-clinical studies in clerkships. Early clinical exposure in the pre-clinical phase has been recommended to reduce these transition problems. The aim of this study is to explore differences in students' experiences during the first clerkships between students exclusively trained in a skills laboratory and peers for whom part of their skills training was substituted by early clinical experiences (ECE). Methods Thirty pre-clinical students trained clinical skills exclusively in a skills laboratory; 30 peers received part of their skills training in PHC centers. Within half a year after commencing their clerkships all 60 students shared their experiences in focus group discussions (FGDs). Verbatim transcripts of FGDs were analyzed using Atlas-Ti software. Results Clerkship students who had participated in ECE in PHC centers felt better prepared to perform their clinical skills during the first clerkships than peers who had only practiced in a skills laboratory. ECE in PHC centers impacted positively in particular on students’ confidence, clinical reasoning, and interpersonal communication. Conclusion In the Indonesian setting ECE in PHC centers reduce difficulties commonly encountered by medical students in the first clerkships. PMID:22640419

2012-01-01

154

Fiber optic fluorescence detection of low-level porphyrin concentrations in preclinical and clinical studies  

NASA Astrophysics Data System (ADS)

A significant clinical problem in the local treatment of cutaneous metastases of breast cancer (by any modality--surgery, radiation therapy or photodynainic therapy) is the fact that the disease almost always extends beyond the boundary of visible lesions in the form of microscopic deposits. These deposits may be distant from the site of visible disease but are often in close proximity to it and are manifested sooner or later by the development of recurrent lesions at the border of the treated area, thus the "marginal miss" in radiation therapy, the "rim recurrence" in photodynamic therapy, and the "incisional recurrence" following surgical excision. More intelligent use of these treatment modalities demands the ability to detect microscopic deposits of tumor cells using non-invasive methodology. In vivo fluorescence measurements have been made possible by the development of an extremely sensitive fiber optic in vivo fluorescence photometer. The instrument has been used to verify that fluorescence correlated with injected porphyrin levels in various tissues. The delivery of light to excite and detect background fluorescence as well as photosensitizer fluorescence in tissues has been accomplished using two HeNe lasers emitting at 632.8 nm and 612 nm delivered through a single quartz fiber optic. Chopping at different frequencies, contributions of fluorescence may be separated. Fluorescence is picked up via a 400 micron quartz fiber optic positioned appropriately near the target tissue. Validation of these levels was made by extraction of the drug from the tissues with resultant quantitation. Recently, an extensive study was undertaken to determine if fluorescence could be used for the detection of occult, clinically non-palpable metastases in the lymph node of rats. This unique model allowed for the detection of micrometastases in lymph nodes using very low injected doses of the photosensitizer Photofrin II. Data obtained revealed the ability to detect on the order of 50-100 cells using 0.25 mg/kg of sensitizer, a level 20 times lower than normally used for treatment of animal tumors. These results indicate that Photofrin II could be used for fluorescence detection of small metastatic tumors, while substantially reducing the major side effect of PDT; namely, prolonged photosensitivity. Results to be presented demonstrate the ability of this technique to detect microscopic deposits of malignant tumor cells in patients with metastatic breast cancer. These deposits were found in clinically negative areas of the chest wall.

Mang, Thomas S.; McGinnis, Carolyn; Khan, S.

1990-07-01

155

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

PubMed Central

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

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

2014-01-01

156

Mechanism of Action of Aripiprazole Predicts Clinical Efficacy and a Favourable Side-Effect Profile  

Microsoft Academic Search

The antipsychotic efficacy of aripiprazole is not generally associated with extrapyramidal symptoms, cardiovascular effects, sedation or elevations in serum prolactin that characterize typical or atypical antipsychotics. The aim of this study was to clarify the mechanism of action of aripiprazole that underlies its favourable clinical profiles. The preclinical efficacy and side-effect profiles of aripiprazole were evaluated usingseveral pharmaco-behavioural test systems

Tsuyoshi Hirose; Yasufumi Uwahodo; Sakiko Yamada; Takashi Miwa; Tetsuro Kikuchi; Hisashi Kitagawa; Kevin D. Burris; C. Anthony Altar; Toshitaka Nabeshima

2004-01-01

157

Self-Efficacy Perceptions of Social Studies Candidate Teachers  

ERIC Educational Resources Information Center

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

Simsek, Nihat

2011-01-01

158

Paromomycin-loaded albumin microspheres: efficacy and stability studies.  

PubMed

In the present work, paromomycin-loaded albumin microspheres (PM-MS) have been formulated for passive targeting of paromomycin (PM) to macrophages, for the treatment of visceral leishmaniasis (VL). PM-MS were prepared by spray-drying method with a mean particle size of???3?µm. Thermal and chemical cross-linking methods were used for controlling drug release from the prepared microspheres (MS). PM-MS were then tested for efficacy and stability studies. In efficacy study, in vitro promastigote assay was carried out to assess the susceptibility of promastigote to PM in the concentration range of 5.0-150?µg/ml; cytotoxicity assay was performed to determine possible toxicity of PM for the host cells (peritoneal macrophages) and intracellular amastigote assay was carried out to determine the efficacy of free PM (PM solution) and encapsulated PM (PM-MS). Results obtained indicated a significant increase in efficacy of PM-MS in comparison to PM solution at equivalent concentration. Subsequently, stability studies of prepared formulation was carried out at various temperature and humidity conditions, these studies provided stability of formulation at all tested conditions including accelerated conditions. Thus, it can be concluded that present work provides an optimized formulation with stability and enhanced efficacy. PMID:22514145

Khan, Wahid; Kumar, Rajendra; Singh, Sukhvinder; Arora, Sunil Kumar; Kumar, Neeraj

2013-06-01

159

Original article In vivo studies on lysosubtilin. 3. Efficacy for  

E-print Network

- Lysosubtilin is a broad-spectrum preparation of lytic enzymes from Bacillus subtilis designed for veterinary medicine. This study demonstrates its efficacy for the treatment of repro- ductive system diseases and superficial udder lesions, respectively) caused by various mixtures of bacteria (both Gram-positive and Gram

Boyer, Edmond

160

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 Experimental Design for Preclinical Drug Screening in the ALS Mouse Model, 2007 10 Years To Validate the Model

161

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

PubMed Central

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

Grounds, Miranda D.; Radley, Hannah G.; Lynch, Gordon S.; Nagaraju, Kanneboyina; De Luca, Annamaria

2008-01-01

162

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

PubMed

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

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

2012-01-01

163

Targeting therapy of hepatocellular carcinoma with doxorubicin prodrug PDOX increases anti-metastatic effect and reduces toxicity: a preclinical study  

PubMed Central

Background This study was to investigate the effects and safety of cathepsin B-cleavable doxorubicin (DOX)-prodrug (PDOX) for targeting therapy of metastatic human hepatocellular carcinoma (HCC) using DOX as a positive control drug. Methods The orthotopic nude mice model of highly metastatic HCC was established and the animals were randomized and treated with PDOX, DOX and saline, respectively. Hematology, biochemistry and tumor markers were studied. At autopsy, liver tumor weight and size, ascites, abdominal lymph nodes metastases, experimental peritoneal carcinomatosis index (ePCI), and tumor-host body weight ratio were investigated. Immunohistochemical studies and western blotting were done to investigate key molecules involved in the mechanism of action. Results Compared with Control, both PDOX and DOX could similarly and significantly reduce liver tumor weight and tumor volume by over 40%, ePCI values, retroperitoneal lymph node metastases and lung metastases and serum AFP levels (P?efficacy and reduced side effects especially cardio-toxicities in this HCC model. PMID:23961994

2013-01-01

164

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

PubMed Central

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

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

2011-01-01

165

Learning style preferences and academic success of preclinical allied health students.  

PubMed

Student learning style modality preferences, in preclinical classes, were assessed using the visual-aural-read/write-kinesthetic (VARK) inventory. Preferences were assessed for 137 preclinical students, including those in nursing, physician's assistant, physical therapy, athletic training, and natural science programs using the online VARK inventory. All classes contained a majority of multimodal and a significantly high proportion of kinesthetic learners. No correlations were noted between modality preference strength and assessment performance in general biology classes; significant correlations were discovered for kinesthetic preference among the same cohort in subsequent human anatomy (negative correlation) and general physiology (positive correlation) classes. Assessment performance of nursing students in an anatomy and physiology class resulted in correlations with aural (negative correlation) and visual (positive correlation) preference strengths. Study findings are used to evaluate the efficacy of non-omnimodal delivery of content-focused science classes, before the students have developed the background knowledge or skills required to contextualize the learning. PMID:24326923

Good, Jonathan P; Ramos, Diane; D'Amore, Domenic C

2013-01-01

166

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

PubMed

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

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

2010-01-01

167

[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

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.

DeNardo, S.J.

1995-12-31

168

The basics of preclinical drug development for neurodegenerative disease indications  

Microsoft Academic Search

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

Karen L Steinmetz; Edward G Spack

2009-01-01

169

Contrasting gray and white matter changes in preclinical Huntington disease  

E-print Network

Contrasting gray and white matter changes in preclinical Huntington disease An MRI study DD ABSTRACT Background: In Huntington disease (HD), substantial striatal atrophy precedes clinical motor of view; GM gray matter; HD Huntington disease; MRI magnetic resonance imaging; pre-HD preclinical HD

Aron, Adam

170

Management of ErbB2-positive breast cancer: insights from preclinical and clinical studies with lapatinib.  

PubMed

The management of human epidermal growth factor receptor 2-positive (ErbB2+) breast cancer is challenging; patients with ErbB2+ breast tumors have more aggressive disease and a poor prognosis. The increasing incidence of breast cancer in Asia and the limitations of existing treatments pose additional challenges. In this review, we summarize the preclinical and clinical evidence that indicates how lapatinib, a novel inhibitor that targets the human epidermal growth factor receptor (ErbB1) and ErbB2 may help clinicians address four particularly challenging issues in the management of ErbB2+ breast cancer. These issues are: (i) trastuzumab therapy failure, (ii) development of central nervous system metastases, (iii) minimizing toxicity and (iv) selecting the most appropriate partners (chemotherapy and non-chemotherapy) for combination therapy with lapatinib. Lapatinib, in combination with chemotherapeutic agents, such as capecitabine, provides clinical benefits to patients with ErbB2+ breast cancer, including patients who develop progressive disease on trastuzumab. Lapatinib, in combination with non-chemotherapeutic agents, such as letrozole, may also provide a chemotherapy-free treatment option for postmenopausal patients with estrogen receptor-positive/ErbB2+ metastatic breast cancer. Encouraging results have also emerged regarding the synergistic effects of lapatinib in combination with other agents for the treatment of ErbB2+ breast cancer. Promising findings have also been reported for the use of lapatinib to prevent and treat central nervous system metastases. Collectively, these results indicate that the judicious use of lapatinib, an effective oral therapy with a manageable toxicity profile, can enhance the management of patients with ErbB2+ breast cancer. PMID:20542996

Vogel, Charles; Chan, Arlene; Gril, Brunilde; Kim, Sung-Bae; Kurebayashi, Junichi; Liu, Li; Lu, Yen-Shen; Moon, Hanlim

2010-11-01

171

Do self?efficacy beliefs predict the primiparous labour and birth experience? A longitudinal study  

Microsoft Academic Search

The objective of this longitudinal study was to determine the predictive role of birth self?efficacy beliefs in primiparous women's childbirth experiences (n=230). The study had three aims: (1) to determine whether birth self?efficacy beliefs predict pain tolerance and pain perceptions in labour, (2) whether self?efficacy beliefs predict obstetric events and birth satisfaction, and (3) whether the relationships between self?efficacy and

Kate M. Scott; Paul E. Jose

2009-01-01

172

Characterization of Novel PI3K? Inhibitors as Potential Therapeutics for SLE and Lupus Nephritis in Pre-Clinical Studies.  

PubMed

SLE is a complex autoimmune inflammatory disease characterized by pathogenic autoantibody production as a consequence of uncontrolled T-B cell activity and immune-complex deposition in various organs, including kidney, leading to tissue damage and function loss. There is a high unmet need for better treatment options other than corticosteroids and immunosuppressants. Phosphoinositol-3 kinase ? (PI3K?) is a promising target in this respect as it is essential in mediating B- and T-cell function in mouse and human. We report the identification of selective PI3K? inhibitors that blocked B-, T-, and plasmacytoid dendritic cell activities in human peripheral blood and in primary cell co-cultures (BioMAP(®)) without detecting signs of undesired toxicity. In an IFN?-accelerated mouse SLE model, our PI3K? inhibitors blocked nephritis development, whether administered at the onset of autoantibody appearance or the onset of proteinuria. Disease amelioration correlated with normalized immune cell numbers in the spleen, reduced immune-complex deposition as well as reduced inflammation, fibrosis, and tissue damage in the kidney. Improvements were similar to those achieved with a frequently prescribed drug for lupus nephritis, the potent immunosuppressant mycophenolate mofetil. Finally, we established a pharmacodynamics/pharmacokinetic/efficacy model that revealed that a sustained PI3K? inhibition of 50% is sufficient to achieve full efficacy in our disease model. These data demonstrate the therapeutic potential of PI3K? inhibitors in SLE and lupus nephritis. PMID:24904582

Haselmayer, Philipp; Camps, Montserrat; Muzerelle, Mathilde; El Bawab, Samer; Waltzinger, Caroline; Bruns, Lisa; Abla, Nada; Polokoff, Mark A; Jond-Necand, Carole; Gaudet, Marilène; Benoit, Audrey; Bertschy Meier, Dominique; Martin, Catherine; Gretener, Denise; Lombardi, Maria Stella; Grenningloh, Roland; Ladel, Christoph; Petersen, Jørgen Søberg; Gaillard, Pascale; Ji, Hong

2014-01-01

173

Diagnosing Self-Efficacy in Intelligent Tutoring Systems: An Empirical Study  

E-print Network

Diagnosing Self-Efficacy in Intelligent Tutoring Systems: An Empirical Study Scott W. Mc {swmcquig, lester}@ncsu.edu Abstract. Self-efficacy is an individual's belief about her ability to perform well in a given situation. Because self-efficacious students are effective learners, endowing

Young, R. Michael

174

A Study of Teacher Efficacy of Special Education Teachers of English Language Learners With Disabilities  

Microsoft Academic Search

This study examined the teacher efficacy of special education teachers of English language learners (ELLs) with disabilities by surveying 202 elementary special education teachers. Overall participant teacher efficacy scores were high. No statistically significant differences in efficacy scores were found for levels of teacher preparation, number of years of teaching experience, or socioeconomic status of the students. A statistically significant

Oneyda M. Paneque; Patricia M. Barbetta

2006-01-01

175

A Study of Teacher Efficacy of Special Education Teachers of English Language Learners with Disabilities  

ERIC Educational Resources Information Center

This study examined the teacher efficacy of special education teachers of English language learners (ELLs) with disabilities by surveying 202 elementary special education teachers. Overall participant teacher efficacy scores were high. No statistically significant differences in efficacy scores were found for levels of teacher preparation, number…

Paneque, Oneyda M.; Barbetta, Patricia M.

2006-01-01

176

Preclinical antitumor activity of a nanoparticulate SN38.  

PubMed

The present studies were carried out to examine the efficacy of a nanoparticulate formulation of SN38, the potent topoisomerase I inhibitor and active metabolite of irinotecan. Metabolism of irinotecan to SN38 is inefficient and subject to considerable patient-to-patient variability. One approach to more controlled administration of the anticancer agent is direct administration of the active SN38. A nanoparticulate formulation of SN38 was prepared by a method of precipitation with compressed antisolvent. Nanoparticulate SN38 efficiently inhibited the proliferation of colorectal, ovarian, and mesothelial cancer cell lines in vitro. Concentrations resulting in 50 % inhibition of proliferation were approximately 1000 fold lower for nanoparticulate SN38 compared to irinotecan. In vivo effects were examined using colorectal and ovarian mouse model systems. In a mouse model of peritoneally disseminated ovarian cancer intraperitoneal administration of irinotecan was favorable to intravenous delivery however intraperitoneal delivery of nanoparticulate SN38 was significantly more effective than intraperitoneal irinotecan. In addition, in a mouse colorectal cancer model administration of nanoparticulate SN38 once weekly exhibited greater activity compared to daily or weekly administration of irinotecan. Additional studies demonstrated nanoparticulate SN38 administered as a combination therapy with mitomycin C was more effective than the combination of irinotecan and mitomycin C. Results from the present studies using preclinical colorectal and ovarian cancer model systems demonstrate the efficacy of nanoparticulate SN38 and substantiate continued development. PMID:23299391

Al-Kasspooles, Mazin F; Williamson, Stephen K; Henry, David; Howell, Jahna; Niu, Fengui; Decedue, Charles J; Roby, Katherine F

2013-08-01

177

Preclinical Cardiorenal Interrelationships in Essential Hypertension  

PubMed Central

A diseased heart causes numerous adverse effects on kidney function, and vice versa renal disease can significantly impair cardiac function. Beyond these heart-kidney interrelationships at the clinical level, a reciprocal association has been suggested to exist even in the early stages of those organs' dysfunction. The aim of the present review is to provide evidence of the presence of a preclinical cardiorenal syndrome in the particular setting of essential hypertension, focusing on the subsequent hypertensive sequelae on heart and kidneys. In particular, a plethora of studies have demonstrated not only the predictive role of kidney damage, as expressed by either decreased glomerular filtration or increased urine albumin excretion, for adverse left ventricular functional and structural adaptations but also preclinical heart disease, i.e. left ventricular hypertrophy that is associated with deterioration of renal function. Notably, these reciprocal interactions seem to exist even at the level of microcirculation, since both coronary flow reserve and renal hemodynamics are strongly related with clinical and preclinical renal and cardiac damage, respectively. In this preclinical setting, common pathophysiological denominators, including the increased hemodynamic load, sympathetic and renin-angiotensin system overactivity, increased subclinical inflammatory reaction, and endothelial dysfunction, account not only for the reported associations between overt cardiac and renal damage but also for the parallel changes that occur in coronary and renal microcirculation. PMID:23946723

Tsioufis, Costas; Tsiachris, Dimitrios; Kasiakogias, Alexandros; Dimitriadis, Kyriakos; Petras, Dimitris; Goumenos, Dimitris; Siamopoulos, Konstantinos; Stefanadis, Christodoulos

2013-01-01

178

Paclitaxel-hyaluronic nanoconjugates prolong overall survival in a preclinical brain metastases of breast cancer model.  

PubMed

Brain (central nervous system; CNS) metastases pose a life-threatening problem for women with advanced metastatic breast cancer. It has recently been shown that the vasculature within preclinical brain metastasis model markedly restricts paclitaxel delivery in approximately 90% of CNS lesions. Therefore to improve efficacy, we have developed an ultra-small hyaluronic acid (HA) paclitaxel nanoconjugate (?5 kDa) that can passively diffuse across the leaky blood-tumor barrier and then be taken up into cancer cells (MDA-MB-231Br) via CD44 receptor-mediated endocytocis. Using CD44 receptor-mediated endocytosis as an uptake mechanism, HA-paclitaxel was able to bypass p-glycoprotein-mediated efflux on the surface of the cancer cells. In vitro cytoxicity of the conjugate and free paclitaxel were similar in that they (i) both caused cell-cycle arrest in the G2-M phase, (ii) showed similar degrees of apoptosis induction (cleaved caspase), and (iii) had similar IC50 values when compared with paclitaxel in MTT assay. A preclinical model of brain metastases of breast cancer using intracardiac injections of Luc-2 transfected MDA-MB-231Br cells was used to evaluate in vivo efficacy of the nanoconjugate. The animals administered with HA-paclitaxel nanoconjugate had significantly longer overall survival compared with the control and the paclitaxel-treated group (P < 0.05). This study suggests that the small molecular weight HA-paclitaxel nanoconjugates can improve standard chemotherapeutic drug efficacy in a preclinical model of brain metastases of breast cancer. PMID:24002934

Mittapalli, Rajendar K; Liu, Xinli; Adkins, Chris E; Nounou, Mohamed I; Bohn, Kaci A; Terrell, Tori B; Qhattal, Hussaini S; Geldenhuys, Werner J; Palmieri, Diane; Steeg, Patricia S; Smith, Quentin R; Lockman, Paul R

2013-11-01

179

Phase II study evaluating the efficacy and safety of sagopilone (ZK-EPO) in patients with metastatic breast cancer that has progressed following chemotherapy.  

PubMed

Sagopilone is a novel, fully synthetic epothilone that has shown promising preclinical activity in a range of tumor models, including platinum-resistant ovarian cancer and metastatic breast cancer (MBC). This open-label, multicenter, Phase II study investigated the efficacy, safety, and tolerability of sagopilone administered to patients with MBC. Women with MBC whose previous chemotherapy regimen included a taxane and an anthracycline received sagopilone 16 or 22 mg/m(2) as a 3-h intravenous infusion every 21 days. Efficacy (using modified Response Evaluation Criteria in Solid Tumors), safety, and tolerability were assessed in this population. A total of 65 patients received sagopilone at either 16 mg/m(2) (N = 39) or 22 mg/m(2) (N = 26). Patients received a median of two cycles of sagopilone. Among the 65 patients who were evaluable for efficacy, there were three confirmed tumor responses over both treatment arms; however, the primary target of the study was not reached. The main treatment-related adverse events were sensory neuropathy (81.5%) and fatigue (44.6%). There were no deaths related to the study drug. Sagopilone was moderately tolerated in both treatment arms and showed limited activity in heavily pre-treated patients with MBC. PMID:20697802

Morrow, Phuong K; Divers, Stephen; Provencher, Louise; Luoh, Shiuh-Wen; Petrella, Teresa M; Giurescu, Marius; Schmelter, Thomas; Wang, Yao; Hortobagyi, Gabriel N; Vahdat, Linda T

2010-10-01

180

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)

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.

Li, Baoqiang; Berti, Romain; Abran, Maxime; Lesage, Frédéric

2014-05-01

181

Ultrasound guided fluorescence molecular tomography with improved quantification by an attenuation compensated Born-normalization and in vivo preclinical study of cancer.  

PubMed

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. PMID:24880378

Li, Baoqiang; Berti, Romain; Abran, Maxime; Lesage, Frédéric

2014-05-01

182

Preclinical Dose-Finding Study With a Liver-Tropic, Recombinant AAV-2/8 Vector in the Mouse Model of Galactosialidosis  

PubMed Central

Galactosialidosis (GS) is a lysosomal storage disease linked to deficiency of the protective protein/cathepsin A (PPCA). Similarly to GS patients, Ppca-null mice develop a systemic disease of the reticuloendothelial system, affecting most visceral organs and the nervous system. Symptoms include severe nephropathy, visceromegaly, infertility, progressive ataxia, and shortened life span. Here, we have conducted a preclinical, dose-finding study on a large cohort of GS mice injected intravenously at 1 month of age with increasing doses of a GMP-grade rAAV2/8 vector, expressing PPCA under the control of a liver-specific promoter. Treated mice, monitored for 16 weeks post-treatment, had normal physical appearance and behavior without discernable side effects. Despite the restricted expression of the transgene in the liver, immunohistochemical and biochemical analyses of other systemic organs, serum, and urine showed a dose-dependent, widespread correction of the disease phenotype, suggestive of a protein-mediated mechanism of cross-correction. A notable finding was that rAAV-treated GS mice showed high expression of PPCA in the reproductive organs, which resulted in reversal of their infertility. Together these results support the use of this rAAV-PPCA vector as a viable and safe method of gene delivery for the treatment of systemic disease in non-neuropathic GS patients. PMID:22008912

Hu, Huimin; Gomero, Elida; Bonten, Erik; Gray, John T; Allay, Jim; Wu, Yanan; Wu, Jianrong; Calabrese, Christopher; Nienhuis, Arthur; d'Azzo, Alessandra

2012-01-01

183

Preclinical dose-finding study with a liver-tropic, recombinant AAV-2/8 vector in the mouse model of galactosialidosis.  

PubMed

Galactosialidosis (GS) is a lysosomal storage disease linked to deficiency of the protective protein/cathepsin A (PPCA). Similarly to GS patients, Ppca-null mice develop a systemic disease of the reticuloendothelial system, affecting most visceral organs and the nervous system. Symptoms include severe nephropathy, visceromegaly, infertility, progressive ataxia, and shortened life span. Here, we have conducted a preclinical, dose-finding study on a large cohort of GS mice injected intravenously at 1 month of age with increasing doses of a GMP-grade rAAV2/8 vector, expressing PPCA under the control of a liver-specific promoter. Treated mice, monitored for 16 weeks post-treatment, had normal physical appearance and behavior without discernable side effects. Despite the restricted expression of the transgene in the liver, immunohistochemical and biochemical analyses of other systemic organs, serum, and urine showed a dose-dependent, widespread correction of the disease phenotype, suggestive of a protein-mediated mechanism of cross-correction. A notable finding was that rAAV-treated GS mice showed high expression of PPCA in the reproductive organs, which resulted in reversal of their infertility. Together these results support the use of this rAAV-PPCA vector as a viable and safe method of gene delivery for the treatment of systemic disease in non-neuropathic GS patients. PMID:22008912

Hu, Huimin; Gomero, Elida; Bonten, Erik; Gray, John T; Allay, Jim; Wu, Yanan; Wu, Jianrong; Calabrese, Christopher; Nienhuis, Arthur; d'Azzo, Alessandra

2012-02-01

184

Preclinical studies with the anti-CD19-saporin immunotoxin BU12-SAPORIN for the treatment of human-B-cell tumours.  

PubMed Central

The immunotoxin BU12-SAPORIN was constructed by covalently coupling the single-chain ribosome-inactivating protein saporin to the anti-CD19 monoclonal antibody BU12 via a disulphide linker using the heterobifunctional reagent SPDP. The immunoreactivity and specificity of BU12-SAPORIN was identical to that of unmodified native BU12 antibody. BU12-SAPORIN was selectively cytotoxic in vitro in a dose-dependent manner for the CD19+ human common acute lymphoblastic leukaemia (cALL) cell line NALM-6 but exhibited no toxicity for the CD19- T-cell acute lymphoblastic leukaemia (T-ALL) cell line HSB-2. The survival of severe combined immunodeficient (SCID) mice with disseminated NALM-6 leukaemia was significantly prolonged compared with sham-treated control animals by a course of therapy with BU12-SAPORIN but not with the irrelevant anti-CD7 immunotoxin HB2-SAPORIN. BU12-SAPORIN had no therapeutic effect in SCID mice with disseminated CD19- HSB-2 leukaemia. These preclinical studies have clearly demonstrated the selective cytotoxicity of BU12-SAPORIN for CD19+ target cells both in vitro and in vivo. This, taken together with the lack of expression of the CD19 molecule by any normal life-sustaining tissue and its ubiquitous and homogeneous expression by the majority of cALL and B-NHL cells, provides the rationale for undertaking a phase I trial of systemic therapy with BU12-SAPORIN. Images Figure 1 PMID:8519647

Flavell, D. J.; Flavell, S. U.; Boehm, D. A.; Emery, L.; Noss, A.; Ling, N. R.; Richardson, P. R.; Hardie, D.; Wright, D. H.

1995-01-01

185

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

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

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

2013-01-01

186

Typhoid fever vaccines: a meta›analysis of studies on efficacy and toxicity  

Microsoft Academic Search

Objective: To estimate the efficacy and toxicity of typhoid fever vaccines. Design: Meta›analysis of randomised efficacy trials and both randomised and non›randomised toxicity studies of the parenteral whole cell, oral Ty21a, and parenteral Vi vaccines. Subjects: 1 866 951 subjects in 17 efficacy trials; 11 204 subjects in 20 toxicity studies. Main outcome measures: Pooled estimates of three year cumulative

Eric A Engels; Matthew E Falagas; Joseph Lau; Michael L Bennish

1998-01-01

187

Evaluation of diethylnitrosamine- or hepatitis B virus X gene-induced hepatocellular carcinoma with 18F-FDG PET/CT: A preclinical study.  

PubMed

The aim of this study was to evaluate whether the development of hepatocellular carcinoma (HCC) in murine models resembles tumor progression in humans, using non?invasive molecular imaging methods. Murine HCC models were generated by treating mice with diethylnitrosamine (DEN) or by the transgenic expression of hepatitis B virus X (HBx) protein (HBx-Tg model). Tumor development was detected using 18F-fluoro-2-deoxyglucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT) and magnetic resonance imaging (MRI). The histopathological changes and expression of glucose transporter 1 (Glut1) and hexokinase 2 (HK2) were evaluated using hematoxylin and eosin and immunohistochemical staining, respectively. Tumor lesions as small as 1 mm in diameter were detected by MRI. Tumor development was monitored using 18F-FDG PET/CT at 6.5?10 months after DEN treatment or 11?20 months after birth of the HBx-Tg model mice. A correlation study between the 18F-FDG uptake levels and expression levels of HK2 and Glut1 in developed HCC showed a high 18F-FDG uptake in poorly differentiated HCCs that expressed high levels of HK2, in contrast to that in well-differentiated tumors. The progression of primary HCCs resembling human HCC in murine models was detected and monitored by 18F-FDG PET/CT. The correlation between tumor size and SUVmax was verified in the two HCC models. To the best of our knowledge, this is the first study to demonstrate that in vivo 18F-FDG uptake varies in HCCs according to differentiation grade in a preclinical study. PMID:25371060

Park, Ju Hui; Kang, Joo Hyun; Lee, Yong Jin; Kim, Kwang Il; Lee, Tae Sup; Kim, Kyeong Min; Park, Ji Ae; Ko, Yin Ohk; Yu, Dae-Yeul; Nahm, Sang-Soep; Jeon, Tae Joo; Park, Young-Seo; Lim, Sang Moo

2015-01-01

188

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

Microsoft Academic Search

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

Christine Heim; Charles B. Nemeroff

2001-01-01

189

Preclinical cognitive decline in late middle-aged asymptomatic apolipoprotein Ee4\\/4 homozygotes: a replication study  

Microsoft Academic Search

In a previous cross-sectional study of 100 asymptomatic individuals aged 49–69, we reported age-related decline in immediate and delayed memory that was steeper in apolipoprotein E (apoE)-e4\\/4 homozygotes than in members of other genetic subgroups. These findings were preliminarily based upon the statistical problem of multiple comparisons. We therefore sought to replicate these findings in a new cohort. From 1998

Richard J. Caselli; David Osborne; Eric M. Reiman; Joseph G. Hentz; Carolyn J. Barbieri; Ann M. Saunders; John Hardy; Neill R. Graff-Radford; Geri R. Hall; Gene E. Alexander

2001-01-01

190

Emotional intelligence and teacher efficacy: a study of Turkish EFL pre-service teachers  

Microsoft Academic Search

This study investigated the relationship between emotional intelligence and teacher efficacy among 90 English language pre-service teachers from a university in Turkey. Data sources included Tschannen-Moran and Woolfolk-Hoy’s Teachers’ Sense of Efficacy Scale and Reuven Bar-On’s Emotional Quotient Inventory. The findings indicated that Turkish EFL pre-service teachers felt more efficacious in managing the class rather than in making the class

Zeynep Koço?lu

2011-01-01

191

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

Microsoft Academic Search

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

André Brouwers; Welko Tomic

2000-01-01

192

Creative self-efficacy and its factors: An empirical study of information system analysts and programmers  

Microsoft Academic Search

Based on a survey of 94 information systems developers, this study explored how personal factors (i.e. computer self-efficacy and domain-specific information technology skills), contextual factors (i.e. strength of ties and degree centrality) and creative self-efficacy are related. Regression analysis results demonstrate that system analysts and programmers differ in terms of influencing factors on creative self-efficacy. Domain-specific skills were the main

Heng-Li Yang; Hsiu-Hua Cheng

2009-01-01

193

In Situ Mass Spectrometry Imaging and Ex Vivo Characterization of Renal Crystalline Deposits Induced in Multiple Preclinical Drug Toxicology Studies  

PubMed Central

Drug toxicity observed in animal studies during drug development accounts for the discontinuation of many drug candidates, with the kidney being a major site of tissue damage. Extensive investigations are often required to reveal the mechanisms underlying such toxicological events and in the case of crystalline deposits the chemical composition can be problematic to determine. In the present study, we have used mass spectrometry imaging combined with a set of advanced analytical techniques to characterize such crystalline deposits in situ. Two potential microsomal prostaglandin E synthase 1 inhibitors, with similar chemical structure, were administered to rats over a seven day period. This resulted in kidney damage with marked tubular degeneration/regeneration and crystal deposits within the tissue that was detected by histopathology. Results from direct tissue section analysis by matrix-assisted laser desorption ionization mass spectrometry imaging were combined with data obtained following manual crystal dissection analyzed by liquid chromatography mass spectrometry and nuclear magnetic resonance spectroscopy. The chemical composition of the crystal deposits was successfully identified as a common metabolite, bisulphonamide, of the two drug candidates. In addition, an un-targeted analysis revealed molecular changes in the kidney that were specifically associated with the area of the tissue defined as pathologically damaged. In the presented study, we show the usefulness of combining mass spectrometry imaging with an array of powerful analytical tools to solve complex toxicological problems occurring during drug development. PMID:23110069

Bjurstrom, Sivert; Goodwin, Richard J. A.; Basmaci, Elisa; Gustafsson, Ingela; Annas, Anita; Hellgren, Dennis; Svanhagen, Alexander; Andren, Per E.; Lindberg, Johan

2012-01-01

194

Adjuvant Anticholinesterase Therapy for the Management of Epilepsy-Induced Memory Deficit: A Critical Pre-clinical Study.  

PubMed

Epilepsy is one of the major neurological disorders still awaiting safer drugs with improved antiepileptic effect and lesser side effects. Apart from epilepsy itself, AEDs also have been shown to induce cognitive impairment in patients with epilepsy. There are limited data for the treatment of this menace. As cholinergic approach has widely been practiced for the restoration of memory in various neurodegenerative disorders, this study was envisaged to evaluate add on effect of acetylcholinesterase inhibitor (tacrine) with phenytoin in pentylenetetrazole-kindling-induced learning and memory deficit in mice. In this study, mice were kindled using subconvulsive dose of pentylenetetrazole (35 mg/kg, i.p.; at interval of 48 ± 2 hr) and successfully kindled animals were divided into different groups and treated with vehicle, phenytoin and phenytoinin in combination with tacrine (0.3 mg/kg), atropine (1 mg/kg) and tacrine + atropine. Effect of different interventions on learning and memory was evaluated using elevated plus maze and passive shock avoidance on days 5, 10, 15 and 20. Phenytoin-treated kindled animals were associated with learning and memory deficit, while tacrine supplementation improved memory deficit with increased seizure severity score. Atropine treatment significantly reversed the protective effect of tacrine. Neurochemical findings also support the behavioural finding of the study. Our results suggest the use of anticholinesterases, with better seizure tolerance, for the management of cognitive impairment of epilepsy, as adjunct therapy. PMID:24890882

Mishra, Awanish; Goel, Rajesh Kumar

2014-12-01

195

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

PubMed Central

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

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

196

Preclinical cognitive decline in late middle-aged asymptomatic apolipoprotein E-e4/4 homozygotes: a replication study.  

PubMed

In a previous cross-sectional study of 100 asymptomatic individuals aged 49-69, we reported age-related decline in immediate and delayed memory that was steeper in apolipoprotein E (apoE)-e4/4 homozygotes than in members of other genetic subgroups. These findings were preliminarily based upon the statistical problem of multiple comparisons. We therefore sought to replicate these findings in a new cohort. From 1998 to 2000, 80 asymptomatic residents of Maricopa County, AZ were recruited through newspaper ads. 20 apoE-e4/4 homozygotes, 20 e3/4 heterozygotes, and 40 e4 noncarriers were matched (1:1:2) by age, gender, and years of education. All had normal neurologic and psychiatric examinations, including Folstein minimental status exam (MMSE) and Hamilton depression scale, and underwent a battery of neuropsychological tests identical to those in our previous study. The groups were well-matched for age (55.9+/-5.9 years), gender (60% women), and education (15.9+/-2.2 years), and were demographically similar to our previous cohort. Complex figure test recall was lower in e3/4 heterozygotes than noncarriers, but there was no significant difference between e4/4 homozygotes and noncarriers. There were no other significant differences in mean test scores between groups, but Wechsler adult intelligence scale-revised (WAIS-R) digit span showed a significant negative correlation with age in the e4/4 homozygote group relative to e4 noncarriers (p=0.008) as we had found in our previous study. In conclusion, we found a significant negative correlation of WAIS-R digit span with age in apoE-e4/4 homozygotes relative to e4 noncarriers in two separate cohorts, possibly reflecting an age-related effect on frontal lobe function in this genetic subgroup. PMID:11535238

Caselli, R J; Osborne, D; Reiman, E M; Hentz, J G; Barbieri, C J; Saunders, A M; Hardy, J; Graff-Radford, N R; Hall, G R; Alexander, G E

2001-08-15

197

Chimeric rodents with humanized liver: bridging the preclinical/clinical trial gap in ADME/toxicity studies.  

PubMed

1. Immunocompromised mice with humanized livers were developed in the mid-1990s to allow the study of human hepatotropic viruses, which normally replicate only in higher primates. The production of the uPA/SCID mouse was the vanguard of these models and remains the most widely worked upon model for an ever increasing range of applications. 2. Since toxicology is conducted in laboratory animal species with the implicit intent of predicting the outcome of accidental, or intentional, human exposure, the potential for using an in vivo model with a humanised metabolism opens up the possibility of better predicting the human response following exposure to drugs and industrial chemicals. Chimeric humanised mice provide the tool for bridging between the non-clinical laboratory safety and metabolism studies, carried out in rodent and non-rodent species, and the first in man clinical trials. 3. Chimeric mice carrying a human liver have now been validated against a wide range of different drugs and chemical classes, and have been shown to clearly differentiate metabolically from the recipient mouse, and to show metabolic pathways more similar to those expected from human liver. 4. This review critically appraises the available animal models carrying human livers and where future developments would improve the existing systems. PMID:24320885

Foster, John R; Lund, Garry; Sapelnikova, Svetlana; Tyrrell, D Lorne; Kneteman, Norman M

2014-01-01

198

A comparative study of students' performance in preclinical physiology assessed by multiple choice and short essay questions.  

PubMed

This study was designed to compare the performance of medical students in physiology when assessed by multiple choice questions (MCQs) and short essay questions (SEQs). The study also examined the influence of factors such as age, sex, O/level grades and JAMB scores on performance in the MCQs and SEQs. A structured questionnaire was administered to 264 medical students' four months before the Part I MBBS examination. Apart from personal data of each student, the questionnaire sought information on the JAMB scores and GCE O' Level grades of each student in English Language, Biology, Chemistry, Physics and Mathematics. The physiology syllabus was divided into five parts and the students were administered separate examinations (tests) on each part. Each test consisted of MCQs and SEQs. The performance in MCQs and SEQs were compared. Also, the effects of JAMB scores and GCE O/level grades on the performance in both the MCQs and SEQs were assessed. The results showed that the students performed better in all MCQ tests than in the SEQs. JAMB scores and O' level English Language grade had no significant effect on students' performance in MCQs and SEQs. However O' level grades in Biology, Chemistry, Physics and Mathematics had significant effects on performance in MCQs and SEQs. Inadequate knowledge of physiology and inability to present information in a logical sequence are believed to be major factors contributing to the poorer performance in the SEQs compared with MCQs. In view of the finding of significant association between performance in MCQs and SEQs and GCE O/level grades in science subjects and mathematics, it was recommended that both JAMB results and the GCE results in the four O/level subjects above may be considered when selecting candidates for admission into the medical schools. PMID:11713989

Oyebola, D D; Adewoye, O E; Iyaniwura, J O; Alada, A R; Fasanmade, A A; Raji, Y

2000-01-01

199

Fluorine-18-fluorodeoxygglucose-guided breast cancer surgery with a positron-sensitive probe: Validation in preclinical studies  

SciTech Connect

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.

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

200

Child and Adolescent Behavior Inventory (CABI): A New Instrument for Epidemiological Studies and Pre-Clinical Evaluation  

PubMed Central

Background: Some questionnaires have already been elaborated to collect information from parents of children and adolescents, both as preparation for clinical evaluation and for screening and epidemiological studies. Here a new questionnaire, the CABI, is proposed, and it is validated in a population of 8-10 year-old children. Compared to existing questionnaires, the CABI has been organized so as to be of medium length, with items concerning the most significant symptoms indicated by the DSM-IV-TR for the pertinent disorders, and covering a wider range than existing instruments. There is no charge for its use. Methods: The answers of the parents of 302 children in the last 3 years of primary school provided the normative data. A discriminant validation was done for internalizing and externalizing disorders and as a comparison with self-administered anxiety and depression scales. Exploratory factor analysis and internal consistency were also performed. Results: Distribution of scores on the main scales in the normal population shows positive skewness, with the most frequent score being zero. A highly discriminant capability was found in regard to the sample of children with internalizing and externalizing disorders, with high correlation with the self-administered anxiety and depression scales. Conclusion: The CABI appears to be capable, at least for 8-10 year-old children, of effectively discriminating those with pathological symptoms from those without. Compared with the widely- used CBCL, it has the advantages of a lower number of items, which should facilitate parental collaboration especially in epidemiological studies, and of being free of charge. PMID:23539369

Cianchetti, Carlo; Pittau, Andrea; Carta, Valeria; Campus, Grazia; Littarru, Roberta; Ledda, Maria Giuseppina; Zuddas, Alessandro; Fancello, Giuseppina Sannio

2013-01-01

201

177Lu-EC0800 combined with the antifolate pemetrexed: preclinical pilot study of folate receptor targeted radionuclide tumor therapy.  

PubMed

Targeted radionuclide therapy has shown impressive results for the palliative treatment of several types of cancer diseases. The folate receptor has been identified as specifically associated with a variety of frequent tumor types. Therefore, it is an attractive target for the development of new radionuclide therapies using folate-based radioconjugates. Previously, we found that pemetrexed (PMX) has a favorable effect in reducing undesired renal uptake of radiofolates. Moreover, PMX also acts as a chemotherapeutic and radiosensitizing agent on tumors. Thus, the aim of our study was to investigate the combined application of PMX and the therapeutic radiofolate (177)Lu-EC0800. Determination of the combination index (CI) revealed a synergistic inhibitory effect of (177)Lu-EC0800 and PMX on the viability of folate receptor-positive cervical (KB) and ovarian (IGROV-1) cancer cells in vitro (CI < 0.8). In an in vivo study, tumor-bearing mice were treated with (177)Lu-EC0800 (20 MBq) and a subtherapeutic (0.4 mg) or therapeutic amount (1.6 mg) of PMX. Application of (177)Lu-EC0800 with PMXther resulted in a two- to four-fold enhanced tumor growth delay and a prolonged survival of KB and IGROV-1 tumor-bearing mice, as compared to the combination with PMXsubther or untreated control mice. PMXsubther protected the kidneys from undesired side effects of (177)Lu-EC0800 (20 MBq) by reducing the absorbed radiation dose. Intact kidney function was shown by determination of plasma parameters and quantitative single-photon emission computed tomography using (99m)Tc-DMSA. Our results confirmed the anticipated dual role of PMX. Its unique features resulted in an improved antitumor effect of folate-based radionuclide therapy and prevented undesired radio-nephrotoxicity. PMID:24030631

Reber, Josefine; Haller, Stephanie; Leamon, Christopher P; Müller, Cristina

2013-11-01

202

Determination of doxorubicin and its metabolites in rat serum and bile by LC: application to preclinical pharmacokinetic studies.  

PubMed

A simple, accurate and precise high-performance liquid chromatographic method was developed and validated for the simultaneous determination of doxorubicin and its three metabolites, including doxorubicinol, doxorubicinolone and doxorubicinone, in rat serum and bile. Following a single protein precipitation step, chromatographic separation was accomplished using a C-18 column with a mobile phase consisting of 50 mM sodium phosphate buffer-acetonitrile-1-propanol (65:25:2, v/v), pH 2.0. The analytes were measured by fluorescence detection with excitation wavelength of 480 nm and emission wavelength of 560 nm. The lower limits of quantitation were 10 ng/ml for doxorubicin, and 5 ng/ml for the three metabolites. The calibration curves were linear over a concentration range of 10-2500 ng/ml for doxorubicin, and 5-1250 ng/ml for its three metabolites. The average recoveries were greater than 89% for all analytes. The within-day and between-day coefficients of variation were generally less than 13%. Doxorubicin and its metabolites were stable in the precipitated serum and bile samples at room temperature in darkness for at least 48 h. This method permitted the analysis of samples without the presence of the anticoagulant sodium citrate and thus was applied to serum and bile samples collected from rats that were administered doxorubicin intravenously in a pharmacokinetic study. PMID:12408897

Zhou, Qingyu; Chowbay, Balram

2002-11-01

203

Preclinical studies relating to the use of thiotepa in the high-dose setting alone and in combination.  

PubMed

In vitro and in vivo studies with N,N',N''-triethylene-thiophosphoramide (thiotepa) alone and in combination with cyclophosphamide (CTX) were carried out using the MCF-7 human breast carcinoma cell line and the EMT6 mouse mammary carcinoma cell line. In vitro, survival curves were essentially linear. The cytotoxicity of thiotepa toward MCF-7 cells was markedly dependent on the presence of oxygen during the period of drug exposure, with a 3-log greater cell kill at 500 mumol with cells that were normally oxygenated compared with hypoxic cells. Incubation of thiotepa with an Aroclor 1254-induced rat liver S-9 homogenate in the presence of a reduced nicotinamide adenine dinucleotide phosphate-regenerating system resulted in an eightfold increase in cytotoxicity toward the MCF-7 cells over a wide range of drug concentrations. The thiotepa metabolite N,N',N''-triethylenephosphoramide (TEPA) was significantly less cytotoxic toward the MCF-7 cells than was thiotepa. Simultaneous and immediately sequential treatments with thiotepa and CTX produced supra-additive cell killing of both cell lines, although the magnitude of the supra-additivity was greater in the MCF-7 cell line than in the EMT6 cell line. These drugs Vppeared to be equally effective as thiol-depleting agents. By DNA alkaline elution, there was a pattern of increasing DNA cross-linking similar to the increasing levels of cytotoxicity of this drug combination as the concentrations of thiotepa increased. In the EMT6 tumor in vivo, the maximally tolerated combination therapy (5 mg/kg x 6, thiotepa, and 100 mg/kg x 3, CTX) produced about 25 days of tumor growth delay, which was not significantly different than expected for additivity of the individual drugs. The survival of EMT6 tumor cells after treatment of the animals with the various single doses of thiotepa and CTX was assayed. Tumor cell killing by thiotepa produced a very steep, linear survival curve through 5 logs with increasing dose. The tumor cell survival cure for CTX to 500 mg/kg had linear tumor cell kill through almost 4 logs. In vivo modeling of quasicontinuous exposure (3 intraperitoneal over 9 hours) versus pulse (single-dose) administration of thiotepa and CTX compared EMT6 tumor cell survival with survival of bone marrow as a representative sensitive normal tissue. With CTX, there was a considerable increase in the therapeutic index (killing of tumor cells/killing of colony forming units-granulocyte macrophage) when the same total dose of drug was administered in multiple injections versus a single injection. For thiotepa, smaller increases in therapeutic index were also observed with the multiple-injection schedule.(ABSTRACT TRUNCATED AT 400 WORDS) PMID:2106164

Teicher, B A; Holden, S A; Eder, J P; Herman, T S; Antman, K H; Frei, E

1990-02-01

204

An Exploratory Study into the Efficacy of Learning Objects  

ERIC Educational Resources Information Center

Learning objects have quickly become a widely accepted approach to instructional technology, particularly in on-line and computer-based learning environments. While there is a substantial body of literature concerning learning objects, very little of it verifies their efficacy. This research investigated the effectiveness of learning objects by…

Farha, Nicholas W.

2009-01-01

205

A Gender Study Investigating Physics Self-Efficacy  

ERIC Educational Resources Information Center

The underrepresentation of women in physics has been well documented and a source of concern for both policy makers and educators. My dissertation focuses on understanding the role self-efficacy plays in retaining students, particularly women, in introductory physics. I use an explanatory mixed methods approach to first investigate quantitatively…

Sawtelle, Vashti

2011-01-01

206

Preclinical Pharmacology and Toxicology Studies  

Cancer.gov

OF RECEIPT for determining TIMELY DELIVERY is the address provided for the OFFICE OF ACQUISITIONS. IF YOUR PROPOSAL IS NOT RECEIVED BY THE CONTRACTING OFFICER OR HIS DESIGNEE AT THE PLACE AND TIME SPECIFIED FOR THE OFFICE OF ACQUISITIONS, THEN IT WILL BE CONSIDERED LATE AND HANDLED IN ACCORDANCE WITH subparagraph (c)(3) of FAR Clause 52.215-1, Instructions to Offerors--Competitive Acquisition," LOCATED IN SECTION L.1. OF THIS SOLICITATION. 10.

207

Emotional Intelligence and Teacher Efficacy: A Study of Turkish EFL Pre-Service Teachers  

ERIC Educational Resources Information Center

This study investigated the relationship between emotional intelligence and teacher efficacy among 90 English language pre-service teachers from a university in Turkey. Data sources included Tschannen-Moran and Woolfolk-Hoy's Teachers' Sense of Efficacy Scale and Reuven Bar-On's Emotional Quotient Inventory. The findings indicated that Turkish EFL…

Kocoglu, Zeynep

2011-01-01

208

Developing Teaching Self-Efficacy in Research Institutions: A Study of Award-Winning Professors  

ERIC Educational Resources Information Center

The purpose of this study was to assess the sources of award-wining research professors' (six women; six men) teaching self-efficacy through the framework of Bandura's (1986) social cognitive theory. Semi-structured interviews revealed that mastery experiences and social persuasions were particularly influential sources of self-efficacy and that…

Morris, David B.; Usher, Ellen L.

2011-01-01

209

The Impact of Study Abroad on Students' Self-Efficacy Perceptions  

ERIC Educational Resources Information Center

This article reports the findings of an investigation into the impact of study abroad experiences on self-efficacy perceptions among foreign language (FL) learners. Thirty-nine American college students taking part in both short-term and semester-long academic programs in France and Spain completed self-efficacy surveys at the beginning and at the…

Cubillos, Jorge H.; Ilvento, Thomas

2012-01-01

210

Using Mathematics in Teaching Science Self-Efficacy Scale--UMSSS: A Validity and Reliability Study  

ERIC Educational Resources Information Center

In this study, an instrument, Using Mathematics in Science Self-efficacy Scale (UMSSS), was developed in order to determine preservice science teachers' self-efficacy toward the use of mathematics in their lessons. Data gathered from 250 preservice science teachers were used for Exploratory Factor Analysis (EFA) and Confirmatory Factor Analysis…

Can, Bilge Taskin; Gunhan, Berna Canturk; Erdal, Sevinc Ongel

2012-01-01

211

Advances in Preclinical SPECT Instrumentation  

PubMed Central

Preclinical SPECT imaging of rodents is both in demand and very demanding. The need for high spatial resolution in combination with good sensitivity has given rise to considerable innovation in the areas of detectors, collimation, acquisition geometry, and image reconstruction. Some of the developments described herein are beginning to carry over into clinical imaging as well. PMID:22586145

Peterson, Todd E.; Shokouhi, Sepideh

2012-01-01

212

Bridging the preclinical - clinical gap  

Microsoft Academic Search

TO THE EDITOR: Basic or preclinical research in addiction has moved on enormou- sly in the last decade, but in order for clinical research to benefit there need to be new efforts in translational research. We can approach this question in a number of ways. The first is to use well-established but indirect technologies, such as challenge tests. In these,

David J. Nutt; Anne Lingford-Hughes; Mark Daglish; Tim Williams; Lindsay Taylor; Sue Wilson; Simon Davies; Jan Melichar; Judy Myles

213

Data file. Summary clinical efficacy PNP: Comparison analyses results across studies - comparison efficacy results studies additional analyses indication treatment duration changes NPRS baseline (HIV-AN) (part 1). 2009. Astellas Pharma Europe Ltd. Staines Middlesex UK.  

EPA Pesticide Factsheets

Search instead for Data file. Summary clinical efficacy PNP: Comparison analyses results across studies - comparison efficacy results studies additional analyses indication treatment duration changes NPRS baseline (HIV-AN) (part 1). 2009. Astellas Pharma Europe Ltd. Staines Middlesex UK. ?

214

Discovery of a selective small-molecule melanocortin-4 receptor agonist with efficacy in a pilot study of sexual dysfunction in humans.  

PubMed

The relevance of the melanocortin system to sexual activity is well established, and nonselective peptide agonists of the melanocortin receptors have shown evidence of efficacy in human sexual dysfunction. The role of the MC4 receptor subtype has received particular scrutiny, but the sufficiency of its selective activation in potentiating sexual response has remained uncertain owing to conflicting data from studies in preclinical species. We describe here the discovery of a novel series of small-molecule MC4 receptor agonists derived from library hit 2. The addition of methyl substituents at C3 and C5 of the 4-phenylpiperidin-4-ol ring was found to be markedly potency-enhancing, enabling the combination of low nanomolar potencies with full rule-of-five compliance. In general, the series shows only micromolar activity at other melanocortin receptors. Our preferred compound 40a provided significant systemic exposure in humans on both sublingual and oral administration and was safe and well tolerated up to the maximum tested dose. In a pilot clinical study of male erectile dysfunction, the highest dose of 40a tested (200 mg) provided a similar level of efficacy to sildenafil. PMID:20329799

Lansdell, Mark I; Hepworth, David; Calabrese, Andrew; Brown, Alan D; Blagg, Julian; Burring, Denise J; Wilson, Peter; Fradet, David; Brown, T Bruce; Quinton, Faye; Mistry, Neela; Tang, Kim; Mount, Natalie; Stacey, Peter; Edmunds, Nick; Adams, Cathryn; Gaboardi, Samantha; Neal-Morgan, Stevie; Wayman, Chris; Cole, Susan; Phipps, Joanne; Lewis, Mark; Verrier, Hugh; Gillon, Val; Feeder, Neil; Heatherington, Anne; Sultana, Stefan; Haughie, Scott; Martin, Steven W; Sudworth, Maria; Tweedy, Sarah

2010-04-22

215

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

PubMed

Vascular endothelial growth factor B (VEGF-B) has recently been shown to be a promising novel neuroprotective agent for several neurodegenerative conditions. In the current study we extended previous work on neuroprotective potential for Parkinson's disease (PD) by testing an expanded dose range of VEGF-B (1 and 10 ?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=1.9e-50) of the expression of VEGF-B with nuclear-encoded mitochondrial genes involved in fatty acid metabolism in rat midbrain, pointing to the mitochondria as a site of action of VEGF-B. GDNF showed a positive correlation with nuclear-encoded mitochondrial genes that was not nearly as strong (p=0.018). VEGF-B counteracted rotenone-induced reduction of (a) fatty acid transport protein 1 and 4 levels and (b) both Akt protein and phosphorylation levels in SH-SY5Y cells. We further verified VEGF-B expression in the human SN pars compacta of healthy controls and PD 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

Yue, X; Hariri, D J; Caballero, B; Zhang, S; Bartlett, M J; Kaut, O; Mount, D W; Wüllner, U; Sherman, S J; Falk, T

2014-01-31

216

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

NASA Astrophysics Data System (ADS)

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.

de Laat, Jenny; Watters, James J.

1995-12-01

217

A cross cultural study of gender-role orientation and entrepreneurial self-efficacy  

Microsoft Academic Search

The study of gender differences in entrepreneurial self-efficacy to date has produced inconclusive results. Cross-cultural\\u000a studies are virtually non-existent. The present study seeks to understand the complex interplay of biological sex, socialized\\u000a gender-roles, and culture on entrepreneurial self-efficacy and motivation to become an entrepreneur. Findings indicate that\\u000a among American business students the traditional view of “entrepreneur as male” is fading.

Stephen L. Mueller; Mary Conway Dato-on

218

The critical need for defining preclinical biomarkers in Alzheimer's disease.  

PubMed

The increasing number of afflicted individuals with late-onset Alzheimer's disease (AD) poses significant emotional and financial burden on the world's population. Therapeutics designed to treat symptoms or alter the disease course have failed to make an impact, despite substantial investments by governments, pharmaceutical industry, and private donors. These failures in treatment efficacy have led many to believe that symptomatic disease, including both mild cognitive impairment (MCI) and AD, may be refractory to therapeutic intervention. The recent focus on biomarkers for defining the preclinical state of MCI/AD is in the hope of defining a therapeutic window in which the neural substrate remains responsive to treatment. The ability of biomarkers to adequately define the at-risk state may ultimately allow novel or repurposed therapeutic agents to finally achieve the disease-modifying status for AD. In this review, we examine current preclinical AD biomarkers and suggest how to generalize their use going forward. PMID:24924671

Fiandaca, Massimo S; Mapstone, Mark E; Cheema, Amrita K; Federoff, Howard J

2014-06-01

219

Evaluation Of Microdosing Strategies For Studies In Preclinical Drug Development: Demonstration Of Linear Pharmacokinetics In Dogs Of A Nucleoside Analogue Over A 50-Fold Dose Range  

SciTech Connect

The technique of accelerator mass spectrometry (AMS) was validated successfully and utilized to study the pharmacokinetics and disposition in dogs of a preclinical drug candidate (Compound A), after oral and intravenous administration. The primary objective of this study was to examine whether Compound A displayed linear kinetics across sub-pharmacological (microdose) and pharmacological dose ranges in an animal model, prior to initiation of a human microdose study. The AMS-derived disposition properties of Compound A were comparable to data obtained via conventional techniques such as LC-MS/MS and liquid scintillation counting analyses. Thus, Compound A displayed multiphasic kinetics and possessed low plasma clearance (4.4 mL/min/kg), a long terminal elimination half-life (19.4 hr) and high oral bioavailability (82%). Currently there are no published comparisons of the kinetics of a pharmaceutical compound at pharmacological versus sub-pharmacological doses employing microdosing strategies. The present study thus provides the first description of the pharmacokinetics of a drug candidate assessed under these two dosing regimens. The data demonstrated that the pharmacokinetic properties of Compound A were similar following dosing at 0.02 mg/kg as at 1 mg/kg, indicating that in the case of Compound A, the kinetics of absorption, distribution and elimination in the dog appear to be linear across this 50-fold dose range. Moreover, the exceptional sensitivity of AMS provided a pharmacokinetic profile of Compound A, even following a microdose, which revealed aspects of the disposition of this agent that were inaccessible by conventional techniques. The applications of accelerator mass spectrometry (AMS) are broad ranging and vary from studying environmental and ecological issues such as the isotopic composition of the atmosphere, soil and water (Hughen et al., 2000; Beck et al., 2001; Keith-Roach et al., 2001; Mironov et al., 2002), to archaeology and volcanology (Stafford et al., 1984; Vogel et al., 1990; Smith et al., 1999) to its use as a bioanalytical tool for nutritional research (Buchholz et al., 1999; Deuker et al., 2000; Weaver and Liebman, 2002). Biomedical applications of AMS and its use in the arena of pharmaceutical research also have been detailed in review articles (Barker and Garner, 1999; Garner, 2000; Turteltaub and Vogel, 2000). To date, most studies on the metabolism and disposition of xenobiotics by AMS have focused on how carcinogens bind to DNA and proteins to form adducts (Turteltaub et al., 1990, 1997; Frantz et al., 1995; Dingley et al., 1999; Li et al., 2003). Its application to the field of pharmaceutical sciences has been limited to a few studies (Kaye et al., 1997; Young et al., 2001; Garner et al., 2002). However, the pharmaceutical industry is becoming increasingly aware of the potential benefits that may accrue from the ultra high sensitivity afforded by AMS in terms of evaluating the pharmacokinetics of lead drug candidates in early development. Specifically, AMS allows administration of sub-pharmacological doses (microdoses) of carbon-14 or tritium-labeled investigational drugs to animals or humans at radiologically insignificant levels with the goal of obtaining preliminary information regarding the absorption, distribution, metabolism, and excretion of test compounds (Turteltaub and Vogel, 2000). An unresolved issue, however, is whether the pharmacokinetics determined following a microdose are representative of those following a conventional (pharmacological) dose (Lappin and Garner, 2003). This paper examines the linearity of kinetics of an antiviral nucleoside analogue, Compound A, across sub-pharmacological and pharmacological dose ranges in the dog prior to initiation of a human microdose study. The specific objectives of this study, therefore, were (1) to assess the pharmacokinetics of Compound A in dogs by a conventional dosing approach utilizing LC-MS/MS for sample analysis, (2) to assess the pharmacokinetics of Compound A in dogs by the microdose approach utilizing AMS for sample ana

Sandhu, P; Vogel, J S; Rose, M J; Ubick, E A; Brunner, J E; Wallace, M A; Adelsberger, J K; Baker, M P; Henderson, P T; Pearson, P G; Baillie, T A

2004-04-22

220

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

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

Chen, Chun-Hsi Vivian; Kao, Rui-Hsin

2011-01-01

221

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

Federal Register 2010, 2011, 2012, 2013

...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...

2012-02-29

222

Development of an in vitro model for the simultaneous study of the efficacy and hematotoxicity of antileukemic compounds.  

PubMed

Hematopoietic system displays a wide spectrum of cell populations hierarchically organized in the bone marrow. Homeostasis in this system requires equilibrium between the self-renewal of the stem cells and their capacity of differentiation. Any failure on this equilibrium could lead to fatal consequences, such as the development of leukemia. Due to its rapid rate of renewal, hematopoietic tissue is a major target for antitumoral compounds and often becomes a dose limiting factor in the development of antineoplastics. Our aim was to develop an in vitro model for predicting the efficacy of antitumoral compounds on leukemic cells and their toxic effects on the healthy hematopoietic cells. The mouse myelomonocytic leukemia WEHI-3b was transduced with a lentiviral vector for expressing the green fluorescence protein. Mixed semisolid clonogenic cultures of transduced WEHI-3b and murine bone marrow cells were exposed to five pharmaceuticals: daunorubicin (positive control), atropine sulphate (negative control) and three in different stages of clinical development (trabectedin, Zalypsis(®) and PM01183). Colonies of leukemic cells were distinguishable from healthy CFU-GM under fluorescence microscope. The sensitivity of leukemic cells to daunorubicin, trabectedin, Zalypsis(®) and PM01183 was higher compared to healthy cells. The effect of a non-antitumoral compound, atropine sulphate, was the same on both populations. Our results show that this in vitro model is a valuable tool for studying the effect of antitumoral compounds in both tumoral and normal hematopoietic cells under the same toxic microenvironment and could safe time and facilitate the reduction of the number of animals used in preclinical development of pharmaceuticals. PMID:20883753

Valeri, Antonio; Alonso-Ferrero, María Eugenia; Cerrato, Laura; Martínez, Sandra; Bueren, Juan A; Albella, Beatriz

2010-12-15

223

Applicability of the intratumor aromatase preclinical model to predict clinical trial results with endocrine therapy.  

PubMed

Preclinical models and clinical studies have shown that aromatase inhibitors (AIs) are powerful inhibitors of estrogen synthesis and significantly suppress estrogen in vivo. For more than 20 years, standard first-line treatment for postmenopausal women with metastatic breast cancer has been the antiestrogen tamoxifen, a selective estrogen receptor modulator (SERM) with differential effects on breast, endometrial, bone, and vascular tissues. The estrogenic activity of tamoxifen is associated with deleterious clinical side effects, including vaginal bleeding, endometrial cancer, and thromboembolism. AIs are established second-line treatments in patients who progress with tamoxifen. Compared with progestins, such as megestrol acetate, or the earlier AIs aminoglutethimide and fadrozole, the new AIs, including exemestane, anastrozole, and letrozole, have increased efficacy and clinical benefit and cause fewer side effects in patients with metastatic breast cancer. Letrozole and anastrozole are approved first-line therapy for patients with metastatic breast cancer and as second-line treatment after tamoxifen failure. Studies in the intratumoral aromatase xenograft preclinical model have shown better responses with AIs than with antiestrogens in first-line therapy, and these data are consistent with the results from clinical trials. This model is now being used to assess whether combined or sequential administration of AIs with other agents may provide additional benefit. PMID:12902873

Brodie, Angela H; Mouridsen, Henning T

2003-08-01

224

Efficacy of Vardenafil in Men with Erectile Dysfunction: A Flexible-Dose Community Practice Study  

Microsoft Academic Search

Objective: To determine the efficacy and tolerability of flexible dosing with vardenafil in a broad population of men with erectile dysfunction (ED).Methods: 10-week, open-label, flexible-dose study starting with vardenafil 10mg, titrating to 5mg or 20mg at weeks 2 and 6 based on efficacy and tolerability, set in 78 community practice centers in Germany and France. Participants comprised 398 men aged

Axel-Jürg Potempa; Ernst Ulbrich; Ingo Bernard; Manfred Beneke

2004-01-01

225

Self-Efficacy After Life Skills Training: A Case-Control Study  

PubMed Central

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.

Rezayat, Fatemeh; Dehghan Nayeri, Nahid

2013-01-01

226

Effects of Achievement Goal Orientation of Dental School Students on Self-motivation, Self-regulated Learning Strategies, and Self-efficacy  

Microsoft Academic Search

Purpose: The present study seeks to achieve two goals: to verify the correlation between achieve- ment goal orientation, self-motivation, self-regulated learning strategies, and self-efficacy in students who are enrolled in preclinical practice instruction in a dental hygienist program; and to validate the effect of achievement goal orientation as an independent variable on self-motivation, self-regulated learning strategies, and self-efficacy. Methods: The

Young Sang Kim

2008-01-01

227

Preclinical Alzheimer disease and risk of falls  

PubMed Central

Objective: We determined the rate of falls among cognitively normal, community-dwelling older adults, some of whom had presumptive preclinical Alzheimer disease (AD) as detected by in vivo imaging of fibrillar amyloid plaques using Pittsburgh compound B (PiB) and PET and/or by assays of CSF to identify A?42, tau, and phosphorylated tau. Methods: We conducted a 12-month prospective cohort study to examine the cumulative incidence of falls. Participants were evaluated clinically and underwent PiB PET imaging and lumbar puncture. Falls were reported monthly using an individualized calendar journal returned by mail. A Cox proportional hazards model was used to test whether time to first fall was associated with each biomarker and the ratio of CSF tau/A?42 and CSF phosphorylated tau/A?42, after adjustment for common fall risk factors. Results: The sample (n = 125) was predominately female (62.4%) and white (96%) with a mean age of 74.4 years. When controlled for ability to perform activities of daily living, higher levels of PiB retention (hazard ratio = 2.95 [95% confidence interval 1.01–6.45], p = 0.05) and of CSF biomarker ratios (p < 0.001) were associated with a faster time to first fall. Conclusions: Presumptive preclinical AD is a risk factor for falls in older adults. This study suggests that subtle noncognitive changes that predispose older adults to falls are associated with AD and may precede detectable cognitive changes. PMID:23803314

Roe, Catherine M.; Grant, Elizabeth A.; Hollingsworth, Holly; Benzinger, Tammie L.; Fagan, Anne M.; Buckles, Virginia D.; Morris, John C.

2013-01-01

228

[Study on immune efficacy of Newcastle disease chitosan microsphere vaccine].  

PubMed

Newcastle disease is an acute and highly contagious disease caused by Newcastle disease virus (NDV), one of which does great harms to the poultry industry. The most basic measure of controlling New Castle disease is to alid vaccine, now we usually use La Sota live vaccine and inactivated NDV vaccine, but these two vaccines both have more or less limitation. It can produce higher mucosal immunity titers by taking vaccine orally, meanwhile it can induce humoral and cell-mediated immune response and mucosal immunity strongly. Therefore, it becomes the focus of the research, which prepare new pattern vaccines taking orally. NDV chitosan microsphere vaccine was prepared using chitosan as capsule wall material, NDV as core material, glutaraldehyde as cross-linking material, and its even particle diameter was 5.83um, and its surface was smooth and glossy, no obviously pore space, yellow brown pykno-ball, and its safety and potency were evaluated. The SPF chickens were immunized with NDV chitosan microsphere vaccine, La Sota live vaccine and inactivated NDV vaccine respectively. To evaluate vaccine's immune efficacy, using MTT to measure lymphocytes proliferation in vitro, using HI to measure serum special IgG and using ELISA tests to detect mucosal sIgA titers. The results show that NDV chitosan microsphere vaccine was safe, could induce humoral and cell-mediated immune response and mucosal immunity strongly. The results of the potency tests conformed that the vaccine could produce good protective effect. PMID:17944374

Zhai, Rong-ling; Xu, Huai-ying; Wang, You-ling; Qin, Zhuo-ming; Jiang, Shi-jin

2007-08-01

229

Comparative efficacy and safety study of etidronate and alendronate in postmenopausal osteoporosis. Effect of adding hormone replacement therapy  

Microsoft Academic Search

Objectives. To compare the efficacy and safety of etidronate and alendronate in patients with postmenopausal osteoporosis and to assess the efficacy of either bisphosphonate in combination with hormone replacement therapy (HRT). Patients and methods. In this pragmatic study, the main efficacy criterion was the mean annual change in bone mineral density (BMD). Patients who had a past or current history

Bernard Cortet; Anne Béra-Louville; Patrick Gauthier; Alain Gauthier; Xavier Marchandise; Bernard Delcambre

2001-01-01

230

Intravenous immunoglobulin (IVIG) treatment exerts antioxidant and neuropreservatory effects in preclinical models of Alzheimer's disease.  

PubMed

Intravenous immunoglobulin (IVIG) has shown limited promise so far in human clinical studies on Alzheimer's disease (AD), yet overwhelmingly positive preclinical work in animals and human brain cultures support the notion that the therapy remains potentially efficacious. Here, we elaborate on IVIG neuropreservation by demonstrating that IVIG protects human primary neurons against oxidative stress in vitro and that IVIG preserves antioxidant defense mechanisms in vivo. Based on these results, we propose the following translational impact: If the dosage and treatment conditions are adequately optimized, then IVIG treatment could play a significant role in preventing and/or delaying the progression of neurodegenerative diseases, such as AD. We suggest that IVIG warrants further investigation to fully exploit its potential as an anti-oxidant, neuroprotective and synapto-protecting agent. PMID:24760109

Counts, Scott E; Ray, Balmiki; Mufson, Elliott J; Perez, Sylvia E; He, Bin; Lahiri, Debomoy K

2014-07-01

231

PREVENT Cancer Preclinical Drug Development Program  

Cancer.gov

The PREVENT Cancer Drug Development Program is a National Cancer Institute-supported pipeline to bring new cancer preventing interventions and biomarkers through preclinical development towards clinical trials.

232

Clinical research and diagnostic efficacy studies in the oral and maxillofacial radiology literature: 1996-2005  

PubMed Central

Objectives The aim of this study was to determine the level of evidence that is published in the oral and maxillofacial radiology (OMR) literature. Methods OMR papers published in Dentomaxillofacial Radiology and Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology and Endodontology between 1996 and 2005 were classified using epidemiological study design and diagnostic efficacy hierarchies. The country of origin and number of authors were noted. Results Of the 725 articles, 384 could be classified with the epidemiological study design hierarchy: 155 (40%) case reports/series and 207 (54%) cross-sectional studies. The distribution of study designs was not statistically significant across time (Fisher's exact test, P = 0.06) or regions (P = 0.89). The diagnostic efficacy hierarchy was applicable to 246 articles: 71 (29%) technical efficacy and 166 (67%) diagnostic accuracy studies. The distribution of efficacy levels was not statistically significant across time (P = 0.22) but was significant across regions (P < 0.01). Authors from Japan produced 26% of the papers with a mean ± standard deviation of 5.78 ± 1.98 authors per paper (APP); American authors, 23% (3.78 ± 1.72 APP); and all others, 51% (3.76 ± 1.51 APP). Conclusion The OMR literature consisted mostly of case reports/series, cross-sectional, technical efficacy and diagnostic accuracy studies. Such studies do not provide strong evidence for clinical decision making nor do they address the impact of diagnostic imaging on patient care. More studies at the higher end of the study design and efficacy hierarchies are needed in order to make wise choices regarding clinical decisions and resource allocations. PMID:21697152

Kim, IH; Patel, MJ; Hirt, SL; Kantor, ML

2011-01-01

233

The basics of preclinical drug development for neurodegenerative disease indications  

PubMed Central

Preclinical development encompasses the activities that link drug discovery in the laboratory to initiation of human clinical trials. Preclinical studies can be designed to identify a lead candidate from several hits; develop the best procedure for new drug scale-up; select the best formulation; determine the route, frequency, and duration of exposure; and ultimately support the intended clinical trial design. The details of each preclinical development package can vary, but all have some common features. Rodent and nonrodent mammalian models are used to delineate the pharmacokinetic profile and general safety, as well as to identify toxicity patterns. One or more species may be used to determine the drug's mean residence time in the body, which depends on inherent absorption, distribution, metabolism, and excretion properties. For drugs intended to treat Alzheimer's disease or other brain-targeted diseases, the ability of a drug to cross the blood brain barrier may be a key issue. Toxicology and safety studies identify potential target organs for adverse effects and define the Therapeutic Index to set the initial starting doses in clinical trials. Pivotal preclinical safety studies generally require regulatory oversight as defined by US Food and Drug Administration (FDA) Good Laboratory Practices and international guidelines, including the International Conference on Harmonisation. Concurrent preclinical development activities include developing the Clinical Plan and preparing the new drug product, including the associated documentation to meet stringent FDA Good Manufacturing Practices regulatory guidelines. A wide range of commercial and government contract options are available for investigators seeking to advance their candidate(s). Government programs such as the Small Business Innovative Research and Small Business Technology Transfer grants and the National Institutes of Health Rapid Access to Interventional Development Pilot Program provide funding and 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

Steinmetz, Karen L; Spack, Edward G

2009-01-01

234

Assessing the Effects of Collaborative Professional Learning: Efficacy Shifts in a Three-Year Mathematics Study  

ERIC Educational Resources Information Center

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…

Bruce, Catherine D.; Flynn, Tara

2012-01-01

235

Lesson study: Professional development and its impact on science teacher self-efficacy  

NASA Astrophysics Data System (ADS)

This study focuses on an analysis of a professional development program known as lesson study via data obtained during an in-service professional development program for secondary school science teachers. The purpose of this study was to examine the self-efficacy beliefs of one group of science teachers related to their experiences in a lesson study. Another purpose for this research, aligned with the first, included a theoretical analysis of the lesson study construct to see if its design promoted positive self-efficacy beliefs of its participants. The research is framed within the context of social constructivism and self-efficacy and is qualitative in nature and utilized descriptive analysis as a means of research. Case studies were conducted detailing two of the six participants. Data sources included researcher field notes and transcriptions of all planning and debriefing sessions; individual interviews with each participant and the schools' principal; a participant questionnaire, and the Science Teaching Efficacy Belief Instrument. Themes that emerged included the positive perceptions of lesson study as a collaborative and teacher-centered experience; the understanding that lesson study can instill a sense of professionalism to those who participate in the process; the sense that discussing student learning using objective observations from classroom is a powerful way to assess learning and uncover personal teacher beliefs; and the insight that the time commitment that lesson study requires can inhibit teachers and schools from sustaining it as a form of on-going professional development. Although these themes are consistent with the research on lesson study in Japan and elsewhere in the United States, they also extend the research on self-efficacy and science teacher professional development. In the end, this study supported some of the conclusions of the self-efficacy research as it relates to professional development while also adding that interpersonal relationships is a relevant consideration in the development of science teacher's self-efficacy. From this study, it is apparent that teachers who are collaboratively involved in a supportive setting such as lesson study can increase their level of self-efficacy and thus improve their teaching practice.

Roberts, Megan Rae

236

Screening for pre-clinical disability in different residential settings  

PubMed Central

Background Preventing disability and offering effective interventions to older people during early decline in function is most likely to be effective if those most at risk of progressive disablement are able to be identified. Similarly the ability to easily identify a group with similar functional profile from disparate sectors of the community is of significant benefit to researchers. This study aimed to (1) describe the use of a pre-clinical disability screening tool to select a functionally comparable group of older men and women with early functional limitation from different settings, and (2) explore factors associated with function and disability. Methods Self-reported function and disability measured with the Late-Life Function and Disability Instrument along with a range of physical performance measurements were compared across residential settings and gender in a sample of 471 trial participants identified as pre-clinically disabled after being screened with the Fried pre-clinical disability tool. Factors that might lie on the pathway to progressive disablement were identified using multiple linear regression analysis. Results We found that a sample population, screened for pre-clinical disability, had a functional status and disability profile reflecting early functional limitation, regardless of residential setting or gender. Statistical models identified a range of factors associated with function and disability which explained a greater degree of the variation in function, than disability. Conclusions We selected a group of people with a comparable function and disability profile, consistent with the pre-clinical stage of disability, from a sample of older Australian men and women from different residential settings using the Fried pre-clinical disability screening tool. The results suggest that the screening tool can be used with greater confidence for research, clinical and population health purposes. Further research is required to examine the validity of the tool. These findings offer insight into the type of impairment factors characterising early functional loss that could be addressed through disability prevention initiatives. Trial Registration ACTRN01206000431527 PMID:20678235

2010-01-01

237

Preclinical efficacy of a carboxylesterase 2-activated prodrug of doxazolidine.  

PubMed

Doxazolidine (Doxaz) is a functionally distinct formaldehyde conjugate of doxorubicin (Dox) that induces cancer cell death in Dox-sensitive and resistant cells. Pentyl PABC-Doxaz (PPD) is a prodrug of Doxaz that is activated by carboxylesterase 2 (CES2), which is expressed by liver, non-small-cell lung, colon, pancreatic, renal, and thyroid cancer cells. Here, we demonstrate that in two murine models, PPD was effective at slowing tumor growth and demonstrated markedly reduced cardiotoxic and nephrotoxic effects, as well as better tolerance, relative to Dox. Hepatotoxicity, consistent with liver expression of the murine CES2 homologue, was induced by PPD. Unlike irinotecan, a clinical CES2-activated prodrug, PPD produced no visible gastrointestinal damage. Finally, we demonstrate that cellular response to PPD may be predicted with good accuracy using CES2 expression and Doxaz sensitivity, suggesting that these metrics may be useful as clinical biomarkers for sensitivity of a specific tumor to PPD treatment. PMID:19634903

Barthel, Benjamin L; Zhang, Zhiyong; Rudnicki, Daniel L; Coldren, Christopher D; Polinkovsky, Margaret; Sun, Hengrui; Koch, Gary G; Chan, Daniel C F; Koch, Tad H

2009-12-10

238

Preclinical models in electrochemotherapy: the role of veterinary patients.  

PubMed

Electrochemotherapy is a tumor treatment that adapts the systemic or local delivery of anticancer drugs by the application of permeabilizing electric pulses with appropriate amplitude and waveforms. This allows the use of lipophobic drugs, which frequently have a narrow therapeutic index, with a decreased morbidity for the patient, while maintaining appropriate anticancer efficacy. Electrochemotherapy is used in humans for the treatment of cutaneous neoplasms or the palliation of skin tumor metastases, and a standard operating procedure has been devised. In veterinary oncology, the electrochemotherapy approach is gaining popularity, becoming a first-line treatment in consideration of its high efficacy and low toxicity. This review summarizes the state of the art in veterinary oncology as a preclinical model. PMID:22830403

Spugnini, Enrico Pierluigi; Fanciulli, Maurizio; Citro, Gennaro; Baldi, Alfonso

2012-07-01

239

Flowing together: a longitudinal study of collective efficacy and collective flow among workgroups.  

PubMed

The aim of this study is to extend the Channel Model of Flow (Csikszentmihalyi, 1975, 1990) at the collective level (workgroups) by including collective efficacy beliefs as a predictor of collective flow based on the Social Cognitive Theory (Bandura, 1997, 2001). A two-wave longitudinal lab study was conducted with 250 participants working in 52 small groups. Longitudinal results from Structural Equation Modeling with data aggregated at the group level showed, as expected, that collective efficacy beliefs predict collective flow over time, both being related reciprocally. Findings and their theoretical and practical implications in the light of Social Cognitive Theory are discussed. PMID:24946388

Salanova, Marisa; Rodríguez-Sánchez, Alma M; Schaufeli, Wilmar B; Cifre, Eva

2014-01-01

240

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

ERIC Educational Resources Information Center

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…

Prat-Sala, Merce; Redford, Paul

2010-01-01

241

Learning Strategies and Self-Efficacy as Predictors of Academic Performance: A Preliminary Study  

ERIC Educational Resources Information Center

Empirical research supports the idea that differences in academic performance among students are largely due to their different learning and study strategies. The strategies, in turn, affect the self-efficacy of the students. Two hundred university students were recruited to participate in this study by completing a revised Chinese version of the…

Yip, Michael C. W.

2012-01-01

242

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

ERIC Educational Resources Information Center

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…

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

243

Efficacy and tolerance of a comfrey root extract (Extr. Rad. Symphyti) in the treatment of ankle distorsions: results of a multicenter, randomized, placebo-controlled, double-blind study.  

PubMed

Comfrey (Symphytum officinale L.) is a medicinal plant with anti-inflammatory, analgesic and tissue regenerating properties. In a double-blind, multicenter, randomized, placebo-controlled, group comparison study on patients suffering from unilateral acute ankle sprains (n = 142, mean age 31.8 years, 78.9% male), the percutaneous efficacy of an ointment of comfrey extract (Kytta-Salbe f, four treatments per day for 8 days) was confirmed decisively. Compared to placebo, the active treatment was clearly superior regarding the reduction of pain (tonometric measurement, p<0.0001, as the primary efficacy variable) and ankle edema (figure-of-eight method, p = 0.0001). Statistically significant differences between active treatment and placebo could also be shown for ankle mobility (neutral zero method), and global efficacy. Under active treatment, no adverse drug reactions were reported. The good local and global tolerance of the trial medication could also be confirmed. The study results are consistent with the known pre-clinical and clinical data concerning comfrey. PMID:15500257

Koll, R; Buhr, M; Dieter, R; Pabst, H; Predel, H G; Petrowicz, O; Giannetti, B; Klingenburg, S; Staiger, C

2004-09-01

244

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

PubMed Central

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

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

2013-01-01

245

Some limitations on the external validity of psychotherapy efficacy studies and suggestions for future research.  

PubMed

Increased emphasis on identifying empirically supported treatments (ESTs) has enhanced the scientific basis for psychotherapy practice, but uncritical acceptance of ESTs as the basis for credentialing and policy decisions risks stifling innovation and creativity in the field. There are limitations inherent in efficacy studies of psychotherapy that can constrain external validity. This article discusses several limitations on the external validity of efficacy studies, as well as other issues related to evaluating psychotherapy outcome research. These limitations and concerns include: 1) the practice of maximizing homogeneity by selecting participants diagnosed with a single Axis I disorder; 2) the practice of requiring manualized therapies for efficacy research; 3) the assumption that lasting and meaningful changes occur and can be assessed within a relatively short time frame; 4) the assumption that valid assessments of outcome can be conducted in randomized control trials studies without concern for researcher allegiance; and 5) the view that evidence of effectiveness from non-RCT design studies can be ignored. Finally, alternative research approaches for studying psychotherapy that can potentially supplement knowledge gained from efficacy studies and foster continued innovation and creativity in the field are discussed. PMID:23091884

Shean, Glenn D

2012-01-01

246

[Preclinical safety investigation of GB-115 dipeptide].  

PubMed

Preclinical safety investigations of newly synthesized dipeptide compound GB-115 (amide N-phenylhexanoyl-glycyl-L-tryptophan), an antagonist of cholecystokinin receptors, were performed. No animals were lost after GB-115 acute oral administration at a maximum dose of 6000 mg/kg in mice and at 3500 mg/kg in rats. GB-115 administered per os during 6 months in rabbits and rats (both males and females) at the doses of 0.1 and 10 mg/kg induced no irreversible pathological changes in organs and systems studied. The tested dipeptide exhibited no allergenic, immunotoxic and mutagenic activity, and did not affect generative function and the antenatal and postnatal development of progeny. GB-115 at a dose of 10 mg/kg produced suppression of the inflammatory reaction to concanavalin A. PMID:20726348

Sorokina, A V; Alekseeva, S V; Nemova, E P; Kovalenko, L P; Smol'nikova, N M; Shipaeva, E V; Shreder, O V; Miroshkina, I A; Diukova, S A; Daugel'-Dauge, N O; Kulakova, A V; Kolik, L G; Durnev, A D; Seredenin, S B

2010-06-01

247

[A study of the efficacy and safety of valdoxan in the treatment of a depressive episode].  

PubMed

An open non-randomized controlled prospective study was conducted to investigate the efficacy and safety of valdoxan in the treatment of depression as monotherapy and in the combination with other drugs. Based on the clinical and psychometric measures, author confirmed the high efficacy of valdoxan. The drug can be combined with other antidepressants, no adverse effects are observed in these cases. Positive changes in sleep patterns during the treatment with valdoxan were found. The high tolerability and minimal risk of serious adverse effects were observed. Preliminary data revealed that the age of the patient and scores on some HAMD items were predictors of treatment efficacy. The authors developed a computer program for express-assessment of probability of remission and response to treatment. PMID:24107878

Soldatkin, V A

2013-01-01

248

Study of the comparative efficacy of toltrazuril and diclazuril against ovine coccidiosis in housed lambs.  

PubMed

A blinded, controlled and randomised field study was conducted on a sheep farm with a known history of coccidiosis and a high prevalence mainly of the pathogenic coccidium Eimeria ovinoidalis. The efficacy of treatment with toltrazuril (Baycox 5% suspension) against natural infections with Eimeria crandallis and/or Eimeria ovinoidalis in housed lambs was investigated in comparison with diclazuril and untreated controls. Both drugs were administered either metaphylactically (i.e., in the prepatency of Eimeria spp.) or therapeutically (after onset of oocyst excretion). A total of 145 animals aged 1 to 5 days at the start of the study were included. Examination of faecal samples was performed every second day between days 13 and 49 of the study. The assessment of treatment efficacy was based mainly on total oocyst excretion and the number of E. crandallis and E. ovinoidalis oocysts (OPG) shed throughout the study. Oocyst excretion was reduced significantly in both groups treated with toltrazuril compared with the untreated control group and with both diclazuril-treated groups. The most prevalent and most severe diarrhoea was observed in the untreated control group. In this study, toltrazuril proved to be highly effective in controlling ovine coccidiosis both metaphylactically and therapeutically. The efficacy of toltrazuril was significantly higher than the efficacy of the control substance with regard to the duration and amount of oocyst excretion, both for the comparison of metaphylactic as well as therapeutic treatment. PMID:19575235

Mundt, Hans-Christian; Dittmar, Katja; Daugschies, Arwid; Grzonka, Elmar; Bangoura, Berit

2009-08-01

249

Buprederm™, a New Transdermal Delivery System of Buprenorphine: Pharmacokinetic, Efficacy and Skin Irritancy Studies  

Microsoft Academic Search

Purpose  The pharmacokinetics, analgesic efficacy, and irritancy potential of Buprederm™, a new transdermal delivery system of buprenorphine,\\u000a was evaluated.\\u000a \\u000a \\u000a \\u000a Methods  Single and multiple dose pharmacokinetic studies were conducted in mice and rabbits. The analgesic efficacy and skin irritation\\u000a potential were determined by tail flick and writhing tests in mice and by the Draize dermal scoring system in rabbits.\\u000a \\u000a \\u000a \\u000a Results  Fast absorption of buprenorphine

Dongwon Kim; Jindeog Song; Chang Hoon In; Seung-Wei Jeong; Sang Hun Lee; Bumchan Min; Dongho Lee; Sun-Ok Kim

2008-01-01

250

Assessing Treatment Efficacy in Outcome Studies of Sex Offenders  

Microsoft Academic Search

Because of the enormous human and financial costs society incurs as a result of sexual crimes, any reduction in the recidivism of sex offenders caused by treatment is very worthwhile. Although treatment can be valuable if this reduction is small, the reduction must nevertheless be real. Real effects are statistically significant differences between treated and untreated subjects in controlled studies.

VERNON L. QUINSEY; GRANT T. HARRIS; MARNIE E. RICE; MARTIN L. LALUMIÈRE

1993-01-01

251

Study of the Validity and Reliability of a Self-Efficacy Scale of Teaching Material Utilization  

ERIC Educational Resources Information Center

The main purpose of this study is to develop a scale in order to detect the level of pre-service teachers' utilization from teaching materials based on their perception of self-efficacy. The sample group is composed of 439 students for the first application and 215 students for the second. In order to detect the validity of the scale, exploratory…

Korkmaz, Ozgen

2011-01-01

252

Exercise Self-Efficacy and Perceived Wellness among College Students in a Basic Studies Course  

ERIC Educational Resources Information Center

University basic studies courses provide a valuable opportunity for facilitating the knowledge, skills, and beliefs that develop healthy behaviors to last a lifetime. Belief in one's ability to participate in physical activity, exercise self-efficacy, is a psychological construct that has had a documented impact on physical activity. Although…

Sidman, Cara L.; D'Abundo, Michelle Lee; Hritz, Nancy

2009-01-01

253

Task-Specific Occupational Self-Efficacy Scale: A Predictive Validity Study  

Microsoft Academic Search

Using the social cognitive theory of career and academic behavior as a guide, we conducted a predictive validity study for the Quantitative and Verbal scales of the Task-Specific Occupational Self-Efficacy Scale (TSOSS). The Quantitative and Verbal TSOSS scale scores of a large group of undecided college freshmen were correlated with concurrent quantitative and verbal ability measures (SAT scores) and with

Kevin R. Kelly; Russell C. Nelson

1999-01-01

254

Developing Self-Efficacy within Role Players in Collegiate Athletics: A Mixed Methods Study  

ERIC Educational Resources Information Center

The purpose of this study was to examine the differences in the level of self-efficacy between starting players and role players in a college Midwest Division III men's football team. The research questions were: 1) What differences in satisfaction levels, if any, can be found among starting players and role players with coach leadership,…

Perchinsky, David A.

2012-01-01

255

Study of the efficacy of aerosol versus nonaerosol laundry products. Final report  

Microsoft Academic Search

The California Air Resources Board estimates that 6.6 tons of photochemically reactive organic compounds (PROC) are released into the environment in California every day because of the use of aerosol laundry products. The project studied the efficacy, ease of product use, and PROC content for three major brands of pre-wash stain removers in available product forms and for five starch

R. R. Boggs; B. Belmont

1987-01-01

256

A comparison study of the efficacy and side effects of different light sources in hair removal  

Microsoft Academic Search

Unwanted hairs are a common problem in which different light sources were developed as the treatment of choice. Alexandrite laser, diode laser, and intense pulsed light (IPL) were clinically used for this purpose with long-term scarce comparative results. The objective of the study was to compare the clinical efficacy, complications, and long-term hair reduction of alexandrite laser, diode laser, and

Parviz Toosi; Afshin Sadighha; Ali Sharifian; Gita Meshkat Razavi

2006-01-01

257

The COACH prompting system to assist older adults with dementia through handwashing: An efficacy study  

Microsoft Academic Search

BACKGROUND: Many older adults with dementia require constant assistance from a caregiver when completing activities of daily living (ADL). This study examines the efficacy of a computerized device intended to assist people with dementia through ADL, while reducing caregiver burden. The device, called COACH, uses artificial intelligence to autonomously guide an older adult with dementia through the ADL using audio

Alex Mihailidis; Jennifer N Boger; Tammy Craig; Jesse Hoey

2008-01-01

258

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

Microsoft Academic Search

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

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

259

Integrated Family and Cognitive-Behavioral Therapy for adolescent substance abusers: a Stage I efficacy study  

Microsoft Academic Search

This study evaluated the efficacy of Integrated Family and Cognitive-Behavioral Therapy (IFCBT), a multisystems treatment for adolescent drug abuse, versus a Drugs Harm Psychoeducation curriculum (DHPE). A randomized controlled trial assessed youth and parents at baseline and at 1, 3 and 6-month posttreatment points. Youth participants (N=43) met diagnostic criteria for one or more psychoactive substance use disorders with most

William W. Latimer; Ken C. Winters; Thomas D'Zurilla; Mike Nichols

2003-01-01

260

[Immunological and clinical study on therapeutic efficacy of inosine pranobex].  

PubMed

Many studies in vitro and in vivo have shown immunomodulating and antiviral activities of inosine pranobex. The object of this research was to examine the potential beneficial effects of inosine pranobex (Groprinosin) on immune system in children with cellular immunodeficiency as a prophylaxis of recurrent infections, mainly of viral origin. 50 mg/kg b.w/day of inosine pranobex in divided doses was given to the group of 30 children aged 3-15 years for 10 days in 3 following months. Clinical and immunological investigations were done before and after the treatment. Statistically significant rise of CD3T lymphocytes number (p = 0.02) and in this CD4T lymphocytes number (p = 0.02) as well as statistically significant improvement of their function (p = 0.005) evaluated with blastic transformation method were found. These laboratory findings were parallel to clinical benefits. Control study was performed in the group of children completed by randomization and treated in the same way with garlic (Alliofil). PMID:16358878

Go?ebiowska-Wawrzyniak, Maria; Markiewicz, Katarzyna; Kozar, Agata; Derentowicz, Piotr; Czerwi?ska-Kartowicz, Iwona; Jastrzebska-Janas, Krystyna; Wac?awek, Jolanta; Wawrzyniak, Zbigniew M; Siwi?ska-Go?ebiowska, Henryka

2005-09-01

261

Phase I Study of Paclitaxel and Uracil plus Tegafur Combination in Patients with Pretreated Metastatic Breast Cancer: Drug Sequencing Based on Preclinical Modelling Studies  

Microsoft Academic Search

Objective: Taxanes and fluoropyrimidines are active in metastatic breast cancer (MBC), and their combination has proven effective in anthracycline-refractory patients. We conducted a phase I study to determine the maximum tolerated dose (MTD) of uracil plus tegafur (UFT) given in combination with leucovorin (LV) and paclitaxel (Pacl) in patients with refractory MBC. Methods: Pacl was infused at a fixed dose

A. Passardi; R. Maltoni; C. Milandri; L. Cecconetto; I. Massa; W. Zoli; A. Tesei; F. Fabbri; O. Nanni; D. Amadori

2007-01-01

262

Open, prospective study of the clinical efficacy of ciprofloxacin.  

PubMed Central

One hundred patients with infections mostly outside of the urinary tract were studied in a prospective, open manner to ascertain the effectiveness and safety of ciprofloxacin in a variety of clinical situations. There were 41 instances of bacteremia, including 38 with Salmonella typhi, and 21 respiratory, 17 skin and skin structure, 11 bone or joint, 6 gastrointestinal, and 4 urinary tract infections. The patients were given 500 mg of ciprofloxacin orally every 12 h for 2 to 107 days (mean, 15.1 days). Microorganisms isolated disclosed susceptibilities comparable to those reported previously, with a MIC for 90% of the strains of 0.25 microgram/ml. For Streptococcus pneumoniae the MIC for 90% of the strains was 0.03 microgram/ml, and it was higher for Pseudomonas aeruginosa (0.5 microgram/ml), although still in the therapeutic range. Levels in blood were lower than those reported in other series, and no accumulation of the drug during treatment was detected. In 88 instances there was resolution of the infectious process, in 7 there was improvement, in 3 there was a failure to respond, and in 2 the clinical response was indeterminate. Bacteriological eradication was documented in 87 infections. Despite extensive clinical and laboratory examinations before, during, and after therapy, no major abnormalities related to therapy were seen; only one patient required discontinuation of ciprofloxacin due to gastrointestinal intolerance. Ciprofloxacin is an effective and safe therapeutic alternative in many tissue infections caused by susceptible microorganisms. PMID:2931046

Ramirez, C A; Bran, J L; Mejia, C R; Garcia, J F

1985-01-01

263

[Pharmacokinetic approach to the improvement of clinical predictability in the preclinical test for antitumor agents].  

PubMed

Clinical predictability of preclinical test for antitumor agents has not been significantly improved even after the use of a human tumor/nude mouse model. Such different antitumor activities between preclinical and clinical tests probably due to the fact that therapeutic used in both tests usually each maximum tolerated dose (MTD), are pharmacokinetically not equivalent. Therefore, we introduced a new concept of "clinically equivalent dose (CED)", which can reproduce in the nude mouse the blood level of a given drug observed with human patients received its therapeutic dose. Treatment of human tumors implanted in the nude mice with CEDs of several drugs exhibited much better correlation with their clinical efficacies than those with MTDs. The feasibility of use of CED predicted by animal scale-up procedure as a therapeutic dose in the preclinical test was discussed. PMID:1906701

Inaba, M

1991-07-01

264

The efficacy of long-term oral chemotherapy with 5'-deoxy-5-fluorouridine and cyclophosphamide for recurrent breast cancer  

Microsoft Academic Search

Background 5?-Deoxy-5-fluorouridine (5?-DFUR) is a prodrug of 5-fluorouracil (5-FU), which is known to be converted by thymidine phosphorylase (dThdPase). A recent preclinical study revealed that cyclophosphamide (CPA) upregulated dThdPase activity, specifically in tumor cells. The purpose of the present study was to examine the efficacy of long-term administration of 5?-DFUR\\/CPA for patients with recurrent breast cancer. Methods Fifteen breast cancer

Toshiaki Iba; Akio Kidokoro; Masaki Fukunaga; Kazuyoshi Sugiyama; Nobuyoshi Aihara; Masaru Suda

2004-01-01

265

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

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

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

266

Leukotrienes as Modifiers of Preclinical Atherosclerosis?  

PubMed Central

Preclinical atherosclerosis represents a crucial period associated with several pathophysiological reactions in the vascular wall. Failure to diagnose preclinical atherosclerosis at this stage misses a major opportunity to prevent the long-term consequences of this disease. Surrogate biological and structural vascular markers are available to determine the presence and the extension of preclinical vascular injury in the general population. Examples of surrogate markers are carotid intima media thickness and biomarkers including high-sensitivity C-reactive protein, cell adhesion molecules and matrix metalloproteinases, and leukotrienes. Recently, leukotrienes have been implicated as mediators, biomarkers, and possible therapeutic targets in the context of subclinical atherosclerosis. The aim of this short paper is to focus on the relation between preclinical atherosclerosis and leukotrienes, with particular attention to the recent development on the use of leukotriene modifiers in the treatment of atherosclerosis. PMID:22645425

Riccioni, Graziano; Back, Magnus

2012-01-01

267

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

PubMed Central

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

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

2014-01-01

268

Metacognitive Training for Schizophrenia Patients (MCT): A Pilot Study on Feasibility, Treatment Adherence, and Subjective Efficacy  

Microsoft Academic Search

Objectives: A plethora of studies has confirmed that several cognitive biases (e.g., attributional style, jumping to conclu- sions, bias against disconfirmatory evidence, theory of mind, over-confidence in errors, need for closure, and low self- esteem) may play a pathogenetic role in the emergence and\\/or maintenance of the disorder, particularly delusions. The present study explored the safety, acceptance and subjective efficacy

Steffen Moritz; Todd S. Woodward

269

Self-Efficacy and Equine Assisted Therapy: A Single Subject Study  

Microsoft Academic Search

Equine Assisted Therapy (EAT) is growing in popularity as an alternative to traditional talk therapy in treating a range of presenting concerns; however, there is little empirical research to support its use. In this study, the author added to the body of empirical literature on EAT’s impact on self-efficacy. This study was a single subject A-B-A-B design wherein the subject

Jessica H. Geddes

2010-01-01

270

Self-efficacy, Training Effectiveness, and Deception Detection: A Longitudinal Study of Lie Detection Training  

Microsoft Academic Search

\\u000a Studies examining the ability to detection deception have consistently found that humans tend to be poor detectors. In this\\u000a study, we examine the roles of self-efficacy and training over time. We conducted a field experiment at a military training\\u000a center involving 119 service members. The subjects were given two sessions of deception detection training. Their performance\\u000a history, perceived effectiveness of

Kent Marett; David P. Biros; Monti L. Knode

2004-01-01

271

Role Models, Approaches to Studying, and Self-Efficacy in Forensic and Mainstream High School Students: A Pilot Study  

ERIC Educational Resources Information Center

This study investigated the relationships between role models, approaches to studying, and self-efficacy in students attending a high school specialising in educating those with emotional and behavioural difficulties (EBD, n = 30) and students attending a mainstream high school (n = 41) in the UK. Types and quantity of role models held by students…

Skidmore, Michael; Dede, Yemi U.; Moneta, Giovanni B.

2009-01-01

272

Polyphenols in the prevention and treatment of sepsis syndromes: rationale and pre-clinical evidence.  

PubMed

Sepsis is the overwhelming systemic response to infection of a normally sterile body compartment. Despite advances in elucidating its pathophysiology, severe sepsis remains a leading cause of death in the critically ill. Polyphenols are a family of chemicals found in food and beverages derived from plants, such as cocoa, green tea, turmeric, and soya, as well as in medicinal herbs. These phytochemicals exhibit anti-inflammatory and vasculoprotective properties in clinical and preclinical studies. The oral or systemic administration of polyphenols protects rodents from endotoxinemia and microbial sepsis. Under these circumstances, polyphenols reproducibly attenuate microvascular hyperpermeability, tissue infiltration by leukocytes, oxidative and nitrosative stress, tissue injury, organ dysfunction, shock and vasoplegia, lactate production, and mortality. Importantly, efficacy is maintained in some cases even when treatment is initiated hours after the onset of sepsis. The inhibition of nuclear factor-kappaB activation and subsequent expression of inducible nitric oxide synthase, adhesion molecules, and tumor necrosis factor-alpha by polyphenols is operative in ameliorating the sequelae of sepsis. Enhancement of the endogenous antioxidant capacity probably also contributes to the effectiveness of the polyphenols. Because several of the polyphenols reviewed in this article appear to be safe and to exert anti-inflammatory effects in humans, clinical trials assessing their efficacy in the critically ill are indicated. Whether delivered alone or in combination with nutritional formulas, polyphenols may help to prevent and treat sepsis. PMID:19502006

Shapiro, Haim; Lev, Shaul; Cohen, Jonathan; Singer, Pierre

2009-10-01

273

Preclinical formulations: insight, strategies, and practical considerations.  

PubMed

A lot of resources and efforts have been directed to synthesizing potentially useful new chemical entities (NCEs) by pharmaceutical scientists globally. Detailed physicochemical characterization of NCEs in an industrial setup begins almost simultaneously with preclinical testing. Most NCEs possess poor water solubility posing bioavailability issues during initial preclinical screening, sometimes resulting in dropping out of an NCE with promising therapeutic activity. Selection of right formulation approach for an NCE, based on its physicochemical properties, can aid in improving its solubility-related absorption and bioavailability issues. The review focuses on preclinical formulations stressing upon different preclinical formulation strategies and deciphers the understanding of formulation approaches that could be employed. It also provides detailed information related to a vast pool of excipients available today, which is of immense help in designing preclinical formulations. Few examples mentioned, throw light on key aspects of preclinical formulation development. The review will serve as an important guide for selecting the right strategy to improve bioavailability of NCEs for academic as well as industrial formulation scientists. PMID:24920522

Shah, Sanket M; Jain, Ankitkumar S; Kaushik, Ritu; Nagarsenker, Mangal S; Nerurkar, Maneesh J

2014-10-01

274

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

PubMed Central

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

2014-01-01

275

New cast for a new era: preclinical cancer drug development revisited  

PubMed Central

Molecularly targeted agents promise to revolutionize therapeutics by reducing morbidity and mortality in patients with cancer. However, despite an urgent need for more effective anticancer compounds, current preclinical drug evaluations largely fail to satisfy the demand. New preclinical strategies, including the improvement of sophisticated mouse models and co-clinical study designs, are being used to augment the predictive value of animal-based translational cancer research. Here, we review the development of successful preclinical antineoplastic agents, their associated limitations, and alternative methods to predict clinical outcomes. PMID:23999436

Herter-Sprie, Grit S.; Kung, Andrew L.; Wong, Kwok-Kin

2013-01-01

276

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

NASA Astrophysics Data System (ADS)

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.

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

2014-03-01

277

CTLA-4 blockade in tumor models: an overview of preclinical and translational research  

PubMed Central

Cytotoxic T lymphocyte antigen-4 (CTLA-4) is a key negative regulator of T cell activation. A complex integration of positive and negative co-stimulatory signals in the well-defined B7:CD28/CTLA-4 pathway modulates the generation and maintenance of immune responses. Inhibiting negative regulation through binding of CTLA-4 has been shown to promote stimulation of adaptive immunity and potentiation of T cell activation. CTLA-4-blocking antibodies have demonstrated efficacy in various murine malignancy models when administered as monotherapy; additionally, they have shown synergistic anti-tumor activity when utilized with other agents, such as vaccines, chemotherapy, and radiation. Preclinical studies have supported the rationale for current clinical development of anti-CTLA-4 antibodies, including ipilimumab and tremelimumab, as novel therapeutic strategies to augment anti-tumor immunity in cancer. Both ipilimumab and tremelimumab have been evaluated extensively in melanoma; notably, ipilimumab was recently approved as monotherapy for the treatment of advanced melanoma. Tremelimumab is currently undergoing evaluation in phase II trials as monotherapy in melanoma and malignant mesothelioma, while ipilimumab is under clinical investigation in phase II and III trials in various tumor types, including in melanoma, prostate, and lung cancers as monotherapy and with other therapeutic modalities, such as chemotherapy and radiation. In this review, we will provide a detailed overview of preclinical advances that have delineated many features of CTLA-4 and have helped define its role in T cell response. We will also highlight clinical application of anti-CTLA-4 therapy in cancer and describe knowledge gaps that future studies may address. PMID:23390376

Grosso, Joseph F.; Jure-Kunkel, Maria N.

2013-01-01

278

A Longitudinal Study of the Relationships Among Job Search Self-Efficacy, Job Interviews, and Employment Outcomes  

Microsoft Academic Search

This study investigates the relationships among job search self-efficacy beliefs, number of job interviews participated in, and job search outcomes using data collected from graduating college job seekers at multiple points in their respective job searches. Results indicate that job search self-efficacy is positively related to number of total offers and number of offers from a preferred employer. Consistent with

Lisa M. Moynihan; Mark V. Roehling; Marcie A. LePine; Wendy R. Boswell

2003-01-01

279

Longitudinal Study of Middle Grades Chemistry Professional Development: Enhancement of Personal Science Teaching Self-Efficacy and Outcome Expectancy  

ERIC Educational Resources Information Center

The purpose of this research was to enhance self-efficacy beliefs, chemistry content, and pedagogical content knowledge of middle grades teachers by incorporating specific design elements into professional development. This study analyzed the influence of program design on achieving gains in personal science teaching self-efficacy, outcome…

Khourey-Bowers, Claudia; Simonis, Doris G.

2004-01-01

280

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

ERIC Educational Resources Information Center

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…

Charnsil, Chawanun

2011-01-01

281

21 CFR 330.12 - Status of over-the-counter (OTC) drugs previously reviewed under the Drug Efficacy Study (DESI).  

Code of Federal Regulations, 2012 CFR

...prior to the drug efficacy study implementation. (c) Manufacturers...provided by the Drug Efficacy Study review is valuable information...They are encouraged to perform studies to obtain adequate evidence...into conformity with current medical knowledge and...

2012-04-01

282

21 CFR 330.12 - Status of over-the-counter (OTC) drugs previously reviewed under the Drug Efficacy Study (DESI).  

Code of Federal Regulations, 2010 CFR

...prior to the drug efficacy study implementation. (c) Manufacturers...provided by the Drug Efficacy Study review is valuable information...They are encouraged to perform studies to obtain adequate evidence...into conformity with current medical knowledge and...

2010-04-01

283

21 CFR 330.12 - Status of over-the-counter (OTC) drugs previously reviewed under the Drug Efficacy Study (DESI).  

...prior to the drug efficacy study implementation. (c) Manufacturers...provided by the Drug Efficacy Study review is valuable information...They are encouraged to perform studies to obtain adequate evidence...into conformity with current medical knowledge and...

2014-04-01

284

21 CFR 330.12 - Status of over-the-counter (OTC) drugs previously reviewed under the Drug Efficacy Study (DESI).  

Code of Federal Regulations, 2013 CFR

...prior to the drug efficacy study implementation. (c) Manufacturers...provided by the Drug Efficacy Study review is valuable information...They are encouraged to perform studies to obtain adequate evidence...into conformity with current medical knowledge and...

2013-04-01

285

21 CFR 330.12 - Status of over-the-counter (OTC) drugs previously reviewed under the Drug Efficacy Study (DESI).  

Code of Federal Regulations, 2011 CFR

...prior to the drug efficacy study implementation. (c) Manufacturers...provided by the Drug Efficacy Study review is valuable information...They are encouraged to perform studies to obtain adequate evidence...into conformity with current medical knowledge and...

2011-04-01

286

Pharmacokinetic Characteristics, Efficacy, and Safety of Buccal Testosterone in Hypogonadal Males: A Pilot Study  

Microsoft Academic Search

Transbuccal administration of drugs provides an easy route of administration. To test the safety and efficacy of a novel testosterone (T) product, we performed a randomized, double blind, placebo-con- trolled study in a parallel design. Men with serum T levels below 250 ng\\/dL were administered either an active buccal tablet containing 10 mg T( n5 7) or a buccal placebo

ADRIAN S. DOBS; DONALD R. HOOVER; MIN-CHI CHEN; RICHARD ALLEN

287

Safety and efficacy of shed mediastinal blood transfusion after cardiac surgery: A multicenter observational study  

Microsoft Academic Search

Objective: To examine the efficacy and safety of shed mediastinal blood (SMB) transfusion in preventing allogenic red blood cell (RBC) transfusion.Design: An observational clinical study.Setting: Twelve US academic medical centers.Participants: Six hundred seventeen patients undergoing elective primary coronary artery bypass grafting.Interventions: Patients were administered SMB transfusion or not, according to institutional and individual practice, without random assignment.Measurements and Results: The

Simon C. Body; Jolene Birmingham; Reg Parks; Catherine Ley; Rosemarie Maddi; Stanton K. Shernan; Lawrence C. Siegel; E. Price Stover; Michael N. D'Ambra; Jack Levin; Dennis T. Mangano; Bruce D. Spiess

1999-01-01

288

Self-efficacy and self-regulation and their relationship: a study of Iranian EFL teachers  

Microsoft Academic Search

This article sets out to examine the relationship between EFL teachers’ sense of self-efficacy and their self-regulation. It also explores the relationships between self-regulation on the one hand and length of teaching experience, age and genderrespectively. Ninety-two EFL teachers from different English language institutes in north-eastern Iran took part in the study. The findings indicate a significant relationship between teachers’

Behzad Ghonsooly; Afsaneh Ghanizadeh

2011-01-01

289

A preliminary study into stress in palliative care: Optimism, self-efficacy and social support  

Microsoft Academic Search

Caring for the terminally ill is a demanding, but rewarding area of health care. Stressors unique to this working environment—dealing with patient death rather than cure, and supporting entire family units, for example—put caregivers at risk from stress related illness. This study investigated the buffering effects of optimism, self-efficacy and social support against two measures of stress within the palliative

N. J. Hulbert; V. L. Morrison

2006-01-01

290

A Study of the Mathematics Teaching Efficacy Beliefs of Primary Teachers  

Microsoft Academic Search

The affective domain has in recent years attracted much attention from the mathematics research community; empirical data\\u000a seem to increasingly support expert opinion that affect plays a decisive role in the process of cognitive development. One\\u000a of the less researched dimensions of the affective domain is teachers’ beliefs about the efficacy of their mathematics teaching.\\u000a Though there are studies examining

George Philippou; Constantinos Christou

291

Long-Term Efficacy and Tolerability of Lanthanum Carbonate: Results from a 3Year Study  

Microsoft Academic Search

Background: Control of serum phosphate over the long term is essential in patients with end-stage renal disease. Six-month and 2-year extensions to a 6-month study evaluated the long-term safety, tolerability and efficacy of the new phosphate binder lanthanum carbonate. Methods: Patients who participated in a 6-month, randomized trial comparing lanthanum carbonate with calcium carbonate were eligible for a 24-week, open-label

Alastair J. Hutchison; Bart Maes; Johan Vanwalleghem; Gernot Asmus; Elfatih Mohamed; Roland Schmieder; Wolfgang Backs; Rene Jamar; Andre Vosskühler

2006-01-01

292

An adjudicated hermeneutic single-case efficacy design study of experiential therapy for panic\\/phobia  

Microsoft Academic Search

This article illustrates the application of an adjudicated form of hermeneutic single-case efficacy design, a critical-reflective method for inferring change and therapeutic influence in single therapy cases. The client was a 61-year-old European-American male diagnosed with panic and bridge phobia. He was seen for 23 sessions of individual process-experiential\\/emotion-focused therapy. In this study, affirmative and skeptic teams of researchers developed

Robert Elliott; Rhea Partyka; Rebecca Alperin; Robert Dobrenski; John Wagner; Stanley B. Messer; Jeanne C. Watson; Louis G. Castonguay

2009-01-01

293

A Nicotine Mouth Spray for Smoking Cessation: A Pilot Study of Preference, Safety and Efficacy  

Microsoft Academic Search

Background: Various formulations of nicotine replacement therapy are commercially available. Objectives: It was the aim of this study to test preference, safety and efficacy of a new nicotine mouth spray (1 mg\\/actuation; NicoNovum). Methods: One hundred healthy smokers wanting to quit (mean age 43.1 ± 11.2 years) were included. They were given the mouth spray, as well as 2-mg nicotine

C. T. Bolliger; X. van Biljon; A. Axelsson

2007-01-01

294

Preclinical humanized mouse model with ectopic ovarian tissues  

PubMed Central

The aim of the present study was to establish human ovarian stroma within the mouse subcutaneously, in order for the resulting stroma to serve as a useful preclinical tool to study the progression of human ovarian cancer in a humanized ovarian microenvironment. Normal human ovarian tissues were subcutaneously implanted into severe combined immunodeficient (SCID) mice and then the implants were identified by immunohistochemistry. The implants became vascularized and retained their original morphology for about 4 weeks following implantation. Immunohistochemical staining for cytokeratin-7 confirmed the ovarian origin of the epithelial cells. CD34 staining demonstrated human-derived vessels. Positive estrogen receptor and partially-positive progesterone receptor staining indicated the estrogen and progesterone dependence of the implants. Only vascular pericytes expressed ?-smooth muscle actin, indicating the normal ovarian origin of the xenografts. Human ovarian tissue successfully survived in SCID mice and retained its original properties. This humanized mouse model may be used as preclinical tool to investigate ovarian cancer. PMID:25120592

FU, SHILONG; WANG, JUE; SUN, WU; XU, YI; ZHOU, XIAOYU; CHENG, WENJUN

2014-01-01

295

Prenatal antidepressant exposure: clinical and preclinical findings.  

PubMed

Pharmacological treatment of any maternal illness during pregnancy warrants consideration of the consequences of the illness and/or medication for both the mother and unborn child. In the case of major depressive disorder, which affects up to 10-20% of pregnant women, the deleterious effects of untreated depression on the offspring can be profound and long lasting. Progress has been made in our understanding of the mechanism(s) of action of antidepressants, fetal exposure to these medications, and serotonin's role in development. New technologies and careful study designs have enabled the accurate sampling of maternal serum, breast milk, umbilical cord serum, and infant serum psychotropic medication concentrations to characterize the magnitude of placental transfer and exposure through human breast milk. Despite this progress, the extant clinical literature is largely composed of case series, population-based patient registry data that are reliant on nonobjective means and retrospective recall to determine both medication and maternal depression exposure, and limited inclusion of suitable control groups for maternal depression. Conclusions drawn from such studies often fail to incorporate embryology/neurotransmitter ontogeny, appropriate gestational windows, or a critical discussion of statistically versus clinically significant. Similarly, preclinical studies have predominantly relied on dosing models, leading to exposures that may not be clinically relevant. The elucidation of a defined teratological effect or mechanism, if any, has yet to be conclusively demonstrated. The extant literature indicates that, in many cases, the benefits of antidepressant use during pregnancy for a depressed pregnant woman may outweigh potential risks. PMID:24567054

Bourke, Chase H; Stowe, Zachary N; Owens, Michael J

2014-04-01

296

The marmoset monkey: a multi-purpose preclinical and translational model of human biology and disease.  

PubMed

The development of biologic molecules (monoclonal antibodies, cytokines, soluble receptors) as specific therapeutics for human disease creates a need for animal models in which safety and efficacy can be tested. Models in lower animal species are precluded when the reagents fail to recognize their targets, which is often the case in rats and mice. In this Feature article we will highlight the common marmoset, a small-bodied nonhuman primate (NHP), as a useful model in biomedical and preclinical translational research. PMID:22728226

't Hart, Bert A; Abbott, David H; Nakamura, Katsuki; Fuchs, Eberhard

2012-11-01

297

Tolerance and Efficacy of Sodium Oxybate in Childhood Narcolepsy with Cataplexy: A Retrospective Study  

PubMed Central

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. Citation: Lecendreux M; Poli F; Oudiette D; Benazzouz F; Donjacour CEHM; Franceschini C; Finotti E; Pizza F; Bruni O; Plazzi G. Tolerance and efficacy of sodium oxybate in childhood narcolepsy with cataplexy: a retrospective study. SLEEP 2012;35(5):709-711. PMID:22547897

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

2012-01-01

298

Update of the Stroke Therapy Academic Industry Roundtable Preclinical Recommendations  

PubMed Central

The initial Stroke Therapy Academic Industry Roundtable (STAIR) recommendations published in 1999 were intended to improve the quality of preclinical studies of purported acute stroke therapies. Although recognized as reasonable, they have not been closely followed nor rigorously validated. Substantial advances have occurred regarding the appropriate quality and breadth of preclinical testing for candidate acute stroke therapies for better clinical translation. The updated STAIR preclinical recommendations reinforce the previous suggestions that reproducibly defining dose response and time windows with both histological and functional outcomes in multiple animal species with appropriate physiological monitoring is appropriate. The updated STAIR recommendations include: the fundamentals of good scientific inquiry should be followed by eliminating randomization and assessment bias, a priori defining inclusion/exclusion criteria, performing appropriate power and sample size calculations, and disclosing potential conflicts of interest. After initial evaluations in young, healthy male animals, further studies should be performed in females, aged animals, and animals with comorbid conditions such as hypertension, diabetes, and hypercholesterolemia. Another consideration is the use of clinically relevant biomarkers in animal studies. Although the recommendations cannot be validated until effective therapies based on them emerge from clinical trials, it is hoped that adherence to them might enhance the chances for success. PMID:19246690

Fisher, Marc; Feuerstein, Giora; Howells, David W.; Hurn, Patricia D.; Kent, Thomas A.; Savitz, Sean I.; Lo, Eng H.

2010-01-01

299

Preclinical Models for Neuroblastoma: Establishing a Baseline for Treatment  

PubMed Central

Background Preclinical models of pediatric cancers are essential for testing new chemotherapeutic combinations for clinical trials. The most widely used genetic model for preclinical testing of neuroblastoma is the TH-MYCN mouse. This neuroblastoma-prone mouse recapitulates many of the features of human neuroblastoma. Limitations of this model include the low frequency of bone marrow metastasis, the lack of information on whether the gene expression patterns in this system parallels human neuroblastomas, the relatively slow rate of tumor formation and variability in tumor penetrance on different genetic backgrounds. As an alternative, preclinical studies are frequently performed using human cell lines xenografted into immunocompromised mice, either as flank implant or orthtotopically. Drawbacks of this system include the use of cell lines that have been in culture for years, the inappropriate microenvironment of the flank or difficult, time consuming surgery for orthotopic transplants and the absence of an intact immune system. Principal Findings Here we characterize and optimize both systems to increase their utility for preclinical studies. We show that TH-MYCN mice develop tumors in the paraspinal ganglia, but not in the adrenal, with cellular and gene expression patterns similar to human NB. In addition, we present a new ultrasound guided, minimally invasive orthotopic xenograft method. This injection technique is rapid, provides accurate targeting of the injected cells and leads to efficient engraftment. We also demonstrate that tumors can be detected, monitored and quantified prior to visualization using ultrasound, MRI and bioluminescence. Finally we develop and test a “standard of care” chemotherapy regimen. This protocol, which is based on current treatments for neuroblastoma, provides a baseline for comparison of new therapeutic agents. Significance The studies suggest that use of both the TH-NMYC model of neuroblastoma and the orthotopic xenograft model provide the optimal combination for testing new chemotherapies for this devastating childhood cancer. PMID:21559450

Federico, Sara; Bradley, Cori L.; Brennan, Rachel; Zhang, Jiakun; Johnson, Melissa D.; Sedlacik, Jan; Inoue, Madoka; Zhang, Ziwei M.; Frase, Sharon; Rehg, Jerold E.; Hillenbrand, Claudia M.; Finkelstein, David; Calabrese, Christopher; Dyer, Michael A.; Lahti, Jill M.

2011-01-01

300

Increasing self-efficacy and quality lesson planning using Lesson-Study with elementary preservice teachers  

NASA Astrophysics Data System (ADS)

This qualitative, quasi-experimental study examined if lesson-study could be a successful approach in improving lesson plan quality and increasing self-efficacy levels toward teaching science at the preservice elementary teacher level in North Mississippi. Lesson-Study can be defined as a cycle of instructional improvement in which small groups work together to design and teach a lesson, revising again as needed over the course of a semester. This study described the experiences of two sections of preservice teachers enrolled in a science methods course as they engaged in lesson-study at a comprehensive university in Northeast Mississippi. One section of the class served as the control group while the other section, as the treatment group, received lesson-study over the course of the semester. Data was gathered in the form of interviews, observations, and a self-efficacy survey (STEBI-B). Lesson plans were also graded using a rubric to determine quality level. Findings indicated that, while not statistically significant, the treatment groups scores on the self-efficacy instrument increased more on average than the control groups' scores. There were also positive comments about the lesson study process from the teacher candidates in the treatment group as well as positive behaviors recorded by the researcher. Additionally, according to the external evaluators who graded the final drafts of the lessons, the treatment group had greater gains than the control class on average. These conclusions suggested the lesson study process implemented during the preservice teaching level can be beneficial.

Mitchell, Elizabeth Ann

301

A study of secondary science teacher efficacy and level of constructivist instructional practice implementation in West Virginia science classrooms  

NASA Astrophysics Data System (ADS)

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 sought to determine if differences existed in level of use of the selected constructivist practices and/or teacher efficacy based on selected demographic variables. The study was a mixed-methods design. First, a researcher-developed survey instrument was used to collect data regarding the level of use of constructivist instructional practices. Efficacy data were collected using an adapted (with permission) version of the Teacher Self-Efficacy Scale ( TSES) by Tschannen-Moran, Hoy, and Hoy (1998). The study population consisted of secondary science teachers (middle, junior, and high school) in the state of West Virginia. The last survey question allowed educators to volunteer for a short follow-up interview to clarify the quantitative data. Overall, West Virginia science teachers reported frequent use of the selected constructivist instructional practices. Few significant differences were found based on the selected demographic variables. West Virginia science teachers reported moderately high efficacy levels. Few significant differences were found based on selected demographic variables. A moderate but significant correlation was found between teacher efficacy level and the level of use of the selected constructivist practices. The follow-up interviews clarified concepts and revealed barriers to implementation of new practices in the science classroom.

Knapp, Amanda Kristen

302

Antigen-Specific Dependence of Tr1-Cell Therapy in Preclinical Models of Islet Transplant  

PubMed Central

OBJECTIVE In type 1 diabetes, allogeneic pancreatic islet transplant restores insulin production, but life-threatening immunosuppression is required to avoid graft rejection. Induction of antigen (Ag)–specific tolerance by cell therapy with regulatory T-cells (Tregs) represents an attractive alternative approach but its therapeutic efficacy in islet transplant remains to be determined. Among the different subsets of CD4+ Tregs, the T inducible regulatory type 1 (Tr1) cells can be generated from naive T-cells in the presence of interleukin-10 (IL-10) and represent one promising therapeutic choice. This study was designed to define the efficacy of Tr1-cell therapy in preclinical models of islet transplant. RESEARCH DESIGN AND METHODS Non–Ag-specific polyclonal Tr1 cells and donor Ag-specific Tr1 cells were transferred, in the absence of any pharmacological treatment, in two distinct mouse models of islet transplant. The two models differed in their therapeutic stringency, based on the mean rejection time of untreated mice that underwent a transplant. RESULTS Transfer of polyclonal Tr1 cells engendered graft tolerance only in the nonstringent mouse model. Conversely, cell therapy with Ag-specific Tr1 cells induced an IL-10–dependent tolerance in the stringent mouse model of islet transplant. The therapeutic advantage of Ag-specific Tr1 cells over polyclonal Tr1 cells was due to their donor Ag specificity. CONCLUSIONS These results demonstrate that Tr1-cell therapy leads to tolerance in settings of islet transplant and that its therapeutic efficacy is highly dependent on the antigen specificity of these cells. PMID:19934002

Gagliani, Nicola; Jofra, Tatiana; Stabilini, Angela; Valle, Andrea; Atkinson, Mark; Roncarolo, Maria-Grazia; Battaglia, Manuela

2010-01-01

303

Lentinan: Hematopoietic, Immunological, and Efficacy Studies in a Syngeneic Model of Acute Myeloid Leukemia  

Microsoft Academic Search

Lentinan, a ?-glucan nutritional supplement isolated from the shitake mushroom (Lentula edodes), is a biological response modifier with immunostimulatory properties. Concomitantly, the role of ?-glucans as chemoimmunotherapeutic in a number of solid cancers has been widely documented. We investigated the effects of nutritional grade lentinan upon BN rats and in a preclinical syngeneic model of acute myeloid leukemia. BN rats

Emmet McCormack; Jørn Skavland; Maja Muji?; Øystein Bruserud; Bjørn Tore Gjertsen

2010-01-01

304

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

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

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

305

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

PubMed Central

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

Johnson, Bankole A.; Ait-Daoud, Nassima

2011-01-01

306

Characterization of a preclinical model of chronic ischemic wound  

PubMed Central

Chronic ischemic wounds presenting at wound clinics are heterogeneous with respect to etiology, age of the wound, and other factors complicating wound healing. In addition, there are ethical challenges associated with collecting repeated biopsies from a patient to develop an understanding of the temporal dynamics of the mechanisms underlying chronic wounds. The need for a preclinical model of ischemic wound is therefore compelling. The porcine model is widely accepted as an excellent preclinical model for human wounds. A full-thickness bipedicle flap approach was adopted to cause skin ischemia. Closure of excisional wounds placed on ischemic tissue was severely impaired resulting in chronic wounds. Histologically, ischemic wounds suffered from impaired re-epithelialization, delayed macrophage recruitment and poorer endothelial cell abundance and organization. Compared with the pair-matched nonischemic wound, unique aspects of the ischemic wound biology were examined on days 3, 7, 14, and 28 by systematic screening of the wound tissue transcriptome using high-density porcine GeneChips. Ischemia markedly potentiated the expression of arginase-1, a cytosolic enzyme that metabolizes the precursor of nitric oxide l-arginine. Ischemia also induced the SOD2 in the wound tissue perhaps as survival response of the challenged tissue. Human chronic wounds also demonstrated elevated expression of SOD2 and arginase-1. This study provides a thorough database that may serve as a valuable reference tool to develop novel hypotheses aiming to elucidate the biology of ischemic chronic wounds in a preclinical setting. PMID:19293328

Roy, Sashwati; Biswas, Sabyasachi; Khanna, Savita; Gordillo, Gayle; Bergdall, Valerie; Green, Jeanne; Marsh, Clay B.; Gould, Lisa J.; Sen, Chandan K.

2009-01-01

307

Characterization of a preclinical model of chronic ischemic wound.  

PubMed

Chronic ischemic wounds presenting at wound clinics are heterogeneous with respect to etiology, age of the wound, and other factors complicating wound healing. In addition, there are ethical challenges associated with collecting repeated biopsies from a patient to develop an understanding of the temporal dynamics of the mechanisms underlying chronic wounds. The need for a preclinical model of ischemic wound is therefore compelling. The porcine model is widely accepted as an excellent preclinical model for human wounds. A full-thickness bipedicle flap approach was adopted to cause skin ischemia. Closure of excisional wounds placed on ischemic tissue was severely impaired resulting in chronic wounds. Histologically, ischemic wounds suffered from impaired re-epithelialization, delayed macrophage recruitment and poorer endothelial cell abundance and organization. Compared with the pair-matched nonischemic wound, unique aspects of the ischemic wound biology were examined on days 3, 7, 14, and 28 by systematic screening of the wound tissue transcriptome using high-density porcine GeneChips. Ischemia markedly potentiated the expression of arginase-1, a cytosolic enzyme that metabolizes the precursor of nitric oxide l-arginine. Ischemia also induced the SOD2 in the wound tissue perhaps as survival response of the challenged tissue. Human chronic wounds also demonstrated elevated expression of SOD2 and arginase-1. This study provides a thorough database that may serve as a valuable reference tool to develop novel hypotheses aiming to elucidate the biology of ischemic chronic wounds in a preclinical setting. PMID:19293328

Roy, Sashwati; Biswas, Sabyasachi; Khanna, Savita; Gordillo, Gayle; Bergdall, Valerie; Green, Jeanne; Marsh, Clay B; Gould, Lisa J; Sen, Chandan K

2009-05-13

308

Imaging technologies for preclinical models of bone and joint disorders  

PubMed Central

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

2011-01-01

309

Safety and Efficacy of ARA 290 in Sarcoidosis Patients with Symptoms of Small Fiber Neuropathy: A Randomized, Double-Blind Pilot Study  

PubMed Central

ARA 290 (a peptide designed to activate the innate repair receptor that arrests injury and initiates cytoprotection, antiinflammation and healing) reduces allodynia in preclinical neuropathy models. We studied the safety and efficacy of ARA 290 to reduce symptoms of small fiber neuropathy (SFN) in patients with sarcoidosis. A total of 22 patients diagnosed with sarcoidosis and symptoms of SFN were enrolled in a double-blind, placebo-controlled exploratory trial consisting of three times weekly intravenous dosing of ARA 290 (2 mg; n = 12) or placebo (n = 10) for 4 wks. Inclusion criteria were a diagnosis of neuropathy and a spontaneous pain score of ?5 (Brief Pain Inventory [BPI]). Endpoints assessed were changes in pain intensity and the small fiber neuropathy screening list (SFNSL) score, quality of life (SF-36), depressive symptoms (Inventory of Depressive Symptomatology [IDS]) and fatigue (Fatigue Assessment Scale [FAS]). No safety concerns were raised by clinical or laboratory assessments. The ARA 290 group showed significant (p < 0.05) improvement at wk 4 in SFNSL score compared with placebo (? ?11.5 ± 3.04 versus ? ?2.9 ± 3.34 [standard error of the mean]). Additionally, the ARA 290 group showed a significant change from baseline in the pain and physical functioning dimensions of the SF-36 (? ?23.4 ± 5.5 and ? ?14.6 ± 3.9, respectively). The mean BPI and FAS scores improved significantly but equivalently in both patient groups. No change was observed in the IDS. ARA 290 appears to be safe in patients with sarcoidosis and can reduce neuropathic symptoms. PMID:23168581

Heij, Lara; Niesters, Marieke; Swartjes, Maarten; Hoitsma, Elske; Drent, Marjolein; Dunne, Ann; Grutters, Jan C; Vogels, Oscar; Brines, Michael; Cerami, Anthony; Dahan, Albert

2012-01-01

310

Can a self-efficacy-based intervention decrease burnout, increase engagement, and enhance performance? A quasi-experimental study  

Microsoft Academic Search

Using the Social Cognitive Theory as a theoretical framework, this study evaluated a 4-month, individual cognitive-behavioral\\u000a intervention program to decrease burnout and increase self-efficacy, engagement, and performance among university students.\\u000a The main objective of the intervention was to decrease the anxiety the students coped with before exams in order to increase\\u000a their beliefs of self-efficacy. Besides the study group intervened,

Edgar Bresó; Wilmar B. SchaufeliMarisa Salanova; Marisa Salanova

2011-01-01

311

The combined effect of self-efficacy and academic integration on higher education students studying IT majors in Taiwan  

Microsoft Academic Search

The purpose of this study is to examine the combined effect of self-efficacy and academic integration on higher education\\u000a students studying IT (Information Technology) majors in Taiwan. We introduced self-efficacy, which is a psychological factor\\u000a that affects students’ academic outcomes, as a new factor in Tinto’ theory, a well-known framework in student retention research.\\u000a Academic integration is the main proposition

Fumei Weng; France Cheong; Christopher Cheong

2010-01-01

312

Efficacy and safety of anti-tuberculosis drugs in HIV-positive patients: A prospective study  

PubMed Central

Objectives: To assess the efficacy and safety of anti-tuberculosis drugs in HIV-positive patients at a tertiary care teaching hospital. Materials and Methods: As a part of an ongoing study of opportunistic infections (OIs) in HIV-positive patients, drug treatment in patients suffering from tuberculosis was assessed to determine its efficacy and safety. Based on prevalence data for last three years, a purposive sampling of study population was carried out in this observational, prospective, single centre study. Tuberculosis (TB) was the most common OI observed. The selected patients were followed up for a period of one year to evaluate the clinical course and outcome of OIs, and the efficacy and safety of drugs used was checked. Results: Tuberculosis was observed in 89 out of 134 enrolled patients. These included 79 adults and 10 children. Males (66.2%) were commonly affected. Extra pulmonary TB (73%) was the most common manifestation with abdominal TB observed in 55 (61.7%) patients. All patients were treated in accordance with the Revised National Tuberculosis Control Programme (RNTCP) guidelines as recommended by National AIDS Control Organization (NACO), India. Outcome of TB was assessable in 70 patients. Majority (82.8%) of the patients were cured, while 12 patients (17.1%) died during the course of treatment. A total of 149 ADRs were observed in 67 (75.2%) patients. Majority of ADRs (n = 147) were non-serious and did not warrant a change in therapy. Discoloration of urine was the most common ADR observed. Conclusion: TB is the most common opportunistic infection in HIV-positive patients with abdominal TB being the most common manifestation. RNTCP and NACO guidelines are adhered to in these patients. Anti-tuberculosis drugs are well tolerated and effective in majority of the patients. PMID:24130377

Kapadia, Jigar D.; Desai, Chetna K.; Solanki, Manish N.; Shah, Asha N.; Dikshit, R. K.

2013-01-01

313

Efficacy and tolerability of potato juice in dyspeptic patients: a pilot study.  

PubMed

In Europe, use of potatoes (Solani tuberosi tuberecens) is a traditional remedy for stomach complaints. We performed a pilot study on the effectiveness and tolerability of freshly squeezed potato juice in patients suffering from dyspeptic symptoms. After informed written consent, 44 patients with various dyspeptic symptoms were enrolled, to drink for 1 week twice daily 100ml or more of potato juice (Biotta, if complaints persisted, a further 100ml was recommended. Validated outcome measures included the gastrointestinal symptom (GIS) profile, a disease-specific health assessment questionnaire (QOLRAD) and self-rated treatment success (efficacy, a 5-point Likert Scale). The study was completed by 42 patients. The GIS and QOLRAD scores improved significantly by 41.9+/-40.8% (p=0.001) and 50.7+/-36.1% (p<0.001), respectively (ITT); the absolute values changed from 11.5+/-5.1 to 6.3+/-5.3 (GIS) and 62.0+/-25.7 to 32.0+/-28.8 (QORAD). Sixteen, 18 and 26 patients, respectively, rated the effectiveness of the treatment as very good or good on the GIS, QOLRAD (improvements >60%) and on efficacy, respectively. Poor treatment success was achieved in 13 (GIS), 11 (QOLRAD) and 10 (Efficacy), not necessarily by the same patients. Since about two-thirds of the patients benefited to some extent from the treatment, potato juice in its present formulation may be useful for self-treatment. However, placebo-controlled studies with a longer treatment period are needed to confirm this. PMID:16360927

Chrubasik, S; Chrubasik, C; Torda, T; Madisch, A

2006-01-01

314

Sniffing out pain: An in vivo intranasal study of analgesic efficacy  

PubMed Central

Background: Orofacial pain is a common encounter in dentistry (affecting 12% of the population) and is a primary reason for patients seeking emergency care. Dentists often prescribe oral analgesics, which have disadvantages of decreased absorption rates and delayed onset. Intranasal (IN) delivery takes advantage of a large surface area of mucosal tissue for rapid absorption. The purpose of this study was to evaluate the efficacy of IN ketorolac for endodontic pain using a randomized, double-blind, placebocontrolled parallel design study. Materials & Methods: Twenty patients presenting with moderate to severe endodontic pain were selected to receive IN treatment with placebo (n = 10) or ketorolac (n = 10) 30 minutes before endodontic treatment was started and immediately after the completion of endodontic treatment. Baseline pain levels were recorded before IN treatment. Pain levels were also recorded at 15 and 30 minutes after the initial IN dosing (before endodontic treatment); 30 minutes after completion of endodontic treatment; and 4, 8, and 12 hours after the initial IN spray. Results: IN ketorolac alone or with endodontic treatment showed significantly better pain relief compared with IN placebo spray alone or with endodontic treatment at 30 minutes after the first or second intranasal dose and at 4 hours after the first intranasal dose. Conclusions: These results suggest that IN ketorolac may provide a novel and efficacious method for pain relief in endodontic pain patients. How to cite the article: Maroli S, Srinath HP, Goinka C, Yadav NS, Bhardwaj A, Varghese RK. Sniffing out pain: An in vivo intranasal study of analgesic efficacy. J Int Oral Health 2014;6(1):66-71. PMID:24653606

Maroli, Sohani; Srinath, H P; Goinka, Chanchal; Yadav, Naveen S; Bhardwaj, Archana; Varghese, Rana K

2014-01-01

315

Efficacy of dexpanthenol in skin protection against irritation: a double-blind, placebo-controlled study.  

PubMed

Dexpanthenol is popular in treating various dermatoses and in skin care, but few controlled clinical trials have been performed. We investigated the efficacy of dexpanthenol in skin protection against irritation in a randomized, prospective, double-blind, placebo-controlled study. 25 healthy volunteers (age 18-45 years) were treated for the inner aspect of both forearms with either Bepanthol Handbalsam containing 5% dexpanthenol or placebo x2 daily for 26 days. From day 15-22, sodium lauryl sulfate (SLS) 2% was applied to these areas x2 daily. Documentation comprised sebumetry, corneometry, pH value and clinical appearance (photographs). 21 volunteers completed the study, 3 were excluded because of non-compliance and 1 experienced a non-study-related, severe, adverse event. Only corneometry yielded a statistically significant difference, with decreased values following SLS challenge at the placebo sites (P < 0.05). Intraindividual comparisons showed superior results at the dexpanthenol-treated sites in 11 cases and in only 1 case at the placebo site. 6 volunteers experienced an irritant contact dermatitis, with more severe symptoms at the placebo site in 5 cases. In conclusion, dexpanthenol exhibits protective effects against skin irritation. The initiation of a study to evaluate the efficacy of dexpanthenol in preventing irritant occupational contact dermatitis under real workplace conditions is validated. PMID:14641355

Biro, Kathrin; Thaçi, Diamant; Ochsendorf, Falk R; Kaufmann, Roland; Boehncke, Wolf-Henning

2003-08-01

316

Assessing the efficacy of molecularly targeted agents on cell line-based platforms by using system identification  

PubMed Central

Background Molecularly targeted agents (MTAs) are increasingly used for cancer treatment, the goal being to improve the efficacy and selectivity of cancer treatment by developing agents that block the growth of cancer cells by interfering with specific targeted molecules needed for carcinogenesis and tumor growth. This approach differs from traditional cytotoxic anticancer drugs. The lack of specificity of cytotoxic drugs allows a relatively straightforward approach in preclinical and clinical studies, where the optimal dose has usually been defined as the "maximum tolerated dose" (MTD). This toxicity-based dosing approach is founded on the assumption that the therapeutic anticancer effect and toxic effects of the drug increase in parallel as the dose is escalated. On the contrary, most MTAs are expected to be more selective and less toxic than cytotoxic drugs. Consequently, the maximum therapeutic effect may be achieved at a "biologically effective dose" (BED) well below the MTD. Hence, dosing study for MTAs should be different from cytotoxic drugs. Enhanced efforts to molecularly characterize the drug efficacy for MTAs in preclinical models will be valuable for successfully designing dosing regimens for clinical trials. Results A novel preclinical model combining experimental methods and theoretical analysis is proposed to investigate the mechanism of action and identify pharmacodynamic characteristics of the drug. Instead of fixed time point analysis of the drug exposure to drug effect, the time course of drug effect for different doses is quantitatively studied on cell line-based platforms using system identification, where tumor cells' responses to drugs through the use of fluorescent reporters are sampled over a time course. Results show that drug effect is time-varying and higher dosages induce faster and stronger responses as expected. However, the drug efficacy change along different dosages is not linear; on the contrary, there exist certain thresholds. This kind of preclinical study can provide valuable suggestions about dosing regimens for the in vivo experimental stage to increase productivity. PMID:23134733

2012-01-01

317

Examining the Efficacy of Adjunctive Aripiprazole in Major Depressive Disorder: A Pooled Analysis of 2 Studies  

PubMed Central

Background: Patients with major depressive disorder (MDD) who fail to achieve complete remission with antidepressant therapy may benefit from augmentation therapy with an atypical antipsychotic. Method: A pooled analysis was performed on 2 identical 14-week studies (8-week prospective antidepressant therapy treatment phase followed by 6-week randomized double-blind phase) evaluating the efficacy of adjunctive aripiprazole (2–20 mg/day) in DSM-IV-TR–defined MDD patients with an inadequate response to antidepressant therapy. Primary efficacy endpoint was the mean change in Montgomery-Asberg Depression Rating Scale (MADRS) total score from end of the prospective phase (week 8) to end of randomized phase (week 14, last observation carried forward). Subgroup analyses were performed. The key secondary endpoint was mean change in Sheehan Disability Scale (SDS) mean score. Results: At endpoint, mean change in MADRS total score was significantly greater with adjunctive aripiprazole (–8.7) than with adjunctive placebo (–5.7; p < .001). Except for a differential treatment-by-sex interaction, change in MADRS total scores were consistently greater with adjunctive aripiprazole than with adjunctive placebo, regardless of race, age, episode duration, prior antidepressant therapy response, number of historical treatment failures, severity of depressive symptoms, and antidepressant. At endpoint, MADRS remission rates were significantly greater with adjunctive aripiprazole than with placebo (25.7% vs. 15.4%; p < .001). Adjunctive aripiprazole also demonstrated significantly greater improvements in mean change from baseline in SDS total score than adjunctive placebo (–1.2 vs. –0.6; p = .001). Conclusion: Augmentation of antidepressant therapy with the atypical antipsychotic aripiprazole resulted in significant efficacy benefits across a range of subgroups of patients with MDD. Further study of a treatment-by-sex interaction is needed. Trial Registration: www.clinicaltrials.gov Identifiers: NCT00095823 and NCT00095758 PMID:19287552

Thase, Michael E.; Trivedi, Madhukar H.; Nelson, J. Craig; Fava, Maurizio; Swanink, Rene; Tran, Quynh-Van; Pikalov, Andrei; Yang, Huyuan; Carlson, Berit X.; Marcus, Ronald N.; Berman, Robert M.

2008-01-01

318

Development of an Aotus nancymaae model for Shigella Vaccine immunogenicity and efficacy studies.  

PubMed

Several animal models exist to evaluate the immunogenicity and protective efficacy of candidate Shigella vaccines. The two most widely used nonprimate models for vaccine development include a murine pulmonary challenge model and a guinea pig keratoconjunctivitis model. Nonhuman primate models exhibit clinical features and gross and microscopic colonic lesions that mimic those induced in human shigellosis. Challenge models for enterotoxigenic Escherichia coli (ETEC) and Campylobacter spp. have been successfully developed with Aotus nancymaae, and the addition of a Shigella-Aotus challenge model would facilitate the testing of combination vaccines. A series of experiments were designed to identify the dose of Shigella flexneri 2a strain 2457T that induces an attack rate of 75% in the Aotus monkey. After primary challenge, the dose required to induce an attack rate of 75% was calculated to be 1 × 10(11) CFU. Shigella-specific immune responses were low after primary challenge and subsequently boosted upon rechallenge. However, preexisting immunity derived from the primary challenge was insufficient to protect against the homologous Shigella serotype. A successive study in A. nancymaae evaluated the ability of multiple oral immunizations with live-attenuated Shigella vaccine strain SC602 to protect against challenge. After three oral immunizations, animals were challenged with S. flexneri 2a 2457T. A 70% attack rate was demonstrated in control animals, whereas animals immunized with vaccine strain SC602 were protected from challenge (efficacy of 80%; P = 0.05). The overall study results indicate that the Shigella-Aotus nancymaae challenge model may be a valuable tool for evaluating vaccine efficacy and investigating immune correlates of protection. PMID:24595138

Gregory, Michael; Kaminski, Robert W; Lugo-Roman, Luis A; Galvez Carrillo, Hugo; Tilley, Drake Hamilton; Baldeviano, Christian; Simons, Mark P; Reynolds, Nathanael D; Ranallo, Ryan T; Suvarnapunya, Akamol E; Venkatesan, Malabi M; Oaks, Edwin V

2014-05-01

319

Development of an Aotus nancymaae Model for Shigella Vaccine Immunogenicity and Efficacy Studies  

PubMed Central

Several animal models exist to evaluate the immunogenicity and protective efficacy of candidate Shigella vaccines. The two most widely used nonprimate models for vaccine development include a murine pulmonary challenge model and a guinea pig keratoconjunctivitis model. Nonhuman primate models exhibit clinical features and gross and microscopic colonic lesions that mimic those induced in human shigellosis. Challenge models for enterotoxigenic Escherichia coli (ETEC) and Campylobacter spp. have been successfully developed with Aotus nancymaae, and the addition of a Shigella-Aotus challenge model would facilitate the testing of combination vaccines. A series of experiments were designed to identify the dose of Shigella flexneri 2a strain 2457T that induces an attack rate of 75% in the Aotus monkey. After primary challenge, the dose required to induce an attack rate of 75% was calculated to be 1 × 1011 CFU. Shigella-specific immune responses were low after primary challenge and subsequently boosted upon rechallenge. However, preexisting immunity derived from the primary challenge was insufficient to protect against the homologous Shigella serotype. A successive study in A. nancymaae evaluated the ability of multiple oral immunizations with live-attenuated Shigella vaccine strain SC602 to protect against challenge. After three oral immunizations, animals were challenged with S. flexneri 2a 2457T. A 70% attack rate was demonstrated in control animals, whereas animals immunized with vaccine strain SC602 were protected from challenge (efficacy of 80%; P = 0.05). The overall study results indicate that the Shigella-Aotus nancymaae challenge model may be a valuable tool for evaluating vaccine efficacy and investigating immune correlates of protection. PMID:24595138

Gregory, Michael; Lugo-Roman, Luis A.; Galvez Carrillo, Hugo; Tilley, Drake Hamilton; Baldeviano, Christian; Simons, Mark P.; Reynolds, Nathanael D.; Ranallo, Ryan T.; Suvarnapunya, Akamol E.; Venkatesan, Malabi M.; Oaks, Edwin V.

2014-01-01

320

Comparison of the Efficacy of Chemicomechanical Caries Removal with Conventional Methods - A Clinical Study  

PubMed Central

Background: There has been considerable interest in developing alternative methods of cavity preparation and caries removal due to disadvantages of using traditional rotating instruments which can result in heat, pressure ,dentin dessication, vibration and pain. Hence, the aim of this study was to compare different methods of caries removal in terms of efficacy, time taken and pain during caries removal. Materials & Methods: A total of 150 carious teeth were selected among 80 children of 6-10 years of age, following Radiovisiography (RVG) according to specific inclusion criteria and caries removal was done by hand instruments ,air rotor and carisolv respectively. The efficacy, time taken and pain threshold were evaluated during caries removal by Ericson D et al scale, Time scale (Raber H et al), visual analogue scale (Nayak R et al) and verbal pain scale (Cinzia Brunelli et al) respectively. Data was collected and statistically analysed. Results: Mean value of time taken for removal of caries by carisolv group (580.26 sec) was found to be significantly higher as compared to conventional hand excavation and air rotor. Air rotor was found to be the most efficient method (mean value 1.20). Mean value of pain perception was significantly less with carisolv (0.82) as compared to air rotor and hand instrument. Conclusion: It was concluded that chemicomechanical removal of caries with Carisolv was found to be effective measure of caries removal and could be considered as viable alternatives to painful procedures like airotor in management of dental caries especially in children. How to cite this article: Goomer P, Jain R L, Kaur H, Sood R. Comparison of the Efficacy of Chemicomechanical Caries Removal with Conventional Methods - A Clinical Study. J Int Oral Health 2013; 5(3):42-47. PMID:24155601

Goomer, Pallvi; Jain, R L; Kaur, Harsimrat; Sood, Rahul

2013-01-01

321

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

PubMed

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?preclinical treatment efficacy studies to test new antitumoral drugs, and begets translational potential for early response detection in clinical studies. Copyright © 2014 John Wiley & Sons, Ltd. PMID:25208348

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

2014-11-01

322

Negative preclinical results with stealth nanospheres-encapsulated Doxorubicin in an orthotopic murine brain tumor model.  

PubMed

Previous results have shown that PEG-coated poly(hexadecylcyanoacrylate) (PEG-PHDCA) nanospheres displayed a significant accumulation within an orthotopic 9L gliosarcoma model, after i.v. administration to rats. Hence, the aim of the present study was to evaluate in the same model the pre-clinical efficacy of this carrier when loaded with Doxorubicin, an anticancer drug which poorly distributes in the CNS. Free and nanospheres-encapsulated Doxorubicin were administered with a multiple dose treatment. Their maximum tolerated dose (MTD) and increase in life span were respectively assessed in healthy and intracranially 9L-bearing rats. A comparative biodistribution study of Doxorubicin-loaded and unloaded PEG-PHDCA nanospheres was also performed in the tumor-bearing group. The results showed that the cumulative MTD of nanoparticulate doxorubicin was 1.5 times higher than this of free Doxorubicin. Nevertheless, encapsulated Doxorubicin was unable to elicit a better therapeutic response in the 9L gliosarcoma. Biodistribution study revealed that the Doxorubicin-loaded nanospheres accumulated to a 2.5-fold lesser extent in the 9L tumor as compared to the unloaded nanospheres and that they were mainly localized in the lungs and the spleen. Such a typical profile indicated aggregation with plasma proteins as a consequence of the positive surface charge of these loaded particles; this ionic interaction resulting from drug encapsulation was mainly responsible for 9L treatment failure. PMID:15491808

Brigger, Irène; Morizet, Jackie; Laudani, Lysiane; Aubert, Geneviève; Appel, Martine; Velasco, Valérie; Terrier-Lacombe, Marie-Josée; Desmaële, Didier; d'Angelo, Jean; Couvreur, Patrick; Vassal, Gilles

2004-11-01

323

Efficacy of electroacupuncture for symptoms of menopausal transition: study protocol for a randomized controlled trial  

PubMed Central

Background Previous studies have shown that acupuncture can alleviate postmenopausal symptoms, such as hot flashes, but few studies have assessed symptoms during the menopausal transition (MT) period. Thus, the effect of acupuncture upon MT symptoms is unclear. We designed a large-scale trial aimed at evaluating the efficacy of electroacupuncture for MT symptoms compared with sham electroacupuncture and at observing the safety of electroacupuncture. Methods/design In this multicenter randomized controlled trial, 360 women will be randomized to either an electroacupuncture group or a sham electroacupuncture group. During the 8-week-long treatment, a menopause rating scale, average 24-hour hot flash score, Menopause-Specific Quality of Life Questionnaire score, and level of female hormones will be observed. Follow-ups at the 20th and 32nd week will be made. Discussion Though there is no completely inert placebo acupuncture and blinding is difficult in acupuncture trials, the placebo effect of EA can still be partially excluded in this study. For the placebo control, we use non-points and a tailor-made sham needle. This needle is different from a retractable needle, which is usually used for sham acupuncture. The needle in this trial is more simply constructed and more acceptable to Chinese people. We expect to evaluate the efficacy of electroacupuncture for MT symptoms and clarify its effect on these symptoms. Trial registration ClinicalTrials.gov Identifier: NCT01849172 (Date of registration: 05/05/2013). PMID:24950841

2014-01-01

324

Pharmacokinetic evaluation of a 1,3-dicyclohexylurea nanosuspension formulation to support early efficacy assessment  

NASA Astrophysics Data System (ADS)

Time and resource constraints necessitate increasingly early decisions to advance or halt pre-clinical drug discovery programs. Early discovery or “tool” compounds may be potent inhibitors of new targets, but all too often they exhibit poor pharmaceutical and pharmacokinetic properties that make early assessment of in vivo efficacy difficult. 1,3-Dicyclohexylurea, a potent and selective inhibitor of soluble epoxide hydrolase (sEH), reduces blood pressure in hypertensive preclinical animal models when administered intraperitoneally using DMSO/corn oil as a delivery vehicle. However, the poor aqueous solubility of DCU poses a challenge for in vivo dosing in a multiple dose situation. Therefore, we developed a nanosuspension formulation of DCU to support oral, intravenous bolus and intravenous infusion dosing. Use of the nanosuspension formulation maintained DCU free plasma levels above the sEH IC50 and demonstrated that the application of formulation technology can accelerate in vivo evaluation of new targets by enabling pharmacodynamic studies of poorly soluble compounds.

Wahlstrom, Jan L.; Chiang, Po-Chang; Ghosh, Sarbani; Warren, Chad J.; Wene, Steve P.; Albin, Lesley A.; Smith, Mark E.; Roberds, Steven L.

2007-06-01

325

Anti-inflammatory and neuroprotective effects of an orally active apocynin derivative in pre-clinical models of Parkinson's disease  

PubMed Central

Background Parkinson’s disease (PD) is a devastating neurodegenerative disorder characterized by progressive motor debilitation, which affects several million people worldwide. Recent evidence suggests that glial cell activation and its inflammatory response may contribute to the progressive degeneration of dopaminergic neurons in PD. Currently, there are no neuroprotective agents available that can effectively slow the disease progression. Herein, we evaluated the anti-inflammatory and antioxidant efficacy of diapocynin, an oxidative metabolite of the naturally occurring agent apocynin, in a pre-clinical 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. Methods Both pre-treatment and post-treatment of diapocynin were tested in the MPTP mouse model of PD. Diapocynin was administered via oral gavage to MPTP-treated mice. Following the treatment, behavioral, neurochemical and immunohistological studies were performed. Neuroinflammatory markers, such as ionized calcium binding adaptor molecule 1 (Iba-1), glial fibrillary acidic protein (GFAP), gp91phox and inducible nitric oxide synthase (iNOS), were measured in the nigrostriatal system. Nigral tyrosine hydroxylase (TH)-positive neurons as well as oxidative markers 3-nitrotyrosine (3-NT), 4-hydroxynonenal (4-HNE) and striatal dopamine levels were quantified for assessment of the neuroprotective efficacy of diapocynin. Results Oral administration of diapocynin significantly attenuated MPTP-induced microglial and astroglial cell activation in the substantia nigra (SN). MPTP-induced expression of gp91phox and iNOS activation in the glial cells of SN was also completely blocked by diapocynin. Notably, diapocynin markedly inhibited MPTP-induced oxidative markers including 3-NT and 4-HNE levels in the SN. Treatment with diapocynin also significantly improved locomotor activity, restored dopamine and its metabolites, and protected dopaminergic neurons and their nerve terminals in this pre-clinical model of PD. Importantly, diapocynin administered 3 days after initiation of the disease restored the neurochemical deficits. Diapocynin also halted the disease progression in a chronic mouse model of PD. Conclusions Collectively, these results demonstrate that diapocynin exhibits profound neuroprotective effects in a pre-clinical animal model of PD by attenuating oxidative damage and neuroinflammatory responses. These findings may have important translational implications for treating PD patients. PMID:23092448

2012-01-01

326

Comparative study with two different enrichments in the culture media used in the disinfectant efficacy assay.  

PubMed

Recent changes in Brazilian legislation for commercial disinfectants have been published due to the recent epidemic of nosocomial infections caused by rapidly growing mycobacteria (RGM) in many states of Brazil over the last 8years. One of these documents requires that all the manufacturers provide evidence of efficacy of sterilizing and disinfectant products, used for semi critical medical devices, against the Mycobacterium bovis BCG Moreau and Mycobacterium abscessus subsp. bolletii INCQS 00594 strains by using the Confirmative in vitro Test for Determining Tuberculocidal Activity of Disinfectants recommended by the Association of Official Analytical Chemists. These changes have caused additional costs and increased problems for importation of enrichment products at national laboratories where disinfectant efficacy assay service is performed. Middlebrook ADC Enrichment (ADC) is provided by a unique manufacturer and used in the official protocol. The aim of the present study was to evaluate an alternative in house low-cost enrichment composed of fetal bovine serum and glucose (FBSG) with ADC for performance of disinfectant efficacy assay against mycobacteria. After obtaining the growth curves for M. abscessus ATCC 19977, M. abscessus subsp. bolletii INCQS 00594, Mycobacterium chelonae ATCC 35752, and Mycobacterium fortuitum ATCC 6841 by using ADC enrichment and FBSG in Kirchners and 7H9 culture media. Through statistical analysis via the Kruskal-Wallis test on the evaluation of microorganism growth rate, it was observed that there was no inhibition of RGM growth by any of the enrichments used. These results suggest that low-cost enrichment FBSG may be used as a potential substitute of ADC for composition of media for mycobacterial growth, including in disinfectant tests. PMID:22197720

Sabagh, Bruna Peres; Souto, Aline da Silva Soares; Reis, Louise Moreira; Silva, Sérgio Alves da; Pereira, Daniella Cristina Rodrigues; Neves, Marta de Campos; Pinheiro, Rodrigo Rollin; Duarte, Rafael Silva; Miyazaki, Neide Hiromi Tokumaru; Bôas, Maria Helena Simões Villas

2012-02-01

327

[A study of therapeutic efficacy of Koukangning gargle in the treatment of oral mucositis].  

PubMed

A study of therapeutic efficacy was carried out in 118 patients with oral mucositis (recurrent oral aphthous ulceration, erosive lichen planus, herptic stomatitis and infectious oral mucosal hematoma) at random. As a topical medication, Koukangning gargle was applied to 59 patients of the experimental group, 29 patients of the control group 1 applied Dobell's solution to rinse their mouths, and 30 patients of the control group 2 applied Koutai solution. A satisfactory result was observed in the experimental group, its effectiveness and effective rates rose more than those of control group 1 at both treatments for 3 days and 6 days. Between the two groups, there were markedly significant difference (P < 0.005, P < 0.01, P < 0.005, P < 0.005). Koukangning gargle was nontoxic and no side-effects in the clinical tests. Its efficacy was no significant difference compared with the control group 2. Experimental study demonstrates that it possesses anti-inflamation effect and excellent antibiotic effect, therefore it is a new gargle for rinse mouth combined traditional Chinese medicine with Western medicine. PMID:11480052

Zeng, G; Li, B; Zhang, W

1997-02-01

328

Portable high-intensity focused ultrasound system with 3D electronic steering, real-time cavitation monitoring, and 3D image reconstruction algorithms: a preclinical study in pigs  

PubMed Central

Purpose: The aim of this study was to evaluate the safety and accuracy of a new portable ultrasonography-guided high-intensity focused ultrasound (USg-HIFU) system with a 3-dimensional (3D) electronic steering transducer, a simultaneous ablation and imaging module, real-time cavitation monitoring, and 3D image reconstruction algorithms. Methods: To address the accuracy of the transducer, hydrophones in a water chamber were used to assess the generation of sonic fields. An animal study was also performed in five pigs by ablating in vivo thighs by single-point sonication (n=10) or volume sonication (n=10) and ex vivo kidneys by single-point sonication (n=10). Histological and statistical analyses were performed. Results: In the hydrophone study, peak voltages were detected within 1.0 mm from the targets on the y- and z-axes and within 2.0-mm intervals along the x-axis (z-axis, direction of ultrasound propagation; y- and x-axes, perpendicular to the direction of ultrasound propagation). Twenty-nine of 30 HIFU sessions successfully created ablations at the target. The in vivo porcine thigh study showed only a small discrepancy (width, 0.5-1.1 mm; length, 3.0 mm) between the planning ultrasonograms and the pathological specimens. Inordinate thermal damage was not observed in the adjacent tissues or sonic pathways in the in vivo thigh and ex vivo kidney studies. Conclusion: Our study suggests that this new USg-HIFU system may be a safe and accurate technique for ablating soft tissues and encapsulated organs. PMID:25038809

2014-01-01

329

Population Pharmacokinetic Model of the Pregabalin-Sildenafil Interaction in Rats: Application of Simulation to Preclinical PK-PD Study Design  

Microsoft Academic Search

Purpose  Preliminary evidence has suggested a synergistic interaction between pregabalin and sildenafil for the treatment of neuropathic\\u000a pain. The focus of this study was to determine the influence of sildenafil on the pharmacokinetics (PK) of pregabalin with\\u000a the objective of informing the design of a quantitative pharmacodynamic (PD) study.\\u000a \\u000a \\u000a \\u000a Methods  The pharmacokinetics were determined in rats following 2-hr intravenous infusions of pregabalin

Gregor Bender; James Gosset; Jeff Florian; Keith Tan; Mark Field; Scott Marshall; Joost DeJongh; Robert Bies; Meindert Danhof

2009-01-01

330

Cerebral uptake of (ethyl-11C)vinpocetine and 1-(11C)ethanol in cynomolgous monkeys: a comparative preclinical PET study  

Microsoft Academic Search

PET provides the potential to quantify the distribution of radiolabelled drugs in the human body. In cases when radiolabelled compounds undergo metabolic transformation after administration in vivo, it is necessary to examine the kinetics and distribution of both the labeled mother compound and labeled metabolites. The objective of this study was to assess the extent by which 11C-labeled ethanol, the

Balazs Gulyas; Adam Vas; Christer Halldin; Judit Sovago; Johan Sandell; Hans Olsson; Anna Fredriksson; Sharon Stone-Elander; Lars Farde

331

Cerebral uptake of [ ethyl- 11C]vinpocetine and 1-[ 11C]ethanol in cynomolgous monkeys: a comparative preclinical PET study  

Microsoft Academic Search

PET provides the potential to quantify the distribution of radiolabelled drugs in the human body. In cases when radiolabelled compounds undergo metabolic transformation after administration in vivo, it is necessary to examine the kinetics and distribution of both the labeled mother compound and labeled metabolites. The objective of this study was to assess the extent by which 11C-labeled ethanol, the

Balázs Gulyás; Ádám Vas; Christer Halldin; Judit Sóvágó; Johan Sandell; Hans Olsson; Anna Fredriksson; Sharon Stone-Elander; Lars Farde

2002-01-01

332

Preclinical models to evaluate potential pharmacotherapeutic agents in treating alcoholism and studying the neuropharmacological bases of ethanol-seeking behaviors in rats.  

PubMed

The unit outlines four basic protocols designed to systematically evaluate the capacity of potential pharmacotherapeutic agents to effectively treat alcohol addiction and dependence in rats. Also included are procedures designed to study the neural mechanisms regulating alcohol-seeking behaviors. PMID:18428571

June, Harry L

2002-08-01

333

Efficacy of Agnikarma over the padakanistakam (little toe) and Katibasti in Gridhrasi: A comparative study  

PubMed Central

Background and Objectives: Gridhrasi (Sciatica) is one of the Vatavyadhi which is caused by aggravated Vata dosha. This disease is characterized by ruja (pain) in the waist, back, thigh, knee and calf regions along the course of sciatic nerve. In spite of the different types of treatment modalities mentioned in ancient and modern medical sciences, they have some or the other shortcomings and drawbacks. Considering all these, the present study was taken up with the objective of evaluating the efficacy of Agnikarma (treatment done with cauterization) over the padakanistakam (little toe) in the management of Gridhrasi. To consider the significance of the method of Agnikarma, the efficacy of Katibasti in the management of Gridhrasi which has been established in the previous work was also studied. Materials and Methods: The study was performed after obtaining Ethics Committee approval and patients? written informed consent. Forty cases presenting with classical features of Gridhrasi (Sciatica) due to lumbar intervertebral disc prolapse were selected. The management of Gridhrasi by Agnikarma and Katibasti was conducted by including the patients in two groups, namely Group A (study group) and Group B (control group). The data were collected and the observations were made before the treatment, on 8th day, 15th day and on 22nd day of the treatment. The data obtained from the results were subjected for statistical analysis and conclusions were drawn. Results: There was a significant reduction in the parameters, pain (P < 0.01) and straight-leg raising (SLR) test (P < 0.01), of the study group compared to the control group (P < 0.01). Pain was assessed through Numerical Pain Analogue Scale. After the treatment with Agnikarma, the pain was totally relieved in 80% of cases. It was reduced to moderate degree in 20% of cases and in 95% of cases, SLR test became negative. After the treatment with Katibasti, the pain was totally relieved in 50% of cases. It was reduced to moderate degree in 20% and to mild degree in 25% of cases. In 60% of cases, SLR test became negative. However, changes in the radiological findings were not found in both the methods of management. Analysis of overall effect of treatment in the present study reveals that Agnikarma was Both the procedures were conducted in to that of Katibasti. Conclusions: The management of Gridhrasi by Agnikarma was more efficacious as compared with Katibasti in reducing pain. However, there were no radiological changes produced by both the methods of treatment. Further studies may be conducted by future scholars by taking more samples with more number of sittings. PMID:21455450

Bali, Yogitha; Vijayasarathi, R; Ebnezar, John; Venkatesh, BA

2010-01-01

334

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

ERIC Educational Resources Information Center

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…

Sangueza, Cheryl Ramirez

2010-01-01

335

Marizomib, a Proteasome Inhibitor for All Seasons: Preclinical Profile and a Framework for Clinical Trials  

PubMed Central

The proteasome has emerged as an important clinically relevant target for the treatment of hematologic malignancies. Since the Food and Drug Administration approved the first-in-class proteasome inhibitor bortezomib (Velcade®) for the treatment of relapsed/refractory multiple myeloma (MM) and mantle cell lymphoma, it has become clear that new inhibitors are needed that have a better therapeutic ratio, can overcome inherent and acquired bortezomib resistance and exhibit broader anti-cancer activities. Marizomib (NPI-0052; salinosporamide A) is a structurally and pharmacologically unique ?-lactone-?-lactam proteasome inhibitor that may fulfill these unmet needs. The potent and sustained inhibition of all three proteolytic activities of the proteasome by marizomib has inspired extensive preclinical evaluation in a variety of hematologic and solid tumor models, where it is efficacious as a single agent and in combination with biologics, che-motherapeutics and targeted therapeutic agents. Specifically, marizomib has been evaluated in models for multiple myeloma, mantle cell lymphoma, Waldenstrom’s macroglobulinemia, chronic and acute lymphocytic leukemia, as well as glioma, colorectal and pancreatic cancer models, and has exhibited synergistic activities in tumor models in combination with bortezomib, the immunomodulatory agent lenalidomide (Revlimid®), and various histone deacetylase inhibitors. These and other studies provided the framework for ongoing clinical trials in patients with MM, lymphomas, leukemias and solid tumors, including those who have failed bortezomib treatment, as well as in patients with diagnoses where other proteasome inhibitors have not demonstrated significant efficacy. This review captures the remarkable translational studies and contributions from many collaborators that have advanced marizomib from seabed to bench to bedside. PMID:21247382

Potts, B.C.; Albitar, M.X.; Anderson, K.C.; Baritaki, S.; Berkers, C.; Bonavida, B.; Chandra, J.; Chauhan, D.; Cusack, J.C.; Fenical, W.; Ghobrial, I.M.; Groll, M.; Jensen, P.R.; Lam, K.S.; Lloyd, G.K.; McBride, W.; McConkey, D.J.; Miller, C.P.; Neuteboom, S.T.C.; Oki, Y.; Ovaa, H.; Pajonk, F.; Richardson, P.G.; Roccaro, A.M.; Sloss, C.M.; Spear, M.A.; Valashi, E.; Younes, A.; Palladino, M.A.

2013-01-01

336

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

PubMed

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 the cement types was used to fixate Lubinus SP2 prostheses with the stem made of titanium alloy. Cemex Rx had a reduced tensile strength, probably because this cement was manually mixed, as recommended by the manufacturer. A standardized labor tory test showed lower curing temperature for Cemex, but measurements at 37 degrees and with prechilled Palacos R and Cemex Rx, as in clinical work, showed no difference. In the clinical study radiostereometric measurements of cup and stem migration showed similar values in the 2 groups up to 5 years after the operation. The cement mantle was stable in both groups, but the stems migrated similarly inside the cement mantle regardless of the type of cement used. Proximal wear was low (0.04-0.05 mm/year) and tended to be lower in the Cemex group (p = 0.02). Aluminum and vanadium levels in serum increased 5 years after the operation, but no difference was noted between the 2 groups. Collagen markers (PICP, ICTP) showed similar increases in bone turnover 6 weeks and 6 months after operation in both groups. PMID:11817871

Nivbrant, B; Kärrholm, J; Röhrl, S; Hassander, H; Wesslén, B

2001-12-01

337

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

PubMed

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

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

338

Chemical Shift MR Imaging Methods for the Quantification of Transcatheter Lipiodol Delivery to the Liver: Preclinical Feasibility Studies in a Rodent Model  

PubMed Central

Purpose: To demonstrate the feasibility of using chemical shift magnetic resonance (MR) imaging fat-water separation methods for quantitative estimation of transcatheter lipiodol delivery to liver tissues. Materials and Methods: Studies were performed in accordance with institutional Animal Care and Use Committee guidelines. Proton nuclear MR spectroscopy was first performed to identify lipiodol spectral peaks and relative amplitudes. Next, phantoms were constructed with increasing lipiodol-water volume fractions. A multiecho chemical shift–based fat-water separation method was used to quantify lipiodol concentration within each phantom. Six rats served as controls; 18 rats underwent catheterization with digital subtraction angiography guidance for intraportal infusion of a 15%, 30%, or 50% by volume lipiodol-saline mixture. MR imaging measurements were used to quantify lipiodol delivery to each rat liver. Lipiodol concentration maps were reconstructed by using both single-peak and multipeak chemical shift models. Intraclass and Spearman correlation coefficients were calculated for statistical comparison of MR imaging–based lipiodol concentration and volume measurements to reference standards (known lipiodol phantom compositions and the infused lipiodol dose during rat studies). Results: Both single-peak and multipeak measurements were well correlated to phantom lipiodol concentrations (r2 > 0.99). Lipiodol volume measurements were progressively and significantly higher when comparing between animals receiving different doses (P < .05 for each comparison). MR imaging–based lipiodol volume measurements strongly correlated with infused dose (intraclass correlation coefficients > 0.93, P < .001) with both single- and multipeak approaches. Conclusion: Chemical shift MR imaging fat-water separation methods can be used for quantitative measurements of lipiodol delivery to liver tissues. © RSNA, 2012 PMID:22623693

Yin, Xiaoming; Guo, Yang; Li, Weiguo; Huo, Eugene; Zhang, Zhuoli; Nicolai, Jodi; Kleps, Robert A.; Hernando, Diego; Katsaggelos, Aggelos K.; Omary, Reed A.

2012-01-01

339

Development and validation of liquid chromatography-tandem mass spectrometric method for quantification of meropenem in rat plasma and its application in a preclinical dose proportionality study.  

PubMed

A simple, rapid, sensitive and selective assay based liquid chromatography-tandem mass spectrometric method was developed and validated for quantitative analysis of meropenem in rat plasma using rolipram as internal standard. Efficient chromatographic separation of analyte from matrix components was achieved by using Kromasil 100 C18 (150×4.6?mm, 5?µm) reversed phase column with mobile phase consisting of acetonitrile and 2?mM ammonium acetate buffer (80:20, v/v) delivered in isocratic mode with constant flow rate of 0.7?mL/min. Detection of meropenem and rolipram was performed in positive mode using multiple reaction monitoring (MRM). The mass transitions 384.1?141.0 and 276.2?191.1 were used to quantify meropenem and rolipram, respectively. A fast and simple solid phase extraction method was optimized for extraction of meropenem from rat plasma. The developed method was validated for selectivity, accuracy, precision, linearity, recovery, stability, matrix effect, dilution integrity as per regulatory guidelines. The developed method was selective with no interfering components at the retention time of meropenem and rolipram. The assay demonstrated acceptable linearity (R(2)>0.99) over a dynamic range of 0.19-201.40?µg/mL. The method exhibited excellent and acceptable precision and accuracy, and produced consistent recoveries. The method demonstrated excellent stability of meropenem in rat plasma under studied conditions investigated. Finally, the validated method was successfully applied to quantify meropenem levels in rat plasma of a dose escalation study. PMID:24227471

Chaursia, B K; Singh, T P; Varshney, B; Sharma, P; Iyer, S S; Khuroo, A H; Monif, T

2014-06-01

340

Quantification of pegylated liposomal doxorubicin and doxorubicinol in rat plasma by liquid chromatography/electrospray tandem mass spectroscopy: Application to preclinical pharmacokinetic studies.  

PubMed

A high-performance liquid chromatography-tandem mass spectrometric method (LC/MS/MS) has been developed and validated for the determination of pegylated liposomal doxorubicin and its metabolite doxorubicinol in rat plasma. One hundred microliters plasma samples were treated with Triton X-100 to immediately disperse the liposome. Then the samples were extracted by a single methanol:acetone protein precipitation step in the presence of additional 50microL of 70% (w/v) zinc sulfate, and subsequently analyzed by LC/MS/MS using positive turbo-ion spray ionization mode operating the instrument in the multiple-reaction-monitoring (MRM) mode. The related compound daunorubicin was used as internal standard. The validated concentration ranges were from 20 to 8000ng/mL for doxorubicin and from 0.05 to 20.0ng/mL for doxorubicinol. An effective LC-MS/MS method was developed to quantify trace amount of doxorubicinol with little interference from doxorubicin. The autosampler carryover was minimized from 285 to 10.5% by increasing the washing times of the valves when the used pentafluorophenylpropyl HPLC column had no contribution to the carryover. The relative matrix effect from six unique lots was absent for both compounds. Results obtained from the GLP validation study demonstrated good accuracy (85-110%) and precision (CV less than 14%) across the calibration ranges for both compounds. This method was applied to study the pharmacokinetic profiles of doxorubicin and doxorubicinol in rats after a single dose administration of Stealth-49 liposomal doxorubicin HCl. The mean AUC value for doxorubicinol was found to be only 0.011% of that of doxorubicin. PMID:18371724

Liu, Yanhong; Yang, Yuhui; Liu, Xiangtao; Jiang, Tao

2008-01-15

341

3D laser optoacoustic ultrasonic imaging system for preclinical research  

NASA Astrophysics Data System (ADS)

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.).

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

2013-03-01

342

Brain Morphometry and the Neurobiology of Levodopa-Induced Dyskinesias: Current Knowledge and Future Potential for Translational Pre-Clinical Neuroimaging Studies  

PubMed Central

Dopamine replacement therapy in the form of levodopa results in a significant proportion of patients with Parkinson’s disease developing debilitating dyskinesia. This significantly complicates further treatment and negatively impacts patient quality of life. A greater understanding of the neurobiological mechanisms underlying levodopa-induced dyskinesia (LID) is therefore crucial to develop new treatments to prevent or mitigate LID. Such investigations in humans are largely confined to assessment of neurochemical and cerebrovascular blood flow changes using positron emission tomography and functional magnetic resonance imaging. However, recent evidence suggests that LID is associated with specific morphological changes in the frontal cortex and midbrain, detectable by structural MRI and voxel-based morphometry. Current human neuroimaging methods however lack sufficient resolution to reveal the biological mechanism driving these morphological changes at the cellular level. In contrast, there is a wealth of literature from well-established rodent models of LID documenting detailed post-mortem cellular and molecular measurements. The combination therefore of advanced neuroimaging methods and rodent LID models offers an exciting opportunity to bridge these currently disparate areas of research. To highlight this opportunity, in this mini-review, we provide an overview of the current clinical evidence for morphological changes in the brain associated with LID and identify potential cellular mechanisms as suggested from human and animal studies. We then suggest a framework for combining small animal MRI imaging with rodent models of LID, which may provide important mechanistic insights into the neurobiology of LID. PMID:24971074

Finlay, Clare J.; Duty, Susan; Vernon, Anthony C.

2014-01-01

343

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

PubMed Central

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

2014-01-01

344

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

PubMed Central

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

2014-01-01

345

A prospective study to determine the efficacy of antibiotics in acute pancreatitis.  

PubMed Central

This study is a double "blind" prospective evaluation of the efficacy of antibiotics (Ampicillin) in the treatment of acute alcohol-induced and idiopathic pancreatitis. Fifty-eight patients with acute pancreatitis were randomly divided into antibiotic and non-antibiotic treatment groups. The two groups were comparable clinically at the onset of the study and other than for antibiotics received identical therapy. The patients without antibiotics had a clinical course equal or slightly more favorable than the antibiotic treatment group in all parameters examined. These data indicate that prophylactic use of Ampicillin is not indicated in patients with routine acute alcohol-induced or idiopathic pancreatitis. The role of prophylactic antibiotics in patients with pancreatitis related to biliary calculi and those with more severe varieties of acute hemorrhagic or necrotizing pancreatitis remains to be more clearly defined. PMID:788655

Finch, W T; Sawyers, J L; Schenker, S

1976-01-01

346

Preclinical and Clinical Studies of Unrelieved Aural Fullness following Intratympanic Gentamicin Injection in Patients with Intractable M?ni?re's Disease  

PubMed Central

Objective To clarify whether gentamicin affects vestibular dark cells in guinea pigs and relieves patients of aural fullness with intractable Ménière’s disease following intratympanic administration. Materials and Methods Purified gentamicin-Texas Red (GTTR) was injected intratympanically in guinea pigs that were sacrificed at 1, 3, 7, 14 and 28 days. GTTR uptake was examined in hair cells, and transitional cells and dark cells in vestibular end-organs were examined. Specific attention was paid to its distribution in dark cells under confocal microscopy, and the ultrastructure of dark cells using electron microscopy, following intratympanic injection. Results Dark cells in the semicircular canals showed weak GTTR uptake at 1, 3, 7, 14 and 28 days after intratympanic injection, with no significant differences at various time points after injection. However, the adjacent transitional cells demonstrated intense GTTR uptake that was retained for at least 28 days. Ultrastructural studies demonstrated negligible characteristics associated with apoptosis or necrosis in these dark cells. The tight junctions between dark cells showed no signs of disruption at 7 or 28 days after injection. Conclusion Intratympanic gentamicin has little direct impact on vestibular dark cells. Clinical Application A modified low-dose titration intratympanic approach was used in 29 patients with intractable vertigo and the clinical outcomes were followed. Aural fullness following intratympanic gentamicin injection was not relieved based on our subjective scales, demonstrated by no statistically significant difference between preinjection (4.16 ± 3.08) and postinjection (3.58 ± 2.93; p > 0.05) aural fullness scores. Vertigo control was achieved in 88% of patients, with hearing deterioration identified in 16% of patients. Intratympanic gentamicin administration might not lead to relief of aural fullness in patients with intractable vertigo, although it can achieve a high vertigo control rate with some cochleotoxicity. PMID:24008307

Zhai, Feng; Zhang, Ru; Zhang, Ting; Steyger, Peter S.; Dai, Chun-Fu

2014-01-01

347

Reduced Kidney Function and Preclinical Atherosclerosis in HIV-Infected Individuals: The Study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM)  

PubMed Central

Background/Aims Reduced kidney function and albuminuria are associated with higher risk for cardiovascular disease (CVD) and mortality in HIV-infected individuals. We investigated whether reduced estimated glomerular filtration rate (eGFR) and albuminuria are associated with subclinical vascular disease, as assessed by carotid intima-medial thickness (cIMT). Methods Cross-sectional analysis of 476 HIV-infected individuals without clinical evidence of CVD enrolled in the Fat Redistribution and Metabolic Change in HIV infection (FRAM) study, using multivariable linear regression. eGFRCys and eGFRCr were calculated from cystatin C and creatinine levels. Albuminuria was defined as a positive urine dipstick (?1+) or urine albumin-to-creatinine ratio ?30 mg/g. Common and internal cIMT were measured by high-resolution B-mode ultrasound. Results In unadjusted analyses, eGFRCys and eGFRCr were strongly associated with common and internal cIMT. Each 10 ml/min/1.73 m2 decrease in eGFRCys and eGFRCr was associated with a 0.008 mm higher common cIMT (p = 0.003, p = 0.01) and a 0.024 and 0.029 mm higher internal cIMT (p = 0.003), respectively. These associations were eliminated after adjustment for age, gender, and race. Albuminuria showed little association with common or internal cIMT in all models. Conclusions In HIV-infected individuals without prior CVD, reduced kidney function and albuminuria were not independently associated with subclinical vascular disease, as assessed by cIMT. These results suggest that research should focus on searching for novel mechanisms by which kidney disease confers cardiovascular risk in HIV-infected individuals. PMID:21508633

Jotwani, Vasantha; Scherzer, Rebecca; Choi, Andy; Szczech, Lynda; Polak, Joseph F.; Kronmal, Richard A.; Grunfeld, Carl; Shlipak, Michael

2011-01-01

348

Open study on efficacy and safety of levofloxacin in treatment of uncomplicated typhoid fever.  

PubMed

The main objective of this study was to determine the clinical efficacy and safety of levofloxacin in an open setting for typhoid fever cases. Patients with clinical signs and symptoms of typhoid fever without previous antimicrobial treatment admitted to affiliated hospitals of the Faculty of Medicine, University Indonesia were included in this study. Adults, 18 years or above, were screened for any serious underlying conditions, pregnancy or possible complications of typhoid fever before final enrollment. Fifty-three subjects were screened, 48 were enrolled. The final diagnosis of enteric fever was made by positive blood culture, polymerase chain reaction or serology, was obtained in 31 cases, in whom one had a concomitant sinus infection and had to be excluded. Thirty patients (11 males, 19 females) aged between 18-58 years (mean 31.7 years) with a history of fever between 1 and 10 days (mean 6.1 days) showed excellent clinical response, becoming afebrile at an average of 2.43 days (range 1-5 days). Adverse effects noted were nausea in 4 patients, vomiting in one and meteorism in another one, which were all difficult to distinguish from the enteric infection. A pruritic rash occurring in two patients may be related to levofloxacin, and insomnia in another patient may be related. Microbiological clearance was obtained both immediately after treatment and at one month. No carrier states were detected in the cases positive for Salmonella typhi or paratyphi. None of the treated typhoid fever cases experienced a clinical relapse. In this open study of levofloxacin 500 mg/day for one week in treatment of uncomplicated typhoid fever, a 100% clinical efficacy was obtained in 30 patients with minimal adverse reactions warranting more intensive studies for this new indication of an old but well known disease in the developing world. PMID:16771224

Nelwan, R H H; Chen, Khie; Nafrialdi; Paramita, Diana

2006-01-01

349

Biodistribution of Mesenchymal Stem/Stromal Cells in a Preclinical Setting  

PubMed Central

Due to their multi/pluripotency and immunosuppressive properties, mesenchymal stem/stromal cells (MSCs) are important tools for treatment of immune disorders and tissue repair. The increasing uses of MSCs lead to the development of production processes that need to be in accordance with good manufacturing practices (GMP). In Europe, MSCs are somatic cell-therapy products, referred to as advanced-therapy medicinal products (ATMPs), and in the United States MSCs must comply with current good tissue practice requirements. The safety and efficacy of MSCs must be ensured, whatever the cell source, and studies of dose and biodistribution are important aspects of safety testing. Preclinical data on biodistribution and pharmacodynamics are mandatory for approval. It is important to demonstrate that MSCs do not have unwanted homing that could drive to inappropriate differentiation in some organ or to support cancer development as suggested in some experiments. All these aspects should be addressed in a risk-based approach according to recently published guidelines by EMA. In the present article, we summarize the main approaches for labeling and tracking of infused MSCs, report on current animal models, and give an overview of available results on biodistribution. PMID:24222773

Sensebe, Luc; Fleury-Cappellesso, Sandrine

2013-01-01

350

Heterologous Prime-Boost HIV-1 Vaccination Regimens in Pre-Clinical and Clinical Trials  

PubMed Central

Currently, there are more than 30 million people infected with HIV-1 and thousands more are infected each day. Vaccination is the single most effective mechanism for prevention of viral disease, and after more than 25 years of research, one vaccine has shown somewhat encouraging results in an advanced clinical efficacy trial. A modified intent-to-treat analysis of trial results showed that infection was approximately 30% lower in the vaccine group compared to the placebo group. The vaccine was administered using a heterologous prime-boost regimen in which both target antigens and delivery vehicles were changed during the course of inoculations. Here we examine the complexity of heterologous prime-boost immunizations. We show that the use of different delivery vehicles in prime and boost inoculations can help to avert the inhibitory effects caused by vector-specific immune responses. We also show that the introduction of new antigens into boost inoculations can be advantageous, demonstrating that the effect of ‘original antigenic sin’ is not absolute. Pre-clinical and clinical studies are reviewed, including our own work with a three-vector vaccination regimen using recombinant DNA, virus (Sendai virus or vaccinia virus) and protein. Promising preliminary results suggest that the heterologous prime-boost strategy may possibly provide a foundation for the future prevention of HIV-1 infections in humans. PMID:20407589

Brown, Scott A.; Surman, Sherri L.; Sealy, Robert; Jones, Bart G.; Slobod, Karen S.; Branum, Kristen; Lockey, Timothy D.; Howlett, Nanna; Freiden, Pamela; Flynn, Patricia; Hurwitz, Julia L.

2010-01-01

351

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

PubMed Central

Cervical, anal, penile and a sub-set of head and neck (HN) tumors are critical health problems caused by high risk Human Papilloma Viruses (HPVs), like HPV type 16. No specific/effective pharmacological treatments exist. A valid preventive vaccination as well as the immunotherapy of persistent infections, pre-cancerous lesions or early-stage cancers could drive the HPV disease burden down. These treatments might be featured through low-cost platforms like those based on DNA and plant biotechnologies to produce tailored and enhanced formulations taking profit from the use of plants as bio-factories and as a source of immune-stimulators. Finally, and regardless of the formulation type, pre-clinical tests and models are crucial to foresee efficacy of immunotherapy before clinical trials. In this study, we created an orthotopic mouse model for HPV-related oral tumors, a subset of HN tumors for which no models have been generated before. The model was obtained by inducing the stable expression of the HPV16 E7 protein into the mouse oral squamous cell carcinoma (OSCC) AT-84 (AT-84 E7). The AT-84 E7 cells were injected into the mouth pavement of C3H mice via an extra-oral route to obtain orthotopic tumors. The model turned out to mimic the natural history of the human HPV oral cancer. From AT-84 E7, through engineering to express luciferase, the bioluminescent AT-84 E7-Luc cells were obtained for a fast and easy monitoring by imaging. The AT-84 E7 and the AT-84 E7-Luc tumors were used to test the efficacy of E7-based therapeutic vaccines that we had previously generated and that had been already proven to be active in mice against non-orthotopic E7-expressing tumors (TC-1 cells). In particular, we used genetic and plant-derived formulations based on attenuated HPV16 E7 variants either fused to plant virus genes with immunological activity or produced by tobacco plants. Mice were monitored by imaging allowing to test the size reduction of the mouth implanted experimental tumors in function of the different regimens used. The proposed tumor model is easy to handle and to reproduce and it is efficacious in monitoring immunotherapy. Furthermore, it is expected to be more predictive of clinical outcome of therapeutic vaccines than non-orthotopic models that are currently used. Finally, imaging offers unique opportunities to predict formulation efficacy through measuring tumor growth in vivo. PMID:23296123

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

2013-01-01

352

Optimisation of region-specific reference gene selection and relative gene expression analysis methods for pre-clinical trials of Huntington's disease  

PubMed Central

Background Transcriptional dysregulation is an early, key pathogenic mechanism in Huntington's disease (HD). Therefore, gene expression analyses have biomarker potential for measuring therapeutic efficacy in pre-clinical trials, particularly those aimed at correcting gene expression abnormalities. Housekeeping genes are commonly used as endogenous references in gene expression studies. However, a systematic study comparing the suitability of candidate reference genes for use in HD mouse models has not been performed. To remedy this situation, 12 housekeeping genes were examined to identify suitable reference genes for use in expression assays. Results We found that commonly used reference genes are dysregulated at later time points in the R6/2 mouse model of HD. Therefore, in order to reliably measure gene expression changes for use as pre-clinical trial biomarkers, we set out to identify suitable reference genes for use in R6/2 mice. The expression of potential reference genes was examined in striatum, cortex and cerebellum from 15 week old R6/2 and matched wild-type littermates. Expression levels of candidate reference genes varied according to genotype and brain region. GeNorm software was used to identify the three most stably expressed genes for each brain region. Relative quantification methods using the geometric mean of three reference genes for normalisation enables accurate determination of gene expression levels in wild-type and R6/2 mouse brain regions. Conclusion Our study has identified a reproducible, reliable method by which we able to accurately determine the relative expression level of target genes in specific brain regions, thus increasing the potential of gene expression analysis as a biomarker in HD pre-clinical trials. PMID:18954449

Benn, Caroline L; Fox, Helen; Bates, Gillian P

2008-01-01

353

Preclinical safety profile of brimonidine.  

PubMed

Brimonidine is a selective alpha 2-adrenergic agonist developed for lowering intraocular pressure in glaucoma patients. Since brimonidine will be used in long-term theraphy, the safety of this drug is an important feature for its clinical success. Brimonidine has been evaluated in a number of safety studies using doses much greater than those in humans. In this paper chronic and carcinogenicity studies are presented. The results of the 6-month ocular/systemic study in rabbits and the 1-year ocular/systemic study in monkeys with 0.2, 0.5, and 0.8% brimonidine ophthalmic formulations showed no ocular or organ toxicity. The highest concentration of 0.8% used in rabbits and monkeys resulted in plasma drug concentrations of 95 (Cmax) and 10 (C2hr) times, respectively, higher than those seen in humans following topical dosing. Dose-related transient exaggerated pharmacologic effects of sedation were observed in the 1-year oral study in monkeys without any organ toxicity. The dose that elicited an apparent pharmacologic effect produced a plasma drug concentration that was approximately 115 times higher than that in humans. In 2-year carcinogenicity studies in mice and rats using doses that produced plasma concentrations 77 and 118 times, respectively, higher than those seen in humans, no oncogenic effect was observed. Based on the extensive safety research on brimonidine, it was concluded that this drug has an excellent safety profile. PMID:8744846

Angelov, O V; Wiese, A G; Tang-Liu, D D; Acheampong, A A; Ismail, I M; Brar, B S

1996-01-01

354

Preclinical testing on insects predicts human haematotoxic potentials.  

PubMed

The substitution of insects for laboratory animals in toxicity testing is likely to become a reality in the framework of prescreening. Haematotoxicological studies of newly developed chemicals, such as food components, drugs, etc. performed on insects can offer advantages in, for example, environmental toxicology. Reliable routine predictions should produce an increase in our knowledge of haemocyte physiology. Although the differences between human physiology and morphology and those of insects are great, the basic functions of insect haemocytes and mammalian leukocytes appear not to have changed during evolution. The use of insects in haematotoxicity assays represents a preclinical testing strategy which will lower costs, accelerate screening and offer ethical benefits. PMID:19505933

Berger, Josef

2009-10-01

355

Preliminary Study of the Autism Self-Efficacy Scale for Teachers (ASSET)  

PubMed Central

The purpose of the current study was to evaluate a new measure, the Autism Self-Efficacy Scale for Teachers (ASSET) for its dimensionality, internal consistency, and construct validity derived in a sample of special education teachers (N = 44) of students with autism. Results indicate that all items reflect one dominant factor, teachers’ responses to items were internally consistent within the sample, and compared to a 100-point scale, a 6-point response scale is adequate. ASSET scores were found to be negatively correlated with scores on two subscale measures of teacher stress (i.e., self-doubt/need for support and disruption of the teaching process) but uncorrelated with teacher burnout scores. The ASSET is a promising tool that requires replication with larger samples. PMID:23976899

Ruble, Lisa A.; Toland, Michael D.; Birdwhistell, Jessica L.; McGrew, John H.; Usher, Ellen L.

2013-01-01

356

Anticancer efficacy and absorption, distribution, metabolism, and toxicity studies of Aspergiolide A in early drug development  

PubMed Central

Since the first anthracycline was discovered, many other related compounds have been studied in order to overcome its defects and improve efficacy. In the present paper, we investigated the anticancer effects of a new anthracycline, aspergiolide A (ASP-A), from a marine-derived fungus in vitro and in vivo, and we evaluated the absorption, distribution, metabolism, and toxicity drug properties in early drug development. We found that ASP-A had activity against topoisomerase II that was comparable to adriamycin. ASP-A decreased the growth of various human cancer cells in vitro and induced apoptosis in BEL-7402 cells via a caspase-dependent pathway. The anticancer efficacy of ASP-A on the growth of hepatocellular carcinoma xenografts was further assessed in vivo. Results showed that, compared with the vehicle group, ASP-A exhibited significant anticancer activity with less loss of body weight. A pharmacokinetics and tissue distribution study revealed that ASP-A was rapidly cleared in a first order reaction kinetics manner, and was enriched in cancer tissue. The maximal tolerable dose (MTD) of ASP-A was more than 400 mg/kg, and ASP-A was not considered to be potentially genotoxic or cardiotoxic, as no significant increase of micronucleus rates or inhibition of the hERG channel was seen. Finally, an uptake and transport assay of ASP-A was performed in monolayers of Caco-2 cells, and ASP-A was shown to be absorbed through the active transport pathway. Altogether, these results indicate that ASP-A has anticancer activity targeting topoisomerase II, with a similar structure and mechanism to adriamycin, but with much lower toxicity. Nonetheless, further molecular structure optimization is necessary. PMID:25378909

Wang, Yuanyuan; Qi, Xin; Li, Dehai; Zhu, Tianjiao; Mo, Xiaomei; Li, Jing

2014-01-01

357

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

PubMed

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

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

2014-05-21

358

Memantine: a review of studies into its safety and efficacy in treating Alzheimer’s disease and other dementias  

PubMed Central

Memantine is an uncompetitive N-methyl-D-aspartate receptor antagonist with moderate affinity. Its mechanism of action is neuroprotective and potentially therapeutic in several neuropsychiatric diseases. It has been approved by the FDA for the treatment of moderate to severe Alzheimer’s disease (AD) either as a monotherapy or in combination with cholinesterase inhibitors. This review covers key studies of memantine’s safety and efficacy in treating moderate to severe AD. It also covers current research into other dementias including but not exclusively mild AD and vascular dementia. Other studies on the efficacy of memantine for other neuropsychiatric diseases are discussed. Memantine is a safe and effective drug that merits further research on several topics. Clinicians should be aware of new studies and potential uses of memantine because of its safety and efficacy. PMID:19851512

Thomas, Stuart J; Grossberg, George T

2009-01-01

359

Dendritic cell functional improvement in a preclinical model of lentiviral-mediated gene therapy for Wiskott-Aldrich syndrome  

PubMed Central

Wiskott-Aldrich syndrome (WAS) is a rare X-linked primary immunodeficiency caused by the defective expression of the WAS protein (WASP) in hematopoietic cells. It has been shown that dendritic cells (DCs) are functionally impaired in WAS patients and was?/? mice. We have previously demonstrated the efficacy and safety of a murine model of WAS gene therapy (GT), using stem cells transduced with a lentiviral vector. The aim of this study was to investigate whether GT can correct DC defects in was?/? mice. As DCs expressing WASP were detected in the secondary lymphoid organs of the treated mice, we tested the in vitro and in vivo function of bone marrow-derived DCs (BMDCs). The BMDCs showed efficient in vitro uptake of latex beads and Salmonella typhimurium. When BMDCs from the treated mice (GT BMDCs) and the was?/? mice were injected into wild type hosts, we found a higher number of cells that had migrated to the draining lymph nodes compared to mice injected with was?/? BMDCs. Finally, we found that OVA-pulsed GT BMDCs or vaccination with anti-DEC205 OVA fusion protein can efficiently induce antigen-specific T cell activation in vivo. These findings show that WAS GT significantly improves DC function, thus adding new evidence of the preclinical efficacy of lentiviral vector-mediated WAS GT. PMID:22189416

Catucci, Marco; Prete, Francesca; Bosticardo, Marita; Castiello, Maria Carmina; Draghici, Elena; Locci, Michela; Roncarolo, Maria Grazia; Aiuti, Alessandro; Benvenuti, Federica; Villa, Anna

2011-01-01

360

Dendritic cell functional improvement in a preclinical model of lentiviral-mediated gene therapy for Wiskott-Aldrich syndrome.  

PubMed

Wiskott-Aldrich syndrome (WAS) is a rare X-linked primary immunodeficiency caused by the defective expression of the WAS protein (WASP) in hematopoietic cells. It has been shown that dendritic cells (DCs) are functionally impaired in WAS patients and was(-/-) mice. We have previously demonstrated the efficacy and safety of a murine model of WAS gene therapy (GT), using stem cells transduced with a lentiviral vector (LV). The aim of this study was to investigate whether GT can correct DC defects in was(-/-) mice. As DCs expressing WASP were detected in the secondary lymphoid organs of the treated mice, we tested the in vitro and in vivo function of bone marrow-derived DCs (BMDCs). The BMDCs showed efficient in vitro uptake of latex beads and Salmonella typhimurium. When BMDCs from the treated mice (GT BMDCs) and the was(-/-) mice were injected into wild-type hosts, we found a higher number of cells that had migrated to the draining lymph nodes compared with mice injected with was(-/-) BMDCs. Finally, we found that ovalbumin (OVA)-pulsed GT BMDCs or vaccination of GT mice with anti-DEC205 OVA fusion protein can efficiently induce antigen-specific T-cell activation in vivo. These findings show that WAS GT significantly improves DC function, thus adding new evidence of the preclinical efficacy of LV-mediated WAS GT. PMID:22189416

Catucci, M; Prete, F; Bosticardo, M; Castiello, M C; Draghici, E; Locci, M; Roncarolo, M G; Aiuti, A; Benvenuti, F; Villa, A

2012-12-01

361

The serotonergic antidepressant nefazodone inhibits the serotonin transporter: In vivo and ex vivo studies  

Microsoft Academic Search

Nefazodone HCl (Serzone®) is a new antidepressant with a chemical structure unrelated to selective serotonin reuptake inhibitors (SSRIs), tricyclics, tetracyclics, or monoamine oxidase inhibitors (MAOIs). Nefazodone is active in a number of preclinical tests for antidepressant activity and shows clinical efficacy in the treatment of depression with a more favorable side-effect profile than the structurally similar antidepressant trazodone. Previous studies

Michael J. Owens; John R. leni; David L Knight; Kevin Winders; Charles B. Nemeroff

1995-01-01

362

An Exploratory Study of Teacher Self-Efficacy Beliefs and Profssional Learning Community  

E-print Network

-Efficacy ....................................................................................................48 Bandura’s Triadic Reciprocal Causation Model .............................................49 5 Teacher Efficacy ..............................................................................................51 Summary... Model Coefficients for Sharing…………………………………………..122 19 Final Model Coefficients for Improvement………………………………….....123 20 Final Model Coefficients for Trust……………………………………………..124 8 LIST OF FIGURES 1. Bandura’s Triadic Reciprocal Causation Model...

Romeo, Susan M.

2010-12-15

363

Political Efficacy: A Comparative Study of the United States, the United Kingdom, and India.  

ERIC Educational Resources Information Center

Investigates the levels of political efficacy reported by college students in the United States, England, and India. Discusses the factors that influence political efficacy in each culture including educational faculty, gender, age, religion, language, residence, economic status, student's characteristics, interest in politics and party…

Shrivastava, Rashmi

1989-01-01

364

Self-Efficacy for Self-Regulated Learning: A Validation Study  

ERIC Educational Resources Information Center

The psychometric properties and multigroup measurement invariance of scores on the Self-Efficacy for Self-Regulated Learning Scale taken from Bandura's Children's Self-Efficacy Scale were assessed in a sample of 3,760 students from Grades 4 to 11. Latent means differences were also examined by gender and school level. Results reveal a…

Usher, Ellen L.; Pajares, Frank

2008-01-01

365

Phenol as a novel sclerosing agent: A safety and efficacy study on experimental animals  

PubMed Central

Background Varicose and ectatic cutaneous vessels are common chronic conditions that might need surgical treatment. There are several treatment modalities, but all can cause complications and have significant recurrence rates. A new effective and safe treatment with low or no recurrence is needed. Phenol seems to be a potential therapeutic agent. Objective To assess the efficacy and safety of phenol as a sclerosing agent in the treatment of varicose veins and other vascular ectatic conditions. Methods The dorsal ear veins of white New Zealand rabbits were injected with 0.1 ml of a sclerosing agent. Four experimental groups were used to test the sclerosant efficacy of different concentrations of phenol (1%, 5%, 20% and 50%). Sodium tetradecyl sulphate (STS), a commonly used sclerosing agent, was used as a positive control, while normal saline was used as a negative control. The blood vessels of the treated ears were photographed before and 1 h, 2 days, 8 days and 45 days after treatment. Biopsies from the treated areas were obtained for histologic examinations. Results A concentration of 1% phenol was too low to cause significant vascular changes, whereas a concentration of 5% phenol caused 90% lumen narrowing. Interestingly, 1% STS only caused 25% lumen narrowing. Concentrations of 20 and 50% phenol caused 100% lumen narrowing but caused haemorrhage and necrosis. Toxicity monitoring showed no apparent haematologic, cardiac, pulmonary, hepatic or renal toxicity associated with the concentrations of phenol used in this study. Conclusion A concentration of 5% phenol appears to be a potent and safe sclerosing agent for ectatic small vessels. This provides a significant new therapeutic option, which may eventually advance to the clinic and have an impact on the treatment of patients suffering from varicose veins and other vascular ectatic conditions. PMID:24493976

AlGhamdi, Khalid M.; Ashour, Abdelkader E.; Rikabi, Ammar C.; Moussa, Noura A.

2013-01-01

366

Temperature Affects Thrombolytic Efficacy Using rt-PA and Eptifibatide, an In Vitro Study  

PubMed Central

The potential for hypothermia as a neuroprotectant during stroke has led to its increase in clinical use. At the same time, combination pharmaceutical therapies for ischemic stroke using recombinant tissue plasminogen activator (rt-PA), and GP IIb-IIIa inhibitors, such as Eptifibatide (Epf?), are under study. However, there is little data on how the reactions triggered by these agents are impacted by temperature. Here, clot lysis during exposure to the combination of rt-PA and Epf is measured in an in vitro human clot model at hypothermic temperatures. The hypothesis is that lytic efficacy of rt-PA and Epf decreases with decreasing temperature. Whole blood clots from 31 volunteers were exposed to rt-PA (0.5??g/mL) and Epf (0.63??g/mL) in human fresh-frozen plasma (rt-PA+Epf?), rt-PA alone in plasma (rt-PA Alone), or to plasma alone (Control), at temperatures from 30°C to 37°C, for 30 minutes. Clot lysis was measured using a microscopic imaging technique; the mean fractional clot loss (FCL) at 30 minutes was used to determine lytic efficacy. Temperature had a significant impact on FCL in clots exposed to rt-PA+Epf, with the FCL being lower at 30°C to 36°C than at 37°C. The FCL remained significantly higher for rt-PA+Epf–treated clots than Controls regardless of temperature, with the exception of measurements made at 30°C when no significant differences in the FCL were observed between groups. The use of hypothermia as a neuroprotectant may negatively impact the therapeutic benefit of thrombolytic agents. PMID:23667777

Chang, Wan-Tsu W.; Bluett, Brent; Wenker, Evan; Lindsell, Christopher J.; Shaw, George J.

2012-01-01

367

Efficacy of certain yogic and naturopathic procedures in premature ejaculation: A pilot study  

PubMed Central

Context: Premature ejaculation (PE) is the most common sexual disorder of young males. Even though there are number of treatment options available for PE, patient's satisfaction and drug side effects remain to be a problem. Non-pharmacological treatment options like Yoga and Naturopathy have been implicated in sexual fulfillment, pleasure and efficacy of some of these approaches has been established in previous studies. Aim: To assess the efficacy of certain yogic and naturopathic procedures in the management of PE. Materials and Methods: A total of 12 patients with PE satisfying the DSM IV TR diagnostic criteria were selected and allotted into two groups, Yoga group and Naturopathic group by following the randomization method. In the Yoga group, various asanas, mudra, bandha and pranayama were practiced 1 hour daily for 21 days. In the Naturopathy group, lower abdomen massage and steam bath, hip bath and lingasnana, mud pack on lower abdomen, and acupressure were done 1 hour daily for 21 days. Criteria of assessment were based on the scoring of Premature Ejaculation Severity Index (PESI). Statistical analysis was done by using paired and unpaired “t” tests. Results: In the Yoga group (n = 6), 7.3% relief was observed (P < 0.01) and in the Naturopathy group (n = 6), 2.4% of relief was observed (P > 0.05) on the total score of PESI. There was no significant difference (P > 0.05) found in between the two groups. Conclusion: Both Yoga and Naturopathic procedures didn’t provide relief (<25%) on total score of PESI. PMID:23930030

Mamidi, Prasad; Gupta, Kshama

2013-01-01

368

One-year double-blind study of the neurocognitive efficacy of olanzapine, risperidone, and haloperidol in schizophrenia  

Microsoft Academic Search

Neurocognitive deficits in schizophrenia can reach 1 to 2 standard deviations below healthy controls. The comparative effect of typical and atypical antipsychotic medications on neurocognition is controversial, and based primarily on studies with small samples and large doses of typical comparator medications. The present study assessed neurocognitive efficacy. It was hypothesized that olanzapine treatment would improve neurocognitive deficits to a

Richard S. E. Keefe; Carrie A. Young; Stephanie L. Rock; Scot E. Purdon; James M. Gold; Alan Breier

2006-01-01

369

Service Learning and Its Influenced to Pre-Service Teachers: Social Responsibility and Self-Efficacy Study  

ERIC Educational Resources Information Center

The purpose of the research was to study pre-service teachers on social responsibility and self-efficacy through service learning. The mixed methodology included two major procedures (i) the actual use of a developed service learning instructional model by means of action research principles and qualitative research and (ii) the study into the…

Prasertsang, Parichart; Nuangchalerm, Prasart; Pumipuntu, Chaloey

2013-01-01

370

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

PubMed Central

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

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

371

To evaluate the efficacy of biodegradable plating system for fixation of maxillofacial fractures: A prospective study  

PubMed Central

Aims: The present study was undertaken to evaluate the efficacy of biodegradable plating system for fixation of maxillofacial fractures and to study the morbidity associated with the use of biodegradable plates and screws. Materials and Methods: This prospective study consisted of 10 patients with maxillofacial fractures requiring open reduction and internal fixation. Fractures with infection, comminuted and pathological fractures were excluded. All were plated with biodegradable system (Inion CPS) using standard plating principles and observed for a total period of 24 weeks. Characteristics of the fractures, ease of use of bioresorbable plate/screw system and post operative complications were assessed. Results: Of total 10 patients, eight patients were of midface fracture and two pediatric patients with mandibular fracture, with nine male and one female. The mean age was 32.8 years. Out of 20 plates and 68 screws applied to the 10 fractures sites; there were three incidences of screw breakage with no other intraoperative difficulties. Paresthesia of the infraorbital nerve was present in two patients, and recovered completely in four weeks after surgery. Fracture reduction was considered to be satisfactory in all cases. One patient developed postsurgical infection and was managed with oral antibiotics and analgesics. Conclusions: Favorable healing can be observed through the use of biodegradable plates and screws to stabilize selected midface fractures in patients of all ages, as well as mandible fractures in early childhood, however further studies with more sample size are required. PMID:24665170

Bali, Rishi K.; Sharma, Parveen; Jindal, Shalu; Gaba, Shivani

2013-01-01

372

Rabeprazole, clarithromycin, and amoxicillin Helicobacter pylori eradication therapy: Report of an efficacy study  

PubMed Central

AIM: To investigate the efficacy of a standard triple therapy (comprising rabeprazole, clarithromycin, and amoxicillin) for Helicobacter pylori (H. pylori) eradication, noting factors that influence the outcome and documenting any adverse events. METHODS: Following institutional ethical approval, fifty consecutive and consenting symptomatic patients with evidence of H. pylori infection by either a positive urea breath test (UBT) and/or a campylobacter-like organism test who presented to the Gastroenterology clinic of Lagos State University Teaching Hospital between 2012 and 2013 were recruited into the study. Patients were openly randomized to either a 7-d or a 10-d regimen of amoxicillin 1 g, clarithromycin 500 mg and rabeprazole 20 mg twice daily. The extent of symptom resolution was noted following the treatment, and at the end of one month after the completion of treatment, a repeat UBT was performed in each patient to document the eradication of the infection. All data (demographics, symptoms, and eradication rates) were collated and analyzed with SPSS version 18. RESULTS: Forty-seven patients completed the study (three were excluded from the analysis for breaching the study protocol). The patients included 18 males and 29 females within the age range of 13-80 years (mean 43.7, SD 16.8). The clinical features of the study subjects were dyspepsia, reflux symptoms and features of gastrointestinal bleeding. The average eradication rate was 87.2%. Eighteen subjects were enrolled in the 7-d arm, while 29 were in the 10-d arm. There was no statistically significant difference in the age or sex distributions of the two arms. There was no significant advantage of the 10-d treatment duration over the 7-d duration (P = 0.78), and the eradication outcomes were not influenced by the gender or age of the subjects. No adverse effects were reported in either arm. CONCLUSION: The triple therapy regime, employing a combination of amoxicillin, clarithromycin and rabeprazole, showed great efficacy and safety in the eradication of H. pylori, and this outcome was not influenced by gender or age. No difference was observed between the 7-d and 10-d regimens. PMID:24707145

Onyekwere, Charles Asabamaka; Odiagah, Joan Nwabuaku; Igetei, Rufina; Duro Emanuel, Amancia Olufunmilayo; Ekere, Francis; Smith, Stella

2014-01-01

373

Successful drug development despite adverse preclinical findings part 2: examples.  

PubMed

To illustrate the process of addressing adverse preclinical findings (APFs) as outlined in the first part of this review, a number of cases with unexpected APF in toxicity studies with drug candidates is discussed in this second part. The emphasis is on risk characterization, especially regarding the mode of action (MoA), and risk evaluation regarding relevance for man. While severe APFs such as retinal toxicity may turn out to be of little human relevance, minor findings particularly in early toxicity studies, such as vasculitis, may later pose a real probl