scholarly journals Considerations and Pitfalls in Selecting the Drug Vehicles for Evaluation of New Drug Candidates: Focus on in vivo Pharmaco-Toxicological Assays Based on the Rotarod Performance Test

2018 ◽  
Vol 21 ◽  
pp. 110-118 ◽  
Author(s):  
Mariana Matias ◽  
Samuel Silvestre ◽  
Amílcar Falcão ◽  
Gilberto Alves
Keyword(s):  
Performance Test ◽  
Motor Impairment ◽  
New Drugs ◽  
Motor Deficit ◽  
Early Evaluation ◽  
Rotarod Performance ◽  
Peg 400 ◽  
The Impact ◽  
Selection Of

Purpose - During the discovery and development of new drugs, compounds with low aqueous solubility pose special challenges in their pharmacological evaluation and, therefore, the selection of appropriate vehicles to administer the compounds of interest is determinant for the quality of the results generated during the in vivo non-clinical studies. This work aimed to evaluate the motor deficit (as a surrogate of neurotoxicity) of several administration/delivery vehicles through the rotarod performance test. Methods - Trained male CD-1 mice were intraperitoneally administered with the following vehicles: dimethyl sulfoxide (DMSO), aqueous sodium chloride (NaCl) 0.9%, aqueous carboxymethylcellulose (CMC) 0.5%, polyethylene glycol (PEG)-400, propylene glycol (PG), and solutions of these vehicles containing 5% and 10% DMSO. Results - It was observed that the aqueous vehicles (NaCl 0.9% and CMC 0.5%) did not affect the performance of the animals on the rod. On the other hand, a vehicle consisting solely of DMSO led to significant motor impairment and only a small improvement was recorded over time. Additionally, a strong neuromotor toxicity was observed in the early evaluation points of the experiment using vehicles constituted by PG and PEG-400 or by mixtures of PG/DMSO (5% and 10%) and PEG-400/DMSO (5% and 10%). Conclusion - This study provides useful data about the neurotoxicity inherent to several vehicles frequently used in non-clinical pharmaco-toxicological assays, aiming to draw especial attention to the need of a careful selection of drug vehicles in order to avoid the impact of such confounding variables on the accuracy of the results and in decision-making processes. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

Exploration of the Mechanism Underlying the Association of Incident Microinfarct and Motor Deficit: A Preliminary Functional MRI Study

2021 ◽  
pp. 1-10
Author(s):  
Xiao Luo ◽  
Hui Hong ◽  
Shuyue Wang ◽  
Kaicheng Li ◽  
Qingze Zeng ◽  
...  
Keyword(s):  
Motor Function ◽  
Inferior Frontal Gyrus ◽  
Motor Impairment ◽  
Motor Dysfunction ◽  
Motor Deficit ◽  
Middle Temporal Gyrus ◽  
Eigenvector Centrality ◽  
Middle Temporal ◽  
Mri Study

Background: Cerebral microinfarcts (CMIs) might cause measurable disruption to brain connections and are associated with cognitive decline, but the association between CMIs and motor impairment is still unclear. Objective: To assess the CMIs effect on motor function in vivo and explore the potential neuropathological mechanism based on graph-based network method. Methods: We identified 133 non-demented middle-aged and elderly participants who underwent MRI scanning, cognitive, and motor assessment. The short physical performance battery (SPPB) assessed motor function, including balance, walking speed, and chair stand. We grouped participants into 34 incident CMIs carriers and 99 non-CMIs carriers as controls, depending on diffusion-weighted imaging. Then we assessed the independent CMIs effects on motor function and explored neural mechanisms of CMIs on motor impairment via mapping of degree centrality (DC) and eigenvector centrality (EC). Results: CMIs carriers had worse motor function than non-carriers. Linear regression analyses showed that CMIs independently contributed to motor function. CMIs carriers had decreased EC in the precuneus, while increased DC and EC in the middle temporal gyrus and increased DC in the inferior frontal gyrus compared to controls (p < 0.05, corrected). Correlation analyses showed that EC of precuneus was related to SPPB (r = 0.25) and balance (r = 0.27); however, DC (r = –0.25) and EC (r = –0.25) of middle temporal gyrus was related with SPPB in all participants (p < 0.05, corrected). Conclusion: CMIs represent an independent risk factor for motor dysfunction. The relationship between CMIs and motor function may be attributed to suppression of functional hub region and compensatory activation of motor-related regions.

scholarly journals Intra-coronary Imaging for the Evaluation of Plaque Modifications Induced by Drug Therapies for Secondary Prevention

2020 ◽  
Vol 22 (12) ◽  
Author(s):  
Ismail Dogu Kilic ◽  
Enrico Fabris ◽  
Elvin Kedhi ◽  
Liviu-Nicolae Ghilencea ◽  
Gianluca Caiazzo ◽  
...  
Keyword(s):  
High Risk ◽  
Secondary Prevention ◽  
Cardiovascular Events ◽  
Lifestyle Changes ◽  
New Drugs ◽  
Coronary Imaging ◽  
Artery Disease ◽  
Therapeutic Lifestyle Changes ◽  
The Impact

Abstract Purpose of Review Patients diagnosed with coronary artery disease are at a high risk of subsequent cardiovascular events; therefore, secondary prevention in the form of therapeutic lifestyle changes, and drug therapies is vital. This article aims to review potential application of intra-coronary imaging for the evaluation of plaque modifications, induced by medications for secondary prevention for CAD. Recent Findings Intra-coronary imaging provides detailed information on the atherosclerotic plaque which is the primary pathological substrate for the recurrent ischemic cardiovascular events. These modalities can detect features associated with high risk and allow serial in vivo imaging of lesions. Therefore, intravascular imaging tools have been used in landmark studies and played a role in improving our understanding of the disease processes. Summary Changes in size and plaque composition over time can be evaluated by these tools and may help understanding the impact of a treatment. Moreover, surrogate imaging end points can be used when testing new drugs for secondary prevention.

scholarly journals Chagas Disease Drug Discovery

2014 ◽  
Vol 20 (1) ◽  
pp. 22-35 ◽  
Author(s):  
Eric Chatelain
Keyword(s):  
Chagas Disease ◽  
New Technologies ◽  
Low Cost ◽  
Screening Strategy ◽  
New Drugs ◽  
In Vivo Models ◽  
The Right ◽  
The Impact

American trypanosomiasis, or Chagas disease, is the result of infection by the Trypanosoma cruzi parasite. Endemic in Latin America where it is the major cause of death from cardiomyopathy, the impact of the disease is reaching global proportions through migrating populations. New drugs that are safe, efficacious, low cost, and adapted to the field are critically needed. Over the past five years, there has been increased interest in the disease and a surge in activities within various organizations. However, recent clinical trials with azoles, specifically posaconazole and the ravuconazole prodrug E1224, were disappointing, with treatment failure in Chagas patients reaching 70% to 90%, as opposed to 6% to 30% failure for benznidazole-treated patients. The lack of translation from in vitro and in vivo models to the clinic observed for the azoles raises several questions. There is a scientific requirement to review and challenge whether we are indeed using the right tools and decision-making processes to progress compounds forward for the treatment of this disease. New developments in the Chagas field, including new technologies and tools now available, will be discussed, and a redesign of the current screening strategy during the discovery process is proposed.

scholarly journals The selection of variable regions affects effector mechanisms of IgA antibodies against CD20

2021 ◽  
Author(s):  
Mitchell Evers ◽  
Thies Rösner ◽  
Anna Duenkel ◽  
J. H. Marco Marco Jansen ◽  
Niklas Baumann ◽  
...  
Keyword(s):  
Cell Killing ◽  
Lymphoma Cell ◽  
In Vivo Models ◽  
Variable Regions ◽  
Effector Cells ◽  
The Impact ◽  
Cd20 Antibodies ◽  
Selection Of ◽  
Effector Mechanisms

Blockade of the CD47-SIRPα axis improves lymphoma cell killing by myeloid effector cells, which is an important effector mechanism for CD20 antibodies in vivo. The approved CD20 antibodies rituximab, ofatumumab and obinutuzumab are of human IgG1 isotype. Here, we investigated the impact of the variable regions of these three CD20 antibodies, when they were expressed as human IgA2 isotype variants. We observed more effective direct tumor cell killing by OBI-IgA2 compared to RTX- and OFA-IgA2, which was caspase-independent and required a functional cytoskeleton. Furthermore, IgA2 variants of all three antibodies triggered complement dependent cytotoxicity, with OBI-IgA2 being less effective than RTX- and OFA-IgA2. All three IgA2 antibodies mediated antibody-dependent cellular phagocytosis (ADCP) by macrophages and antibody-dependent cellular cytotoxicity (ADCC) by PMN. Both effector mechanisms were significantly enhanced in the presence of a CD47 blocking antibody or by glutaminyl cyclase inhibition to interfere with CD47-SIRPα interactions. Interestingly, OBI-IgA2 was consistently more potent than RTX- and OFA-IgA2 in triggering ADCC. When we investigated the therapeutic efficacy of the CD20 IgA2 antibodies in different in vivo models, OBI-IgA2 was therapeutically more effective than RTX- or OFA-IgA2. In vivo efficacy required the presence of a functional IgA receptor on effector cells, and was independent of complement activation or direct lymphoma cell killing. These data characterize the functional activities of human IgA2 antibodies against CD20, which were affected by the selection of the respective variable regions. OBI-IgA2 proved particularly effective in vitro and in vivo, which is potentially relevant in the context of CD47-SIRPα blockade.

scholarly journals Cross-Reactivity of HLA-B*1801-Restricted T-Lymphocyte Clones with Target Cells Expressing Variants of the Human Cytomegalovirus 72kDa-IE1 Protein

2003 ◽  
Vol 77 (12) ◽  
pp. 7139-7142 ◽  
Author(s):  
Virginie Prod'homme ◽  
Christelle Retière ◽  
Ralitza Valtcheva ◽  
Marc Bonneville ◽  
Marie-Martine Hallet
Keyword(s):  
T Lymphocyte ◽  
Cross Reactivity ◽  
Cytolytic Activity ◽  
Target Cells ◽  
Cell Clones ◽  
Natural Polymorphism ◽  
The Impact ◽  
Restricted Epitope ◽  
Selection Of

ABSTRACT The impact of natural polymorphism in a cytomegalovirus-dominant HLA-B*1801-restricted epitope, IE1199-206, on the specific responses of T-cell clones was assessed by measuring their cytolytic activity against target cells expressing mutated recombinant IE1 proteins. Our results suggest an in vivo selection of T lymphocytes that cross-react with multiple IE1 variants.

scholarly journals A Short S-Equol Exposure Has a Long-Term Inhibitory Effect on Adipogenesis in Mouse 3T3-L1 Cells

2021 ◽  
Vol 11 (20) ◽  
pp. 9657
Author(s):  
Gilberto Mandujano-Lázaro ◽  
Carlos Galaviz-Hernández ◽  
César A. Reyes-López ◽  
Julio C. Almanza-Pérez ◽  
Abraham Giacoman-Martínez ◽  
...  
Keyword(s):  
Weight Control ◽  
Inhibitory Effect ◽  
New Drugs ◽  
Metabolic Effects ◽  
In Vitro Assays ◽  
Differentiation Protocol ◽  
Body Weight Control ◽  
The Impact

In the search for new drugs against obesity, the chronic disease that threatens human health worldwide, several works have focused on the study of estrogen homologs because of the role of estrogen receptors (ERs) in adipocyte growth. The isoflavone equol, an ERβ agonist, has shown beneficial metabolic effects in in vivo and in vitro assays; however, additional studies are required to better characterize its potential for body weight control. Here, we showed that the treatment of 3T3-L1 cells with 10 μM of S-equol for the first three days of the adipocyte differentiation protocol was able to prevent cells becoming semi-rounded and having a lipid droplet formation until the seventh day of culture; moreover, lipid accumulation was reduced by about 50%. Congruently, S-equol induced a reduction in mRNA expression of the adipogenic markers C/EBPα and PPARγ, and adipokines secretion, mainly Adiponectin, Leptin, Resistin, and MCP-1, while the release of PAI-1 was augmented. Moreover, it also reduced the expression of ERα and attenuated the subexpression of ERβ associated with adipogenesis. Altogether, our data suggested that S-equol binding to ERβ affects the transcriptional program that regulates adipogenesis and alters adipocyte functions. Future efforts will focus on studying the impact of S-equol on ER signaling pathways.

scholarly journals Multiscale Model of Mycobacterium tuberculosis Infection Maps Metabolite and Gene Perturbations to Granuloma Sterilization Predictions

2016 ◽  
Vol 84 (5) ◽  
pp. 1650-1669 ◽  
Author(s):  
Elsje Pienaar ◽  
William M. Matern ◽  
Jennifer J. Linderman ◽  
Joel S. Bader ◽  
Denise E. Kirschner
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Host Immunity ◽  
New Drugs ◽  
Metabolic Enzyme ◽  
Adaptation To Hypoxia ◽  
Mycobacterium Tuberculosis Infection ◽  
Lipid Inclusion ◽  
Content Type ◽  
The Impact

Granulomas are a hallmark of tuberculosis. Inside granulomas, the pathogenMycobacterium tuberculosismay enter a metabolically inactive state that is less susceptible to antibiotics. UnderstandingM. tuberculosismetabolism within granulomas could contribute to reducing the lengthy treatment required for tuberculosis and provide additional targets for new drugs. Two key adaptations ofM. tuberculosisare a nonreplicating phenotype and accumulation of lipid inclusions in response to hypoxic conditions. To explore how these adaptations influence granuloma-scale outcomesin vivo, we present a multiscalein silicomodel of granuloma formation in tuberculosis. The model comprises host immunity,M. tuberculosismetabolism,M. tuberculosisgrowth adaptation to hypoxia, and nutrient diffusion. We calibrated our model toin vivodata from nonhuman primates and rabbits and apply the model to predictM. tuberculosispopulation dynamics and heterogeneity within granulomas. We found that bacterial populations are highly dynamic throughout infection in response to changing oxygen levels and host immunity pressures. Our results indicate that a nonreplicating phenotype, but not lipid inclusion formation, is important for long-termM. tuberculosissurvival in granulomas. We used virtualM. tuberculosisknockouts to predict the impact of both metabolic enzyme inhibitors and metabolic pathways exploited to overcome inhibition. Results indicate that knockouts whose growth rates are below ∼66% of the wild-type growth rate in a culture medium featuring lipid as the only carbon source are unable to sustain infections in granulomas. By mapping metabolite- and gene-scale perturbations to granuloma-scale outcomes and predicting mechanisms of sterilization, our method provides a powerful tool for hypothesis testing and guiding experimental searches for novel antituberculosis interventions.

scholarly journals A Rat Model of Photothrombotic Capsular Infarct with a Marked Motor Deficit: A Behavioral, Histologic, and microPET Study

2014 ◽  
Vol 34 (4) ◽  
pp. 683-689 ◽  
Author(s):  
Hyung-Sun Kim ◽  
Donghyeon Kim ◽  
Ra Gyung Kim ◽  
Jin-Myung Kim ◽  
Euiheon Chung ◽  
...  
Keyword(s):  
Rat Model ◽  
Motor Performance ◽  
Recovery Period ◽  
Motor Impairment ◽  
Motor Recovery ◽  
Motor Deficit ◽  
Sprague Dawley ◽  
Early Recovery ◽  
Recovery Group ◽  
The Impact

We present a new method for inducing a circumscribed subcortical capsular infarct (SCI), which imposes a persistent motor impairment in rats. Photothrombotic destruction of the internal capsule (IC) was conducted in Sprague Dawley rats (male; n=38). The motor performance of all animals was assessed using forelimb placing, forelimb use asymmetry, and the single pellet reaching test. On the basis of the degree of motor recovery, rats were subdivided into either the poor recovery group (PRG) or the moderate recovery group (MRG). Imaging assessment of the impact of SCI on brain metabolism was performed using 2-deoxy-2-[18F]-fluoro-D-glucose ([18F]-FDG) microPET (positron emission tomography). Photothrombotic lesioning using low light energy selectively disrupted circumscribed capsular fibers. The MRG showed recovery of motor performance after 1 week, but the PRG showed a persistent motor impairment for >3 weeks. Damage to the posterior limb of the IC (PLIC) is more effective for producing a severe motor deficit. Analysis of PET data revealed decreased regional glucose metabolism in the ipsilesional motor and bilateral sensory cortex and increased metabolism in the contralesional motor cortex and bilateral hippocampus during the early recovery period after SCI. Behavioral, histologic, and functional imaging findings support the usefulness of this novel SCI rat model for investigating motor recovery.

scholarly journals Stable differentiation and clonality of murine long-term hematopoiesis after extended reduced-intensity selection for MGMT P140K transgene expression

Blood ◽  
2007 ◽  
Vol 110 (6) ◽  
pp. 1779-1787 ◽  
Author(s):  
Claudia R. Ball ◽  
Ingo H. Pilz ◽  
Manfred Schmidt ◽  
Sylvia Fessler ◽  
David A. Williams ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem ◽  
In Vivo Selection ◽  
Cell Clones ◽  
Selection For ◽  
The Impact ◽  
Reduced Intensity ◽  
Selection Of

AbstractEfficient in vivo selection increases survival of gene-corrected hematopoietic stem cells (HSCs) and protects hematopoiesis, even if initial gene transfer efficiency is low. Moreover, selection of a limited number of transduced HSCs lowers the number of cell clones at risk of gene activation by insertional mutagenesis. However, a limited clonal repertoire greatly increases the proliferation stress of each individual clone. Therefore, understanding the impact of in vivo selection on proliferation and lineage differentiation of stem-cell clones is essential for its clinical use. We established minimal cell and drug dosage requirements for selection of P140K mutant O6-methylguanine-DNA-methyltransferase (MGMT P140K)–expressing HSCs and monitored their differentiation potential and clonality under long-term selective stress. Up to 17 administrations of O6-benzylguanine (O6-BG) and 1,3-bis(2-chloroethyl)-1-nitroso-urea (BCNU) did not impair long-term differentiation and proliferation of MGMT P140K–expressing stem-cell clones in mice that underwent serial transplantation and did not lead to clonal exhaustion. Interestingly, not all gene-modified hematopoietic repopulating cell clones were efficiently selectable. Our studies demonstrate that the normal function of murine hematopoietic stem and progenitor cells is not compromised by reduced-intensity long-term in vivo selection, thus underscoring the potential value of MGMT P140K selection for clinical gene therapy.

Methods for Restricting Maximum Exposure Rate in Computerized Adaptative Testing

Methodology ◽  
2007 ◽  
Vol 3 (1) ◽  
pp. 14-23 ◽  
Author(s):  
Juan Ramon Barrada ◽  
Julio Olea ◽  
Vicente Ponsoda
Keyword(s):  
Measurement Accuracy ◽  
Computerized Adaptive Testing ◽  
Computation Time ◽  
Adaptive Testing ◽  
Exposure Rate ◽  
Control Parameters ◽  
The Impact ◽  
Two Alternatives ◽  
Selection Of ◽  
Maximum Exposure

Abstract. The Sympson-Hetter (1985) method provides a means of controlling maximum exposure rate of items in Computerized Adaptive Testing. Through a series of simulations, control parameters are set that mark the probability of administration of an item on being selected. This method presents two main problems: it requires a long computation time for calculating the parameters and the maximum exposure rate is slightly above the fixed limit. Van der Linden (2003) presented two alternatives which appear to solve both of the problems. The impact of these methods in the measurement accuracy has not been tested yet. We show how these methods over-restrict the exposure of some highly discriminating items and, thus, the accuracy is decreased. It also shown that, when the desired maximum exposure rate is near the minimum possible value, these methods offer an empirical maximum exposure rate clearly above the goal. A new method, based on the initial estimation of the probability of administration and the probability of selection of the items with the restricted method ( Revuelta & Ponsoda, 1998 ), is presented in this paper. It can be used with the Sympson-Hetter method and with the two van der Linden's methods. This option, when used with Sympson-Hetter, speeds the convergence of the control parameters without decreasing the accuracy.

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