Assessing Pharmacodynamic Interactions in Mice Using the Multistate Tuberculosis Pharmacometric and General Pharmacodynamic Interaction Models

The aim of this study was to investigate pharmacodynamic (PD) interactions in mice infected with Mycobacterium tuberculosis using population pharmacokinetics (PKs), the Multistate Tuberculosis Pharmacometric (MTP) model, and the General Pharmacodynamic Interaction (GPDI) model. Rifampicin, isoniazid, ethambutol, or pyrazinamide were administered in monotherapy for 4 weeks. Rifampicin and isoniazid showed effects in monotherapy, whereas the animals became moribund after 7 days with ethambutol or pyrazinamide alone. No PD interactions were observed against fast-multiplying bacteria. Interactions between rifampicin and isoniazid on killing slow and non-multiplying bacteria were identified, which led to an increase of 0.86 log10 colony-forming unit (CFU)/lungs at 28 days after treatment compared to expected additivity (i.e., antagonism). An interaction between rifampicin and ethambutol on killing non-multiplying bacteria was quantified, which led to a decrease of 2.84 log10 CFU/lungs at 28 days after treatment (i.e., synergism). These results show the value of pharmacometrics to quantitatively assess PD interactions in preclinical tuberculosis drug development

Evaluation of the physical interpretability of calibrated building model parameters

Identifying building envelope thermal properties from the calibration of a lumped model raises identifiability issues. Not only needs the simplified model to be structurally identifiable, i.e. deliver unique estimates after calibration, but also the data used might not be informative enough to result in either or both accurate estimates and physically interpretable values. This could particularly be the case when data is extracted from non intrusive in situ measurements, in the sense not disturbing potential occupancy. In this frame, this paper develops a method to investigate the physical interpretation of the parameters of lumped models through a numerical tests procedure. Each test runs a simulation of a comprehensive thermal model of a building, with variations in thermal resistance properties of the envelope. Each simulation delivers data used to calibrate a lumped model. The parameters of the lumped model are then physically interpretable if their value vary according to the variations of the comprehensive model. The overall test procedure is applied to the study of a 2R2C model. Results show that the calibration of this model delivers robust calibration results for all parameters but one and also shows satisfactory robustness of the estimation of the overall thermal resistance. This paper concludes that the numerical test procedure does allow to evaluate practical identifiability of lumped models, and will in future work be used to examine more complex lumped model

Developing a hybrid model of prediction and classification algorithms for building energy consumption

Artificial intelligence algorithms have been applied separately or integrally for prediction, classification or optimization of buildings energy consumption. However, there is a salient gap in the literature on the investigation of hybrid objective function development for energy optimization problems including qualitative and quantitative datasets in their constructs. To tackle this challenge, this paper presents a hybrid objective function of machine learning algorithms in optimizing energy consumption of residential buildings through considering both continuous and discrete parameters of energy simultaneously. To do this, a comprehensive dataset including significant parameters of building envelop, building design layout and HVAC was established, Artificial Neural Network as a prediction and Decision Tree as a classification algorithm were employed via cross-training ensemble equation to create the hybrid function and the model was finally validated via the weighted average of the error decomposed for the performance. The developed model could effectively enhance the accuracy of the objective functions used in the building energy prediction and optimization problems. Furthermore, the results of this novel approach resolved the inclusion issue of both continuous and discrete parameters of energy in a unified objective function without threatening the integrity and consistency of the building energy datasets

Kinome rewiring reveals AURKA limits PI3K-pathway inhibitor efficacy in breast cancer.

Dysregulation of the PI3K-AKT-mTOR signaling network is a prominent feature of breast cancers. However, clinical responses to drugs targeting this pathway have been modest, possibly because of dynamic changes in cellular signaling that drive resistance and limit drug efficacy. Using a quantitative chemoproteomics approach, we mapped kinome dynamics in response to inhibitors of this pathway and identified signaling changes that correlate with drug sensitivity. Maintenance of AURKA after drug treatment was associated with resistance in breast cancer models. Incomplete inhibition of AURKA was a common source of therapy failure, and combinations of PI3K, AKT or mTOR inhibitors with the AURKA inhibitor MLN8237 were highly synergistic and durably suppressed mTOR signaling, resulting in apoptosis and tumor regression in vivo. This signaling map identifies survival factors whose presence limits the efficacy of targeted therapies and reveals new drug combinations that may unlock the full potential of PI3K-AKT-mTOR pathway inhibitors in breast cancer

The candidate antimalarial drug MMV665909 causes oxygen-dependent mRNA mistranslation and synergises with quinoline-derived antimalarials

To cope with growing resistance to current antimalarials, new drugs with novel modes of action are urgently needed. Molecules targeting protein synthesis appear to be promising candidates. We identified a compound (MMV665909) from the MMV Malaria Box of candidate antimalarials that could produce synergistic growth inhibition with the aminoglycoside antibiotic paromomycin, suggesting a possible action of the compound in mRNA mistranslation. This mechanism of action was substantiated with the yeast cell model using available reporters of mistranslation and other genetic tools. Mistranslation induced by MMV665909 was oxygen-dependent, suggesting a role for reactive oxygen species (ROS). Overexpression of Rli1 (a ROS-sensitive, conserved FeS protein essential in mRNA translation) rescued inhibition by MMV665909, consistent with the drug’s action on translation fidelity being mediated through Rli1. The MMV drug also synergised with major quinoline-derived antimalarials which can perturb amino acid availability or promote ROS stress: chloroquine, amodiaquine and primaquine. The data collectively suggest translation-fidelity as a novel target of antimalarial action and support MMV665909 as a promising drug candidate

Polytherapy with a combination of three repurposed drugs (PXT3003) down-regulates Pmp22 over-expression and improves myelination, axonal and functional parameters in models of CMT1A neuropathy

Charcot-Marie-Tooth disease type 1A (CMT1A) is the most common inherited sensory and motor peripheral neuropathy. It is caused by PMP22 overexpression which leads to defects of peripheral myelination, loss of long axons, and progressive impairment then disability. There is no treatment available despite observations that monotherapeutic interventions slow progression in rodent models. We thus hypothesized that a polytherapeutic approach using several drugs, previously approved for other diseases, could be beneficial by simultaneously targeting PMP22 and pathways important for myelination and axonal integrity. A combination of drugs for CMT1A polytherapy was chosen from a group of authorised drugs for unrelated diseases using a systems biology approach, followed by pharmacological safety considerations. Testing and proof of synergism of these drugs were performed in a co-culture model of DRG neurons and Schwann cells derived from a Pmp22 transgenic rat model of CMT1A. Their ability to lower Pmp22 mRNA in Schwann cells relative to house-keeping genes or to a second myelin transcript (Mpz) was assessed in a clonal cell line expressing these genes. Finally in vivo efficacy of the combination was tested in two models: CMT1A transgenic rats, and mice that recover from a nerve crush injury, a model to assess neuroprotection and regeneration. Combination of (RS)-baclofen, naltrexone hydrochloride and D-sorbitol, termed PXT3003, improved myelination in the Pmp22 transgenic co-culture cellular model, and moderately down-regulated Pmp22 mRNA expression in Schwannoma cells. In both in vitro systems, the combination of drugs was revealed to possess synergistic effects, which provided the rationale for in vivo clinical testing of rodent models. In Pmp22 transgenic CMT1A rats, PXT3003 down-regulated the Pmp22 to Mpz mRNA ratio, improved myelination of small fibres, increased nerve conduction and ameliorated the clinical phenotype. PXT3003 also improved axonal regeneration and remyelination in the murine nerve crush model. Based on these observations in preclinical models, a clinical trial of PTX3003 in CMT1A, a neglected orphan disease, is warranted. If the efficacy of PTX3003 is confirmed, rational polytherapy based on novel combinations of existing non-toxic drugs with pleiotropic effects may represent a promising approach for rapid drug development. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13023-014-0201-x) contains supplementary material, which is available to authorized users

Monoamine involvement in the antidepressant-like effect induced by P2 blockade

Peer reviewe

A General Approach to Test for Interaction Among Mixtures of Insecticidal Proteins Which Target Different Orders of Insect Pests

A shift toward transgenic crops which produce combinations of insecticidal proteins has increased the interest (Syngenta Seeds, Inc., Minnetonka, MN) in studying the potential for interactions amongst those proteins. We present a general testing method which accommodates proteins with nonoverlapping spectrums of activity. Our sequential testing approach first investigates groups of the proteins with overlapping activity; e.g., proteins active against Lepidoptera or Coleoptera, respectively. The Colby method is used to test for interactions within each respective group. Subsequently, the mixture of proteins within each group is regarded as a single entity and tests for interactions between the groups (when combined) is conducted using analysis of variance. We illustrate the method using Cry1Ab, Vip3Aa20, and Cry1F (a mixture of proteins active against Lepidoptera), and mCry3A and eCry3.1Ab (a mixture of proteins active against Coleoptera). These insecticidal proteins are produced by Bt11 × MIR162 × TC1507 × MIR604 × 5307 maize. We detected no interactions between Cry1Ab, Vip3Aa20, and Cry1F in tests using larvae of two different lepidopteran species, and possible slight antagonism between mCry3A and eCry3.1Ab with a coleopteran test species. We detected no effect of (eCry3.1Ab + mCry3A) on the potency of (Cry1Ab + Vip3Aa20 + Cry1F) to lepidopteran larvae, and no effect of (Cry1Ab + Vip3Aa20 + Cry1F) on the potency of (mCry3A + eCry3.1Ab) to coleopteran larvae. We discuss implications of these results for characterization of Bt11 × MIR162 × TC1507 × MIR604 × 5307 maize, and the value of the method for characterizing other transgenic crops that produce several insecticidal proteins.</p

Dynamique du transport et du transfert de l'oxygène au sein de l'acinus pulmonaire

The pulmonary acinus is the exchange unit between air and blood into the pulmonary airway system. In this thesis, we were interested more specifically for the oxygen. Its uptake from air to blood in the pulmonary acinus involves several successive processes: convection, diffusion in the gas phases, diffusion through the alveolar membrane and across plasma and finally capture by hemoglobin in the red blood cells. By the determination of the pulmonary diffusive capacity called DL, we can have a clinical evaluation of the efficiency and the performance of these mechanisms. This measure is currently used for the diagnostic in order to show probable deterioration of the alveolar membrane or else an exchange surface leakage. Experimentally, DL is calculated from two clinical measures: the alveolar pressure PA and the uptake V ̇. More precisely, in the case of oxygen, we talk about the oxygen partial pressure into the pulmonary alveolus P_(〖A,O〗_2 ) and the amount of oxygen exchanged in one minute V ̇_(O_2 ). A theoretical value of the oxygen diffusive capacity can be deduced from a classic and empiric formulation well-known in medicine. This theory is always the topic of several publications because it does not exactly report the experimental values. We implemented a numerical dynamical model of the oxygen transport and transfer into the pulmonary acinus able to recover the physiological value of P_(〖A,O〗_2 ) and V ̇_(O_2 ) in healthy patients. This model depends on a single physical parameter called the permeability W. It encloses all the complexity of the oxygen transfer to the blood. It is defined as an equivalent conductance induced by the different mechanisms taking place in the transfer to the blood. Thus, by the determination of the unique parameter W, we built an artificial acinus which is able to reproduce the behavior of the real acinus. From this model, we studied the influence of the asymmetric geometry of the pulmonary acinus on the oxygen transport and transfer. This study has shown an heterogeneity of the oxygen transfer. We can explain that with a phenomenon called diffusional screening, responsible for the fact that the oxygen partial pressure along the acinar tree decreases. This phenomenon is governed by the oxygen absorption across the alveolar membrane and the diffusion along the asymmetric structure of the acinar airways. This effect leads to a bad provision in oxygen in the distal regions, the major part being absorbed in the proximal zones. At rest, the influence of the diffusional screening is important. At exercise, the effects of the screening are weak because of the higher convection velocity. Thus, the quasi-totality of the exchange surface is used.L'acinus pulmonaire constitue l'unité d'échange gazeux entre l'air et le sang dans les voies aériennes pulmonaires. Dans le cadre de cette thèse, nous nous sommes plus particulièrement intéressés à l'oxygène. Plusieurs mécanismes sont mis en jeu depuis son entrée dans l'acinus jusqu'à sa capture par l'hémoglobine : les mécanismes de transport de l'oxygène dans l'air : convection et diffusion, le transfert par diffusion passive de l'oxygène à travers la membrane alvéolo-capillaire et sa capture par l'hémoglobine. Par la détermination de la capacité diffusive pulmonaire DL, il est possible d'évaluer cliniquement le fonctionnement et l'efficacité de ces mécanismes. Cette mesure est couramment employée pour le diagnostic, notamment pour mettre en évidence les détériorations de la membrane alvéolo-capillaire ou encore les pertes de surface d'échange. Expérimentalement, la DL s'exprime à partir des deux mesures cliniques suivantes: la pression alvéolaire PA et la consommation de gaz V. Plus particulièrement, dans le cas qui nous intéresse ici soit celui de l'oxygène, il s'agit de la pression partielle en oxygène contenue dans les alvéoles pulmonaires PA,O2 et de la quantité d'oxygène échangée en une minute VO2. Il est possible de déterminer une valeur théorique de la capacité diffusive pulmonaire grâce à une formulation classique et empirique très utilisée en médecine. Celle-ci est aujourd'hui encore le sujet de nombreuses publications car elle ne reproduit pas exactement les résultats de l'expérience. Nous avons mis en place un modèle numérique dynamique du transport et du transfert de l'oxygène au sein de l'acinus pulmonaire permettant de restituer les valeurs de PA,O2 et VO2 chez les sujets sains. Ce modèle dépend d'un unique paramètre physique ajustable qu'on appelle la perméabilité $W$. Celle-ci traduit toute la complexité du transfert de l'oxygène vers le sang. Elle se définit comme une conductance équivalente imposée par les trois mécanismes acteurs du transfert vers le sang. Par cette approche numérique, nous avons donc construit un acinus artificiel qui, à partir de la seule détermination de la perméabilité $W$ est capable de reproduire le fonctionnement de l'acinus réel. A partir de ce modèle, nous avons pu étudier l'influence de la géométrie asymétrique de l'acinus pulmonaire sur le transport et l'échange. Cette étude a mis en évidence une forte hétérogénéité de la répartition du flux d'oxygène échangé vers le sang dans l'acinus pulmonaire. Ceci peut s'expliquer grâce à un phénomène physique appelé masquage diffusionnel, responsable du fait que la pression partielle en oxygène dans l'acinus diminue. Ce phénomène est gouverné, notamment, par l'absorption à travers la membrane alvéolaire et la diffusion le long de la structure irrégulière de l'acinus. Cet effet entraîne que les parties profondes de l'acinus sont très peu alimentées en oxygène, la majorité ayant été absorbée dans les premières générations. Au repos, l'influence du masquage est élevée et le flux d'oxygène ne dépend que très peu du volume (proportionnel à la surface alvéolaire). A l'effort, l'effet du masquage est moindre, notamment grâce à la vitesse de convection plus élevée. Ainsi, la quasi-totalité de la surface alvéolaire est utilisée