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Olsen L.R.,Copenhagen University | Gabel-Jensen C.,Copenhagen University | Nielsen P.A.,EntomoPharm | Hansen S.H.,Copenhagen University | Badolo L.,Lundbeck
Drug Metabolism and Disposition | Year: 2014

Insects have been proposed as a new tool in early drug development. It was recently demonstrated that locusts have an efflux transporter localized in the blood-brain barrier (BBB) that is functionally similar to the mammalian P-glycoprotein efflux transporter. Two insect BBB models have been put forward, an ex vivo model and an in vivo model. To use the in vivo model it is necessary to fully characterize the locust as an entire organism with regards to metabolic pathways and excretion rate. In the present study, we have characterized the locust metabolism of terfenadine, a compound that in humans is specific to the cytochrome P450 enzyme 3A4. Using high-resolution mass spectrometry coupled to ultra-high-performance liquid chromatography, we have detected metabolites identical to human metabolites of terfenadine. The formation of human metabolites in locusts was inhibited by ketoconazole, a mammalian CYP3A4 inhibitor, suggesting that the enzyme responsible for the human metabolite formation in locusts is functionally similar to human CYP3A4. Besides the human metabolites of terfenadine, additional metabolites were formed in locusts. These were tentatively identified as phosphate and glucose conjugates. In conclusion, not only may locusts be a model useful for determining BBB permeation, but possibly insects could be used in metabolism investigation. However, extensive characterization of the insect model is necessary to determine its applicability. Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.


Andersson O.,EntomoPharm | Hansen S.H.,Copenhagen University | Hellman K.,EntomoPharm | Olsen L.R.,Copenhagen University | And 4 more authors.
Journal of Pharmacology and Experimental Therapeutics | Year: 2013

The aim of the present study was to develop a blood-brain barrier (BBB) permeability model that is applicable in the drug discovery phase. The BBB ensures proper neural function, but it restricts many drugs from entering the brain, and this complicates the development of new drugs against central nervous system diseases. Many in vitro models have been developed to predict BBB permeability, but the permeability characteristics of the human BBB are notoriously complex and hard to predict. Consequently, one single suitable BBB permeability screening model, which is generally applicable in the early drug discovery phase, does not yet exist. A new refined ex vivo insect-based BBB screening model that uses an intact, viable whole brain under controlled in vitro-like exposure conditions is presented. This model uses intact brains from desert locusts, which are placed in a well containing the compound solubilized in an insect buffer. After a limited time, the brain is removed and the compound concentration in the brain is measured by conventional liquid chromatography-mass spectrometry. The data presented here include 25 known drugs, and the data show that the ex vivo insect model can be used to measure the brain uptake over the hemolymph-brain barrier of drugs and that the brain uptake shows linear correlation with in situ perfusion data obtained in vertebrates. Moreover, this study shows that the insect ex vivo model is able to identify P-glycoprotein (Pgp) substrates, and the model allows differentiation between low-permeability compounds and compounds that are Pgp substrates. Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics.


There is provided an ex-vivo insect screening model to determine blood-brain barrier penetration of different chemical compounds. The method comprises the steps: Optionally anesthetizing the insect Fixing the head of the insect Dissecting out the brain of the insect head thereby removing the brain from its cuticle Optinally removing the neural lamella of the brain Treating the brain with a solution of the chemical compound Washing anf homogenising or ultra sound disintegrating the brain Determining the concentration of the chemical compound in the homogenised brain material and Calculating the penetration of the chemical compound through the blood-brain barrier The concentration of the chemical compound is determined by LC/MS and the chemical compound can be a CNS drug.


Patent
EntomoPharm | Date: 2010-08-10

There is provided a new methodology for initial assessment of compound PK. The invention is generally particular useful for efficient screening of and assessment of PK profiles of newly synthesized compounds in the early phase of drug discovery.


There is provided insect screening models to determine gastrointestinal absorption of different chemical compounds in vertebrates, and in particular humans, in order to improve the compound screening procedures/processes in the early drug discovery process. This offers many advantages relative to prior technologies since insect models are more reliable tools for the decision-making process than the existing in vitro models, and will speed up the drug screening process and reduce the late phase attrition rate. Moreover, it will reduce the number of mammals sacrificed during the drug discovery phase.


There is provided an ex-vivo insect screening model to accurately determine blood-brain barrier penetration of different chemical compounds in order to improve the compound screening procedures/processes in the early drug discovery process. This object offers many advantages relative to prior technologies since insect models are more reliable tools for the decision-making process than the existing in vitro models, and will speed up the drug screening process and reduce the late phase attrition rate. Moreover, it will reduce the number of mammals sacrificed during the drug discovery phase.


There is provided a method and model insects for screening the effects of nanoparticles on brain barrier function and integrity. The method involves exposing the insect brain-barrier to the nanoparticle(s) of interest and exposing the nanoparticle treated insect brain barrier to one or more suitable marker(s) of the function and integrity of the brain barrier.


There is provided an ex-vivo insect screening model to accurately determine blood-brain barrier penetration of different nanoparticles in order to improve the compound screening procedures/processes in the early drug discovery process. This object offers many advantages relative to prior technologies since insect models are more reliable tools for the decision-making process than the existing in vitro models, and will speed up the drug screening process and reduce the late phase attrition rate. Moreover, it will reduce the number of mammals sacrificed during the drug discovery phase.


Trademark
EntomoPharm | Date: 2012-05-15

Pharmaceutical and Veterinarian preparations for use in blood brain barrier screening to determine the biomembrane permeability for the treatment of depression, schizophrenia, chronic pain, epilepsy, cancer, spinal cord trauma, neurological diseases, Huntingtons disease, blood-brain barrier related malfunctions, obesity, fungal infections, A.L.S., multiple sclerosis, neuro-AIDS, progressive multifocal leukoenceplalopathy, autism, lysosomal storage disorders, fragile X syndrome, inherited mental retardation, inherited ataxias, prion disease, meningitis, neuromyelitis optica, late-stage neurological trypanosomiasis, parasitic diseases, De Vivo disease, rabies, encephalitis, locked-in syndrome and bacterial infections. Scientific, technological and industrial services, namely, scientific research, analysis, testing in the field of pharmaceutical and drug development; Industrial analysis and research services for human and veterinarian pharmaceuticals. Agriculture advice; Forestry services, namely, vermin and pest control services; forest habitat restoration.

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