1.
Marina, N., et al.
(författare)
Potential Clinical Application of Angiotensin 2 Receptor Agonists
2015
Ingår i: The Protective Arm of the Renin Angiotensin System (RAS): Functional Aspects and Therapeutic Implications. - : Elsevier. - 9780128013649 ; , s. 149-153
Bokkapitel (refereegranskat) abstract
In this chapter, we explore the factors influencing the selection of a clinical target for the early clinical development of an AT2 (AT2R) agonist for use in man. We discuss the requirements for an Investigational New Drug application. The only available oral AT2R agonist with an extensive preclinical documentation, outlined in previous chapters, is used as the model for this discussion. The growing body of preclinical data in a wide range of areas relevant to clinical applications justifies human proof of concept clinical studies with compound 21 or other AT2R agonists in several indication areas. © 2015 Elsevier Inc.
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Davidsson, Johan, 1967, et al.
(författare)
A Sagittal Plane Rotational Injury Rodent Model for Research on Traumatic Brain Injuries
2019
Ingår i: Neuromethods. - New York, NY : Springer New York. - 1940-6045 .- 0893-2336. ; 149, s. 61-75
Bokkapitel (övrigt vetenskapligt/konstnärligt) abstract
The model presented here produce brain injuries following sagittal plane rearward rotational acceleration in rats. During trauma, a rotating bar, which is tightly secured to the animal head, is impacted by a striker that causes the rotating bar and the animal head to rotate rearward; the acceleration phase is followed by a rotation at constant speed and gentle deceleration when the rotating bar contacts a padded stop. The total head angle change range from 25° to 30°. By adjusting the air pressure in the air-driven accelerator used to accelerate the striker, a large range of rotational accelerations can be achieved. This model can, depending on the striker velocity, produce subdural bleedings, graded widespread axonal injuries in the corpus callosum, the border between the corpus callosum, cortex, cerebellum, olfactory bulbs, and in some of the tracts in the brain stem. The model has been shown to produce degenerating axons. For lower rotational accelerations no apparent axonal injuries can be observed. The model produces only limited signs of contusion injury, and macrophage invasions, glial fibrillary acidic protein redistribution or hypertrophy, and blood–brain barrier changes are unusual. The model produces distinct S100 and Neurofilament Light serum concentration changes, thus indicating that blood vessel and glia cell injuries may occur. The rotational acceleration trauma model presented can produce graded axonal injury, is repeatable, and produce limited other types of TBIs and as such is useful in the study of injury biomechanics, diagnostics, and treatment strategies following diffuse axonal injury and most likely also following concussion.
4.
Hammarlund-Udenaes, Margareta
(författare)
In vivo approaches to assessing the blood-brain barrier
2014
Ingår i: The blood-brain barrier (BBB). - Heidelberg New York Dordrecht London : Springer. - 9783662437865 ; , s. 21-48
Bokkapitel (refereegranskat) abstract
Methods for in vivo assessment of blood-brain barrier (BBB) transport are presented, with their advantages and disadvantages. The methods described are brain uptake index, the i.v. injection technique, in situ brain perfusion, brain efflux index, % injected dose, microdialysis, CSF sampling and positron emission tomography, and the combinatorial mapping of unbound drug partitioning across the BBB. The methods are put into a pharmacokinetic context by delineating the type of readings that they give, be it the rate of transport across the BBB or the extent of transport of total drug (unbound and bound), or of the unbound drug.
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6.
Kenna, J. Gerry, et al.
(författare)
Noninvasive preclinical and clinical imaging of liver transporter function relevant to drug-induced liver injury
2018
Ingår i: Methods in Pharmacology and Toxicology. - New York, NY : Springer New York. - 1557-2153 .- 1940-6053. ; , s. 627-651
Bokkapitel (övrigt vetenskapligt/konstnärligt) abstract
Imaging technologies can evaluate many different biological processes in vitro (in cell culture models) and in vivo (in animals and humans), and many are used routinely in investigation of human liver diseases. Some of these methods can help understand liver toxicity caused by drugs in vivo in animals, and drug-induced liver injury (DILI) which arises in susceptible humans. Imaging could aid assessment of the relevance to humans in vivo of toxicity caused by drugs in animals (animal/human translation), plus toxicities observed using in vitro model systems (in vitro/in vivo translation). Technologies and probe substrates for quantitative evaluation of hepatobiliary transporter activities are of particular importance. This is due to the key role played by sinusoidal transporter mediated hepatic uptake in DILI caused by many drugs, plus the strong evidence that inhibition of the hepatic bile salt export pump (BSEP) can initiate DILI. Imaging methods for investigation of these processes are reviewed in this chapter, together with their scientific rationale, and methods of quantitative data analysis. In addition to providing biomarkers for investigation of DILI, such approaches could aid the evaluation of clinically relevant drug–drug interactions mediated via hepatobiliary transporter perturbation.
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9.
Turkez, Hasan, et al.
(författare)
Pivotal role of micronucleus test in drug discovery
2019
Ingår i: Micronucleus Assay: An Overview. - : Nova Science Publishers, Inc.. ; , s. 49-73, s. 49-73
Bokkapitel (övrigt vetenskapligt/konstnärligt) abstract
Early detection of adverse effects of novel compunds during drug discovery and development most probably reduce late stage failures, expenses and exertions for candidate drugs. Although the micronucleus (MN) test is one of the oldest techniques used in biochemical sciences for drug discovery. Flexibility of the technique for both in vitro and in vivo applications and practicability for large scale samples in short time make the MN test an inevitable tool for chemical trails. Drug studies require a formulation that provides the highest exposure to detect clastogenic and aneugenic activities and thus analysis makes it possible to get the necessary safety margin to support clinical trials. The MN test is one of the most important tools of the genotoxicity test battery in preclinical studies to identify negative effects of compounds that induce numerical and structural chromosome alterations in wide spectrum concentrations. The MN assay can be applied various cell types in different protocols. For instance; the most recommended protocols are bone the marrow micronucleus analysis and the in vivo mammalian erythrocyte precursor assay. Also, the rodent ovary cells validation test is a very powerful approach to analyse side effects of a compound. Beside cell types, detection systems can be constituted to obtain a high throughput screening such as integrating flow cytometry analysis into the MN inspections. Since a new compound is needed for such an assay, the MN test can assess abnormalities earlier in the drug discovery pipeline, making structure/genotoxicity connection a possible system for drug characterization.
10.
Alderborn, Göran, et al.
(författare)
Mechanical strength of tablets
2008. - 3
Ingår i: Pharmaceutical Dosage Forms. - New York : Informa Healthcare. - 9780849390166 - 0849390168
Bokkapitel (övrigt vetenskapligt/konstnärligt)
