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Advanced Drug Delivery Reviews (v.59, #11)
Prediction of therapeutic and drug delivery outcomes using animal models
by David J. Brayden Theme Editor; Marilyn N. Martinez Theme Editor (pp. 1071-1072).
Mouse models of inflammatory bowel disease by Stefan Wirtz; Markus F. Neurath (pp. 1073-1083).
Animal models of intestinal inflammation are indispensable for our understanding of the pathogenesis of Crohn disease and Ulcerative colitis, the idiopathic forms of inflammatory bowel disease in humans. The clinical appearance of human IBD is heterogeneous, a fact that is also reflected by the steadily increasing number of mouse strains displaying IBD like intestinal alterations. The analysis of these models together with genetic studies in humans greatly enhanced our insights into immunoregulatory processes in the gut and led to the generally accepted hypothesis that a deregulated immune response against components of the intestinal microbiota is critically involved in IBD pathophysiology. In this article we provide a brief overview of selected mouse models of IBD and discuss their contribution to the current understanding of disease mechanisms that contribute to IBD.
Keywords: Abbreviations; TNF; Tumour necrosis factor; IL; Interleukin; IFN-γ; interferon-γ; TGF-β; transforming growth factor-beta; NFκB; nuclear factor kappa bInflammatory bowel disease; Crohn's disease; Ulcerative colitis; Animal models; Epithelial barrier; Mucosal immune system
Considerations for the sensible use of rodent models of inflammatory disease in predicting efficacy of new biological therapeutics in the clinic by Heather A. Arnett; Joanne L. Viney (pp. 1084-1092).
Successful therapeutics for treating autoimmune and inflammatory diseases must be able to significantly dampen, and ideally reverse, the complex processes involved in the manifestation of inflammatory pathology in intact tissues and organs. Studies on human cells and tissues – both normal and diseased – are obviously critical for moving forward with a particular therapeutic strategy, but these types of studies are oftentimes limited in their complexity and usually fail to fully replicate the biology of the intact inflammatory environment and disease process. It is for this reason that development of a new drug generally relies on data generated from in vivo animal models that have been created to mimic aspects of the complex disease process in whole organs and whole animals. Although the intact animal model of disease provides the opportunity for key elements involved in inflammatory processes to be investigated in natural surroundings, the primary trigger for inflammatory activation in animal models is, by necessity, artificial and, of course, differs from the natural pathogenesis driving disease in humans. Despite the artificial way of inducing inflammatory responses, animal models of disease have proven invaluable for providing insight into the potential efficacy of new drugs, particularly when careful consideration has been given to ensure that the model system under study resembles the inflammatory pathway expected in human disease. The most common artificial approaches for stimulating inflammatory diseases in mice are quite varied, and range from overexpression or targeted deletion of genes in transgenic or knockout animals, immunization of animals with putative autoantigens, all the way to synthetic, chemical challenges. None of these artificial systems or triggers is wholly perfect at mimicking the complexity of human autoimmune and inflammatory diseases, but animal disease model data is an important, and very necessary, step in the path of drug development. This review will focus on the critical aspects of disease modeling in animals that should be considered when embarking on drug discovery programs, with particular attention on three of the major inflammatory diseases — rheumatoid arthritis, multiple sclerosis and asthma. We will discuss the use of rodent models in predicting the outcomes of currently approved medicines with a focus on biological therapeutics, and will highlight ongoing clinical trials where there appears to be strong correlation between animal models and the initial indication of clinical efficacy.
Keywords: Rheumatoid arthritis; Multiple sclerosis; Asthma; Animal models; Inflammation; Biologics
Transgenic animal models of neurodegenerative diseases and their application to treatment development by Edward Rockenstein; Leslie Crews; Eliezer Masliah (pp. 1093-1102).
Neurodegenerative disorders of the aging population affect over 5 million people in the US and Europe alone. The common feature is the progressive accumulation of misfolded proteins with the formation of toxic oligomers. Previous studies show that while in Alzheimer's disease (AD) misfolded amyloid-β protein accumulates both in the intracellular and extracellular space, in Lewy body disease (LBD), Parkinson's disease (PD), Multiple System Atrophy (MSA), Fronto-Temporal dementia (FTD), prion diseases, amyotrophic lateral sclerosis (ALS) and trinucleotide repeat disorders (TNRD), the aggregated proteins accumulate in the plasma membrane and intracellularly. Protein misfolding and accumulation is the result of an altered balance between protein synthesis, aggregation rate and clearance. Based on these studies, considerable advances have been made in the past years in developing novel experimental models of neurodegenerative disorders. This has been in part driven by the identification of genetic mutations associated with familial forms of these conditions and gene polymorphisms associated with the more common sporadic variants of these diseases. Transgenic and knock out rodents and Drosophila as well as viral vector driven models of Alzheimer's disease (AD), PD, Huntington's disease (HD) and others have been developed, however the focus for this review will be on rodent models of AD, FTD, PD/LBD, and MSA. Promising therapeutic results have been obtained utilizing amyloid precursor protein (APP) transgenic (tg) models of AD to develop therapies including use of inhibitors of the APP-processing enzymes β- and γ-secretase as well as vaccine therapies.
Keywords: Transgenic; Models; Neurodegenerative disease; Aging; Alzheimer's; Parkinson's; Lewy bodies; MSA
Animal data: The contributions of the Ussing Chamber and perfusion systems to predicting human oral drug delivery in vivo by Hans Lennernäs (pp. 1103-1120).
Oral administration dominates contemporary drug therapy and will most likely continue to do so as it is considered to be safe, efficient and easily accessible with minimal discomfort to the patient compared to other routes of administration such as intramuscular, subcutaneous, rectal and pulmonary delivery. However, despite these advantages, many of the mechanisms of drug uptake following oral administration remain to be fully characterized. In drug discovery and preclinical development there is a strong demand for the accurate and rapid characterization of processes such as absorption, distribution, metabolism and excretion. These biopharmaceutical/pharmacokinetic variables should also be related to pharmacodynamic and toxicological variables such potency and duration of effect. Although these processes are highly dynamic and complex, they are not yet fully characterized in vivo. Various in vitro pharmacokinetic screening methodologies have significantly increased the amount of experimental data generated in this part of the drug discovery process. In addition to these techniques, there is a strong need for in silico methods that may be used to accurately predict pharmacokinetic properties from molecular structure. For instance, pharmacokinetic filters that can sort out compounds with undesirable pharmacokinetic properties can be applied to virtual screening or compound design to reduce attrition rates. The aim of this review is to summarize reported human permeability values and to evaluate how they correlate to corresponding rat intestinal permeability data obtained in single-pass perfusion and Ussing Chamber experiments. The human permeability data are based on direct in vivo determinations in the human gastrointestinal tract with a single-pass perfusion system. The focus of this attention is particularly justified as the availability of directly determined in vivo permeability data in the literature is limited. In addition, there is a shortage of intestinal permeability studies in other mammals.
Keywords: Human intestinal absorption; Intestinal permeability; Bioavailability; Intestinal efflux; P-glycoprotein; Biopharmaceutics classification system; Model correlations; Absorption prediction; ADME; Pharmacokinetics
Physiology and pharmacology of the brushtail possum gastrointestinal tract: Relationship to the human gastrointestinal tract by Arlene McDowell; Bernie J. McLeod (pp. 1121-1132).
Oral formulations are typically based on studies from eutherian animal models. This review introduces information relating to oral formulations for a marsupial species, the Australian brushtail possum ( Trichosurus vulpecula) that has arisen from research into new methods for controlling this species — a major vertebrate pest in New Zealand. Morphologically, the gastrointestinal tract of the brushtail possum is similar to that of hindgut fermenting eutherian species, but there are some striking differences in function. Limited data suggests that the pharmacokinetics and bioavailability of administered drugs are similar to that in eutherian species, but there is some evidence that possums may have specific mechanisms for handling the intake of plant toxins and xenobiotics. The development of oral formulations for a free-ranging pest species presents several challenges above those encountered in the development of therapeutic formulations for humans and domestic animals. Use of a marsupial animal model may lead to new strategies for oral formulations in humans.
Keywords: Abbreviations; CSM; colonic separating mechanism; GI gastrointestinal; 99m; Tc; radiolabeled technetium; BSA; bovine serum albumin; LHRH; luteinizing hormone releasing hormone; DGGE; denaturing gradient gel electrophoresis; EDTA; ethylenediamine tetra-acetic acid; SDA; sodium deoxycholic acid; DTT; dithiothreitol; PSM; plant secondary metaboliteOral delivery; Marsupial; Caecum; LHRH; Gastrointestinal pH; Transit time; Trichosurus vulpecula
In vivo animal models for drug delivery across the lung mucosal barrier by Sally-Ann Cryan; Neeraj Sivadas; Lucila Garcia-Contreras (pp. 1133-1151).
Over recent years the research focus within the field of respiratory drug delivery has broadened to include a wide range of potential applications for inhalation by delivering drugs not just onto the lung mucosa but across it. The range of drugs being assessed is broad and includes both current and novel therapies and there are a growing number of additives that appear capable of enhancing systemic absorption. Comprehensive characterisation of drug delivery to the lungs is a complex task involving the determination of delivered, deposited and (for systemically-targeted drugs) absorbed dose. As it is difficult to simulate in vitro, in vivo whole animal models are still key to inhaled drug development. Because of the anatomical complexities and interspecies differences in the lungs, the appropriate choice of species and drug delivery method is vital during study design. New delivery devices designed specifically for animal studies as well as more sophisticated methods to determine drug deposition and absorption after inhalation are improving the information derived from these studies.
Keywords: Systemic drug delivery; Respiratory delivery; Inhalation; Aerosol; Pharmacokinetics; Toxicity; Drug deposition; Drug absorption
Transdermal skin delivery: Predictions for humans from in vivo, ex vivo and animal models by Biana Godin; Elka Touitou (pp. 1152-1161).
The assessment of percutaneous permeation of molecules is one of the main steps in the initial design and later in the evaluation of dermal or transdermal drug delivery systems. The literature reports numerous ex vivo, in vitro and in vivo models used to determine drug skin permeation profiles and kinetic parameters, some studies focusing on the correlation of the data obtained using these models with the dermal/transdermal absorption in humans. This paper reviews work from in vitro permeation studies to clinical performance, presenting various experimental models used in dermal/transdermal research, including the use of excised human or animal skin, cultured skin equivalents and animals. Studies focusing on transdermal absorption of a series of drug molecules and various delivery systems as well as mathematical models for skin absorption are reviewed.
Keywords: Transdermal absorption; In vitro; -; in vivo; correlation; Animal skin; Studies in humans; Skin equivalents; Percutaneous permeation
The chick embryo and its chorioallantoic membrane (CAM) for the in vivo evaluation of drug delivery systems by Angelica Vargas; Magali Zeisser-Labouèbe; Norbert Lange; Robert Gurny; Florence Delie (pp. 1162-1176).
Mammalian models are frequently used for preclinical evaluation of new drug delivery systems (DDS). However, valid mammalian models are expensive, time-consuming, and not easy to set up and evaluate. Furthermore, they are often linked to administrative burden with respect to ethical and legal aspects. The present review outlines the possibilities and limitations of using the hen's embryo, and specifically its chorioallantoic membrane (CAM), as an alternative to mammalian models for the evaluation of DDS. Features of the CAM, the anatomy of the embryo, and the blood were investigated to assess properties of the drug carriers such as toxicity and biocompatibility, as well as the activity, toxicity, biodistribution and pharmacokinetics of the drug. The simplicity, rapidity, and low cost of the different assays that can be performed with chick embryos strengthen the interest of routinely using this model in pharmaceutical technology research. It is concluded that there is a big potential for using chick embryos in screening procedures of formulation candidates, thus establishing an intermediate step between in vitro cellular tests and preclinical mammalian models.
Keywords: Abbreviations; AβBA; acetyl-β-boswellic acid; AKαBA; acetyl-11-keto-α-boswellic acid; AKβBA; acetyl-11-keto-β-boswellic acid; 5-ALA; 5-aminolevulinic acid; AMD; age-related macular degeneration; BEPPn; bis(methoxyethyl)-di-; n; -propylporphycene; BMP-2; bone morphogenetic protein-2; BPD-MA; benzoporphyrin derivative monoacid ring A; CAM; chorioallantoic membrane; CD; γ-cyclodextrin; Ce; 6; chlorine e; 6; CNV; choroidal neovascularization; DDS; drug delivery system; DOX; doxorubicin; DPPC; dipalmitoylphosphatidylcholine; DT; diphtheria toxin; EDD; embryo development day; EPC; egg phosphatidylcholine; EVA; ethylene-vinyl acetate; FDA; United States Food and Drug Administration; bFGF; basic fibroblast growth factor; HET-CAM; hen's egg test on the chorioallantoic membrane model; HPLC; high performance liquid chromatography; Hy; hypericin; IP; intraperitoneal; IV; intravenous; MB; methylene blue; MePEG; methoxypoly(ethylene glycol); NMP; N; -methyl pyrrolidone; NP; nanoparticle; PCL; poly(ɛ-caprolactone); PDT; photodynamic therapy; PEG; poly(ethylene glycol); Pheo-a; pheophorbide-a; PLA; poly(; D,L; -lactic acid); PLGA; poly(lactide-co-glycolide); PP IX; protoporphyrin IX; PS photosensitizer (s); PVP; polyvinylpyrrolidone; PVP-I; polyvinylpyrrolidone-iodine; SAIB; sucrose acetate isobutyrate; S1P; sphingosine 1-phosphate; TCPP; meso; -tetra-(carboxyphenyl)porphyrin; TGF-β1; transforming growth factor beta-1; THPC; meso-; tetra(; m; -hydroxyphenyl)chlorin; THPP; meso; -tetra(; p; -hydroxyphenyl)porphyrin; TPP; meso; -tetraphenylporphyrin; VEGF; vascular endothelial growth factorChick chorioallantoic membrane (CAM) model; In vivo; model; Preclinical evaluation; Angiogenesis; Drug activity; Cancer models; Photodynamic therapy; Biocompatibility; Pharmacokinetics; Biodistribution
Application of allometric principles for the prediction of pharmacokinetics in human and veterinary drug development by Iftekhar Mahmood (pp. 1177-1192).
The concept of correlating pharmacokinetic parameters with body weight (termed as pharmacokinetic interspecies scaling) from different animal species has become a useful tool in drug development. Interspecies scaling is based on the power function, where the body weight of the species is plotted against the pharmacokinetic parameter of interest. Clearance, volume of distribution, and elimination half-life are the three most frequently extrapolated pharmacokinetic parameters. The predicted pharmacokinetic parameter clearance can be used for estimating a first-in-human dose. Over the years, many approaches have been suggested to improve the prediction of aforementioned pharmacokinetic parameters in humans from animal data. A literature review indicates that there are different degrees of success with different methods for different drugs. Interspecies scaling is also a very useful tool in veterinary medicine. The knowledge of pharmacokinetics in veterinary medicine is important for dosage selection, particularly in the treatment of large animals such as horses, camels, elephants, or other large zoo animals. Despite the potential for extrapolation error, the reality is that interspecies scaling is needed across many veterinary practice situations, and therefore will be used. For this reason, it is important to consider mechanisms for reducing the risk of extrapolation errors that can seriously affect animal safety and therapeutic response. Overall, although interspecies scaling requires continuous refinement and better understanding, the rationale approach of interspecies scaling has a lot of potential during the drug development process.
Keywords: Pharmacokinetic interspecies scaling; clearance; volume of distribution; elimination half-life; first-in-human dose; veterinary medicine; large animals