Alternative Animal and Non-Animal Models for Drug Discovery and Development: Bonus or Burden?

Abstract

Mammalian models have served as a basis for R&D over the past decades. Nevertheless, these models are expensive, laborious, may yield results that cannot always be translated into the human in vivo situation and, more recently, have reverberated great social and ethical dilemmas. Hence, the prospect of changes in the global scientific scenario and the Three Rs principle (Reduction, Replacement and Refinement) have encouraged the development of alternative methods to the use of mammals. Despite the efforts, suitable alternative tests are not available in all areas of biomedical research, as regulatory acceptance requires time, prior validation and robust financial and scientific investment. In this perspective, we aim to shed light on the concepts, challenges and perspectives for implementation of innovative alternative animal and non-animal methods in scientific research. The applicability and meaningfulness of invertebrate animal models, in silico analysis and reverse pharmacology are discussed, among other aspects of relevance in today's scenario. Overall, the use of alternative models, including Artemia salina (brine shrimp), Caenorhabditis elegans (roundworm), Danio rerio (zebra fish), Drosophila melanogaster (fruit fly), Galleria mellonella (greater waxmoth) and in silico modelling, increased 909% from 1990 to 2015, as compared to 154% of conventional mammals in the same period. Thus, technological and scientific advancements in the fields of toxicology and drug development seem to have diminished the need for mammalian models. Today, however, mammals still remain critically indispensable to provide - in most cases -reliable data subsidizing and validating translation into the clinical setting.

Galleria mellonella - a novel infection model for the Mycobacterium tuberculosis complex

“…The use of invertebrates, such as Caenorhabditis elegans , Drosophila melanogaster and G. mellonella , as models for infection studies have been widely reported as they are considerably cheaper, ethically less contentious than mammals, and although insects lack an acquired immune system they do possess a complex innate immune system [37]. Furthermore D. melanogaster has been used as an infection model for M. abscessus and M. marinum , particularly to study the pathogenesis and metabolic consequences of mycobacterial infection [38–41].…”

Anticancer Effects of Wild Mountain Mentha longifolia Extract in Adrenocortical Tumor Cell Models

“…Recently, hesperidin was found able to potentiate, along with two other natural compounds, the effect of tamoxifen against the breast tumour (Khamis et al, 2018) while eriocitrin to reduce the incidence of oral squamous cell carcinoma induced in hamsters (Baldasquin-Caceres et al, 2014). Subsequently, as we needed to assess the ME potency in a complex living system, we investigated the extract in a vertebrate model of toxicity: the BSLA is an easy and very informative test used to evaluate the potential harmfulness of a novel extract (Freires et al, 2017). Only ME concentrations > 0.5 µg/µl resulted critically toxic in the animal model and thus conceivable useful in cancer (Figure 1).…”

Inappropriate modeling of chronic and complex disorders: How to reconsider the approach in the context of predictive, preventive and personalized medicine, and translational medicine

“…Living systems refer to systems based on animal or human components such as cell, tissue, and organ cultures and systems based on organisms including microorganisms, lower vertebrates, and invertebrates. Non-living systems such as biochemical and physiochemical systems, mathematical and computer models (in silico analysis) [110], and epidemiological data on human can also be applied when there is adequate information accessible [83,107,111,112]. A number of alternative methods are listed in Table 1.…”