Letteratura per approfondimenti

Alcuni articoli presi da riviste scientifiche per approfondimenti, con relativo abstract o riassunto. Purtroppo non tutti gli articoli sono disponibili gratuitamente al pubblico in full text.

Abbott, Alison. Animal testing: more than a cosmetic change. Nature 2005 Nov 10;438(7065):144-146

COMMENT: The toxicology tests on which regulators rely to gather this information are stuck in a time warp, and are largely based on wasteful and often poorly predictive animal experiments. Efforts in Europe are about to change this, and the man charged with bringing toxicology into the twenty-first century is a plain-talking German: Thomas Hartung. Although Hartung acknowledges the immense challenges ahead, he sees this as an opportunity for toxicology “to turn itself at last into a respectable science. The toxicity tests that have been used for decades are “simply bad science.”

Bailey J. Lessons from chimpanzee-based research on human disease: the implications of genetic differences. Altern Lab Anim. 2011 Dec;39(6):527-40.

Bailey J. Non-human primates in medical research and drug development: a critical review. Biogenic Amines 2005; 19(4-6): 235–255. COMMENT: The limitations of nonhuman primate research and the risk of excessive faith in its results have not yet been widely appreciated by many. For a variety of political reasons, few scientists openly question whether primate models are a reliable research method. One of the main obstacles to open discussion and debate is that researchers, threatened by those who oppose their modus operandi, believe that best strategy is to defend all animal research regardless of its actual value.

Balls, M. (2004) Are animal tests inherently valid? ATLA: Alternatives to Laboratory Animals, 32(Suppl. 1B), 755–758. ABSTRACT: The proposition that animal tests are inherently valid, merely because they are animal tests, is discussed and is rejected. It is concluded that there is no justifiable reason for subjecting new or substantially modified animal test procedures or testing strategies to a validation process that is any less stringent than that applied to non-animal tests and testing strategies.

Barnard, Neal D., Kaufman, Stephen R., Animal research is wasteful and misleading . Scientific American, 00368733, Feb97, Vol. 276, Issue 2

COMMENT: The use of animals for research and testing is only one of many investigative techniques available. We believe that although animal experiments are sometimes intellectually seductive, they are poorly suited to addressing the urgent health problems of our era, such as heart disease, cancer, stroke, AIDS and birth defects. Even worse, animal experiments can mislead researchers or even contribute to illnesses or deaths by failing to predict the toxic effects of drugs. Fortunately, other, more reliable methods that represent a far better investment of research funds can be employed.

Brady C.A . Of mice and men: the potential of high resolution human immune cell assays to aid the preclinical to clinical transition of drug development projects. Drug Discovery world 2008/9:74-78. ABSTRACT: The effort to develop drugs that interact with the human immune system (whether by accident or design) has been dogged by a mismatch between the data derived from animal models (mice in particular) and that found in man. Although the mouse provides the most common model for many aspects of the human immune system, the 65 million years of divergence has introduced significant differences between these species, which can and has impeded the reliable transition of pre-clinical mouse data to the clinic.The industry is littered with examples of delays, reiterations or even abandoned drug programmes arising from poor translation of animal responses to man.This article highlights some of the species differences and forwards the rationale to utilise high-resolution human immune cell assays to improve the successful transition from pre-clinical project to proof-of-concept in clinical trial.

Davis MM. A prescription for human immunology. Immunity. 2008 Dec 19;29(6):835-8. Summary: Mice are lousy models for clinical studies. This is readily apparent in autoimmunity and in cancer immunotherapy, where of dozens (if not hundreds) of protocols that work well in mice, very few have been successful in humans. Similarly, in neurological diseases, the mouse models have also been disappointing (Schnabel, 2008). Why has the mouse been so unsuccessful as a clinical model? A number of possibilities have been put forward. One is that the use of inbred strains creates a wealth of homozygous recessive defects that skew the regulation of the immune response. Another potential culprit is the artificiality of many disease-inducing protocols, and third is the sheer evolutionary distance (65 million years) between mice and humans and the likelihood that the immune system of a short-lived, ground-dwelling mammal that can replicate quickly may be substantially different than that of a long-lived, somewhat higher off-the-ground mammal that replicates very slowly (and thus has more of an evolutionary investment in individual survival).

Greek R., Pippus A. and Hansen A.L. The Nuremberg Code subverts human health and safety by requiring animal modeling BMC Medical Ethics 2012 Summary: The requirements for animal testing found in the Nuremberg Code were based on scientifically outdated principles, compromised by people with a vested interest in animal experimentation, serve no useful function, increase the cost of drug development, and prevent otherwise safe and efficacious drugs and therapies from being implemented.

Hackam & Redelmeier. Translation of research evidence from animals to humans. [research letter]. JAMA 2006;296(14):1731-2. COMMENTO: Nel Journal of American Medical Association, la rivista scientifica dell’Associazione dei Medici Americani, e’ stato pubblicato nel numero di ottobre 2006 un articolo in forma di “lettera al direttore”, intitolato “Traslazione dei risultati delle ricerche dagli animali agli umani”, che mostra come, tra gli studi su animali più citati nel mondo, solo nel 33% dei casi i risultati ottenuti sono sovrapponibili a quelli che si riscontrano sugli umani, per quanto riguarda interventi preventivi o terapie. L’autore conclude che anche ammesso che la qualità metodologica di tali studi sia ottimale, estrapolare i risultati ottenuti su altre specie per applicarli all’uomo è da considerarsi rischioso. “We believe these findings (that only about a third of highly cited animal research translated at the level of human randomized trials)  have important implications. First, patients and physicians should remain cautious about extrapolating the findings of prominent animal research to the care of human disease. Second, major opportunities for improving study design and methodological quality are available for preclinical research. Finally, poor replication of even high-quality animal studies should be expected by those who conduct clinical research.”

Hartung T. Per aspirin ad astra… Altern Lab Anim. 2009 Dec;37 Suppl 2:45-7. CAAT, Johns Hopkins University, Baltimore, USA. Abstract: Taking the 110th anniversary of marketing of aspirin as starting point, the almost scary toxicological profile of aspirin is contrasted with its actual use experience. The author concludes that we are lucky that, in 1899, there was no regulatory toxicology. Adding, for the purpose of this article, a fourth R to the Three Rs, i.e. Realism, three reality-checks are carried out. The first one comes to the conclusion that the tools of toxicology are hardly adequate for the challenges ahead. The second one concludes that, specifically, the implementation of the EU REACH system is not feasible with these tools, mainly with regard to throughput. The third one challenges the belief that classical alternative methods, i.e. replacing animal test-based tools one by one, is actually leading to a new toxicology – it appears to change only patches of the patchwork, but not to overcome any inherent limitations other than ethical ones. The perspective lies in the Toxicology for the 21st Century initiatives, which aim to create a new approach from the scratch, by an evidence-based toxicology and a global “Human Toxicology Programme”. Commento: Thomas Hartung uno dei più noti tossicologi critici nei confronti della s.a. sottolinea come l’aspirina, farmaco utilizzato da oltre 100 anni per una grande varietà di affezioni, la dobbiamo al fatto che allora non esisteva l’obbligo di testare i candidati farmaci sugli animali. L’aspirina è infatti tossica e teratogena per la quasi totalità dei mammiferi e con ogni probabilità sarebbe stata eliminata in fase pre clinica.

Khanna R., Scott R Burrows, Human immunology: a case for the ascent of non-furry immunology. Immunology and Cell Biology 89, 330–331 – 2011 Summary: Over the last two decades, well over a thousand papers have been published where model antigens such as ovalbumin have been used to study efficacy of cancer vaccines and novel therapies for autoimmune diseases in mice. Similarly, use of murine models to study the immunobiology of infectious diseases, such as malaria and herpes simplex virus, has severely skewed our understanding of immune control of these pathogens in humans, and it could be argued that over reliance on these model systems may have slowed progress in the development of effective vaccines against many human pathogens. Confidence in these model systems has eroded, as we now know that there are significant differences in human physiology and the immune regulatory pathways from these animal models. Indeed, clinical testing of the anti-CD28 monoclonal antibody TGN1412 illustrates this very well.

Knight A, Bailey J, Balcombe J. Animal carcinogenicity studies: implications for the REACH system. Alternatives to Laboratory Animals 2006; 34 suppl 1:139-147 COMMENTO: Un articolo pubblicato sulla rivista “Alternatives to Laboratory Animals” (Alternative agli animali di laboratorio) del maggio 2006 che mette in luce come i test previsti dal progetto REACH dell’Unione Europea atti a valutare se una sostanza chimica e’ cancerogena siano decisamente poco affidabili (sono svolti su animali) e quindi se si mettera’ in atto questo progetto senza prima rinnovare il tipo di test effettuati, si otteranno risultati privi di valore.

Knight A, Bailey J, Balcombe J. Which drugs cause cancer? Animal tests yield misleading results. BMJ USA 2005; 331: E389-E391. Summary: There is a longstanding tradition of animal testing, and virtually all human carcinogens, when tested in sufficient animal species, have generated positive results. However, if enough animal testing is conducted, it appears that carcinogenesis will eventually occur in some species regardless of human risk. Of 20 human non-carcinogens studied in animals, 19 produced carcinogenic effects. The problem with animal carcinogenicity tests is not their lack of sensitivity for human carcinogens, but rather their lack of human specificity. A positive result has poor predictive value for humans.

Knight A. Systematic reviews of animal experiments demonstrate poor human clinical and toxicological utility. Altern Lab Anim 2007; 35(6): 641-659. COMMENTO: Il modello animale viene considerato rilevante per l’uomo sulla base di un’assunzione, un dogma universalmente accettato. Questo articolo mostra l’inconsistenza di una simile assunzione in base all’esame di 20 revisioni sistematiche riguardanti la concordanza tra risultati ottenuti sugli animali ed applicazioni cliniche in diversi ambiti.

Knight A. The poor contribution of chimpancé experiments to biomedical progress. REDVET. Revista Electrónica de Veterinaria, vol. IX, núm. 10B, octubre, 2008, pp. 1-34 Veterinaria Organización Málaga, Españ. COMMENTO: Questo articolo dimostra lo scarsissimo contributo degli esperimenti sugli scimpanzé per il progresso biomedico e nello stesso tempo l’elevato contributo di altre metodologie.

Lynch VJ. Use with caution: developmental systems divergence and potential pitfalls of animal models. Yale J Biol Med 2009; 82: 53-66. Summary: The assumption that gene functions and genetic systems are conserved between models and humans is taken for granted, often in spite of evidence that gene functions and networks diverge during evolution. In this review, I discuss some mechanisms that generate functional divergence and highlight recent examples demonstrating that gene functions and regulatory networks diverge through time. These examples suggest that annotation of gene functions based solely on mutant phenotypes in animal models, as well as assumptions of conserved functions between species, can be wrong. Therefore, animal models of gene function and human disease may not provide appropriate information, particularly for rapidly evolving genes and systems.

Matthews RA. Medical progress depends on animal models – doesn’t it? J R Soc Med 2008: 101: 95–8.  COMMENT: Animal models are widely recognized as being essential to the progress of medical science. In countering the critics’ arguments of the use of animals in medicine, one statement has acquired almost talismanic importance: ‘Virtually every medical achievement of the last century has depended directly or indirectly on research with animals.’ In this essay, the origins and justification of this oft-repeated statement are examined. Despite its endorsement by leading academic bodies, it is far from clear that the statement has been, or even could be, formally validated.

Odom et al., Tissue-specific transcriptional regulation has diverged significantly between human and mouse,  Nat Genet, 39:730?2, June 2007.

Perel P, Roberts I, Sena E, Wheble P, Briscoe C, Sandercock P, Macleod M, Mignini LE, Jayaram P, Khan KS. Comparison of treatment effects between animal experiments and clinical trials: systematic review. BMJ. 2007 Jan 27;334(7586):197. Epub 2006 Dec 15.

COMMENTO: Da studi di concordanza tra modelli animali e uomo per gli effetti di 6 tipologie diverse di interventi e/o cure mediche (1 – corticosteroidi in trauma cranico, 2 – antifibrinolitici in emorragia, 3-trombolisi in ictus ischemico acuto, 4 -tirilazad in ictus ischemico acuto, 5 – corticosteroidi prenatali per prevenire la sindrome da stress respiratorio nei neonati, e 6 – trattamento con bifosfonati per prevenire l’osteoporosi) emerge che vi è concordanza tra gli effetti riscontrati sul modello animale e sull’uomo in circa il 50% dei casi. Gli autori concludono che la discordanza osservata tra modelli animali e pratica clinica può essere dovuta a bias oppure all’incapacità del modello animale di riprodurre i processi fisio-patologici umani (vedi Sena et al. 2010, per valutare meglio tali conclusioni).

Pound P., Shah Ebrahim, Peter Sandercock, Michael B Bracken, Ian Roberts Where is the evidence that animal research benefits humans? BMJ. 2004 February 28; 328(7438): 514–517.

COMMENT: Clinicians and the public often consider it axiomatic that animal research has contributed to the treatment of human disease, yet little evidence is available to support this view. Few methods exist for evaluating the clinical relevance or importance of basic animal research, and so its clinical (as distinct from scientific) contribution remains uncertain.1 Anecdotal evidence or unsupported claims are often used as justification — for example, statements that the need for animal research is “self evident” or that “Animal experimentation is a valuable research method which has proved itself over time.”  Such statements are an inadequate form of evidence for such a controversial area of research. We argue that systematic reviews of existing and future research are needed.

Rice JM, The institutional review board is an impediment to human research: the result is more animal-based research. Philosophy, Ethics, and Humanities in Medicine 2011 6:12.

Sena, E., van der Worp, H., Bath, P., Howells, D., & Macleod, M. (2010). Publication Bias in Reports of Animal Stroke Studies Leads to Major Overstatement of Efficacy PLoS Biology, 8(3) COMMENT: the authors performed a metaanalysis of animal models of acute ischemic stroke to try to estimate the effect of publication bias on the reported results. Neutral or negative animal studies may be more likely to remain unpublished than neutral clinical trials, giving the impression that the first are more often positive than the second. Si può notare come alla luce di questi dati anche lo studio di la maggior propensione a pubblicare i risultati positivi, rispetto a quelli negativi o neutri,   porti ad una sovrastima della concordanza tra risultati ottenuti sull’animale ed i riscontri clinici. Publication bias confounds attempts to use systematic reviews to assess the efficacy of various interventions tested in experiments modeling acute ischemic stroke, leading to a 30% overstatement of efficacy of interventions tested in animals. Alla luce di tale fatto possiamo ragionevolmente credere che le revisioni sistematiche, compresa quella di Perel et al. 2010 portino ad una sovrastima della concordanza uomo-animale… che risulterebbe quindi ancora più bassa.

Seok J, et al. Genomic responses in mouse models poorly mimic human inflammatory diseases. Proc Natl Acad Sci U S A. 2013 Feb 26;110(9):3507-12. doi: 10.1073/pnas.1222878110. Epub  2013 Feb 11.

Abstract:A cornerstone of modern biomedical research is the use of mouse models to explore basic pathophysiological mechanisms, evaluate new therapeutic approaches, and make go or no-go decisions to carry new drug candidates forward into clinical trials. Systematic studies evaluating how well murine models mimic human inflammatory diseases are nonexistent. Here, we show that, although acute inflammatory stresses from different etiologies result in highly similar genomic responses in humans, the responses in corresponding mouse models correlate poorly with the human conditions and also, one another. Among genes changed significantly in humans, the murine orthologs are close to random in matching their human counterparts (e.g., R(2) between 0.0 and 0.1). In addition to improvements in the current animal model systems, our study supports higher priority for translational medical research to focus on the more complex human conditions rather than relying on mouse models to study human inflammatory diseases.

Shanks, R. G. Greek , J.Greek, Are animal models predictive for humans? Philos Ethics Humanit Med. 2009; 4: 2. Published online 2009 January 15. doi: 10.1186/1747-5341-4-2 COMMENTO: Questo articolo, di stampo epistemologico, critica l’utilizzo dell’ animale come modello causale analogo (CAM) o predittivo ed introduce le basi della critica scientifica alla s.a. In particolare l’impiego dei modelli animali per lo studio delle patologie umane e negli studi farmacologici/tossicologici non sarebbero giustificati e si configurerebbero addirittura come un possibile ostacolo al progresso scientifico. Ciò non stupisce – affermano gli autori – se consideriamo ciò che sappiamo dalla biologia evoluzionistica e dello sviluppo, dai concetti di espressione e regolazione genica, dall’ epigenetica e genomica comparata.

Stingl L, Völkel M & Lindl T. 20 years of hypertension research using genetically modified animals: no clinically promising approaches in sight. ALTEX 2009; 26(1): 41-51.

van der Worp HB, Howells DW, Sena ES, Porritt MJ, Rewell S, O’Collins V et al.: Can animal models of disease reliably inform human studies? PLoS Med 2010, 7: e1000245 COMMENT: The value of animal experiments for  predicting the effectiveness of treatment strategies in clinical trials has remained controversial, mainly because of a recurrent failure of interventions apparently promising in animal models to translate to the clinic.

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