Complement Activation-Related Pathophysiological Changes in Anesthetized Rats: Activator-Dependent Variations of Symptoms and Mediators of Pseudoallergy

Dézsi, László; Mészáros, Tamás; Őrfi, Erik; Fülöp, Tamás; Hennies, Mark; Rosivall, László; Hamar, Péter; Szebeni, János; Szénási, Gábor

doi:10.3390/molecules24183283

Cited by 14 publications

(15 citation statements)

References 19 publications

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“…As for the concordance of blood cells changes in pigs and man, leukopenia followed by leukocytosis and/or thrombocytopenia were described during drug-induced HSRs in man as C-activationrelated [108][109][110][111], just as in pigs [15], rats [58,112], mice [20], and monkeys [113].…”

Section: Concordant Symptoms Of Pseudoallergy In Pigs and Humansmentioning

confidence: 99%

Human Clinical Relevance of the Porcine Model of Pseudoallergic Infusion Reactions

Szebeni

Bawa

2020

Biomedicines

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Pigs provide a highly sensitive animal model for pseudoallergic infusion reactions, which are mild-to-severe hypersensitivity reactions (HSRs) that arise following intravenous administration of certain nanoparticulate drugs (nanomedicines) and other macromolecular structures. This model has been used in research for three decades and was also proposed by regulatory bodies for preclinical assessment of the risk of HSRs in the clinical stages of nano-drug development. However, there are views challenging the human relevance of the model and its utility in preclinical safety evaluation of nanomedicines. The argument challenging the model refers to the “global response” of pulmonary intravascular macrophages (PIM cells) in the lung of pigs, preventing the distinction of reactogenic from non-reactogenic particles, therefore overestimating the risk of HSRs relative to its occurrence in the normal human population. The goal of this review is to present the large body of experimental and clinical evidence negating the “global response” claim, while also showing the concordance of symptoms caused by different reactogenic nanoparticles in pigs and hypersensitive man. Contrary to the model’s demotion, we propose that the above features, together with the high reproducibility of quantifiable physiological endpoints, validate the porcine “complement activation-related pseudoallergy” (CARPA) model for safety evaluations. However, it needs to be kept in mind that the model is a disease model in the context of hypersensitivity to certain nanomedicines. Rather than toxicity screening, its main purpose is specific identification of HSR hazard, also enabling studies on the mechanism and mitigation of potentially serious HSRs.

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Section: Concordant Symptoms Of Pseudoallergy In Pigs and Humansmentioning

confidence: 99%

Human Clinical Relevance of the Porcine Model of Pseudoallergic Infusion Reactions

Szebeni

Bawa

2020

Biomedicines

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“…While the porcine model is exceptional for modeling cardiovascular responses, it has become a substantial question in the field as to whether they are appropriate for translation of nanomedicines because of the infusion responses [12,13]. So, while one can obtain infusion responses to nanomedicines in mice and rats [18][19][20], the porcine response is a better predictor of the human response [14][15][16][17]21].…”

Section: Motivating Scenariomentioning

confidence: 99%

Temporal Progression: A case study in Porcine Survivability through Hemostatic Nanoparticles

Kulkarni

Maisha

et al. 2021

Preprint

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This paper focuses on the analysis of time series representation of blood loss and cytokines in animals experiencing trauma to understand the temporal progression of factors affecting survivability of the animal. Trauma related grave injuries cause exsanguination and lead to death. 50% of deaths especially in the armed forces are due to trauma injuries. Restricting blood loss usually requires the presence of first responders, which is not feasible in certain cases. Hemostatic nanoparticles have been developed to tackle these kinds of situations to help achieve efficient blood coagulation. Hemostatic nanoparticles were administered into trauma induced porcine animals (pigs) to observe impact on the cytokine and blood loss experienced by them. In this paper we present temporal models to study the impact of the hemostatic nanoparticles and provide snapshots about the trend in cytokines and blood loss in the porcine data to study their progression over time. We utilized Piecewise Aggregate Approximation, Similarity based Merging and clustering to evaluate the impact of the different hemostatic nanoparticles administered. In some cases the fluctuations in the cytokines may be too small. So in addition we highlight situations where temporal modelling that produces a smoothed time series may not be useful as it may remove out the noise and miss the overall fluctuations resulting from the nanoparticles. Our results indicate certain nanoparticles stand out and lead to novel hypothesis formation.

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“…Although rodents also react to certain iv. nanomedicines with hemodynamic changes, the effect is seen only at extremely high doses that are clinically not relevant (59)(60)(61). Thus, it does not seem reasonable to replace the pig model with a rat or mouse model to mimic human HSRs, and the idea to use a cirrhotic rat model seems even more far-fetched (6).…”

Section: The Similarity Between Hboc-induced Aggravation Of Hemorrhagmentioning

confidence: 99%

The Critical Choice of Animal Models in Nanomedicine Safety Assessment: A Lesson Learned From Hemoglobin-Based Oxygen Carriers

Bedőcs

Szebeni

2020

Front. Immunol.

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Intravenous injection of nanopharmaceuticals can induce severe hypersensitivity reactions (HSRs) resulting in anaphylactoid shock in a small percentage of patients, a phenomenon explicitly reproducible in pigs. However, there is a debate in the literature on whether the pig model of HSRs can be used as a safety test for the prediction of severe adverse reactions in humans. Given the importance of using appropriate animal models for toxicity/safety testing, the choice of the right species and model is a critical decision. In order to facilitate the decision process and to expand the relevant information regarding the pig or no pig dilemma, this review examines an ill-fated clinical development program conducted by Baxter Corporation in the United States 24 years ago, when HemeAssist, an αα (diaspirin) crosslinked hemoglobin-based O 2 carrier (HBOC) was tested in trauma patients. The study showed increased mortality in the treatment group relative to controls and had to be stopped. This disappointing result had far-reaching consequences and contributed to the setback in blood substitute research ever since. Importantly, the increased mortality of trauma patients was predicted in pig experiments conducted by US Army scientists, yet they were considered irrelevant to humans. Here we draw attention to that the underlying cause of hemoglobin-induced aggravation of hemorrhagic shock and severe HSRs have a common pathomechanism: cardiovascular distress due to vasoconstrictive effects of hemoglobin (Hb) and reactogenic nanomedicines, manifested, among others, in pulmonary hypertension. The main difference is that in the case of Hb this effect is due to NO-binding, while nanomedicines can trigger the release of proinflammatory mediators. Because of the higher sensitivity of cloven-hoof animals to this kind of cardiopulmonary

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Complement Activation-Related Pathophysiological Changes in Anesthetized Rats: Activator-Dependent Variations of Symptoms and Mediators of Pseudoallergy

Cited by 14 publications

References 19 publications

Human Clinical Relevance of the Porcine Model of Pseudoallergic Infusion Reactions

Human Clinical Relevance of the Porcine Model of Pseudoallergic Infusion Reactions

Temporal Progression: A case study in Porcine Survivability through Hemostatic Nanoparticles

The Critical Choice of Animal Models in Nanomedicine Safety Assessment: A Lesson Learned From Hemoglobin-Based Oxygen Carriers

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