Search Results (3)

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. Full article

Anaphylactoid shock is a fatal hypersensitivity response caused by non-IgE mediated mast cell activation. These reactions are mediated by a family of G protein-coupled receptors (GPCRs) known as Mas related GPCRX2 (MRGPRX2). Several US FDA approved drugs which are used in day to day life have been reported to cause anaphylactoid shock. Surprisingly, no therapeutic drugs are available which can directly target MRGPRX2 for treatment of anaphylactoid shock. Genistein is a non-steroidal polyphenol known for its diverse physiological and pharmacological activities. In recent studies, Genistein has been reported for its anti-inflammatory activity on mast cells. However, the effects and mechanistic pathways of Genistein on anaphylactoid reaction remain unknown. In the present study, we designed a battery of in-vitro, in-silico and in-vivo experiments to evaluate the anti-anaphylactoid activity of Genistein in order to understand the possible molecular mechanisms of its action. The in-vitro results demonstrated the inhibitory activity of Genistein on MRGPRX2 activation. Further, a mouse model of anaphylactoid shock was used to evaluate the inhibitory activity of Genistein on blood vessel leakage and hind paw edema. Taken together, our findings have demonstrated a therapeutic potential of Genistein as a lead compound in the treatment of anaphylactoid shock via MRGPRX2. Full article

Besides crystalloids, colloids are used for the treatment of hypovolemia and shock. They are high-molecular-weight proteins of bovine origin with properties of more rapid replacement of circulating blood volume. Iso-oncotic character provides the volume effect (»100%) close to the volume intravenously infused with the duration of action for 2–4 hours. Gelatin solutions are excreted with urine and feces in unchanged form without prolonged fixation in organism. Even in case of acute renal failure, gelatin peptides do not accumulate due to increased activity of proteolytic enzymes; therefore, they are the first-choice colloids. Gelatin solutions do not change coagulation as other colloids; just they may cause hemodilution as crystalloids do, so they are safe in case of hemorrhage and thrombocytopenia. There is a decreased risk of bleeding when gelatin solutions are used in surgery as compared with other colloids; in addition, they protect from hypotension due to vasodilatation in epidural or spinal analgesia. Gelatin solutions may cause compensatory hyperemia and increase of cardiac output, cardiac index, myocardial contractility, mean arterial blood pressure, and diuresis; in addition, oxygen delivery to the tissues improves. The dosage depends on clinical condition of a patient, and it is suggested to be 100–2000 mL and even more, for isovolemic hemodilution – 20 mL/kg of body weight. Adverse reactions such as anaphylactoid or anaphylactic to gelatin derivates are rare and similar to other colloids. Full article