Formononetin Inhibits Mast Cell Degranulation to Ameliorate Compound 48/80-Induced Pseudoallergic Reactions.

Formononetin (FNT) is a plant-derived isoflavone natural product with anti-inflammatory, antioxidant, and anti-allergic properties. We showed previously that FNT inhibits immunoglobulin E (IgE)-dependent mast cell (MC) activation, but the effect of FNT on IgE-independent MC activation is yet unknown. Our aim was to investigate the effects and possible mechanisms of action of FNT on IgE-independent MC activation and pseudoallergic inflammation. We studied the effects of FNT on MC degranulation in vitro with a cell culture model using compound C48/80 to stimulate either mouse bone marrow-derived mast cells (BMMCs) or RBL-2H3 cells. We subsequently measured ß-hexosaminase and histamine release, the expression of inflammatory factors, cell morphological changes, and changes in NF-κB signaling. We also studied the effects of FNT in several in vivo murine models of allergic reaction: C48/80-mediated passive cutaneous anaphylaxis (PCA), active systemic anaphylaxis (ASA), and 2,4-dinitrobenzene (DNCB)-induced atopic dermatitis (AD). The results showed that FNT inhibited IgE-independent degranulation of MCs, evaluated by a decrease in the release of ß-hexosaminase and histamine and a decreased expression of inflammatory factors. Additionally, FNT reduced cytomorphological elongation and F-actin reorganization and attenuated NF-κB p65 phosphorylation and NF-κB-dependent promoter activity. Moreover, the administration of FNT alleviated pseudoallergic responses in vivo in mouse models of C48/80-stimulated PCA and ASA, and DNCB-induced AD. In conclusion, we suggest that FNT may be a novel anti-allergic drug with great potential to alleviate pseudoallergic responses via the inhibition of IgE-independent MC degranulation and NF-κB signaling.

Guiding Chemically Synthesized Peptide Drug Lead Optimization by Derisking Mast Cell Degranulation-Related Toxicities of a NaV1.7 Peptide Inhibitor.

Studies have shown that some peptides and small molecules can induce non IgE-mediated anaphylactoid reactions through mast cell activation. Upon activation, mast cells degranulate and release vasoactive and proinflammatory mediators, from cytoplasmic granules into the extracellular environment which can induce a cascade of severe adverse reactions. This study describes a lead optimization strategy to select NaV1.7 inhibitor peptides that minimize acute mast cell degranulation (MCD) toxicities. Various in vitro, in vivo, and PKPD models were used to screen candidates and guide peptide chemical modifications to mitigate this risk. Anesthetized rats dosed with peptides demonstrated treatment-related decreases in blood pressure and increases in plasma histamine concentrations which were reversible with a mast cell stabilizer, supporting the MCD mechanism. In vitro testing in rat mast cells with NaV1.7 peptides demonstrated a concentration-dependent increase in histamine. Pharmacodynamic modeling facilitated establishing an in vitro to in vivo correlation for histamine as a biomarker for blood pressure decline via the MCD mechanism. These models enabled assessment of structure-activity relationship (SAR) to identify substructures that contribute to peptide-mediated MCD. Peptides with hydrophobic and cationic characteristics were determined to have an elevated risk for MCD, which could be reduced or avoided by incorporating anionic residues into the protoxin II scaffold. Our analyses support that in vitro MCD assessment in combination with PKPD modeling can guide SAR to improve peptide lead optimization and ensure an acceptable early in vivo tolerability profile with reduced resources, cycle time, and animal use.

Therapeutic Potential of MRGPRX2 Inhibitors on Mast Cells.

Mast cells (MCs) act as primary effectors in inflammatory and allergic reactions by releasing intracellularly-stored inflammatory mediators in diseases. The two major pathways for MC activation are known to be immunoglobulin E (IgE)-dependent and -independent. Although IgE-dependent signaling is the main pathway to MC activation, IgE-independent pathways have also been found to serve pivotal roles in the pathophysiology of various inflammatory conditions. Recent studies have shown that human and mouse MCs express several regulatory receptors such as toll-like receptors (TLRs), CD48, C300a, and GPCRs, including mas-related GPCR-X2 (MRGPRX2). MRGPRX2 has been reported as a novel GPCR that is expressed in MCs activated by basic secretagogues, neurokinin peptides, host defense antimicrobial peptides, and small molecule compounds (e.g., neuromuscular blocking agents) and leads to MC degranulation and eicosanoids release under in vitro experimental condition. Functional analyses of MRGPRX2 and Mrgprb2 (mouse ortholog) indicate that MRGPRX2 is involved in MC hypersensitivity reactions causing neuroinflammation such as postoperative pain, type 2 inflammation, non-histaminergic itch, and drug-induced anaphylactic-like reactions. In this review, we discuss the roles in innate immunity through functional studies on MRGPRX2-mediated IgE-independent MC activation and also the therapeutic potential of MRGPRX2 inhibitors on allergic and inflammatory diseases.

[A pseudoallergic reaction involved in developing bullous oral lichen planus in patients with increased gastric acid-producing function]. / Rol' psevdoallergicheskoi reaktsii v razvitii bulleznoi formy krasnogo ploskogo lishaya slizistoi obolochki rta u bol'nykh s povyshennoi kislotoobrazuyushchei funktsiei zheludka.

Lichen planus of the oral mucosa (LPOOR) is a chronic autoimmune disease. With a complicated course of the disease, other clinical and pathomorphological signs are added to the clinical picture of the reticular form, including blisters in the bullous form of the disease. It is known that LPOOR develops mainly by the mechanism of delayed-type hypersensitivity reaction, and in complicated forms - with the addition of a true allergic reaction of immediate-type hypersensitivity. OBJECTIVE: To determine the role of pseudo-allergic reaction in the development of the bullous form of LPR in patients with increased acid-forming function of the stomach. MATERIAL AND METHODS: The level of histamine in blood was studied by high-performance liquid chromatography and blood IgE by the immunochemiluminescent method in 38 patients with the bullous form of LPOOR against the background of acid-dependent diseases and 14 patients with the reticular form of LP RR with the absence of hyperchlorhydria. For the treatment of patients with the bullous form of LPOOR, drugs were used - H1 and H2 receptor blockers and proton pump inhibitors. RESULTS: A positive result was obtained in 68.4% of cases. CONCLUSION: Thus, a pseudoallergic component has been established in the development of the bullous form of the LP of ROS against the background of increased acid-forming function of the stomach.

Pseudoallergic Reactions of Xuebijing Injection and Its Rational Drug Use / 中国实验方剂学杂志

Objective:To investigate whether the adverse reactions of Xuebijing injection (XBJJ) are mainly pseudoallergic reactions and explore the influencing factors of its pseudoallergic reactions. Method:Mouse model of pseudoallergic reaction was used to study the anaphylactoid reaction of XBJJ which at 0.5, 1 and 2 times of the highest clinical concentration. Next, we compared the differences in pseudoallergic reactions caused by XBJJ for different storage times after preparation. Specifically, XBJJ was prepared into different concentrations, stored for 10 minutes, 2.5 hours, 6 hours and 24 hours, and then injected into the tail vein of mice. Finally, three different injection speeds of 3 seconds, 45 seconds and 90 seconds were selected for XBJJ injection, and then the differences in the paeudoallergic reactions induced by XBJJ in mice under different injection speeds were compared. Result:XBJJ induces pseudoallergic reactions in mice when the drug concentration is higher than the clinically recommended concentration. Compared with storage for 10 minutes after preparation, the degree of pseudoallergic reaction in mice induced by the same concentration of XBJJ increased with the extension of storage time. In addition, when XBJJ was injected in 3 s (the injection rate was 0.083 mL·s^-1), it produced the strongest pseudoallergic reaction. Conclusion:The adverse reactions induced by XBJJ are mainly pseudoallergic reactions. Excessive storage time after preparation and fast injection speed of XBJJ will lead to aggravation of pseudoallergic reactions in mice. When XBJJ is used clinically, it should strictly follow the usage, dosage, concentration, and drip rate recommended in the drug instruction manual. Rational drug use is of positive significance for improving the safety of XBJJ.

Eremomycin pyrrolidide: a novel semisynthetic glycopeptide with improved chemotherapeutic properties.

PURPOSE: Development of new semisynthetic glycopeptides with improved antibacterial efficacy and reduced pseudoallergic reactions. METHODS: Semisynthetic glycopeptides 3-6 were synthesized from vancomycin (1) or eremomycin (2) by the condensation with pyrrolidine or piperidine. The minimum inhibitory concentration (MIC) for the new derivatives was measured by the broth micro-dilution method on a panel of clinical isolates of Staphylococcus and Enterococcus. Acute toxicity (50% lethal dose, maximum tolerated doses), antibacterial efficacy on model of systemic bacterial infection with S. aureus and pseudoallergic inflammatory reaction (on concanavalin A) of eremomycin pyrrolidide (5) were evaluated in mice according to standard procedures. RESULTS: The eremomycin pyrrolidide (5) was the most active compound and showed a high activity against Gram-positive bacteria: vancomycin-susceptible staphylococci and enterococci (minimum inhibitory concentrations [MICs] 0.13-0.25 mg/L), as well as vancomycin-intermediate resistant Staphylococcus aureus (MICs 1 mg/L). Antimicrobial susceptibility tested on a panel of 676 isolates showed that 5 had similar activity for the genera Staphylococcus and Enterococcus with MIC90=0.5 mg/L, while vancomycin had MIC90=1-2 mg/L. The number of resistant strains of Enterococcus faecium (vancomycin-resistant enterococci) (MIC =64 mg/L) with this value was 7 (8%) for vancomycin (1) and 0 for the compound 5. In vivo comparative studies in a mouse model of systemic bacterial infection with S. aureus demonstrated that the efficacy of 5 was notably higher than that of the original antibiotics 1 and 2. In contrast to 1, compound 5 did not induce pseudoallergic inflammatory reaction (on concanavalin A). CONCLUSION: The new semisynthetic derivative eremomycin pyrrolidide (5) has high activity against staphylococci and enterococci including vancomycin-resistant strains. Compound 5 has a higher efficacy in a model of staphylococcal sepsis than vancomycin (1) or eremomycin (2). In striking contrast to natural antibiotics, the novel derivative 5 does not induce a pseudoallergic inflammatory reaction to concanavalin A and therefore has no histamine release activity. These results indicate the advantages of a new semisynthetic glycopeptide antibiotic eremomycin pyrrolidide (5) which may be a prospective antimicrobial agent for further pre-clinical and clinical evaluations.

Infusion Reactions Associated with the Medical Application of Monoclonal Antibodies: The Role of Complement Activation and Possibility of Inhibition by Factor H.

Human application of monoclonal antibodies (mAbs), enzymes, as well as contrast media and many other particulate drugs and agents referred to as "nanomedicines", can initiate pseudoallergic hypersensitivity reactions, also known as infusion reactions. These may in part be mediated by the activation of the complement system, a major humoral defense system of innate immunity. In this review, we provide a brief outline of complement activation-related pseudoallergy (CARPA) in general, and then focus on the reactions caused by mAb therapy. Because the alternative pathway of complement activation may amplify such adverse reactions, we highlight the potential use of complement factor H as an inhibitor of CARPA.

Pseudoallergic reactions of traditional chinese medicine injections and the approaches for risk prevention and control / 中国药学杂志

Allergic hypersensitivity reactions (AHRs) are the most commonly reported adverse reactions of traditional Chinese medicine injections, mainly including skin and mucosa redness, itching, abdominal pain, chest tightness, dyspnea and nausea, blood pressure decline, with clinical symptoms, and even shock or death. In this paper, we analyzed the characteristics of clinical adverse reactions and preclinical study results of traditional Chinese medicine injections, and proposed a view of point that the main adverse reactions of traditional Chinese medicine injections are nonallergic hypersensitivity reactions (NHRs) or pseudoallergic reactions (PARs) instead of real AHRs. Because there are absolute differences in the characteristics and the pathogenesis mechanisms between PARs and AHRs, they should not be confused, otherwise, the clinical processing measures and the direction of basic research on the adverse reactions of traditional Chinese medicine injections would be misleading. This paper also discussed the approaches for risk prevention and control of PARs of traditional Chinese medicine injections.

Lack of association of plasma histamine with diamine oxidase in chronic idiopathic urticaria.

BACKGROUND: Chronic idiopathic urticaria (CIU) is considered a complex and multifactorial disease. Excessive histamine intake may induce an attack of urticaria. The main enzyme for histamine metabolism is diamine oxidase (DAO). OBJECTIVE: Plasma histamine concentrations and DAO activities were evaluated to determine whether there are abnormalities in the histamine metabolism of CIU patients. METHODS: Seventy-five CIU patients and twenty-five healthy control subjects were included in the study. Blood was taken from all subjects to measure plasma levels of the histamine and DAO. RESULTS: Mean plasma histamine levels were significantly higher in CIU patients (11.59±10.98 nM) than in the control subjects (8.75±2.55 nM) (p=0.04). Mean DAO activities were lower in patients of CIU (80.86±26.81 histamine degrading unit [HDU]/ml) than in the controls (81.60±9.67 HDU/ml), but without significant difference. In 15 CIU patients with gastrointestinal symptoms, the mean histamine concentration was higher (12.43±7.97 nM) and DAO activity was lower (77.93±27.53 HDU/ml) than in the remaining 60 CIU patients without gastrointestinal symptoms (11.38±11.67 nM and 81.58±26.82 HDU/ml), without significant difference. The relationship between DAO activity and plasma histamine concentrations showed a significant negative linear value (p=0.001). There were no significant relationships between plasma histamine concentrations and symptom severity score. CONCLUSION: In CIU patients, a high plasma histamine concentration may not be explained by DAO activity. CIU patients with gastrointestinal (GI) symptoms showed no significantly lower DAO activity. Larger group studies are required to elucidate the relationship between plasma histamine concentrations and DAO activity, especially of CIU patients with GI symptomsto understand the difference in CIU patients with and without GI symptoms.

Lack of Association of Plasma Histamine with Diamine Oxidase in Chronic Idiopathic Urticaria

BACKGROUND: Chronic idiopathic urticaria (CIU) is considered a complex and multifactorial disease. Excessive histamine intake may induce an attack of urticaria. The main enzyme for histamine metabolism is diamine oxidase (DAO). OBJECTIVE: Plasma histamine concentrations and DAO activities were evaluated to determine whether there are abnormalities in the histamine metabolism of CIU patients. METHODS: Seventy-five CIU patients and twenty-five healthy control subjects were included in the study. Blood was taken from all subjects to measure plasma levels of the histamine and DAO. RESULTS: Mean plasma histamine levels were significantly higher in CIU patients (11.59+/-10.98 nM) than in the control subjects (8.75+/-2.55 nM) (p=0.04). Mean DAO activities were lower in patients of CIU (80.86+/-26.81 histamine degrading unit [HDU]/ml) than in the controls (81.60+/-9.67 HDU/ml), but without significant difference. In 15 CIU patients with gastrointestinal symptoms, the mean histamine concentration was higher (12.43+/-7.97 nM) and DAO activity was lower (77.93+/-27.53 HDU/ml) than in the remaining 60 CIU patients without gastrointestinal symptoms (11.38+/-11.67 nM and 81.58+/-26.82 HDU/ml), without significant difference. The relationship between DAO activity and plasma histamine concentrations showed a significant negative linear value (p=0.001). There were no significant relationships between plasma histamine concentrations and symptom severity score. CONCLUSION: In CIU patients, a high plasma histamine concentration may not be explained by DAO activity. CIU patients with gastrointestinal (GI) symptoms showed no significantly lower DAO activity. Larger group studies are required to elucidate the relationship between plasma histamine concentrations and DAO activity, especially of CIU patients with GI symptomsto understand the difference in CIU patients with and without GI symptoms.