α-Gal on Crotalidae-polyvalent Fab antivenom (CroFab): Investigating the relevance to immediate hypersensitivity reactions.
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ABSTRACT:
SUBMITTER: Straesser M
PROVIDER: S-EPMC7870545 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Investigating delayed-onset Drug Hypersensitivity Reactions Prospectively
| PRJNA994264 | ENA
Project description:Investigating delayed-onset Drug Hypersensitivity Reactions Prospectively
| PRJNA994263 | ENA
Project description:Background:Antivenoms are the only validated treatment against snakebite envenoming. Numerous drawbacks pertaining to their availability, safety and efficacy are becoming increasingly evident due to low sustainability of current productions. Technological innovation of procedures generating therapeutics of higher purity and better physicochemical characteristics at acceptable cost is necessary. The objective was to develop at laboratory scale a compact, feasible and economically viable platform for preparation of equine F(ab')2 antivenom against Vipera ammodytes ammodytes venom and to support it with efficiency data, to enable estimation of the process cost-effectiveness. Methods:The principle of simultaneous caprylic acid precipitation and pepsin digestion has been implemented into plasma downstream processing. Balance between incomplete IgG breakdown, F(ab')2 over-digestion and loss of the active drug's protective efficacy was achieved by adjusting pepsin to a 1:30 substrate ratio (w/w) and setting pH at 3.2. Precipitation and digestion co-performance required 2 h-long incubation at 21 °C. Final polishing was accomplished by a combination of diafiltration and flow-through chromatography. In vivo neutralization potency of the F(ab')2 product against the venom's lethal toxicity was determined. Results:Only three consecutive steps, performed under finely tuned conditions, were sufficient for preservation of the highest process recovery with the overall yield of 74%, comparing favorably to others. At the same time, regulatory requirements were met. Final product was aggregate- and pepsin-free. Its composition profile was analyzed by mass spectrometry as a quality control check. Impurities, present in minor traces, were identified mostly as IgG/IgM fragments, contributing to active drug. Specific activity of the F(ab')2 preparation with respect to the plasma was increased 3.9-fold. Conclusion:A highly streamlined mode for production of equine F(ab')2 antivenom was engineered. In addition to preservation of the highest process yield and fulfillment of the regulatory demands, performance simplicity and rapidity in the laboratory setting were demonstrated. Suitability for large-scale manufacturing appears promising.
| S-EPMC7384442 | biostudies-literature
Project description:Backgroundβ-lactam antibiotics are associated with a variety of immune-mediated or hypersensitivity reactions, including immediate (type I) reactions mediated by antigen-specific IgE.ObjectiveWe sought to identify genetic predisposing factors for immediate reactions to β-lactam antibiotics.MethodsPatients with a clinical history of immediate hypersensitivity reactions to either penicillins or cephalosporins, which were immunologically confirmed, were recruited from allergy clinics. A genome-wide association study was conducted on 662 patients (the discovery cohort) with a diagnosis of immediate hypersensitivity and the main finding was replicated in a cohort of 98 Spanish cases, recruited using the same diagnostic criteria as the discovery cohort.ResultsGenome-wide association study identified rs71542416 within the Class II HLA region as the top hit (P = 2 × 10-14); this was in linkage disequilibrium with HLA-DRB1∗10:01 (odds ratio, 2.93; P = 5.4 × 10-7) and HLA-DQA1∗01:05 (odds ratio, 2.93, P = 5.4 × 10-7). Haplotype analysis identified that HLA-DRB1∗10:01 was a risk factor even without the HLA-DQA1∗01:05 allele. The association with HLA-DRB1∗10:01 was replicated in another cohort, with the meta-analysis of the discovery and replication cohorts showing that HLA-DRB1∗10:01 increased the risk of immediate hypersensitivity at a genome-wide level (odds ratio, 2.96; P = 4.1 × 10-9). No association with HLA-DRB1∗10:01 was identified in 268 patients with delayed hypersensitivity reactions to β-lactams.ConclusionsHLA-DRB1∗10:01 predisposed to immediate hypersensitivity reactions to penicillins. Further work to identify other predisposing HLA and non-HLA loci is required.
| S-EPMC8100096 | biostudies-literature
Project description:The reported incidence of immediate hypersensitivity reactions (IHR) including anaphylaxis after COVID-19 vaccination is 10-fold higher than for other vaccines. Several patient groups are theorized to be at particular risk. Since specific vaccination guidelines for these patients are based on expert opinion, we performed a retrospective monocentric analysis of the tolerability of adenoviral vector and mRNA-based COVID-19 vaccines in a cohort of patients allegedly at high risk of IHR. Reactions were assessed immediately on-site by allergists during a monitored vaccination protocol and after 3-7 days through telephone interviews. The cohort included 196 patients (aged 12-84 years) with primary mast cell disease (pMCD, 50.5%), idiopathic anaphylaxis (IA, 19.9%), hereditary angioedema (HAE, 5.1%) or miscellaneous indications (24.5%). Twenty-five immediate reactions were observed in 221 vaccine doses (11.3%). Most occurred in IA or miscellaneous patients. None fulfilled anaphylaxis criteria and most were mild and self-limiting. Reaction occurrence was significantly associated with female sex. In total, 13.5% of pMCD patients reported mast cell activation-like symptoms within 72 h post-vaccination. All pediatric pMCD patients (n = 9, 12-18 years) tolerated both mRNA-based vaccine doses. In summary, adenoviral vector and mRNA-based COVID-19 vaccines were safe and well-tolerated in patients with pMCD, HAE, and IA. No anaphylaxis was observed. The mild and subjective nature of most reactions suggests a nocebo effect associated with vaccination in a medicalized setting. Patients with pMCD could experience mild flare-ups of mast cell activation-like symptoms, supporting antihistamine premedication.
| S-EPMC8879861 | biostudies-literature
Project description:The European continent is inhabited by medically important venomous Viperinae snakes. Vipera ammodytes, Vipera berus, and Vipera aspis cause the greatest public health problems in Europe, but there are other equally significant snakes in specific regions of the continent. Immunotherapy is indicated for patients with systemic envenoming, of which there are approximately 4000 annual cases in Europe, and was suggested as an indication for young children and pregnant women, even if they do not have systemic symptoms. In the present study, the safety and venom-neutralizing efficacy of Inoserp Europe-a new F(ab')₂ polyvalent antivenom, designed to treat envenoming by snakes in the Eurasian region-were evaluated. In accordance with World Health Organization recommendations, several quality control parameters were applied to evaluate the safety of this antivenom. The venom-neutralizing efficacy of the antivenom was evaluated in mice and the results showed it had appropriate neutralizing potency against the venoms of several species of Vipera, Montivipera, and Macrovipera. Paraspecificity of the antivenom was demonstrated as well, since it neutralized venoms of species not included in the immunization schemes and contains satisfactory levels of total proteins and F(ab')₂ fragment concentration. Therefore, this new polyvalent antivenom could be effective in the treatment of snake envenoming in Europe, including Western Russia and Turkey.
| S-EPMC6468668 | biostudies-other
Project description:Kovax® antivenom is the main treatment for toxins produced by the Gloydius species. However, research on adverse reactions after Kovax® antivenom administration is scarce. We aimed to identify the incidence and characteristics of adverse reactions after Kovax® antivenom administration. We conducted a retrospective review of the medical records of snakebite patients in Korea between January 2008 and September 2019. We identified the frequency, characteristics, and treatments of adverse reactions to Kovax® antivenom. There were 150 patients with snakebites, of whom 121 (80.7%) patients received Kovax® antivenom. Adverse reactions occurred in five patients (4.1%). Acute adverse reactions within 24 h of antivenom administration occurred in two patients (1.7%). The symptoms of patients with acute adverse reactions were nausea, diaphoresis, dizziness, and hypotension. Delayed adverse reactions that occurred 24 h after antivenom administration were reported in three patients (2.5%). One patient had a skin rash after 10 days, and two patients had fever 37 and 48 h after antivenom use. In conclusion, most patients were managed safely after Kovax® antivenom, and the incidence of adverse reactions was low. Severe adverse reactions occurred in a small percentage of patients, and there were no deaths.
| S-EPMC7472312 | biostudies-literature
Project description:IntroductionAlpha-gal syndrome (AGS) is characterized by delayed hypersensitivity to non-primate mammalian meat in people having specific immunoglobulin E (sIgE) to the oligosaccharide galactose-alpha-1,3-galactose. AGS has been linked to tick bites from Amblyomma americanum (Aa) in the U.S. A small animal model of meat allergy is needed to study the mechanism of alpha-gal sensitization, the effector phase leading to delayed allergic responses and potential therapeutics to treat AGS.MethodsEight- to ten-weeks old mice with a targeted inactivation of alpha-1,3-galactosyltransferase (AGKO) were injected intradermally with 50 μg of Aa tick salivary gland extract (TSGE) on days 0, 7, 21, 28, 42, and 49. Total IgE and alpha-gal sIgE were quantitated on Day 56 by enzyme-linked immunosorbent assay. Mice were challenged orally with 400 mg of cooked pork kidney homogenate or pork fat. Reaction severity was assessed by measuring a drop in core body temperature and scoring allergic signs.ResultsCompared to control animals, mice treated with TSGE had 190-fold higher total IgE on Day 56 (0.60 ± 0.12 ng/ml vs. 113.2 ± 24.77 ng/ml; p < 0.001). Alpha-gal sIgE was also produced in AGKO mice following TSGE sensitization (undetected vs. 158.4 ± 72.43 pg/ml). Further, sensitized mice displayed moderate clinical allergic signs along with a drop in core body temperature of ≥2°C as an objective measure of a systemic allergic reaction. Interestingly, female mice had higher total IgE responses to TSGE treatment but male mice had larger declines in mean body temperature.ConclusionTSGE-sensitized AGKO mice generate sIgE to alpha-gal and demonstrate characteristic allergic responses to pork fat and pork kidney. In keeping with the AGS responses documented in humans, mice reacted more rapidly to organ meat than to high fat pork challenge. This mouse model establishes the central role of tick bites in the development of AGS and provides a small animal model to mechanistically study mammalian meat allergy.
| S-EPMC8342229 | biostudies-literature
Project description:BackgroundDentine hypersensitivity (DH) can occur after gum recession or enamel loss and may impact quality of life. Treatments include toothpastes that decrease DH by occluding dentine tubules. One effective occluding ingredient used in toothpastes is stannous fluoride (SnF2), but this can be unstable in aqueous formulation. These three studies aimed to characterise the short-term effects of an experimental, anhydrous SnF2 dentifrice on DH.MethodsThree examiner-blind, parallel-group studies evaluated DH in participants with the condition after a single brushing and after 3d brushing with an experimental anhydrous 0.454% SnF2/polyphosphate toothpaste (Test) or a toothpaste containing 0.76% sodium monofluorophosphate (Control). Test treatment participants brushed two pre-identified sensitive teeth first, then their remaining dentition for ≥1 min ('focused brushing'). Control treatment participants brushed their whole dentition for ≥1 min. DH was measured after single brushing and after 3d twice-daily use, via evaporative (air) (Schiff Sensitivity Scale) and tactile (Yeaple probe) stimuli and analysed using an ANCOVA model.ResultsIn all studies, after 3d treatment, the Test toothpaste/brushing regimen significantly reduced DH compared to the Control regimen by both evaporative and tactile stimuli assessment (p < 0.0001 for all). The Test regimen also significantly reduced DH from baseline at both time-points by both measures in all studies (p < 0.0001 for all). Mean Schiff sensitivity score differences (95% confidence intervals) between Test and Control regimens after 3d were: Study 1: - 0.45 (- 0.577, - 0.319); Study 2: - 0.40 (- 0.505, - 0.300); Study 3: - 1.31 (- 1.500, - 1.128). Mean tactile score differences were: Study 1: 11.30 (7.927, 14.662); Study 2: 3.57 (2.531, 4.614); Study 3: 24.54 (20.349, 28.736). After single use, in Studies 2 and 3, the Test toothpaste/brushing regimen significantly reduced DH versus Control by both measures (p < 0.001 for all); in Study 1, treatment differences were not significant. Toothpastes were generally well-tolerated.ConclusionsTaken together, these studies indicated focused brushing with an experimental anhydrous 0.454% SnF2/polyphosphate toothpaste reduces DH compared to brushing with a conventional toothpaste after single use, with greater reduction after 3d.Trial registrationRegistrations at ClinicalTrials.gov : Study 1: NCT02832375 (registered 26.July.2016); Study 2: NCT02731833 (registered 26.April.2016); Study 3: NCT02923895 (registered 5.October.2016).
| S-EPMC6549378 | biostudies-literature
Project description:Metabolites/impurities (MIs) of penicillin are normally considered to be the main substances inducing immediate hypersensitivity reactions in penicillin treatment. Our previous research found that penicillin can cause non-allergic hypersensitivity reactions (NAHRs) by directly triggering vascular hyperpermeability and exudative inflammation. However, the chief culprits and underlying mechanisms involved in penicillin-induced NAHRs have not yet been fully elucidated. In this study, we used a combination of approaches including a mouse non-allergic hypersensitivity reaction model, UPLC-MS/MS analyses of arachidonic acid metabolites (AAMs), immunoblotting technique, and molecular docking, etc to investigate the culprits involved in penicillin-induced hypersensitivity reactions. We found penilloic acid, one of the main MIs of penicillin, could trigger NAHRs via inducing increased vascular permeability, while the other MIs did no exhibit similar effect. Penilloic acid-induced reactions were not IgE-dependent. Significantly increased arachidonic acids and cascade metabolites in lungs, and activation of RhoA/ROCK signaling pathway in the ears and lungs of mice were noticed after once administration of penilloic acid. This study revealed that penilloic acid was the chief culprit involved in penicillin-induced immediate NAHRs in mice, which mainly associated with direct stimulation of vascular hyperpermeability and exudative inflammation. The activations of AAMs and RhoA/ROCK signaling pathway played important roles in these reactions.
| S-EPMC9443931 | biostudies-literature