Ant Venom-Based Ceramide Therapy Is Effective Against Atopic Dermatitis In Vivo.

BACKGROUND: Atopic dermatitis (AD) is a common skin condition with relatively few therapeutic alternatives. These include corticosteroids, which address inflammation but not superinfection, and Januse kinase (JAK) inhibitors, which have a US Food and Drug Administration (FDA) black box for potential carcinogenicity. METHODS: We demonstrate that S14, a synthetic derivative of ant venom-derived solenopsin, has potent anti inflammatory effects on the OVA murine model of atopic dermatitis. S14 has demonstrated prior activity in murine psoriasis and has the benefit of ceramide anti-inflammatory effects without being able to be metabolized into proinflammatory sphingosine-1 phosphate. RESULTS: The efficacy of S14 accompanied by the induction of IL-12 suggests a commonality in inflammatory skin disorders, and our results suggest that pharmacological ceramide restoration will be broadly effective for inflammatory skin disease. CONCLUSIONS: Solenopsin derivative S14 has anti-inflammatory effects in murine models of AD and psoriasis. This makes S14 a strong candidate for human use, and pre-IND studies are warranted.J Drugs Dermatol. 2023;22(10):1001-1006 doi:10.36849/JDD.7308.

Fire ant Immunotherapy with inteRvals Extended to 12 weekS: The FIRES study.

BACKGROUND: There are no studies describing 12-week extended maintenance interval (EMI) immunotherapy (IT) efficacy in preventing anaphylaxis to imported fire ant (IFA) stings. OBJECTIVE: The purpose of this study was to determine the safety and efficacy of 12-week maintenance intervals in patients treated with IFA IT. METHODS: After a minimum of 3 months of conventional maintenance interval IT and verification of baseline efficacy, adults with IFA hypersensitivity were prospectively enrolled and extended their maintenance doses to 6-, 8-, and 12-week intervals. Efficacy was confirmed by means of an annual IFA sting challenge. RESULTS: A total of 25 patients initiated EMI. The severity of their initial systemic reactions was mild in 8 patients (32%), moderate in 10 patients (40%), and severe in 7 patients (28%). Maintenance IT duration at trial entry was less than 3 years in 18 patients (mean 11 months; range 3-28 months), 3 to 5 years in 4 patients (mean 46 months; range 36-57 months), and greater than 5 years in 5 patients (mean 111 months; range 67-197 months). The treatment cohort did not experience systemic reactions to extended interval injections, cluster refill injections, field stings, or sting challenges. CONCLUSION: This prospective longitudinal cohort study revealed that in adults 18 years old or older who have received at least 3 months of maintenance dose IFA-whole body extract IT with proven efficacy, extension to a 12-week EMI is a safe effective treatment option. The benefits of EMI include a reduced number of injections, clinic visits, and lapses in maintenance IT.

Spread of stinging ants to oceanic islands, and the need to raise awareness of prevention and treatment of ant stings.

OBJECTIVE: Venomous invasive ants are rapidly dispersing throughout oceanic islands. Medics unfamiliar with envenomation or venom-induced anaphylaxis may be unprepared for the range of possible reactions and corresponding treatments. We detail the suboptimal treatment of a patient suffering anaphylaxis from an ant sting on a remote island and describe what treatment should have been provided. METHODS: The patient experienced stings on his feet from an ant later identified as tropical fire ant, Solenopsis geminata. Clinical examination revealed throat swelling without obstruction of the airway or pharynx. RESULTS: The patient was provided the following suboptimal treatment: intravenously-administered antihistamine and saline perfusion. Injected epinephrine should be the standard first line of treatment for anaphylaxis, even when not all symptoms are present. CONCLUSION: A rise in invasive hymenopteran stings on oceanic islands is inevitable, and proactively improving public awareness and medical training could save lives.

Long-term adherence to imported fire ant subcutaneous immunotherapy.

BACKGROUND: Imported fire ant (IFA) whole-body extract subcutaneous immunotherapy (IT) is a safe and effective treatment for IFA hypersensitivity, with a recommended length of treatment of 3 to 5 years. OBJECTIVE: To evaluate long-term IFA IT adherence in patients with IFA allergy living in an endemic area. METHODS: During 2007 to 2014, patients with IFA-sting systemic reactions and a recommendation to start IFA IT were prospectively enrolled in this study. Subjects were contacted annually for interval IT adherence. Institutional review board approval was obtained. RESULTS: A total of 87 subjects, ages 2 to 64 years, with a recommendation to initiate IFA IT, were enrolled. Subjects were predominantly adult (76%) and female (55%), and 30% had asthma. Of these patients, 77 (89%) initiated treatment within 1 year of recommendation; 18 (23%) adhered to a 3-year course; and 10 (13%) adhered to a 5-year course. At 3 years, there were no significant differences in adherence between male and female subjects (28% vs 19%, P = .33), children and adults (25% vs 22%, P = .79), or those with or without asthma (30% vs 20%, P = .31). Adherence in subjects with mild initial reactions was lower than in subjects with moderate-to-severe reactions (0% vs 25%, P = .05) at 3 years only. Conventional buildup and concurrent flying Hymenoptera venom immunotherapy were predictive of adherence. Reasons for discontinuation were relocation to a nonendemic area (29%) and inconvenience (27%). CONCLUSION: This study showed poor long-term adherence to IFA IT at 3 and 5 years. Initial sting severity, buildup protocol, and concurrent flying Hymenoptera venom immunotherapy were predictors for long-term IT adherence.

Venenos animais como possíveis ferramentas terapéuticas contra o estresse oxidativo em diversas doengas: Revisao da Literatura / Animal venoms as possible therapeutic tools against oxidative stress in several diseases: Literature Review

Resumo Venenos sao uma substancia tóxica (composta por uma ou mais toxinas) que podem causando lesao fisiológica dependente da dose. As toxinas sao moléculas bioativas formadas principalmente por compostos enzimáticos e nao enzimático que porque provocam consequéncias indesejáveis nas presas, além disso, exibem atividades biológicas únicas, diversas e específicas que perturbam os processos fisiológicos normais. Entretanto, muitas toxinas, de diferentes animais, tém sido isoladas e muitas delas sao consideradas ótimas ferramentas para pesquisa básica e alvos terapéuticos. Foi relatado que o estresse oxidativo desempenha um papel fundamental na patogénese de várias doengas, como distúrbios neurodegenerativos, distúrbios cardiovasculares e cáncer. O mecanismo pelo qual as toxinas animais atuam nos parametros de estresse oxidativo em várias doengas, ainda nao está estabelecido. O foco principal desta revisao é destacar os principais estudos com toxinas animais como ferramenta terapéutica em diversas doengas, atuando no balango redox do organismo.

Abstract Venoms are a toxic substance (comprised of one or more toxins) that can cause dose-dependent physiological injury. Toxins are bioactive molecules formed primarily by enzymatic and non-enzymatic compounds that cause undesirable conse-quences in prey, in addition, exhibit unique, diverse and specific biological activities that disrupt normal physiological processes. However, many toxins, from different animals, have been isolated and many of them are considered great tools for basic research and therapeutic targets. Oxidative stress has been reported to play a key role in the pathogenesis of various diseases such as neurodegenerative disorders, cardiovascular disorders and cancer. How animal toxins act on oxidative stress parameters in several diseases is not yet established. The main focus of this review is to highlight the main studies with animal toxins as a therapeutic tool in several diseases, acting on the organism's redox balance.

Resumen Los venenos son sustancias tóxicas (compuestas por una o más toxinas) que pueden causar daño fisiológico dependiente de la dosis. Las toxinas son moléculas bioactivas formadas principalmente por compuestos enzimáticos y no enzimáticos que debido a que causan consecuencias indeseables en las presas, además, exhiben actividades biológicas únicas, diversas y específicas que alteran los procesos fisiológicos normales. Sin embargo, se han aislado muchas toxinas de diferentes animales, y muchos de ellos se consideran grandes herramientas para la investigación básica y dianas terapéuticas. Se ha informado que el estrés oxidativo juega un papel clave en la patogenia de diversas enfermedades, como los trastornos neurodegenerativos, enfermedades cardiovasculares y cáncer. El mecanismo por el cual las toxinas animales actúan sobre los parámetros de estrés oxidativo en vários enfermedades, aún no está establecido. El enfoque principal de esta revisión es resaltar los principales estudios con toxinas animales como herramienta terapéutica en diversas enfermedades, actuando en el equilibrio redox del organismo.

Imported fire ant immunotherapy prescribing patterns in a large health care system during an 11-year period.

BACKGROUND: The first large-scale evaluation of prescribing patterns for imported fire ant (IFA) in a large US health care system was published by Haymore et al in 2009. In this first evaluation of prescriptions from 1990 to 2007, the most often prescribed maintenance IFA prescription was 0.5 mL of 1:200 wt/vol. OBJECTIVE: To provide an updated description of IFA prescribing patterns over the ensuing 11 years from same large health care system. METHODS: We reviewed 1349 new IFA prescriptions written from 2007 to 2018, from a large nationwide health care system, with primary end points being maintenance prescription strength and prescribing patterns. RESULTS: In comparison to the data published by Haymore et al in 2009, which reported that 17% of the prescriptions were written for 0.5 mL of 1:100 wt/vol maintenance, we found that 69% (95% CI: 66.4%-71.4%) of IFA prescriptions written in the past 11 years were for the maintenance concentration of 0.5 mL of 1:100 wt/vol. We further studied the linear trend over time of percentage of prescriptions written for individual concentrations and observed that the percentage of 1:100 wt/vol prescriptions increased 3.5% yearly (R2 = 0.68, P < .001) from 2007 (40.0%, 95% CI: 24.6%-57.7%) to 2018 (84.4%, 95% CI: 77.4%-89.5%). CONCLUSION: Our study shows significant improvement in the accuracy and precision of IFA immunotherapy dosing for patients with IFA hypersensitivity, with ascendancy of 0.5 mL 1:100 wt/vol as the predominant treatment dose. A total of 87% of patients within our study were treated within the parameter recommendations, a stark improvement from findings in the 2009 Haymore study.

Safety of Repeated Imported Fire Ant Ultra-Rush Protocols.

Treatment of imported fire ant (IFA) hypersensitivity includes avoidance and venom immunotherapy (VIT) that reduces the risk of reactions to less than 5%. Previous studies have shown that rush immunotherapy (RIT) is safe and efficacious. It is unknown if multiple RIT procedures on individuals with breaks in VIT are safe and effective. This is a retrospective chart review of three patients who have undergone six IFA VIT rush protocols at our institution. Patients were all female with a median age of 27 years. All are active duty service members without medical problems who reside in an IFA endemic area. Reviewed protocols consisted of 10 injections of IFA whole body extract given in 1 day. Local reactions were the only side effect noted. All patients completed the protocols without further incident. Following each protocol, median VIT adherence was 9 months (range 2-72 months). Reasons for stopping VIT were deployment and pregnancy. Non-adherence is common and leads to breaks in VIT. The risk of VIT resumption in patients with previous RIT or VIT is unknown. This case series illustrates the safety and efficacy of repeated IFA VIT rush procedures in patients who for personal and service related reasons had breaks in VIT.

Samsum Ant Venom Exerts Anticancer Activity Through Immunomodulation In Vitro and In Vivo.

Samsum ant venom (SAV) is a rich repertoire of natural compounds with tremendous pharmacological properties. The present work explores its antineoplastic activity in different cell lines followed by its confirmation in vivo. The cell lines, HepG2, MCF-7, and LoVo showed the differential dose-dependent antineoplastic effect with an increased level of significant cytokines, including Interleukin (IL)-1ß, IL-6, and IL-8 and transcription factor, Nuclear factor-kappa B (NF-κB). However, the venom was more effective on HepG2 and MCF-7 cells than LoVo cells. Furthermore, the extract was administered to four groups (n = 8) of rats. Group I was taken as a control without any treatment, whereas group II received CCl4 (1 mL/kg) for induction of mild hepatoma. Group III was given 100 µg/kg of SAV twice a week for 1 month. Group IV was pretreated with the CCl4 (like group II) followed by dosing with SAV (100 µg/kg) for 2 months as per the authors' prestandardized dosing schedule. Intriguingly, the rats of group IV demonstrated significant decrease in key cytokines, IL-1ß and IL-6, as well as the transcription factors, including Tumor Necrosis Factor-alpha (TNF-α), NF-κB, and Inhibitor-kappa B (I-κB) as compared with group II. Furthermore, increase in IL-10 and First apoptosis signal (FAS) in the same group confirmed that SAV induces apoptosis at the given dose through immunomodulation leading to enhanced tumor killing in vivo. Hence, SAV has an excellent antineoplastic activity that can be directly used to treat certain types of cancer. Moreover, study of its ingredients can pave ways to design novel anticancer drugs. However, further in-depth investigation is required before its clinical trials.

Antiparasitic effect of Dinoponera quadriceps giant ant venom.

Neglected tropical diseases (NTD) are treated with toxic therapy of limited efficacy. Previously, we studied the antimicrobial effect of Dinoponera quadriceps venom (DqV) against bacteria. To continue the study, we report in this short communication the antimicrobial effect of DqV against Leishmania amazonensis and Trypanosoma cruzi. DqV inhibits the promastigote forms of L. amazonensis and all T. cruzi developmental forms, with low toxicity in host cells. DqV causes cell death in T. cruzi through necrotic and apoptotic mechanisms observed by staining the cells with annexin V-FITC (AX) and propidium iodide (PI), loss of mitochondrial membrane potential by flow cytometry analyses and confocal microscopy and morphological alterations, such as loss of membrane integrity and cell shrinkage by scanning electron microscopy (SEM). In conclusion, we suggest there is an antimicrobial effect also on parasites.

Pro- and Anticonvulsant Effects of the Ant Dinoponera quadriceps (Kempf) Venom in Mice.

Epilepsy affects at least 50 million people worldwide, and the available treatment is associated with various side effects. Approximately 20-30% of the patients develop seizures that persist despite careful monitored treatment with antiepileptic drugs. Thus, there is a clear need for the development of new antiepileptic drugs, and the venoms can be an excellent source of probes. In this context, while there are studies on venoms from snakes, scorpions, and spiders, little is known regarding venom from ants. The aim of this study was to investigate the potential pro- and anticonvulsant effects of the venom from the ant Dinoponera quadriceps (Kempf) in Swiss mice. After the injection of the crude venom (DqTx-5, 50, and 500 mg/mL) in the lateral ventricle of mice, we observed a reduction of exploration and grooming behaviors, as well as an increase in immobility duration. In addition, the crude venom induced procursive behavior and tonic-clonic seizures at the highest concentration. Conversely, the preadministration of the denatured venom (AbDq) at the concentration of 2 mg/mL protected the animals against tonic-clonic seizures (66.7%) and death (100%) induced by administration of bicuculline. Taken together, the findings demonstrate that D. quadriceps venom might be potential source of new pro- and anticonvulsants molecules.

Ant venom immunotherapy in Australia: the unmet need.

Jack jumper ant (JJA) venom allergy is an important cause of anaphylaxis in south-eastern Australia. The efficacy and real-world effectiveness of JJA venom immunotherapy (VIT) to prevent anaphylaxis in allergic patients are now well established, with an evidence base that is at least equivalent to that supporting VIT for allergy to other insect species. The tolerability and safety of JJA VIT are comparable with those of honeybee VIT.

Imported fire ant field reaction and immunotherapy safety characteristics: the IFACS study.

BACKGROUND: Imported fire ants (IFAs) are endemic in the southeastern United States, including Texas; can sting multiple times; and are a well-known cause of anaphylaxis. There are few data available on how many stings typically lead to systemic reactions (SRs). Likewise, there are no reports currently in the literature that characterize the safety of IFA subcutaneous immunotherapy (SCIT). OBJECTIVE: We sought to analyze a case-cohort sample of patients for IFA SCIT risk factors and to characterize the index field reactions of these patients. METHODS: A case-cohort study based on a 3-year retrospective chart review (2005-2008) at a single institution was performed for patients receiving IFA SCIT. Field reactions leading to initiation of IFA SCIT were also reviewed. RESULTS: Seventy-seven patients (40 female patients; mean age, 34 years) received 1,887 injections, and 7 patients experienced 8 SRs, for a rate of 0.4% per injection and 9.1% per patient. SRs were mild. Having an SR to skin testing was associated with increased odds of having an SR to IFA SCIT (odds ratio, 4.75; 95% CI, 1.13-20.0), as were large local reactions (odds ratio, 34.5; 95% CI, 6.52-182). No other risk factors were identified. Of the index field reactions leading to IFA SCIT, 59% were the result of 1 sting, and 87% of subjects experienced only 1 SR before initiation of IFA SCIT. Two of 4 patients who experienced loss of consciousness during the index field reaction required an increased maintenance dose for optimal response. CONCLUSIONS: IFA SCIT is safe; however, having an SR to skin testing or the presence of large local reactions increases the odds of having an SR to IFA SCIT. The majority of SRs to IFA field stings resulted from 1 sting.

Imported fire ant immunotherapy prescribing patterns in a large health care system during a 17-year period.

BACKGROUND: No large evaluation has been performed of the maintenance vial concentration commonly used by physicians when prescribing imported fire ant (IFA) immunotherapy since the publication of the first Stinging Insect Hypersensitivity Practice Parameter 10 years ago. OBJECTIVE: To describe the prescribing patterns for IFA immunotherapy among practicing allergists in a large health care setting and the impact of published Practice Parameter recommendations. METHODS: Data from the US Army Centralized Allergen Extract Laboratory were analyzed to determine IFA immunotherapy prescribing patterns from 1990 to May 2007. This extract laboratory provides prescriptions for more than 320 US Department of Defense, US Department of Veterans Affairs, and US Public Health Service clinics. RESULTS: A total of 1,091 patients were given 1,437 new or revised prescriptions for IFA immunotherapy. Monotherapy for Solenopsis invicta and Solenopsis richteri was prescribed in 169 (11.8%) and 3 (0.1%) instances, respectively, with the remainder of patients given both IFA antigens. The most commonly prescribed maintenance vial dose was 0.5 mL of a 1:200 (wt/vol) dilution, accounting for 36.3% of prescriptions. A total of 17.3% of prescriptions had a maintenance vial dose of 0.5 mL of a 1:100 (wt/vol) dilution, 4.6% had a dilution of 1:10 (wt/vol), and 50.6% had a dilution between 1:10 and 1:100 (wt/vol). The mean starting dose was 4.4 10-fold dilutions below the maintenance dose (5.4 vials per treatment set). CONCLUSIONS: The most commonly prescribed maintenance dose was 0.5 mL of a 1:200 (wt/vol) dilution, although most prescriptions used a maintenance dose consistent with recommended dosing in the Stinging Insect Practice Parameters. Both IFA antigens were used by most physicians. Further study evaluating the effective dose range for IFA immunotherapy is needed.

Anafilaxia por picadura de hormiga colorada: casos clínicos pediátricos. Importancia del diagnóstico y tratamiento / Anaphylaxis for sting of red ant: paediatric clinical cases. Importance of the diagnose and treatment

Debido a la alta incidencia de reacciones adversas a la picadura de la hormiga colorada (HC) en la ciudad de Villa María, sudeste de la provincia de Córdoba, Argentina, y a la escasa bibliografía respecto de su prevención y posterior tratamiento en pacientes pediátricos, el presente trabajo tuvo como objetivo demostrar la gravedad de las reacciones y su importancia clínica y diagnóstica en niños, para su prevención y tratamiento. Para ello fueron seleccionados pacientes pediátricos entre 5 y 10 años con clínica de anafilaxia grave a picadura de HC, con antecedentes personales y familiares de atopía o sin ellos. Los pacientes ingresaron al Servicio de Alergia de la Clínica FUSAVIM en el período comprendido entre enero de 2003 y julio de 2004. Fueron sometidos a ensayos in vivo e in vitro de sensibilización a picaduras de HC y dosaje de Inmunoglobulina E total. Los resultados obtenidos demostraron la importancia de la prevención y diagnóstico a través del Prick Test, y la seguridad y eficacia de la inmunoterapia con extractos de cuerpo entero de HC (AU)

Ant venom immunotherapy: a double-blind, placebo-controlled, crossover trial.

BACKGROUND: The jack jumper ant Myrmecia pilosula is responsible for about 90% of ant venom anaphylaxis in southeastern Australia. We aimed to establish whether M pilosula venom immunotherapy (VIT) prevents lifethreatening sting anaphylaxis in otherwise healthy adults. METHODS: We did a double-blind, placebo-controlled crossover trial of M pilosula VIT. Participants were randomly allocated either immunotherapy, in accordance with the semirush hyposensitisation regimen, or placebo. The primary endpoint was systemic reaction after a deliberate sting challenge. Analysis was per protocol. FINDINGS: We randomly allocated 68 healthy volunteers (aged 20-63 years) who were allergic to M pilosula venom to placebo (33) and VIT (35). Four on placebo were stopped early and 12 on VIT had their treatment allocations revealed before the sting challenge, thus 29 on placebo and 23 on VIT were included in the primary analysis. Objectively defined systemic reactions to sting challenges arose in 21 of 29 participants (72%) on placebo (8 reactions were associated with hypotension) and none of 23 on VIT (p<0.0001). Of the remaining 12 on VIT who underwent sting challenges after treatment allocations were revealed, only one reacted to sting challenge with transient urticaria that did not require treatment. After crossover of the placebo group to VIT, one of 26 had a reaction to sting challenge (transient urticaria). In all patients who had VIT, we recorded objective systemic reactions in 22 of 64 (34%) during VIT; two of which were hypotensive. INTERPRETATION: In well motivated, highly allergic, but otherwise healthy adults, VIT is highly effective in prevention of M pilosula sting anaphylaxis. The risk of systemic reactions during VIT means that treatment should be given where there is immediate access to resuscitation facilities.