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Aims: This study investigated histamine intake and its associations with clinical and biochemical findings in patients with Behçet syndrome. Methods: Patients with Behçet syndrome were prospectively enrolled using a cross-sectional, multicenter, and online survey design. Sociodemographic parameters, including age, gender, smoking and alcohol intake, nutritional counseling history, anthropometric measurements, clinical characteristics, and biochemical results, were obtained using an online questionnaire. Dietary histamine intake was determined using a food frequency questionnaire. Results: The study included 66 patients (mean age: 37.5±11.3 years, women: 53%. Food consumption was reported to trigger oral aphthae in 81% of the individuals, and the most frequently reported triggers were eggplant (37.5%), tomatoes (37.5%), and citrus fruits (34.3%). There was a significant positive correlation between dietary histamine intake and white blood cell counts (r=0.650; p=0.050). There were no significant differences in the clinical characteristics, including oral aphthae, genital ulcers, uveitis, dermatologic lesions, gastrointestinal system involvement, joint involvement, and vascular involvement between patients with low and high dietary histamine intake. A positive correlation was found between dietary histamine intake and the frequency of attacks (r=0.324; p=0.008). Conclusions: This study showed that increased dietary histamine intake was associated with an increased frequency of attacks in patients with Behçet syndrome. Oral aphthae are associated with certain foods, such as eggplant, tomatoes, and citrus fruit.

Abstract Introduction The development of several experimental migraine provocation models has significantly contributed to an understanding of the signaling mechanisms of migraine. The early history of this development and a view to the future are presented as viewed by the inventor of the models. Methods Extensive knowledge of the literature was supplemented by scrutiny of reference lists. Results Early studies used methodologies that were not blinded. They suggested that histamine and nitroglycerin (Glyceryl trinitrate, GTN) could induce headache and perhaps migraine. The development of a double blind, placebo-controlled model, and the use of explicit diagnostic criteria for induced migraine was a major step forward. GTN, donor of nitric oxide (NO), induced headache in people with- and without migraine as well as delayed migraine attacks in those with migraine. Calcitonin gene-related peptide (CGRP) did the same, supporting the development of CGRP antagonists now widely used in patients. Likewise, pituitary adenylate cyclase activating peptide (PACAP) provoked headache and migraine. Recently a PACAP antibody has shown anti migraine activity in a phase 2 trial. Increase of second messengers activated by NO, CGRP and PACAP effectively induced migraine. The experimental models have also been used in other types of headaches and have been combined with imaging and biochemical studies. They have also been used for drug testing and in genetic studies. Conclusion Conclusion. Human migraine provocation models have informed about signaling mechanisms of migraine leading to new drugs and drug targets. Future use of these models in imaging-, biochemistry- and genetic studies as well as in the further study of animal models is promising.

Introduction: Cis-atracurium has a neuromuscular blocking capacity approximately three times that of atracurium besylate. The Effective Dose (ED) 95 of cis-atracurium is 0.04 mg/kg, while that of atracurium is 0.2 mg/kg. Cis-atracurium is preferred over atracurium due to the lack of histamine release, providing better cardiovascular stability. This study compares these two drugs in terms of haemodynamic parameters, neuromuscular blocking properties, intubating conditions, and safety profiles. Aim: To assess the efficacy of atracurium and cis-atracurium from various perspectives, including neuromuscular blockade, haemodynamic stability, and safety profiles. Materials and Methods: A double-blinded, randomised clinical study was conducted from January 2019 to October 2019 in Rajkot, Gujarat, India. Sixty patients undergoing abdominal surgeries under general anaesthesia were allocated to two groups. Group A received a loading dose of atracurium 0.5 mg/kg followed by a maintenance dose of 0.1 mg/kg, while Group B received a loading dose of cis-atracurium 0.2 mg/kg followed by a maintenance dose of 0.03 mg/kg. During the surgical procedure, parameters studied included neuromuscular blockade, hemodynamic changes, intubating conditions, and safety profiles in terms of complications. Student’s t-test was used to analyse normally distributed continuous variables, and the chi-square test was used for qualitative variables. Results: The demographic profiles were comparable in both groups in terms of age (p-value=0.800), sex (p-value=0.393), weight (p-value=0.101), and American Society of Anaesthesiologists (ASA) grading (p-value=0.509). A significant increase in heart rate (99.46±8.06 (/minute) vs. 91.66±9.11 (/minute)) and mean arterial blood pressure (104.44±10.16 (mm of Hg) vs. 93.4±12.77 (mm of Hg)) was noted post-intubation in Group A compared to Group B. Patients in Group A (3.5±0.62 minutes) had a faster onset of neuromuscular blockade compared to Group B (4.6±0.49 (minutes)), while the duration of action of the first loading dose and the 25% recovery time from the last supplemental dose was longer in Group B (52.86±5.18 minutes and 41.66±3.60 minutes) than in Group A (31.2±4.82 minutes and 20.86±4.37 minutes). Fewer patients experienced complications (hypotension, erythema of the skin) in Group A compared to Group B. Conclusion: Cis-atracurium releases less histamine compared to atracurium and has a longer duration of action. Cis-atracurium can be a better alternative to atracurium as it offers better haemodynamic, neuromuscular, and safety profiles with similar intubating conditions.

Oral submucous fibrosis (OSMF), a potentially malignant disorder, is developed by progressive fibrous tissue deposition in connective tissue along with atrophy of oral mucosa. Histological sections also show the mast cell infiltration in submucosa which may indicate their possible role in this entity. Abundant availability of biochemicals in mast cells like histamine and serine proteases like chymase may be released and play specific pathways in the disease pathophysiology. Possibly, if the histamine release has some part to play, diamine oxidase may also be found to have a relationship as it metabolizes histamine. The present study is proposed to identify the presence of chymase, histamine, and diamine oxidase in both, serum as well as tissue by enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry (IHC) respectively. This study may provide probable insight into the mast cell-related chemicals and their association with OSMF.

Background: To assess the prevalence of diamine oxidase (DAO) enzyme deficiency caused by single nucleotide polymorphisms (SNPs) of the AOC1 gene in a sample of patients with symptoms of insomnia. Methods: A total of 167 adult patients (>18 years of age) with symptoms of insomnia attended a specialized institute for healthy sleep, in Barcelona (Spain), between May and November 2023, and underwent genotyping analysis of the four most relevant SNP variants, including c.691G>7 (rs2052129), c.47C>T (rs10156191), c.995C>T (rs1049742), and c.1990C>G (rs1049793). Results: Genetic DAO deficiency was present in 138 patients, with a prevalence rate of 82.6% (95% CI 76–88.1%). Difficulties in staying asleep were the most common complaints in 88% of patients followed by trouble falling asleep in 60.5%. More than half of patients suffered from insomnia symptoms every day. Also, 99.4% reported daytime consequences of insomnia, with fatigue (79.6%), mood changes (72.5%), and impaired concentration in 70.1%. When patients were grouped by DAO-score, which reflected the number of heterozygous and homozygous SNPs variants, the group with a DAO-score ≥ 4 vs. 1 showed higher percentages of insomnia-related symptoms, in particular, trouble staying asleep and early morning awakening. These two symptoms were also more common in the presence of the c.1990C>G (rs1049793) variant. Conclusions: This preliminary real-world study presents novel evidence of a potential link between a DAO enzyme deficiency of a genetic origin and clinical symptoms of insomnia, which may suggest the potential benefit of DAO supplementation to improve the quality of sleep in these subjects. The study was registered at ClinicalTrials.gov (NCT06488027).

The modulation of biological processes with light-sensitive chemical probes promises precise temporal and spatial control. Yet, the design and synthesis of suitable probes is a challenge for medicinal chemists. This article introduces a photocaging strategy designed to modulate the pharmacology of histamine H3 receptors (H3R) and H4 receptors (H4R). Employing the photoremovable group BODIPY as the caging entity for two agonist scaffolds—immepip and 4-methylhistamine—for H3R and H4R, respectively, we synthesized two BODIPY-caged compounds, 5 (VUF25657) and 6 (VUF25678), demonstrating 10–100-fold reduction in affinity for their respective receptors. Notably, the caged H3R agonist, VUF25657, exhibits approximately a 100-fold reduction in functional activity. The photo-uncaging of VUF25657 at 560 nm resulted in the release of immepip, thereby restoring binding affinity and potency in functional assays. This approach presents a promising method to achieve optical control of H3R receptor pharmacology.

Aim:We aimed first to investigate patients who received C1 inhibitor therapy in the emergency department (ED). The patients’ complaints, examination findings, length of stay in the ED and whether the patients were treated with anything other than C1 inhibitor were investigated. Next, we examined the response of patients who received C1 inhibitor therapy in the presence of angiotensin converting enzyme inhibitor (ACEI)-induced angioedema.Materials and Methods:A retrospective descriptive study was designed. Patients who received C1 inhibitor therapy between January 2011 and February 2018 were reviewed using the hospital’s records on file.Results:Data were evaluated from 62 admissions for 23 different patients. The diagnosis of hereditary angioedema (HAE) was present in 65.2% (n=15) of the patients, and 85.5% (n=53) of the admissions were related to acute HAE episodes. The main complaints of these patients were nausea, vomiting and abdominal pain and swell of the face, lips, throat and extremities. It was determined that C1 inhibitor treatment was given to 8% (n=5) admissions due to ACEI-induced angioedema. The complaints of these patients (5 admissions for 4 patients) were swelling of the tongue (n=3), lip (n=1) and face (n=1). Clinical improvement was observed in admission symptoms after treatment of C1 inhibitor in all patients with angioedema induced by HAE episodes or ACEIs.Conclusion:C1 inhibitor treatment is effective in treating acute HAE episodes. Although more evidence is needed for the treatment of ACEI-induced angioedema attacks, C1 inhibitor therapy may be considered in patients who do not respond to classical treatment.

We found that histamine (10−9 M) did not have any effect on the in vitro capture of Escherichia coli by neutrophils but accelerated its intracellular killing. In contrast, histamine (10−6 M) delayed the capture of Escherichia coli by neutrophils and reduced the amounts of pHrodo zymosan particles inside acidic mature phagosomes. Histamine acted through the H4R and the H2R, which are coupled to the Src family tyrosine kinases or the cAMP/protein kinase A pathway, respectively. The protein kinase A inhibitor H-89 abrogated the delay in bacterial capture induced by histamine (10−6 M) and the Src family tyrosine kinase inhibitor PP2 blocked histamine (10−9 M) induced acceleration of bacterial intracellular killing and tyrosine phosphorylation of proteins. To investigate the role of histamine in pathogenicity, we designed an Acinetobacter baumannii strain deficient in histamine production (hdc::TOPO). Galleria mellonella larvae inoculated with the wild-type Acinetobacter baumannii ATCC 17978 strain (1.1 × 105 CFU) died rapidly (100% death within 40 h) but not when inoculated with the Acinetobacter baumannii hdc::TOPO mutant (10% mortality). The concentration of histamine rose in the larval haemolymph upon inoculation of the wild type but not the Acinetobacter baumannii hdc::TOPO mutant, such concentration of histamine blocks the ability of hemocytes from Galleria mellonella to capture Candida albicans in vitro. Thus, bacteria-producing histamine, by maintaining high levels of histamine, may impair neutrophil phagocytosis by hijacking the H2R.

Introduction There is growing interest in the relationship between fibromyalgia and processes related to food, such as food intolerances. In fact, different associations have been described between the control of dietary habits and the improvement of the different symptoms of fibromyalgia. Material and methods We collected the results of applying a specific test of histamine release related to the diet of patients with fibromyalgia, and evaluated the changes in terms of the symptoms usually described by the patients. A total of 84 patients who met the established criteria were recruited; 40 of them underwent the exclusion diet for a period of 6 months, while the remaining ones continued with their usual dietary habits. All patients were instructed not to modify any other parameter during the study, such as medication, exercise, or other complementary treatments. The parameters studied were as follows: the Fibromyalgia Impact Questionnaire (FIQ), the Gastrointestinal Symptoms Rating Scale (GSRS), the pain Visual Analogue Scale (VAS), as well as the patients’ body weight was controlled. Results There was a significant improvement (p

The article presents an analysis of the literature on food intolerance (FS) associated with the presence in the diet of fermentable oligodimosaccharides and polyols FODMAP (fermentable oligosaccharides, disaccharides, monosaccharides and polyols), histamine and food additives. The relationship between FS and insufficient activity of enzymes of the small intestine mucosa, in particular, in patients with irritable bowel syndrome, is discussed. FS often noted in them forces them to strictly adhere to the elimination diet and significantly impair the quality of life due to dissatisfaction with the results of treatment. Analysis of the literature has confirmed in many patients with irritable bowel syndrome an etiotropic relationship with poor food tolerance and dictates the need for randomized studies to further study the pathogenetic mechanisms of increasing food tolerance under the influence of cytoprotective therapy.

Speer allergic tension-fatigue syndrome (SATFS) is a classic allergy syndrome characterized by allergy-like symptoms, muscle tension, headaches, chronic fatigue, and other particular behaviors that were initially described in the fifties. The particular behaviors displayed include symptoms such as hyperkinesis, hyperesthesia (i.e., insomnia), restlessness, and distractibility, among others. Interestingly, these symptoms are very similar to descriptions of attention deficit hyperactivity disorder (ADHD), the most prevalent neurodevelopmental disorder worldwide, which is characterized by inattention, hyperactivity, and impulsivity. The clinical description of SATFS precedes the nomination of ADHD in 1960 by Stella Chess. In this conceptual paper, we stress that there is a gap in the research on the relationship between ADHD and allergic pathologies. The hypotheses of this conceptual paper are (1) SATFS is probably one of the first and best historical descriptions of ADHD alongside a common comorbidity (allergy) displayed by these patients; (2) SATFS (ADHD) is a systemic disease that includes both somatic and behavioral manifestations that may influence each other in a bidirectional manner; (3) The role of neuroinflammation and histamine is key for understanding the pathophysiology of ADHD and its frequent somatic comorbidities; (4) The deficiency of the diamine oxidase (DAO) enzyme, which metabolizes histamine extracellularly, may play a role in the pathophysiology of ADHD. Decreased DAO activity may lead to an accumulation of histamine, which could contribute to core ADHD symptoms and comorbid disorders. Further empirical studies are needed to confirm our hypotheses.

Abstract Background Mast cells are closely associated with epithelium, serving as sentinels responsible for the recognition of tissue injury and coordination of the initial inflammatory response. Upon detection of the injured cell content, mast cells then tailor the release of preformed and newly produced chemical mediators to the detected challenge, via an array of pathogen receptors. In addition to immunoglobulin E receptor-triggered mast cell activation, commonly referred to as allergic or atopic disorders, non-immunoglobulin E receptor mediated mast cell activation follows engagement of toll-like receptors, immunoglobulin G receptors, and complement receptors. Upon containment of the extrinsic challenge, acute inflammation is downregulated, and repair of the injured tissue ensues. The mast cell compartments must return to a baseline steady state to remain tolerant towards self-antigens and harmless entities, including environmental conditions, to prevent unnecessary immune activation and chronic hypersensitivity disorders. Over the past 50 years, an increasing number of patients are experiencing episodes of aberrant mast cell activation, not associated with allergen-specific mast cell disease or systemic mastocytosis. This led to proposed diagnostic criteria of mast cell activation syndrome. Mast cell activation syndrome is a heterogeneous disorder, defined by a combination of (1) recurrent symptoms typical of mast cell activation, (2) an increase of validated mast cell derived mediators, and (3) response to treatment with mast cell stabilizing or mast cell mediator-targeted therapies. Onset of mast cell activation syndrome ostensibly reflects the loss of tolerance in the mast cell compartment to nonthreatening entities and nonhazardous environmental conditions. The etiology of chronic mast cell dysregulation and associated intolerance to self-antigens or harmless entities is not well understood, but a growing number of studies point to exposure of the epithelial borders, which leads to inappropriate or excessive mast cell activation or impaired resolution of acute inflammation following neutralization of the identified pathogen. Case presentation Here we present a case of adult onset mast cell activation syndrome following scombroid poisoning. Scombroid toxicity is usually a self-limited illness, but there are individuals who have been shown to have severe symptoms or persistent illness following histamine fish poisoning. We describe a 74-year-old Caucasian woman, with a history of drug-induced urticaria, who developed a constellation of hypersensitivity illnesses consistent with the diagnosis of mast cell activation syndrome after ingestion of tainted fish. Conclusion Mast cell activation disease causes problems of increased complexity in children and adults. The increased prevalence and severity of mast cell activation disease has been attributed to dramatic changes in our lifestyles and modern living environments. These changes likely impact the integrity of the epithelial barriers, leading to loss of tolerance in the mast cell compartment. Here, we present a case of a nonatopic, 74-year-old female who developed mast cell activation disease after exposure to a potent environmental toxin. Mast cell activation disease commonly involves several organ systems, with patients often referred to a succession of different specialists. This results in delayed diagnosis and suboptimal care. Instead, early recognition of mast cell activation disease would lead to better outcomes. We review the literature, describing the diagnostic criteria for mast cell activation disorders that can improve recognition of this multiorgan system syndrome. Further research is needed into the interaction of epithelial barrier disruption and the dysregulation of the immune system.

Allergic rhinitis (AR) is an allergic disease induced by the T helper 2 (TH2) lymphocyte immune response, where its mediators are the primary cause of clinical symptoms. Environmental factors are the primary determinants of the allergic response in genetically susceptible individuals. This study investigates the effects of climate conditions (warm, cold, humid, and dry) on allergic rhinitis. AR models were created in mice under 4 different conditions. We investigated AR-related behavior (sneezing and nose rubbing), as well as total immunoglobulin E (IgE), histamine, interleukin-4 (IL-4), leukotriene (LT) B4 and LTC4 levels, and gene expression of CysLT1R, HRH1, and MUC5a. Nose rubbing, histamine levels, and the expression of MUC5a and HRH1 were increased in AR models in cold conditions, and sneezing was increased in AR models kept in dry conditions. LTB4 and LTC4 levels and the expression of CysLT1R in AR models kept in a wet environment also significantly increased compared with the control group. The levels of total IgE and IL-4 showed no significant changes. Air temperature and humidity affect AR pathophysiology, and weather conditions can be essential in controlling AR.

Breast cancer (BC) is currently the most commonly diagnosed cancer in women. BC is most often derived from the epithelial tissue of the mammary gland and is a global problem due to the steady increase in morbidity and mortality in most countries. A particular problem today is the triple negative subtype (TNBC), which accounts for approximately 10-15% of breast cancer cases. BC occurs most frequently in young women and is characterised by various biological characteristics, an unfavourable clinical course and a poor prognosis. Recent studies to detect the effects of histamine receptors on breast cancer have shown that all H1R-H4R receptors are also hyperactive in the cancer microenvironment. Chronically maintaining a high level of histamine in the tumour-affected tissue contributes to increased angiogenesis at this site, induction of cancer cells proliferation and T lymphocyte dysfunction. The rising incidence of breast cancer is contributing to an increasing amount of research into targeted therapies. Studies on the effect of histamine antagonists through H1R-H4R receptors have proven their effectiveness in the treatment of breast cancer. Among those in the study, there was a reduction in tumour growth, cell proliferation and an increase in apoptosis. The use of histamine antagonists also contributed to a reduced risk of death from breast cancer and increased overall survival (OS). Therefore, targeted therapy is needed to improve the prognosis of patients with breast cancer.

The relationship between migraines and allergies is controversial. Though they are epidemiologically linked, the underlying pathophysiological connection between them remains unclear. Migraines and allergic disorders have various underlying genetic and biological causes. As per the literature, these conditions are epidemiologically linked, and some common pathophysiological pathways have been hypothesized. The histaminergic system may be the clue to understanding the correlation among these diseases. As a neurotransmitter in the central nervous system with a vasodilatory effect, histamine has a well-documented influence on the allergic response and could be involved in the pathophysiology of migraines. Histamine may influence hypothalamic activity, which may play a major role in migraines or may simply influence their severity. In both cases, antihistamine drugs could prove useful. This review examines whether the histaminergic system, particularly H3 and H4 receptors, may provide a mechanistic link between the pathophysiology of migraines and allergic disorders, two common and debilitating conditions. Identifying their connection could help identify novel therapeutic strategies.

Histamine can change the force of cardiac contraction and alter the beating rate in mammals, including humans. However, striking species and regional differences have been observed. Depending on the species and the cardiac region (atrium versus ventricle) studied, the contractile, chronotropic, dromotropic, and bathmotropic effects of histamine vary. Histamine is present and is produced in the mammalian heart. Thus, histamine may exert autocrine or paracrine effects in the mammalian heart. Histamine uses at least four heptahelical receptors: H1, H2, H3 and H4. Depending on the species and region studied, cardiomyocytes express only histamine H1 or only histamine H2 receptors or both. These receptors are not necessarily functional concerning contractility. We have considerable knowledge of the cardiac expression and function of histamine H2 receptors. In contrast, we have a poor understanding of the cardiac role of the histamine H1 receptor. Therefore, we address the structure, signal transduction, and expressional regulation of the histamine H1 receptor with an eye on its cardiac role. We point out signal transduction and the role of the histamine H1 receptor in various animal species. This review aims to identify gaps in our knowledge of cardiac histamine H1 receptors. We highlight where the published research shows disagreements and requires a new approach. Moreover, we show that diseases alter the expression and functional effects of histamine H1 receptors in the heart. We found that antidepressive drugs and neuroleptic drugs might act as antagonists of cardiac histamine H1 receptors, and believe that histamine H1 receptors in the heart might be attractive targets for drug therapy. The authors believe that a better understanding of the role of histamine H1 receptors in the human heart might be clinically relevant for improving drug therapy.

Current medications to treat allergic rhinitis (AR) include antihistamines, corticosteroids, and anti-leukotrienes. In the present study, we investigated the effects of combination therapy; using these drugs, and evaluates the AR-related markers and parameters in an animal model. After inducing BALB/c mice AR models, the animals were treated with either pranlukast, loratadine, fluticasone, loratadine + fluticasone, loratadine + pranlukast, fluticasone + pranlukast, or loratadine + fluticasone + pranlukast. Clinical symptoms, Immunoglobulin (Ig)G1, ovalbumin (OVA)-specific and total IgE, leukotriene (LT)B4, LTC4, histamine, thymic stromal lymphopoietin (TSLP) serum levels, and interleukin 4 level in the nasal lavage fluid were determined. The expressions of HRH1, CysLT1R, NLR3, Caspase-1, and MUC5a were studied. Allergic symptoms (nasal rubbing and sneezing), serum Igs (IgG1, total and OVA-specific IgE), eicosanoids (LTB4 and LTC4), histamine, TSLP, and IL-4 as well as gene expressions of MUC5a, Caspase-1, NLR3, HRH1, and CysLT1R were reduced in the animals receiving each of the therapeutic regimens; however, more pronounced effects were seen in the group treated with the triple combined protocol (loratadine + fluticasone + pranlukast). The combination of the loratadine, fluticasone, and pranlukast can effectively control the symptoms of AR probably via modulating several related mechanisms at early and late phases of allergic responses.

The effects of quercetin and histamine separately or in combination on the free radical state of rat erythrocytes were estimated in vitro. Quercetin (0.1; 0.5; 3.0; 5.0 mM) or histamine (0.01; 10.0 μM) were added to whole blood separately or in combination. The content of hydroperoxides, TBA-active products and carbonyl groups of proteins in erythrocytes after hemolysis was determined. The greatest influence of quercetin and histamine on erythrocytes state indicators was revealed under their combined action, when the level of TBA-active products and the content of carbonyl groups of proteins were found to be increased substantially.

Atopic dermatitis (AD) is a common highly pruritic chronic inflammatory skin disorder affecting 5–20% of children worldwide, while the prevalence in adults varies from 7 to 10%. Patients with AD experience intense pruritus that could lead to sleep disturbance and impaired quality of life. Here, we analyze the pathophysiology of itchiness in AD. We extensively review the histamine-dependent and histamine-independent pruritogens. Several receptors, substance P, secreted molecules, chemokines, and cytokines are involved as mediators in chronic itch. We also, summarize the new emerging antipruritic drugs in atopic dermatitis.

Background and Objectives Histamine has been suggested to play an important role during allergic and inflammatory reactions, affecting allergic rhinitis and chronic rhinosinusitis. CXCL8 is a pro-inflammatory chemokine and a critical factor that causes many airway inflammatory diseases including allergic rhinitis and chronic rhinosinusitis. Materials and Method Histamine cytotoxicity was measured by MTT assay. Real-time polymerase chain reaction was used to identify histamine type 1 receptor in nasal fibroblasts. The fibroblasts were then treated with histamine with or without a histamine type 1 receptor antagonist and the CXCL8 protein was assessed using an enzyme-linked immunosorbent assay (ELISA). The downstream signaling molecules, including phospholipase C and phospho-p50, were evaluated by western blot and immunofluorescent staining. Results Histamine had no significant cytotoxic effect until the concentration reached 1,000 μM. Histamine type 1 receptor mRNA was expressed in nasal fibroblasts. CXCL8 protein expression level was significantly increased following histamine stimulation. However, the expression level of CXCL8 decreased when phospholipase C was inhibited by U73122. Histamine increased phospho-p50 expression as seen in western blot results. The BAY11-7082, NF-κB inhibitor significantly reduced CXCL8 production in histamine-stimulated nasal fibroblasts. Conclusion Histamine can induce the production of NF-κB controlled-chemokine CXCL8 by nasal fibroblasts, which supports a role for histamine in upper airway inflammatory diseases.

The significance of the issues of allergic diseases is not in doubt. It is difficult to find a person who has not suffered at least some Allergy symptom, not everyone develops diseases, but most people face Allergy symptoms. The prevalence of various allergic diseases is increasing every year, currently reaching 30% of the population, and the world health organization predicts it will reach 50% in the next few decades. The most common nosologies are allergic rhinitis, bronchial asthma, atopic dermatitis, urticaria, but there are many other conditions of hypersensitivity. This article addresses the issues of inflammatory reactions in General and specifically allergic inflammation, discusses the main aspects of the pathogenesis of allergic rhinitis and urticaria, and questions of drug therapy for these diseases. Most people are sure that they can take anti-allergic medications for allergies, and most often they are referring to antihistamines. Unfortunately, even some medical specialists lack an understanding of the specifics of antihistamine therapy. some people still believe that there are three or four generations of antihistamines, and patients use drugs not as prescribed by doctors, but on the recommendation of friends or pharmacists. Irrational use of antihistamines leads to a decrease in effectiveness, and it is not uncommon to discredit specific drugs and groups of drugs in General. This article demonstrates the results of various European and Asian studies on the effectiveness and safety of antihistamines and bilastin in particular, as well as their own experience of using antihistamines in practice.

Monoamine oxidase (MAO) deficiency and imbalanced levels of brain monoamines have been associated with developmental delay, neuropsychiatric disorders and aggressive behavior. Animal models are valuable tools to gain mechanistic insight into outcomes associated with MAO deficiency. Here, we report a novel genetic model to study the effects of mao loss of function in zebrafish. Quantitative PCR, in situ hybridization and immunocytochemistry were used to study neurotransmitter systems and expression of relevant genes for brain development in zebrafish mao mutants. Larval and adult fish behavior was evaluated through different tests. Stronger serotonin immunoreactivity was detected in mao+/− and mao−/− larvae compared with their mao+/+ siblings. mao−/− larvae were hypoactive, and presented decreased reactions to visual and acoustic stimuli. They also had impaired histaminergic and dopaminergic systems, abnormal expression of developmental markers and died within 20 days post-fertilization. mao+/− fish were viable, grew until adulthood, and demonstrated anxiety-like behavior and impaired social interactions compared with adult mao+/+ siblings. Our results indicate that mao−/− and mao+/− mutants could be promising tools to study the roles of MAO in brain development and behavior. This article has an associated First Person interview with the first author of the paper.

Neurotransmitters are generated by de novo synthesis and are essential for sustained, high-frequency synaptic transmission. Histamine, a monoamine neurotransmitter, is synthesized through decarboxylation of histidine by histidine decarboxylase (Hdc). However, little is known about how histidine is presented to Hdc as a precursor. Here, we identified a specific histidine transporter, TADR (torn and diminished rhabdomeres), which is required for visual transmission in Drosophila. Both TADR and Hdc localized to neuronal terminals, and mutations in tadr reduced levels of histamine, thus disrupting visual synaptic transmission and phototaxis behavior. These results demonstrate that a specific amino acid transporter provides precursors for monoamine neurotransmitters, providing the first genetic evidence that a histidine amino acid transporter plays a critical role in synaptic transmission. These results suggest that TADR-dependent local de novo synthesis of histamine is required for synaptic transmission.

We studied the simultaneous influence of histamine and sodium hypochlorite (SH) on lipid peroxidation processes, as well as the level of structural changes in membranes (via the content of sialic acid) in rat erythrocytes. We established that histamine affects lipid peroxidation processes with the formation of lipid hydroperoxides, damages proteins and reduces the content of sialic acids, which leads to changes in the surface charge of red blood cells. However, the simultaneous action of histamine and low SH concentration has a positive effect in that it corrects the pro-oxidant state of erythrocytes. Hence, the content of lipid hydroperoxides, TBA-active products, carbonyl groups of proteins and sialic acids were mainly reduced after the simultaneous action of histamine and SH at all studied concentrations during the rehabilitation period.

Scombroid syndrome, or histamine poisoning, results from the consumption of inadequately preserved and improperly frozen fish as well as contaminated cheese. It most commonly presents with sudden redness of the face and neck, an erythematous rash, urticaria, diarrhoea, and headache, usually soon after the consumption of contaminated food. It is often misdiagnosed as a seafood allergy since the clinical picture is similar. The condition is usually self-limiting. If treatment is necessary, H1 and H2 antihistamines are usually sufficient. In this article, we present two paediatric cases of the scombroid syndrome, which were discovered due to a similar epidemiological history.

Background: Excessive plasma histamine concentrations cause symptoms in mast cell activation syndrome, mastocytosis, or anaphylaxis. Anti-histamines are often insufficiently efficacious. Human diamine oxidase (hDAO) can rapidly degrade histamine and therefore represents a promising new treatment strategy for conditions with pathological histamine concentrations. Methods: Positively charged amino acids of the heparin-binding motif of hDAO were replaced with polar serine or threonine residues. Binding to heparin and heparan sulfate, cellular internalization and clearance in rodents were examined. Results: Recombinant hDAO is rapidly cleared from the circulation in rats and mice. After mutation of the heparin-binding motif, binding to heparin and heparan sulfate was strongly reduced. The double mutant rhDAO-R568S/R571T showed minimal cellular uptake. The short α-distribution half-life of the wildtype protein was eliminated, and the clearance was significantly reduced in rodents. Conclusions: The successful decrease in plasma clearance of rhDAO by mutations of the heparin-binding motif with unchanged histamine-degrading activity represents the first step towards the development of rhDAO as a first-in-class biopharmaceutical to effectively treat diseases characterized by excessive histamine concentrations in plasma and tissues. Funding: Austrian Science Fund (FWF) Hertha Firnberg program grant T1135 (EG); Sigrid Juselius Foundation, Medicinska Understödsförening Liv och Hälsa rft (TAS and SeV).

Background/Aims Food intolerance/malabsorption, particularly histamine intolerance (HIT), may cause nonspecific functional gastrointestinal and extraintestinal symptoms. We evaluated gastrointestinal and extraintestinal symptoms in patients with HIT. Methods In an analysis of outpatients’ charts we identified 133 patients, who presented with recurring nonspecific functional gastrointestinal, extraintestinal symptoms, and a diamine oxidase value

Introduction & aims: Deficiency of Diamine Oxidase (DAO) enzyme, the main enzyme responsible for histamine-food metabolism, is being used as a new diagnosis to justify the appearance of different clinical symptoms, such as migraine, urticaria or some digestive disorders, among others. All of them could be related to the intake of histamine-rich food. The aim in both cases was to assess the efficacy of a lowhistamine diet in two patients with migraine and DAO deficiency. Material and methods: The two case study involves the follow-up of a 39-year-old woman and a 49- yearold woman. Both of them diagnosed with migraine that did not improve following the usual medical treatment prescribed by the doctor. Therefore, DAO activity was analysed after realizing that DAO deficiency could be related to other symptoms that they presented. Due to the results obtained, it was necessary to follow a dietary treatment with a low-histamine healthy diet and exogenous DAO enzyme supplementation. Results: After some weeks following the dietary treatment, the first case began to notice improvement in neurological symptoms. After months of follow-up she has improved not only the migraine and headache, but also respiratory, digestive and fatigue symptoms. On the other hand, in the second case, it seems to be a little improvement but migraine episodes continue almost as in the beginning. Conclusions: A low-histamine diet supplemented with exogenous DAO enzyme should be considerate as a new management in patients with migraine and DAO deficiency.

Allergic rhinitis is a global public health problem at the present stage, given the high prevalence, the formation of therapy-resistant phenotypes, high comorbidity and the negative impact on all aspects of a patient’s life. Histamine is one of the main mediators of allergy, and therefore drugs number one in the treatment of patients with AR of all options are antihistamine drugs or H1-blockers. The innovative antihistamine drug of the second generation levocetirizine (Allerway®) prevents the development and facilitates the course of allergic reactions, also has anti-inflammatory and antiallergic action. Allerway® is bioequivalent to the original drug, has broad indications for use, has established itself as an effective drug with a good safety profile.

Abstract Objective To review the existing literature on histamine and migraine with a focus on the molecule, its receptors, its use in inducing migraine, and antihistamines in the treatment of migraine. Background Histamine has been known to cause a vascular type headache for almost a hundred years. Research has focused on antihistamines as a possible treatment and histamine as a migraine provoking agent but there has been little interest in this field for the last 25 years. In recent years two additional histamine (H3 and H4) receptors have been discovered and a series of non-sedating antihistamines have been developed. It is therefore timely to review the field again. Methods For this review the PubMed/MEDLINE database was searched for eligible studies. We searched carefully for all articles on histamine, antihistamines and histamine receptors in relation to migraine and the nervous system. The following search terms were used: histamine, migraine disorders, migraine, headache, antihistamines, histamine antagonists, clinical trials, induced headache, histamine H3 receptor, histamine H4 receptor and pharmacology. Four hundred thirty-six titles were read, 135 abstracts were read, 112 articles were read in full and 53 articles were used in this review. Review process resulted in 12 articles added to a total of 65. Findings Early studies of H1 and H2 antihistamines lack scientific strength and show conflicting results. Most of the antihistaminic drugs used in these trials bind also to other receptors which makes it difficult to conclude on the antihistaminic effect. Histamine is an efficient inducer of migraine attacks in migraine patients by an H1 mechanism most likely extracerebrally. These findings merit further investigation of antihistamines in clinical drug trials. The H3 and H4 receptors are found in primarily in CNS and immune tissues, respectively. H3 is likely to be involved in antinociception and has been linked with cognitive, neurodegenerative and sleep disorders. The only marketed H3 agent, pitolisant, is a brain penetrant H3 antagonist/inverse agonist which increases central histamine and causes headache. The experimental H3 agonist Nα-methylhistamine has shown promising results as a migraine preventative in studies of uncertain quality. With the current limited knowledge of the H4 receptor it is questionable whether or not the receptor is involved in migraine. Conclusion There is insufficient support for first generation antihistamines (both H1 and H2) as preventive migraine medications and sedation and weight gain are unacceptable side effects. Non-sedating H1 antihistamines need to be appropriately tested. Central H3 receptors seem to have a role in migraine that merit further investigation. The histaminergic system may be a goal for novel migraine drugs.

Abstract Background Administration of endogenous mediators or exogenous chemicals in migraine patients provoke early headaches and delayed migraine-like attacks. Although migraine provoking substances are normally vasodilators, dilation of arterial vessels does not seem to be the sole contributing factor, and the underlying mechanisms of the delayed migraine pain are mostly unknown. Sustained mechanical allodynia is a common response associated with the local administration of various proalgesic substances in experimental animals and humans. Here, we investigated the ability of a series of endogenous mediators which provoke or do not provoke migraine in patients, to cause or not cause mechanical allodynia upon their injection in the mouse periorbital area. Methods Mechanical allodynia was assessed with the von Frey filament assay. Stimuli were given by subcutaneous injection in the periorbital area of C57BL/6J mice; antagonists were administered by local and systemic injections. Results Calcitonin gene related peptide (CGRP), but not adrenomedullin and amylin, pituitary adenylyl cyclase activating peptide (PACAP), but not vasoactive intestinal polypeptide (VIP), histamine, prostaglandin E2 (PGE2) and prostacyclin (PGI2), but not PGF2α, evoked a dose-dependent periorbital mechanical allodynia. The painful responses were attenuated by systemic or local (periorbital) administration of antagonists for CGRP (CLR/RAMP1), PACAP (PAC-1), histamine H1, PGE2 (EP4), and PGI2 (IP) receptors, respectively. Conclusions The correspondence between substances that provoke (CGRP; PACAP, histamine, PGE2, PGI2), or do not provoke (VIP and PGF2α), migraine-like attacks in patients and periorbital allodynia in mice suggests that the study of allodynia in mice may provide information on the proalgesic mechanisms of migraine-provoking agents in humans. Results underline the ability of migraine-provoking substances to initiate mechanical allodynia by acting on peripheral terminals of trigeminal afferents.

The Central Sensitivity Syndrome is defined as a physiological condition where the endocrine system, the nervous system and the immunological systems are altered causing the overexcitement of the neurons and consequently the organism is oversensitive to harmful or harmless stimuli. In the last 30 years there have been an increase in the research related to CSS. The understanding of the common physiopathology shared by the different syndromes which form it is a useful tool to be able to play an efficient role as health professionals. Not only doctors should be enable to treat patients with such symptoms but also nutritionists, among others, must have the necessary tools to try to improve the quality of these people's lives. This bibliographic review is supported by a number of researches approved by the scientific world regarding the components, physiopathology and symptoms of this syndrome, even so with the relationship and the role played on a nutritional level. Currently, Spain has several teams of professionals working and looking into the scientific evidence of some nutritional treatments for this problem, as for example the function of the Histamine in CSS. Finally it finishes with the importance diet and microbiota have in the development and maintenance of the symptoms.

Early Huntington’s disease (HD) include over-activation of dopamine D1 receptors (D1R), producing an imbalance in dopaminergic neurotransmission and cell death. To reduce D1R over-activation, we present a strategy based on targeting complexes of D1R and histamine H3 receptors (H3R). Using an HD mouse striatal cell model and HD mouse organotypic brain slices we found that D1R-induced cell death signaling and neuronal degeneration, are mitigated by an H3R antagonist. We demonstrate that the D1R-H3R heteromer is expressed in HD mice at early but not late stages of HD, correlating with HD progression. In accordance, we found this target expressed in human control subjects and low-grade HD patients. Finally, treatment of HD mice with an H3R antagonist prevented cognitive and motor learning deficits and the loss of heteromer expression. Taken together, our results indicate that D1R - H3R heteromers play a pivotal role in dopamine signaling and represent novel targets for treating HD.

Aim. The purpose of the study: to pay attention to the urgency of the problem for further deeper study of diseases in children, which is based on the violation of histamine metabolism in the body, namely, increase in the level of extracellular histamine. To study the syndrome of intolerance to histamine (CIS), the diagnosis and treatment of diaminoxidase deficiency (DAO).Results. Understanding the etiology and pathogenesis of the CIS, studying the diagnosis and treatment of DAO deficiency gives new opportunities in successful treatment, and most importantly prevention of food hypersensitivity in children.

Transcranial focal stimulation (TFS) is a non-invasive neuromodulation strategy with neuroprotective effects. On the other hand, 6-hidroxidopamine (6-OHDA) induces neurodegeneration of the nigrostriatal system producing modifications in the dopaminergic, serotoninergic, and histaminergic systems. The present study was conducted to test whether repetitive application of TFS avoids the biogenic amines’ changes induced by the intrastriatal injection of 6-OHDA. Experiments were designed to determine the tissue content of dopamine, serotonin, and histamine in the brain of animals injected with 6-OHDA and then receiving daily TFS for 21 days. Tissue content of biogenic amines was evaluated in the cerebral cortex, hippocampus, amygdala, and striatum, ipsi- and contralateral to the side of 6-OHDA injection. Results obtained were compared to animals with 6-OHDA, TFS alone, and a Sham group. The present study revealed that TFS did not avoid the changes in the tissue content of dopamine in striatum. However, TFS was able to avoid several of the changes induced by 6-OHDA in the tissue content of dopamine, serotonin, and histamine in the different brain areas evaluated. Interestingly, TFS alone did not induce significant changes in the different brain areas evaluated. The present study showed that repetitive TFS avoids the biogenic amines’ changes induced by 6-OHDA. TFS can represent a new therapeutic strategy to avoid the neurotoxicity induced by 6-OHDA.

Allergic conjunctivitis (AC), which is characterized by ocular itching, hyperemia, and edema, deteriorates quality of life. In this study, effects of anti-allergic drugs were evaluated by assessing eye-scratching behavior, the number of eosinophils in conjunctiva epithelial tissues, and concentrations of chemical mediators in the tears of the guinea pig model of ovalbumin (OA)-induced AC.

Pterjium is an ocular surface disorder and is a pathologic result of corneal invasion of the fibro-vascular proliferation of the bulb conjunctiva in the region corresponding to the lid space. Pterjium is a disease with high rates of recurrence after surgery. Nowadays, along with several new techniques that are used to prevent recurrence, antineoplastics are also used to stop the growth. Various growth factors and mediators, like some neoplasms, have been found to be effective in pterygium growth, invasion and relapse. In addition to growth factors such as stem cell factor and VEGF, an increase in histamine, carbonic anhydrase activity, in number of eph B4, and in nestin release was found while a decrease in IGFBP3 release was found. Studies are currently underway to stop the growth of pterygium and prevent recurrence.

Allergic rhinitis as one of the most common non-infectious respiratory inflammatory diseases is a global public health problem. The course of allergic rhinitis, its effect on the pathology of other organs and systems, the likelihood of complications and many other aspects of this pathology are largely determined by timely diagnosis and adequate treatment. At the heart of the pathogenesis of allergic rhinitis is the immediate allergic reaction. Histamine is the most important biogenic amine, the physiological regulator of the activity of various cells and systems and one of the main mediators of allergic reactions of immediate type. In the treatment of allergic rhinitis, one of the key places is occupied by antihistamines. One of such highly effective modern antihistamines is levocetirizine – a blocker of H1 histamine receptors of the second generation. Leveltzetirizine affects the histamine-dependent stage of allergic reactions, reduces vascular permeability and eosinophil migration, limits the release of inflammatory mediators, significantly influences the formation of edema of the tissues and the production of mucus, prevents development and greatly facilitates the course of the allergic reaction, has antiexudative, antipruritic and anti-inflammatory effects, and a pronounced ability to eliminate nasal obstruction in patients with seasonal allergic rhinitis. The drug levocetirizine Allerway®, bioequivalent to the original drug, is of definite interest to physicians of various specialties.

The mast cells are initial effective lineage in both humoral and adaptive immunity. They are ubiquitous in skin, mucosa, and in function. They contain biologically essential and dynamic mediators in healthy and harmful conditions of tissue. Mast cell malfunctioning could be attributed to various chronic allergic diseases. Considerately, emerging evidence of mast cell involvement in various cancers shows them to have both positive and negative roles in tumour growth. It mostly indulges in tumour progression and metastasis via angiogenesis, extracellular matrix degradation, and mitogenic activity in the tumour microenvironment. The current paper reviewed research papers on mast cells in oral squamous cell carcinoma through the PubMed database from 1980 to the present date. The present paper is an attempt to summarise the research reports on the role of mast cells in oral squamous cell carcinoma. Further to this note, this paper also outlines the role of mast cells in normal physiological processes and tumour biology.

Urticaria and angioedema are characterized by pruritic hives and sometimes swelling of deeper mucocutaneous layers. Urticaria is caused by release of histamine and other mediators from mast cells. A cut-off of six weeks distinguishes acute and chronic forms, as these seem to differ regarding etiological and response patterns. Angioedema may be histaminergic or due to factors involving the bradykinin pathway. Medications such as ACE-Inhibitors or conditions affecting the C1-esterase inhibitor enzyme are potential causes. Acute urticaria may be related to triggers such as infections, medications or food allergy. When occurring with systemic symptoms and a temporal relationship to food or drug ingestion, IgE mediated allergy could be considered. Chronic Inducible Urticaria (CInd) is suspected on history and may be confirmed by provocation testing where physical and other specific trigger factors elicit the wheals. The term Chronic Spontaneous Urticaria (CSU) is used when symptoms persist for more than six weeks in the absence of inducible factors. A single cause is seldom found but a thorough history and clinical evaluation may elicit trigger factors and associated medical conditions such as auto-immune or thyroid disorders. Indiscriminate food allergy testing is unhelpful, but additive intolerance may be implicated in some cases. Modern non-sedating antihistamines are the mainstay of treatment, and omalizumab or immunosuppressives may be considered for refractory cases. Emotional support is needed as the condition is associated with psychological distress. If there are unusual features, vasculitis, auto-inflammatory or haematological conditions should be considered and skin biopsy or detailed immunological work-up may be indicated.

Spiders belong to the class Arachnida in the phylum Arthropoda. Although the bite of the spider is feared as much as that of venomous snakes in Sri Lanka, spider bite related deaths are not reported in this country. A 43-year-old patient presented with local swelling, pain, bleeding from puncture site and muscle cramps after a Poecilotheria subfusca (Ivory-billed ornamental or montane tiger spider) bite; and a 45-year-old patient presented with numbness, burning pain and muscle cramps after a Poecilotheria fasciata (Ceylon Hunting Spider/Ornamental Tarantula) bite. Both patients recovered completely without residual effects.

Atherosclerosis is developed due to the formation of atheroma plaques in the coronary arteries. In this process, M1 macrophages and vascular smooth muscle cells (VSMCs) are the main functional cells. Inflammatory mediators such as histamine may inflame M1 macrophages. The aim of this study was to determine the effect of M1 macrophage secretion contents on the gene and protein expression levels of focal adhesion kinase (FAK), vasodilator-stimulated phosphoprotein (VASP), and thrombospondin1 (THBS1). Whole blood samples from the six healthy subjects (stenosis70%) were prepared and peripheral blood mononuclear cells (PBMCs) were isolated. Then monocytes were differentiated into M1 macrophages using 100 ng/mL granulocyte-macrophage colony stimulating factor (GM-CSF). The differentiated M1 macrophages were treated with histamine (10-6 M), and their secretion contents were harvested and added to the culture medium of VSMCs. The FAK, VASP, and THBS1 gene expression and protein levels were measured using RT-qPCR and western blot techniques in VSMCs, respectively. The FAK and THBS1 gene expression levels significantly increased in VSMCs after adding secretion contents obtained from histamine-treated M1 macrophages (p=0.023 and 0.05, respectively), while significant results were not observed for VASP gene (p=0.45). In converse with the phosphorylated VASP (pVASP) (p

Angioedema is defined by non-dependent, non-pitting edema that affects several different sites and is potentially life-threatening due to laryngeal edema. This narrative review provides emergency physicians with a focused overview of the evaluation and management of angioedema. Two primary forms include histamine-mediated and bradykinin-mediated angioedema. Histamine-mediated forms present similarly to anaphylaxis, while bradykinin-mediated angioedema presents with greater face and oropharyngeal involvement and higher risk of progression. Initial evaluation and management should focus on evaluation of the airway, followed by obtaining relevant historical features, including family history, medications, and prior episodes. Histamine-mediated angioedema should be treated with epinephrine intramuscularly, antihistaminergic medications, and steroids. These medications are not effective for bradykinin-mediated forms. Other medications include C1-INH protein replacement, kallikrein inhibitor, and bradykinin receptor antagonists. Evidence is controversial concerning the efficacy of these medications in an acute episode, and airway management is the most important intervention when indicated. Airway intervention may require fiberoptic or video laryngoscopy, with preparation for cricothyrotomy. Disposition is dependent on patient's airway and respiratory status, as well as the sites involved. [ABSTRACT FROM AUTHOR]