Topical Antiedematogenic Activity of the Essential Oil of Psidium brownianum Mart. (OEPB) in Murine Ear Edema Models.

Psidium brownianum Mart is reported in the literature by antinociceptive and antioxidant activities, indicating that this species' secondary metabolites might be used to control inflammatory processes. The present study aimed to characterize the topical antiedematogenic activity of the essential oil of Psidium brownianum Mart. (OEPB) in ear edema models by different inflammatory agents. Female Swiss mice (25-35 g) and Wistar albino rats (200-300 g) were used throughout tests (n=6/group) on acute or chronic edema models induced by single and multiple topical applications. The OEPB is administered topically pure or at a concentration of 100 or 200 mg/mL. The antiedematogenic mechanism of OEPB was analyzed by administering capsaicin, arachidonic acid, histamine, and phenol at the best effective dose (200 mg/mL). The results showed a significant reduction of edema-induced single (28.87 %) and multiple (50.13 %) applications of croton oil compared to the negative control group. Regarding potential mechanisms of action, OEPB (200 mg/mL) inhibited the development of edema triggered by capsaicin (29.95 %), arachidonic acid (22.66 %), phenol (23.35 %), and histamine (75.46 %), suggesting an interference with the histaminergic pathway. These results indicate that OEPB presents a topical antiedematogenic effect in acute and chronic murine models, possibly interfering with inflammatory pathways triggered by mediators such as histamine.

An insular cortical circuit required for itch sensation and aversion.

Itch encompasses both sensory and emotional dimensions, with the two dimensions reciprocally exacerbating each other. However, whether a shared neural circuit mechanism governs both dimensions remains elusive. Here, we report that the anterior insular cortex (AIC) is activated by both histamine-dependent and -independent itch stimuli. The activation of AIC elicits aversive emotion and exacerbates pruritogen-induced itch sensation and aversion. Mechanistically, AIC excitatory neurons project to the GABAergic neurons in the dorsal bed nucleus of the stria terminalis (dBNST). Manipulating the activity of the AIC → dBNST pathway affects both itch sensation and itch-induced aversion. Our study discovers the shared neural circuit (AIC â†’ dBNST pathway) underlying the itch sensation and aversion, highlights the critical role of the AIC as a central hub for the itch processing, and provides a framework to understand the neural mechanisms underlying the sensation and emotion interaction.

Histamine- and pruritogen-induced itch is inhibited by a TRPM8 agonist: a randomized vehicle-controlled human trial.

BACKGROUND: Allergies often present challenges in managing itch and the effects of histamine. Cooling agents that act via transient receptor potential melastatin 8 (TRPM8) agonism have shown potential in itch management. However, animal studies on itch have limitations, as animals cannot communicate subjective events and their fur-coated skin differs from that of humans. Human studies offer more direct and reliable information. OBJECTIVES: To investigate the effects of a specific TRPM8 agonist gel (cryosim-1) on itch induced by various pruritogens in human skin. METHODS: Calcium imaging experiments determined the binding of cryosim-1 and histamine to their respective receptors. Thirty healthy volunteers underwent skin prick tests with pruritogens and a control vehicle. Itch and pain intensity were measured using a numerical rating scale (NRS) across 10 min. Participants were randomly assigned to pretreatments with vehicle or TRPM8 agonist gel. Tests were repeated at a later date, and skin moisture, transepidermal water loss and mechanical sensitivity were measured. RESULTS: The in vitro study confirmed that histamine is not a TRPM8 agonist and cryosim-1 does not act as an agonist or antagonist on the human histamine 1 receptor. The TRPM8 agonist gel significantly reduced the itch intensity for all pruritogens compared with the vehicle-only gel. It also reduced itch NRS and the integrated itch score. Mechanical sensitivity was also reduced. CONCLUSIONS: The specific TRPM8 agonist gel effectively suppressed human skin itch induced by various pruritogens. These versatile actions suggest that cooling agents may be promising treatments for multiple forms of itch stimuli.

Managing itching and the effects of histamine can be difficult for people with allergies. Cooling the skin or applying menthol provides some relief from itch, but the way they work is not fully understood. Cooling agents interact with a protein called TRPM8 (also known as the 'cold and menthol receptor') and have shown potential for the management of itch. However, much of the research has been done on animals and has limitations when compared with human studies. Antihistamine medications can help with histamine-induced itching, but they may not work for other causes of itch. This study investigated the effects of a specific TRPM8 agonist (a chemical that activates a receptor to produce a biologic response) gel called cryosim-1 on itch in human skin. To do this, we conducted tests on 30 healthy people using five different substances that cause itching. Participants rated the itch intensity and pain using a scale and we measured various aspects of their skin. The results showed that all substances caused significant itching compared to a control substance, but itchiness gradually decreased over time. Histamine and compound 48/80 also caused pain. However, when participants applied the TRPM8 activator gel before exposure, they experienced less itching and lower itch intensity versus the gel without the activator. There were no significant differences in pain between the TRPM8 activator and the gel without it. In summary, our findings showed that activating TRPM8 receptors with a specific substance effectively relieved itching caused by various irritants on human skin. This suggests its potential as a treatment for itch-related conditions. Further research is needed to understand its mechanisms better and evaluate its effectiveness in real-life situations.

Functional brain alterations in symptomatic dermographism patients-An exploratory magnetoencephalography study.

Symptomatic dermographism (SD) is a common form of urticaria, which is triggered by stroking the skin. Brain involvement in its aetiology was investigated by means of magnetoencephalography (MEG) after provocation with histamine and dermography. Wheals were induced by histamine skin prick test and dermography in twelve SD patients and fourteen controls. Itch severity was scored on a Visual Analogue Scale (VAS). Relative power and functional connectivity (FC) were measured using a 306-channel whole-head MEG system at baseline and 10 min after histamine and dermography, and contrasted between groups and conditions. Furthermore, wheal diameter and itch scores after these procedures were correlated with the MEG values. SD patients had higher itch scores after histamine and dermography. No significant group-differences were observed in relative power or FC for any condition. In both groups, power decreases were mostly observed in the beta band, and power increases in the alpha bands, after provocation, with more regions involved in patients compared to controls. Increased FC was seen after histamine in patients, and after dermography in controls. In patients only, dermography and histamine wheal size correlated with the alpha2 power in the regions of interest that showed significant condition effects after these procedures. Our findings may be cautiously interpreted as aberrant itch processing, and suggest involvement of the central nervous system in the aetiology of SD.

Electrical matrix stimulation suppresses acute itch independently of activation of sleeping nociceptors.

INTRODUCTION: Itch can be reduced by pain. Activation of sleeping nociceptors (CMi) is a crucial mechanism for the peripheral component of intense and long-lasting pain. Thus, activation of CMi might be especially effective in itch reduction. Electrical stimulation using sinusoidal pulses activates CMi with tolerable pain intensity, whereas short rectangular pulses with low intensity do not. In humans, histaminergic itch is mediated by histamine-sensitive CMi, whereas other pruritogens activate polymodal nociceptors (CM). METHODS: In a psychophysical approach in a balanced crossover repeated-measures design in healthy volunteers, we activated nociceptors by two different electrical stimulation paradigms via a matrix electrode: 4 Hz sinusoidal pulses that activate C-nociceptors including CMi or 4 Hz rectangular stimuli to activate nociceptors excluding CMi. After 5-min stimulation, itch was induced by either histamine iontophoresis or application of cowhage spicules. Itch ratings were assessed via a numerical rating scale (NRS). RESULTS: Electrical 4 Hz sine wave stimulation (0.1 mA) with low pain ratings of 1.5 (NRS; 0-10) induced an axon reflex erythema (3 cm2 ), indicating activation of CMi, whereas rectangular 0.2 ms pulses (average 0.91 mA) with the same pain rating did not. Both electrical stimulation paradigms reduced itch magnitude over time evoked by either histamine or cowhage to a similar extent. Peak maximum itch evoked by histamine was reduced by both stimulation paradigms, but not cowhage maximum itch. DISCUSSION: Since electrical stimulation with the rectangular pulse paradigm reduces itch to a similar extent as the sine wave stimulation paradigm, the input of CMi is not necessarily required for itch suppression. The input of A-fibres and polymodal nociceptors, similarly, as also achieved by scratching, seems to be sufficient for both forms of chemically evoked itch. SIGNIFICANCE: Since activation of CMi does not provide additional benefit for itch suppression, spinal pain pathways transmitted via CM versus CMi have differential effects on itch-processing circuits. This is important knowledge for using electrical matrix stimulation as itch suppressor since activation of sleeping nociceptors either requires significantly painful stimulation paradigms or specialized stimulation paradigms as sinusoidal pulses. An alternative approach using half-sine wave pulses with low pain intensity activating specifically polymodal nociceptors to suppress itch via matrix electrode stimulation may be considered.

Epinastine Cream: A Novel Once-Daily Therapeutic Agent for Allergic Conjunctivitis.

Purpose: To investigate the in vivo efficacy of epinastine cream in type I allergic models. Methods: The dose, timing, and antiallergic effect of epinastine cream on the conjunctiva were evaluated postapplication to the eyelid skin of guinea pigs with histamine- or ovalbumin-induced allergic conjunctivitis. Additionally, we assessed its antiallergic effects on the skin postapplication to the dorsal skin of guinea pigs with ovalbumin-induced passive cutaneous anaphylaxis. Efficacy was estimated by determining the amount of dye that leaked from conjunctival or dorsal skin tissue vessels as a measure of vascular permeability, scoring the severity of allergic symptoms, and observing the scratching behaviors using clinical parameters. Results: In the histamine-induced conjunctivitis model, epinastine cream strongly inhibited conjunctival vascular permeability in a dose-dependent manner. The inhibitory effect of 0.5% epinastine cream 24 h postapplication was significantly higher than that of 0.1% epinastine hydrochloride ophthalmic solution 8 h postadministration. Additionally, the 0.5% epinastine cream inhibited conjunctival vascular permeability 15 min postapplication, and the effect was sustained over 24 h. Furthermore, the 0.5% epinastine cream effectively suppressed clinical symptom scores and exhibited ameliorated scratching bouts in conjunctival allergic reactions in the experimental allergic conjunctivitis model. Additionally, it significantly inhibited vascular permeability in skin allergic reactions in the passive cutaneous anaphylaxis model. Conclusions: The results suggest that epinastine cream is a strong, long-lasting, and skin-penetrating inhibitor of type I allergic reactions. The 0.5% epinastine cream applied once daily could be a promising, potent, and long-acting therapeutic agent for allergic conjunctivitis.

Antiedematogenic and Analgesic Activities of Abietic Acid in Mice.

Exacerbated inflammatory responses to harmful stimuli can lead to significant pain, edema, and other complications that require pharmacological intervention. Abietic acid (AA) is a diterpene found as a significant constituent in pine species, and evidence has identified its biological potential. The present study aimed to evaluate abietic acid's antiedematogenic and anti-inflammatory activity in mice. Swiss mice (Mus musculus) weighing 20-30 g were treated with AA at 50, 100, and 200 mg/kg. The central nervous system (CNS) effects were evaluated using open-field and rotarod assays. The antinociceptive and anti-inflammatory screening was assessed by the acetic acid and formalin tests. The antiedematogenic activity was investigated by measuring paw edema induced by carrageenan, dextran, histamine, arachidonic acid, and prostaglandin, in addition to using a granuloma model. The oral administration of abietic acid (200 mg/Kg) showed no evidence of CNS effects. The compound also exhibited significant antiedematogenic and anti-inflammatory activities in the carrageenan and dextran models, mostly related to the inhibition of myeloperoxidase (MOP) activity and histamine action and, to a lesser extent, the inhibition of eicosanoid-dependent pathways. In the granuloma model, abietic acid's effect was less expressive than in the acute models investigated in this study. In conclusion, abietic acid has analgesic and antiedematogenic activities related to anti-inflammatory mechanisms.

Effects of oral morphine on experimentally evoked itch and pain: a randomized, double-blind, placebo-controlled trial.

OBJECTIVES: Pain and itch share similar neuronal networks; hence, it is difficult to explain why opioids can relieve pain but provoke itching. The present human volunteer study aimed to investigate the similarities and differences in responses to experimentally provoked pain and itching to explore the underlying fundamental mechanisms. METHODS: Twenty-four healthy volunteers were enrolled in this single-center, randomized, double-blind, placebo-controlled, parallel-group trial. Three volar forearms and two mandibular areas were marked, and participants randomly received morphine (20 mg) or identical placebo tablets. Heat, cold, and pressure pain thresholds, and vasomotor responses were assessed at baseline and after oral morphine administration. Itch provocations were induced by intradermal application of 1 % histamine or a topical cowhage (non-histaminergic itch) to a marked area of the skin. The participants were subsequently asked to rate their itching and pain intensities. The assessments were repeated for all marked areas. RESULTS: Morphine caused analgesia, as assessed by the significant modulation of cold and pressure pain thresholds (p<0.05). There were no significant differences in histaminergic or non-histaminergic itch or pain intensity between the morphine and placebo groups. Superficial blood perfusion (vasomotor response) following histamine provocation was significantly increased by morphine (p<0.05) in both areas. No correlation was found between the provoked itch intensity and analgesic efficacy in any area or group. CONCLUSIONS: Oral administration of morphine caused analgesia without modulating itch intensities but increased neurogenic inflammation in response to histamine, suggesting that different opioid mechanisms in histaminergic and non-histaminergic neurons evoke neurogenic inflammation.

The Use of DAO as a Marker for Histamine Intolerance: Measurements and Determinants in a Large Random Population-Based Survey.

Histamine intolerance (HIT) is a common adverse reaction to food where elimination and reintroduction of histamine-rich food is part of the investigation. Analysis of the enzyme diamine oxidase (DAO) is sometimes used as an additional tool for diagnosis. This study aimed to describe the distribution of DAO in a large representative cohort of adults and to determine the association between DAO activity and possible associated factors. The study is based on the population-based West Sweden Asthma Study and includes 1051 subjects. Subjects underwent structured interviews including questions on demography, asthma, allergy symptoms, and lifestyle factors. Subjects were assessed for specific-IgE-antibodies and measurement of DAO activity in serum. Previously suggested cut-off levels for low values (<3 U/mL), normal values (>10 U/mL), and median levels of DAO were used. In the group of 1051 subjects, only a few presented reactions upon histamine intake, whereas 44% presented DAO levels below the suggested normal cut-off levels. BMI and age were shown to have an impact on DAO activity among women with increasing activity of DAO with increasing BMI and age. Among men, only increasing age was seen to have an impact on DAO levels. There was no difference in DAO levels with different sensitization status to common foods or airborne allergens. No association between DAO levels and reported symptoms to histamine-rich foods could be found. In conclusion, the determination of the DAO enzyme needs to be re-evaluated and may not be used as a valuable tool for histamine intolerance using current cut-off values. Further studies are needed to improve the use of DAO as a biomarker for histamine intolerance.

Modulating Effects of the Hydroethanolic Leaf Extract of Persicaria lanigera R. Br. Soják (Polygonaceae) against Acute Inflammation.

Plant species have been used traditionally to treat numerous inflammatory disorders because of their known medicinal properties. This study aimed to assess the anti-inflammatory effect of aqueous ethanolic leaf extract of Persicaria lanigera using acute inflammatory models. The safety profile of the Persicaria lanigera extract was assessed using an acute toxicity model. The anti-inflammatory effect of the Persicaria lanigera leaf extract (100-600 mg·kg-1, p.o.) was studied in carrageenan-induced paw oedema, zymosan-induced knee joint arthritis, and histamine-induced paw oedema in Sprague-Dawley rats (n = 5). It was observed that the Persicaria lanigera leaf extract administered prophylactically significantly inhibited paw oedema from 99.01 ± 12.59 to 59.10 ± 4.94%, 56.08 ± 3.65%, and 48.62 ± 3.27% at 100 mg·kg-1, 300 mg·kg-1, and 600 mg·kg-1, while the standard drug, aspirin, showed 41.84 ± 9.25% in carrageenan-induced paw oedema, respectively. Furthermore, the extract decreased knee joint inflammation significantly from 62.43 ± 5.73% to 32.07 ± 2.98% and 24.33 ± 8.58% at 300 mg·kg-1 and 600 mg·kg-1 in zymosan-induced knee joint inflammation, respectively. In the histamine-induced paw oedema model, the extract significantly inhibited oedema to 61.53 ± 9.17%, 54.21 ± 9.38%, and 54.22 ± 9.37% at the same doses. Aqueous ethanolic leaf extract of Persicaria lanigera is safe and attenuates inflammation in acute inflammation models.

Gastroprotective and ulcer healing effects of Nauclea pobeguinii (Rubiaceae) on experimentally induced gastric ulcers in male Wistar rats.

OBJECTIVES: In this study, we determined the gastroprotective and ulcer-healing effects of extracts (aqueous and methanolic) of Nauclea pobeguinii stem-back. METHODS: Gastroprotective and healing activity were evaluated following a HCl/ethanol and an indomethacin-induced acute ulcers models; acetic acid, pylorus-ligature, pylorus ligature/histamine and pylorus ligature/acetylcholine-induced chronic ulcers models. RESULTS: It emerges from this study that, at 100, 200 and 400 mg/kg, the extracts significantly reduced the various ulceration parameters. Compared to negative control male rats, the aqueous (100 mg/kg) and methanolic (400 mg/kg) extracts of Nauclea pobeguinii inhibited the ulcers induced by HCl/ethanol by 80.76 % and 100 % respectively, as well as ulcers induced by indomethacin by 88.28 % and 93.47 % respectively. Animals that received 200 mg/kg of both extracts showed a significant reduction in the levels of monocytes, lymphocytes, nitric oxide, MDA and a significant increase in the activities of SOD and catalase. Histological analysis showed repaired mucous epithelium at all doses of both extracts. Aqueous and methanol extracts inhibited ulceration indices by 89.33 % and 88.53 % for pylorus ligature, 83.81 % and 61.07 % for pylorus ligature/acetylcholine and 87.29 % and 99.63 % for pylorus ligature/histamine respectively. Both extracts protected the stomach lining with percentages inhibition of 79.49 % and 81.73 %, respectively in the ethanol test. The extracts induced a significant increase in mucus mass (p<0.001). CONCLUSIONS: The aqueous and methanol extracts of Nauclea pobeguinii healed ulcers thanks to their anti-inflammatory, anti-oxidant, anti-secretory and cytoprotective properties.

Enhancement of receptor-mediated calcium responses by phenytoin through the suppression of calcium excretion in human gingival fibroblasts.

BACKGROUND AND OBJECTIVES: Gingival overgrowth caused by phenytoin is proposed to be associated with Ca2+ signaling; however, the mechanisms that increase the intracellular Ca2+ concentration ([Ca2+ ]i ) are controversial. The current study aimed to elucidate the mechanism underlying the phenytoin-induced increase in [Ca2+ ]i in human gingival fibroblasts (HGFs). METHODS: Effects of 100 µM phenytoin on [Ca2+ ]i in HGFs were examined at the single-cell level using fluorescence images of fura-2 captured by an imaging system consisting of an EM-CCD camera coupled to an inverted fluorescence microscope at room temperature. RESULTS: Exposure of HGFs to 100 µM phenytoin induced a transient increase in [Ca2+ ]i in the absence of extracellular Ca2+ , indicating that the phenytoin-induced increase in [Ca2+ ]i does not require an influx of extracellular Ca2+ . In addition, phenytoin increased [Ca2+ ]i in HGFs depleted of intracellular Ca2+ stores by thapsigargin, indicating that neither Ca2+ release from stores nor inhibition of Ca2+ uptake is involved. Furthermore, the phenytoin-induced [Ca2+ ]i elevation was reduced to 18.8% in the absence of extracellular Na+ , and [Ca2+ ]i elevation upon removal of extracellular Na+ was reduced to 25.9% in the presence of phenytoin. These results imply that phenytoin increases [Ca2+ ]i of HGFs by suppressing the Na+ /Ca2+ exchanger. Suppression of intracellular Ca2+ excretion is thought to enhance the Ca2+ responses induced by various stimuli. Analysis at the single-cell level showed that stimulation with 1 µM ATP or 3 µM histamine increased [Ca2+ ]i in 20-50% of cells, and [Ca2+ ]i increased in many unresponsive cells in the presence of phenytoin. CONCLUSION: Our findings demonstrate that phenytoin induced increase in [Ca2+ ]i by the inhibition of Ca2+ efflux in HGFs. It was also found that phenytoin strongly enhanced small Ca2+ responses induced by stimulation with a low concentration of ATP or histamine by inhibiting Ca2+ efflux. These findings suggest a possibility that phenytoin causes drug-induced gingival overgrowth by interacting with inflammatory bioactive substances in the gingiva.

[Food Intolerance]. / Intolerancia alimentaria.

The term food intolerance has been used non-specifically to define a wide range of disorders related to food intake. Recently, the use of the term "non-immunological adverse reactions to foods" (RANIAs) was recommended as a more correct clinical definition. The pathophysiological mechanisms can be diverse, sometimes unknown, and there are no validated diagnostic tests, making it difficult to obtain accurate data. The clinical manifestations of non-immunological adverse reactions to foods affect more than one organ or system; and gastrointestinal symptoms (pain, abdominal distension, flatulence, and diarrhea) are the most common. Non-immunological adverse reactions to foods are divided into independent and dependent on host factors. Foods may contain chemicals with pharmacological activity and be present naturally, such as vasoactive amines (histamine) and salicylates, or added for preservation, to improve appearance or flavor (monosodium glutamate, tartrazine, sulfites, and benzoates). In some cases, these types of reactions may be like to hypersensitivity reactions. Concomitant alcohol consumption may worsen symptoms by inhibiting histamine breakdown and increasing intestinal permeability. In patients diagnosed with non-immunological adverse reactions to foods, it is important to rule out some psychological problems: aversions or eating disorders.

El término intolerancia alimentaria se ha utilizado de manera inespecífica para definir una amplia gama de trastornos relacionados con la ingesta de alimentos. Recientemente se recomendó el uso de la expresión "reacciones adversas no inmunológicas a alimentos" (RANIAs) como una definición clínica más correcta. Los mecanismos fisiopatológicos pueden ser diversos, a veces desconocidos, y no existen pruebas diagnósticas validadas, por lo que es difícil obtener datos certeros. Las manifestaciones clínicas de las reacciones adversas no inmunológicas a alimentos afectan a más de un órgano o sistema; y los síntomas gastrointestinales (dolor, distensión abdominal, flatulencias y diarrea) son los más frecuentes. Las reacciones adversas no inmunológicas a alimentos se dividen en independientes y dependientes de factores del huésped. Los alimentos pueden contener productos químicos con actividad farmacológica y estar presentes en forma natural, como las aminas vasoactivas (histamina) y los salicilatos, o añadirse para su conservación, mejorar la apariencia o el sabor (glutamato monosódico, tartrazina, sulfitos y benzoatos). En algunos casos, este tipo de reacciones pueden ser similares, desde el punto de vista clínico, a las reacciones de hipersensibilidad. El consumo de alcohol concomitante puede empeorar los síntomas, al inhibir la degradación de la histamina y aumentar la permeabilidad intestinal. En pacientes con diagnóstico de reacciones adversas no inmunológicas por alimentos es importante descartar algunos problemas de índole psicológica: aversiones o trastornos de la conducta alimentaria.

Evaluation of anti-inflammatory and analgesic effects of Hertia intermedia (Boiss.) Kuntze extract.

Hertia intermedia is a traditional medicinal plant of Balochistan, used for pain management and stomach problems. Current research work was intended to evaluate the anti-inflammatory and analgesic activities of crude ethanolic extract of H. intermedia. Anti-inflammatory activity was determined by the carrageenan-induced and histamine-induce Rat paw edema in rats, analgesic activity was determined by acetic acid-Induced writhing test, formalin-induced hind paw licking in mice and Tail immersion test. H. intermedia crude ethanolic extract showed significant (p<0.05) effect in both carrageenan and histamine-induced rat paw edema at both 250 and 500 mg/kg oral doses. There were significant analgesic activities in comparison with standard drug and control (p<0.05). It is concluded that H. intermedia crude ethanolic extract possesses significant anti-inflammatory and analgesic effects. However further studies may be carried out to isolate the phytochemicals responsible for anti-inflammatory and analgesic activities.

Footedness for scratching itchy eyes in rodents.

The neural bases of itchy eye transmission remain unclear compared with those involved in body itch. Here, we show in rodents that the gastrin-releasing peptide receptor (GRPR) of the trigeminal sensory system is involved in the transmission of itchy eyes. Interestingly, we further demonstrate a difference in scratching behaviour between the left and right hindfeet in rodents; histamine instillation into the conjunctival sac of both eyes revealed right-foot biased laterality in the scratching movements. Unilateral histamine instillation specifically induced neural activation in the ipsilateral sensory pathway, with no significant difference between the activations following left- and right-eye instillations. Thus, the behavioural laterality is presumably due to right-foot preference in rodents. Genetically modified rats with specific depletion of Grpr-expressing neurons in the trigeminal sensory nucleus caudalis of the medulla oblongata exhibited fewer and shorter histamine-induced scratching movements than controls and eliminated the footedness. These results taken together indicate that the Grpr-expressing neurons are required for the transmission of itch sensation from the eyes, but that foot preference is generated centrally. These findings could open up a new field of research on the mechanisms of the laterality in vertebrates and also offer new potential therapeutic approaches to refractory pruritic eye disorders.

Nafamostat is a Potent Human Diamine Oxidase Inhibitor Possibly Augmenting Hypersensitivity Reactions during Nafamostat Administration.

Nafamostat is an approved short-acting serine protease inhibitor. However, its administration is also associated with anaphylactic reactions. One mechanism to augment hypersensitivity reactions could be inhibition of diamine oxidase (DAO). The chemical structure of nafamostat is related to the potent DAO inhibitors pentamidine and diminazene. Therefore, we tested whether nafamostat is a human DAO inhibitor. Using different activity assays, nafamostat reversibly inhibited recombinant human DAO with an IC50 of 300-400 nM using 200 µM substrate concentrations. The Ki of nafamostat for the inhibition of putrescine and histamine deamination is 27 nM and 138 nM, respectively For both substrates, nafamostat is a mixed mode inhibitor with P values of <0.01 compared with other inhibition types. Using 80-90% EDTA plasma, the IC50 of nafamostat inhibition was approximately 360 nM using 20 µM cadaverine. In 90% EDTA plasma, the IC50 concentrations were 2-3 µM using 0.9 µM and 0.18 µM histamine as substrate. In silico modeling showed a high overlap compared with published diminazene crystallography data, with a preferred orientation of the guanidine group toward topaquinone. In conclusion, nafamostat is a potent human DAO inhibitor and might increase severity of anaphylactic reaction by interfering with DAO-mediated extracellular histamine degradation. SIGNIFICANCE STATEMENT: Treatment with the short-acting anticoagulant nafamostat during hemodialysis, leukocytapheresis, extracorporeal membrane oxygenator procedures, and disseminated intravascular coagulation is associated with severe anaphylaxis in humans. Histamine is a central mediator in anaphylaxis. Potent inhibition of the only extracellularly histamine-degrading enzyme diamine oxidase could augment anaphylaxis reactions during nafamostat treatment.

Serum Diamine Oxidase Values, Indicating Histamine Intolerance, Influence Lactose Tolerance Breath Test Results.

Lactose intolerance (LIT) is one of the major causes of irritable bowel syndrome (IBS) spectrum complaints. Differences in inadequate lactose digestion are described as various LIT phenotypes with basically unknown pathophysiology. In LIT patients, we retrospectively assessed the effect of histamine intolerance (HIT) on expiratory hydrogen (H2) during H2 lactose breath tests. In a retrospective evaluation of charts from 402 LIT patients, 200 patients were identified as having only LIT. The other 202 LIT patients were found to additionally have diamine oxidase (DAO) values of <10 U/mL, which indicates histamine intolerance (HIT). To identify HIT, standardized questionnaires, low serum DAO values and responses to a histamine-reduced diet were used. Patients were separated into three diagnostic groups according to the result of H2 breath tests: (1) LIT, with an H2 increase of >20 parts per million (ppm), but a blood glucose (BG) increase of >20 mg/dL, (2) LIT with an H2 increase of 20 ppm in combination with a BG increase of <20 mg/dL, and (3) LIT with an exhaled H2 increase of <20 ppm and BG increase of <20 mg/dL. Pairwise comparison with the Kruskal Wallis test was used to compare the areas under the curve (AUC) of LIT and LIT with HIT patients. Exhaled H2 values were significantly higher in H2 > 20 ppm and BG < 20 mg/dL patients with LIT and HIT (p = 0.007). This diagnostic group also showed a significant higher number of patients (p = 0.012) and a significant higher number of patients with gastrointestinal (GI) symptoms during H2 breath tests (p < 0.001). Therefore, low serum DAO values, indicating HIT, influence results of lactose tolerance breath tests.

PAF-induced inflammatory and immuno-allergic ophthalmic diseases and their mitigation with PAF receptor antagonists: Cell and nuclear effects.

Ocular allergies are becoming more prevalent as more airborne pollutants, irritants and microbes pervade our environment. Inflammatory and allergic mediators released by dendritic and mast cells within the conjunctiva cause allergic conjunctivitis (AC), a prevalent ocular surface disorder that affects >40% of the world's human population on a seasonal or perennial basis. Even though histamine is a major culprit, platelet-activating factor (PAF) also contributes to AC, acting either directly or synergistically with histamine and other mediators. PAF receptor-meditated inflammatory reactions, via cell-membrane-bound and nuclear-membrane-bound and nuclear PAF receptors, are also implicated in the etiology of other eye diseases such as uveitis, diabetic retinopathy, corneal and choroidal neovascularization, and age-related macular degeneration which cause serious visual impairment and can lead to blindness. This review highlights the various deleterious elements implicated in the pathological aspects of ocular allergic reactions and inflammation and provides concepts and treatment options to mitigate these eye disorders with a special focus on PAF and PAF receptor antagonists.

Intestinal Dysbiosis in Patients with Histamine Intolerance.

An underlying cause of histamine intolerance is diamine oxidase (DAO) deficiency, which leads to defective homeostasis and a higher systemic absorption of histamine. Impaired DAO activity may have a genetic, pharmacological or pathological origin. A recent proposal also suggests it can arise from an alteration in the gut microbiota, although only one study has explored this hypothesis to date. A greater abundance of histamine-secreting bacteria in the gut could lead to the development of histamine intolerance. Thus, the aim of this study was to characterize the composition of the intestinal microbiota of patients with histamine intolerance symptoms and compare it with that of healthy individuals. The study was performed by sequencing bacterial 16S rRNA genes (V3-V4 region) and analyzing the data using the EzBioCloud Database. Dysbiosis of the gut microbiota was observed in the histamine intolerance group who, in comparison with the healthy individuals, had a significantly lower proportion of Prevotellaceae, Ruminococcus, Faecalibacterium and Faecablibacterium prausnitzii, which are bacteria related to gut health. They also had a significantly higher abundance of histamine-secreting bacteria, including the genera Staphylococcus and Proteus, several unidentified genera belonging to the family Enterobacteriaceae and the species Clostridium perfringens and Enterococcus faecalis. A greater abundance of histaminogenic bacteria would favor the accumulation of high levels of histamine in the gut, its subsequent absorption in plasma and the appearance of adverse effects, even in individuals without DAO deficiency.

Basal Serum Diamine Oxidase Levels as a Biomarker of Histamine Intolerance: A Retrospective Cohort Study.

Background: Histamine Intolerance (HIT) is a multifaceted pseudoallergic disorder possibly due to defective histamine metabolism. Diamine oxidase (DAO) contributes to histamine degradation and can be measured in the serum. The role of DAO measurement in the diagnostic work-up of HIT still remains unclear, and conflicting results have been reported in the literature. Therefore, we aimed to evaluate the possible clinical usefulness and consistency of DAO value ranges as provided by the assay manufacturer and verify whether they could predict the response to treatment. Methods: We retrospectively analyzed 192 outpatients with HIT symptoms and measured serum DAO values at baseline. Patients were prescribed either with low-histamine diet and/or enzymatic supplementation according to symptom severity and re-evaluated six to eight months later. Patients were stratified into three groups according to DAO levels: <3 U/mL, 3−10 U/mL, and >10 U/mL. HIT severity was assessed on a scale of 1 to 5 before and after treatment. Results: A total of 146 patients completed the study. Gastrointestinal and cutaneous symptoms, often associated with headache, were more frequent in subjects with DAO < 10 U/mL. Symptom severity and DAO ranges were correlated. Patients with intermediate DAO levels (3−10 U/mL) showed a more complex clinical phenotype but also a more significant improvement in symptom severity (score reduction 50%, interquartile range (IQR) = 33−60%) when compared to patients with low DAO (40%, IQR = 20−60%; p = 0.045) or high DAO (33%, IQR = 0−50%; p < 0.001). Complex clinical phenotypes were also more frequent in patients with intermediate DAO levels. Conclusions: HIT is characterized by typical symptoms and low levels of DAO activity. Symptom severity was associated with the degree of DAO deficiency. Patients with DAO values between 3 and 10 U/mL show the best response to treatment (low-histamine diet and/or DAO supplementation). DAO value could arguably be considered as a predictor of clinical response to treatment. Prospective studies are needed to confirm these data.