Histamine Receptor Type Research Articles

Therapeutic effects evaluation of vitamin E alone and in combination with ranitidine in stress – induced gastric ulcers in rats

It is noteworthy to examine the morphologic and biochemical efficacies of vitamin E, and its combination with a histamine receptor type 2 blocker on stress gastric ulcers. Animals were divided into (6) groups; group 1 (normal control), group 2 (Cold – restraint stress; CRS), group 3 (ranitidine 20 mg/kg), group 4 (vitamin E 100 mg/kg), group 5 (ranitidine 10 mg/kg + vitamin E 50 mg/kg ), group 6 (ranitidine 5 mg/kg + vitamin E 50 mg/kg ). Rats received treatment orally for 7 consecutive days beginning 1 h after induction of the gastric injury . They were sacrificed for assessment of stomach damage using body weight loss, macroscopic changes, oxidative stress markers (MDA stomach content and SOD enzyme activity). Present findings showed that the combined treatment of vitamin E and ranitidine is dose-dependent, and significantly much more effective in management of stress-induced lesions than using vitamin E alone, which caused remarkable body weight decrease.

Histamine receptor 1 is expressed in leukaemic cells and affects differentiation sensitivity.

Despite the success of immunotherapy in several haematological neoplasms, the effectiveness in acute myeloid leukaemia (AML) is still controversial, partially due to the lack of knowledge regarding immune‐related processes in this disease and similar neoplasias. In this study, we analysed the role and expression of histamine receptor 1 (HRH1) in haematological malignancies. Although the histamine receptor type 1 was widely expressed in healthy and malignant haematopoiesis, especially along the myeloid lineage, HRH1 lacked a relevant role in survival/proliferation and chemoresistance of AML cells, as analysed by HRH1 knockdown (KD) and pharmacological modulation. However, HRH1‐mediated signalling was critical for the activation of the differentiation process induced by several agents including all‐trans retinoic acid, establishing a role for HRH1 in myeloid differentiation. Pharmacological activation of Erk was able to partially restore differentiation capacity in HRH1 KD AML cells, suggesting that HRH1 signalling acts upstream MAPK‐Erk pathway. As an indirect consequence of our results, treatment‐related histamine release is not expected to confer a proliferative advantage in leukaemic cells.

Nootkatone Inhibits Acute and Chronic Inflammatory Responses in Mice.

Nootkatone (NTK) is a sesquiterpenoid found in essential oils of many species of Citrus (Rutaceae). Considering previous reports demonstrating that NTK inhibited inflammatory signaling pathways, this study aimed to investigate the effects of this compound in mice models of acute and chronic inflammation. Murine models of paw edema induced by carrageenan, dextran, histamine, and arachidonic acid, as well as carrageenan-induced peritonitis and pleurisy, were used to evaluate the effects of NTK on acute inflammation. A murine model of granuloma induced by cotton pellets was used to access the impact of NTK treatment on chronic inflammation. In the acute inflammation models, NTK demonstrated antiedematogenic effects and inhibited leukocyte recruitment, which was associated with decreased vascular permeability, inhibition of myeloperoxidase (MPO), interleukin (IL)1-β, and tumor necrosis factor (TNF)-α production. In silico analysis suggest that NTZ anti-inflammatory effects may also occur due to inhibition of cyclooxygenase (COX)-2 activity and antagonism of the histamine receptor type 1 (H1). These mechanisms might have contributed to the reduction of granuloma weight and protein concentration in the homogenates, observed in the chronic inflammation model. In conclusion, NTK exerted anti-inflammatory effects that are associated with inhibition of IL1-β and TNF-α production, possibly due to inhibition of COX-2 activity and antagonism of the H1 receptor. However, further studies are required to characterize the effects of this compound on chronic inflammation.

Anti-Leukemic Properties of Histamine in Monocytic Leukemia: The Role of NOX2.

In patients with acute myeloid leukemia (AML), treatment with histamine dihydrochloride (HDC) and low-dose IL-2 (HDC/IL-2) in the post-chemotherapy phase has been shown to reduce the incidence of leukemic relapse. The clinical benefit of HDC/IL-2 is pronounced in monocytic forms of AML, where the leukemic cells express histamine type 2 receptors (H2R) and the NAPDH oxidase-2 (NOX2). HDC ligates to H2Rs to inhibit NOX2-derived formation of reactive oxygen species, but details regarding the anti-leukemic actions of HDC remain to be elucidated. Here, we report that human NOX2+ myelomonocytic/monocytic AML cell lines showed increased expression of maturation markers along with reduced leukemic cell proliferation after exposure to HDC in vitro. These effects of HDC were absent in corresponding leukemic cells genetically depleted of NOX2 (NOX2−/−). We also observed that exposure to HDC altered the expression of genes involved in differentiation and cell cycle progression in AML cells and that these effects required the presence of NOX2. HDC promoted the differentiation also of primary monocytic, but not non-monocytic, AML cells in vitro. In a xenograft model, immunodeficient NOG mice were inoculated with wild-type or NOX2−/− human monocytic AML cells and treated with HDC in vivo. The administration of HDC reduced the in vivo expansion of NOX2+/+, but not of NOX2−/− human monocytic AML cells. We propose that NOX2 may be a conceivable target in the treatment of monocytic AML.

Omalizumab for the Treatment of Chronic Idiopathic Urticaria: Systematic Review of the Literature.

Omalizumab is recombinant humanized monoclonal antibody to immunoglobulin E. Guidelines for the treatment of chronic idiopathic urticaria (also known as chronic spontaneous urticaria) recommend the use of omalizumab as third-line therapy in addition to high doses of histamine receptor type 1 (H1 ) antihistamines when they are unsuccessful as first- and second-line therapy. We performed a systematic review of the literature to identify studies that evaluated the efficacy of omalizumab for the treatment of chronic idiopathic urticaria, in both controlled and real-world settings, to assess its potential role as a preferred therapy. The PubMed, ScienceDirect, LILACS (Latin American and Caribbean Health Sciences Literature), and Google Scholar databases were searched between January 1, 2000, and November 21, 2016. The search was limited to articles published in peer-reviewed journals in the English language, and 29 studies were included in this review. Omalizumab 300 mg administered every 4 weeks appears to be the most effective and safe dosage, with a rapid response time, for the treatment of chronic idiopathic urticaria, with few minor adverse effects, and appears to be safe in the offspring of pregnant patients who received the drug. However, as published studies of omalizumab are sparse, future studies are warranted. When findings are confirmed in larger studies, due to its efficacy, safety, and increased benefit/cost ratio, omalizumab could become the preferred method of treatment for chronic idiopathic urticaria in patients unresponsive to H1 antihistamines.

Histamine H2 Receptor in Blood Cells: A Suitable Target for the Treatment of Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) consists in a cancer of early hematopoietic cells arising in the bone marrow, most often of those cells that would turn into white blood cells (except lymphocytes). Chemotherapy is the treatment of choice for AML but one of the major complications is that current drugs are highly toxic and poorly tolerated. In general, treatment for AML consists of induction chemotherapy and post-remission therapy. If no further post-remission is given, almost all patients will eventually relapse. Histamine, acting at histamine type-2 (H2) receptors on phagocytes and AML blast cells, helps prevent the production and release of oxygen-free radicals, thereby protecting NK and cytotoxic T cells. This protection allows immune-stimulating agents, such as interleukin-2 (IL-2), to activate cytotoxic cells more effectively, enhancing the killing of tumor cells. Based on this mechanism, post-remission therapy with histamine and IL-2 was found to significantly prevent relapse of AML. Alternatively, another potentially less toxic approach to treat AML employs drugs to induce differentiation of malignant cells. It is based on the assumption that many neoplastic cell types exhibit reversible defects in differentiation, which upon appropriate treatment results in tumor reprogramming and the induction of terminal differentiation. There are promissory results showing that an elevated and sustained signaling through H2 receptors is able to differentiate leukemia-derived cell lines, opening the door for the use of H2 agonists for specific differentiation therapies. In both situations, histamine acting through H2 receptors constitutes an eligible treatment to induce leukemic cell differentiation, improving combined therapies.

Red ginseng extract blocks histamine-dependent itch by inhibition of H1R/TRPV1 pathway in sensory neurons

BackgroundKorean Red Ginseng—a steamed root of Panax ginseng Meyer—has long been used as a traditional medicine in Asian countries. Its antipruritic effect was recently found, but no molecular mechanisms were revealed. Thus, the current study focused on determining the underlying molecular mechanism of Korean Red Ginseng extract (RGE) against histamine-induced itch at the peripheral sensory neuronal level. MethodsTo examine the antipruritic effect of RGE, we performed in vivo scratching behavior test in mice, as well as in vitro calcium imaging and whole-cell patch clamp experiments to elucidate underlying molecular mechanisms. ResultsThe results of our in vivo study confirmed that RGE indeed has an antipruritic effect on histamine-induced scratching in mice. In addition, RGE showed a significant inhibitory effect on histamine-induced responses in primary cultures of mouse dorsal root ganglia, suggesting that RGE has a direct inhibitory effect on sensory neuronal level. Results of further experiments showed that RGE inhibits histamine-induced responses on cells expressing both histamine receptor subtype 1 and TRPV1 ion channel, indicating that RGE blocks the histamine receptor type 1/TRPV1 pathway in sensory neurons, which is responsible for histamine-dependent itch sensation. ConclusionThe current study found for the first time that RGE effectively blocks histamine-induced itch in peripheral sensory neurons. We believe that the current results will provide an insight on itch transmission and will be helpful in understanding how RGE exerts its antipruritic effects.

Ciproxifan improves working memory through increased prefrontal cortex neural activity in sleep-restricted mice

Histamine receptor type 3 (H3) antagonists are promising awakening drugs for treatment of sleep disorders. However, few works have tried to identify their cognitive effects after sleep restriction and their impact on associated neural networks. To that aim, Bl/6J male mice were submitted to acute sleep restriction in a shaker apparatus that prevents sleep by transient (20–40 ms) up and down movements. Number of stimulations (2–4), and delay between 2 stimulations (100–200 ms) were randomized. Each sequence of stimulation was also randomly administered (10–30 s interval) for 20 consecutive hours during light (8 h) and dark (12 h) phases. Immediately after 20 h-sleep restriction, mice were injected with H3 antagonist (ciproxifan 3 mg/kg ip) and submitted 30-min later to a working memory (WM) task using spatial spontaneous alternation behaviour. After behavioural testing, brains were perfused for Fos immunohistochemistry to assess neuronal brain activation in the dorsal dentate gyrus (dDG) and the prefrontal cortex. Results showed that sleep restriction decreased slow wave sleep (from 35.8 ± 1.4% to 9.2 ± 2.7%, p < 0.001) and was followed by sleep rebound (58.2 ± 5.9%, p < 0.05). Sleep restriction did not modify anxiety-like reactivity and significantly decreased WM at long (30 s) but not short (5 s) inter-trial intervals. Whereas sleep restriction failed to significantly modify immunopositive cells in vehicles, ciproxifan administration prevented WM deficits in sleep restricted mice through significant increases of Fos labelling in prelimbic, infralimbic and cingulate 2 cortex.In conclusion, ciproxifan at 3 mg/kg enhanced WM in sleep restricted mice through specific modulation of prefrontal cortex areas.

Granule maturation in mast cells: Histamine in control

Mast cells are derived from committed progenitors that originate in the BM. They mature into histochemically distinguishable, metachromatic mast cells containing numerous cytoplasmic secretory granules. Accumulating evidence demonstrates that mast cell granule maturation is very tightly regulated by many factors including different granule components such as proteoglycans. In this issue of the European Journal of Immunology, Nakazawa et al. [Eur. J. Immunol. 2014. 44: 204-214] highlight a role for mast cell derived histamine as another factor critical for mast cell maturation. Using histidine decarboxylase (HDC) deficient mice that are unable to make histamine, they show poorly formed secretory granules and decreased secretory granule protease expression in peritoneal mast cells. Co-culturing BM-derived mast cells with fibroblasts normally drives granule maturation, but HDC-deficient BM-derived mast cells fail to do so. Exogenously provided histamine partly restores granule differentiation as evidenced by increased tryptase and chymase activity, and this is histamine receptor type H4 -dependent. However, H4 -deficient mice have intact granule formation in peritoneal mast cells, suggesting that when HDC is functional, the intrinsic histamine production is sufficient for most granule maturation processes and H4 is dispensable. This study highlights the role of histamine in the regulation of mast cell maturation, although the cytosolic target remains unknown.

Lactobacillus reuteri-Specific Immunoregulatory Gene rsiR Modulates Histamine Production and Immunomodulation by Lactobacillus reuteri

Human microbiome-derived strains of Lactobacillus reuteri potently suppress proinflammatory cytokines like human tumor necrosis factor (TNF) by converting the amino acid l-histidine to the biogenic amine histamine. Histamine suppresses mitogen-activated protein (MAP) kinase activation and cytokine production by signaling via histamine receptor type 2 (H2) on myeloid cells. Investigations of the gene expression profiles of immunomodulatory L. reuteri ATCC PTA 6475 highlighted numerous genes that were highly expressed during the stationary phase of growth, when TNF suppression is most potent. One such gene was found to be a regulator of genes involved in histidine-histamine metabolism by this probiotic species. During the course of these studies, this gene was renamed the Lactobacillus reuteri-specific immunoregulatory (rsiR) gene. The rsiR gene is essential for human TNF suppression by L. reuteri and expression of the histidine decarboxylase (hdc) gene cluster on the L. reuteri chromosome. Inactivation of rsiR resulted in diminished TNF suppression in vitro and reduced anti-inflammatory effects in vivo in a trinitrobenzene sulfonic acid (TNBS)-induced mouse model of acute colitis. A L. reuteri strain lacking an intact rsiR gene was unable to suppress colitis and resulted in greater concentrations of serum amyloid A (SAA) in the bloodstream of affected animals. The PhdcAB promoter region targeted by rsiR was defined by reporter gene experiments. These studies support the presence of a regulatory gene, rsiR, which modulates the expression of a gene cluster known to mediate immunoregulation by probiotics at the transcriptional level. These findings may point the way toward new strategies for controlling gene expression in probiotics by dietary interventions or microbiome manipulation.

Role of histidine/histamine in carnosine-induced neuroprotection during ischemic brain damage

Urgent need exists for new therapeutic options in ischemic stroke. We recently demonstrated that carnosine, an endogenous dipeptide consisting of alanine and histidine, is robustly neuroprotective in ischemic brain injury and has a wide clinically relevant therapeutic time window. The precise mechanistic pathways that mediate this neuroprotective effect are not known. Following in vivo administration, carnosine is hydrolyzed into histidine, a precursor of histamine. It has been hypothesized that carnosine may exert its neuroprotective activities through the histidine/histamine pathway. Herein, we investigated whether the neuroprotective effect of carnosine is mediated by the histidine/histamine pathway using in vitro primary astrocytes and cortical neurons, and an in vivo rat model of ischemic stroke. In primary astrocytes, carnosine significantly reduced ischemic cell death after oxygen–glucose deprivation, and this effect was abolished by histamine receptor type I antagonist. However, histidine or histamine did not exhibit a protective effect on ischemic astrocytic cell death. In primary neuronal cultures, carnosine was found to be neuroprotective but histamine receptor antagonists had no effect on the extent of neuroprotection. The in vivo effect of histidine and carnosine was compared using a rat model of ischemic stroke; only carnosine exhibited neuroprotection. Taken together, our data demonstrate that although the protective effects of carnosine may be partially mediated by activity at the histamine type 1 receptor on astrocytes, the histidine/histamine pathway does not appear to play a critical role in carnosine induced neuroprotection.

A report on anti-oedemogenic activity of Byttneria herbacea roots – Possible involvement of histamine receptor (type I)

Ethnopharmacological relevanceThe traditional healers of the Kol tribes of West Bengal, Bihar and Jharkhand (India), widely use the woody rootstock of Byttneria herbacea to reduce the swelling of limbs, due to filariasis. Besides filariasis different part of this plant is used for the treatment of cholera, diarrhoea and asthma. Aim of this studyThis study is a preliminary attempt to evaluate the anti-oedemogenic activity of the roots of Byttneria herbacea. Materials and methodsThe anti-oedemogenic activity of the hydroalcoholic extract of the roots of Byttneria herbacea (HBH) was evaluated against carrageenan and histamine induced rat paw oedema, acetic acid induced writhing and histamine induced vascular permeability in mice. Further, the effect of HBH on the expression of human histamine receptor type I (H1R) was studied in HeLa cells. ResultsHBH exhibited significant dose-dependent inhibition (*p<0.05) against carrageenan and histamine induced rat paw oedema. Similar significant dose-dependent inhibition was observed against acetic acid induced writhing and histamine-induced vascular permeability in mice. Moreover, H1R specific mRNA expression was also significantly (*p<0.05) suppressed by HBH. ConclusionHBH was observed to possess anti-oedemogenic activity which is probably mediated through suppression of H1R.

Effects of PPIs and an H2 blocker on the Antiplatelet Function of Clopidogrel in Japanese Patients under Dual Antiplatelet Therapy

Dual antiplatelet therapy (DAPT) with aspirin and clopidogrel is essential after percutaneous coronary intervention (PCI). Clopidogrel is a prodrug and changed into active metabolite by cytochrome p450 enzymes (CYPs), especially CYP2C19. Proton pump inhibitors (PPIs) are used for the prevention of aspirin-induced gastrointestinal bleeding. PPIs are also metabolized by CYP2C19, although the degree of its contribution is dependent on the kind of PPI. Omeprazole, a PPI, has been reported to weaken the antiplatelet effects of clopidogrel. Famotidine, a histamine receptor type 2 (H2) blocker, could also be an alternative to PPIs. The aim of this study was to evaluate the effects of PPIs and an H2 blocker on the antiplatelet function of clopidogrel. Patients receiving DAPT due to prior PCI, who took either omeprazole or rabeprazole, were enrolled (n=25). The initial PPI was changed to the other PPI as a crossover study. In another study, patients undergoing DAPT without taking PPIs or H2 blockers were enrolled (n=30) and famotidine was added. Platelet aggregability when taking omeprazole was higher than when taking rabeprazole, evaluated by an optical aggregometer using collagen as a stimulus (p=0.0051) and by the VerifyNow P2Y12 assay (p=0.0060). Platelet aggregability when taking rabeprazole was comparable to that in control patients (n=15). Concomitant use of famotidine had no effect. Omeprazole significantly reduced the antiplatelet effect of clopidogrel and this effect on clopidogrel was stronger than that of rabeprazole. Concomitant use of famotidine had no effect on the antiplatelet effect of clopidogrel.

Human Memory Th17 Cells Express a Functional Histamine H4 Receptor

The histamine H4 receptor is functionally expressed on CD4(+) T cells and in particular on human CD4(+) Th2-polarized T cells. Interleukin (IL)-17-producing T cells (Th17 cells) represent a newly defined major CD4(+) T-cell subset, having been identified in psoriatic plaques and in acute skin lesions of atopic dermatitis where histamine is also present in high concentrations. To elucidate the role of the histamine H4 receptor (H4R) on these effector T cells, we polarized human memory T cells into Th17 cells. Further, we investigated H4R expression and assessed its function by real-time PCR, by a cytokine secretion assay of IL-17, and by electrophoretic mobility shift assay of activating protein-1 (AP-1). We show that Th17 cells polarized by IL-1β together with IL-23 express the H4R on mRNA and protein level. Additionally, we identified IL-17-positive cells in psoriatic skin lesions. The IL-17-positive lymphocytes were all positive also for functional H4R. Stimulation with histamine or a H4R agonist increased the production of IL-17 and induced activating protein-1 in Th17 cells. In inflammatory skin diseases with enhanced histamine release, such as psoriasis and atopic dermatitis, histamine might foster the immunomodulatory potency of skin-infiltrating Th17 cells.

Cimetidine Enhances Antigen-Specific IgE and Th2 Cytokine Production

Treatment with anti-ulcer drugs has been shown to enhance IgE production against food antigens. However, little is known about the immunological effects of cimetidine, a histamine receptor type 2 (H2R) antagonist that is widely used as an anti-ulcer drug, in allergy. Therefore, the present study investigated the role of cimetidine in Th2 immune responses in mice. BALB/c mice were immunized intraperitoneally with ovalbumin (OVA) with and without cimetidine. The levels of cytokines in supernatants of spleen cells cultured in the presence of OVA for 4 days and the levels of total and OVA-specific IgG(1), IgG(2a) and/or IgE in sera from these mice were determined by ELISA. Administration of cimetidine to OVA-sensitized BALB/c mice promoted Th2 cytokine secretion by OVA-stimulated spleen cells in vitro and increased serum levels of OVA-specific IgE, IgG(1) and IgG(2a). These results indicate that cimetidine can enhance Th2 responses, suggesting that cimetidine may contribute to IgE production in allergies.

Molecular signaling of pruritus induced by endothelin-1 in mice

Endothelin-1 (ET-1) has recently been identified to evoke pruritus/itching sensation in both humans and animals. It is most likely that the signaling is through the specific G-protein-coupled ET(A) and ET(B) receptors, but the downstream signaling mediators for ET-1 remain elusive. In the present study, we examined the potential involvement of several distinct signaling molecules in ET-1-induced pruritus in a murine model. We applied an in vivo pruritus model in C57BL/6J mice by injecting ET-1 intradermally into the scruff, and recording the number of scratching bouts within 30 min after injection. Then specific antagonists/inhibitors for distinct signaling molecules, including cell-surface ET(A) and ET(B) receptors, histamine receptor type 1 (H1 receptor), protein kinases A (PKA) and C (PKC), phospholipase C (PLC) or adenylyl cyclase (AC), were co-injected with ET-1. The results showed that ET-1 induced a vigorous scratching response in mice in a dose-dependent manner. This response was further enhanced by a specific antagonist for ET(B) receptor, BQ-788, reduced by a specific antagonist for ET(A) receptor, BQ-123, and not affected by mepyramine, the specific inhibitor for H1 receptor. In addition, the scratching response was significantly reduced by inhibitors for PKC and AC, but was significantly enhanced by PLC inhibitor, while PKA inhibitors showed no effects in the ET-1-induced scratching response. Our data suggested that ET-1 may signal through the ET(A) receptor, AC and PKC pathway to induce pruritus sensation, while ET(B) receptor and PLC may antagonize the pruritus evoked by ET-1. These results may provide a basis for the future development of antipruritic therapy.

Personal reflections on Sir James Black (1924–2010) and histamine

Sir James Black, Nobel laureate (1988), became interested in the role of histamine in gastric acid secretion in the early 1950s. In 1964, he joined the pharmaceutical company Smith Kline and French Laboratories at their English subsidiary to seek a new type of antagonist that would block those actions of histamine that were not blocked by mepyramine. No such compound was known and working with medicinal chemists it took four years to discover a lead compound. Further work provided the compound burimamide, which was used to define histamine H(2) receptors in 1972 for the first time, and to verify the action in human volunteers. Subsequent work led to the drug metiamide, which was withdrawn during early clinical trials. This was replaced by cimetidine, which was launched in 1977, as the first histamine H(2)-receptor antagonist and which revolutionized the treatment of peptic ulcer disease. The characterisation of a second type of histamine receptor revitalised interest in histamine and led to many later studies on the role of histamine in inflammation.

Role and immunomodulatory profile of histamine receptors by H1 and H2 antagonists

AbstractThe present study was designed to delineate the immunomodulatory role of histamine receptors (H1- and H2-) on induction of antibody response to sheep red blood cells (SRBC), as well as the antibody generation profile, in rabbit system, systemically. The rabbits in two groups received pheniramine (H1-receptor antagonist) and ranitidine (H2-receptor antagonist), respectively, via intramuscular route and were immunized with SRBC intravenously to evaluate suppression or enhancement of antibody responses in sem. A third, control group, received vehicle and were immunized in a similar manner. Histamine released from effector cells (mast cells and basophils) in vivo during inflammatory reactions could influence a detectable antibody response to SRBC as early as day 7-postimmunization (post-I), which lasted until day 28- post-I. Pheniramine-treated rabbits had significantly (&amp;42;Pa &amp;le; 0.05 and &amp;42;&amp;42;Pa &amp;le; 0.01) more suppressed total serum antibody (IgM + IgG) to SRBC as compared to ranitidine-treated ad cotrol rabbits, while ranitidine-treated rabbits showed different pattern (suppressed or enhanced) during the whole study period. Ranitidine suppressed total antibody level at days 7- and 14- post-I, and enhanced at days 21- and 28- post-I. IgM suppression at day 7- and enhancement at days 14-, 21- and 28- post-I, while IgG suppression during whole study period, as compared to control group was significant (&amp;42;Pa &amp;le; 0.05 and &amp;42;&amp;42;Pa &amp;le; 0.01) as assessed by direct hemagglutination assay&amp;42; ad whole SBC-ELISA method&amp;42;&amp;42;. Here we report that histamine receptor type 2 (H2R)-antagonists have a dominant role on immunosuppression and in immunoregulation of humoral immune responses. Histamine receptor type 2 (H2R)-antagonists are mainly involved in B cell differentiation and proliferation over histamine receptor type 1 (H1R)-antagonists.

Randomized, single-blind, crossover comparison of two rupatadine tablet formulations on histamine-induced cutaneous response in healthy adult volunteers

Background: Rupatadine is a histamine receptor type 1 antagonist that has been used to treat allergic rhinitis and urticaria. Objective: The aim of this study was to compare the effect of 2 rupatadine tablet formulations on the inhibition of histamine-induced wheal-and-flare cutaneous responses. Methods: In this single-blind, single oral dose, crossover study, healthy male volunteers were randomized to receive 10 mg of either a rupatadine reference or test formulation after an overnight fast. After a 10-day washout period, the subjects were crossed over to receive the other formulation. Subjects were asked to sit with their arm resting on the table while histamine was injected intradermally. The skin prick test was performed on the upper half of the volunteers' forearms before administration and at 1, 2, 4, 6, 12, and 24 hours after study drug administration. Fifteen minutes after each skin prick test, the wheal-and-flare responses were visualized under a bright lamp. AUC 0–24 was the primary end point.The 90% CI of least squares mean ratio (%) of the test: reference formulations for maximum inhibition of histamine-induced wheal-and-flare response (I max%), T max, AUC 0–24 mm 2/h, and AUC 0–24%/hr were expected to be within 80% to 125% of untransformed data and 80% to 120% of log-transformed data for the 2 formulations to be considered pharmacodynamically equivalent. Subjects were monitored for any spontaneously reported adverse event (AE) throughout the study. In addition, they were specifically asked about the occurrence of any AEs on a checklist (ie, drowsiness, dizziness, dryness of mouth, itching sensation, headache, nausea) throughout the study. Results: Of the 15 subjects assessed for inclusion, 12 healthy male volunteers (mean [SD] age, 30 [5] years; height, 162 [6] cm; weight, 58 [6] kg) participated in the study. Administration of reference and test formulations of rupatadine significantly inhibited the histamine-induced cutaneous responses in all subjects ( P <0.001). Wheal I max% with the reference and test formulations was 67.97% (11.57%) and 66.76% (9.40%), respectively. Flare I max% was 59.06% (11.95%) and 56.92% (16.31%), respectively. None of the subjects withdrew from the study due to AEs. Both formulations were well tolerated except for an itching sensation on injection of histamine in all patients; no subject complained of any adverse drug reaction. Conclusion: In this small study of healthy adult males, the test formulation of the rupatadine tablet was found to be pharmacodynamically equivalent to the reference formulation, as measured by inhibition of histamine-induced cutaneous wheal-and-flare responses.

Histamine ameliorates anti-glomerular basement membrane antibody-induced glomerulonephritis in rats

Anti-glomerular basement membrane (anti-GBM)-induced glomerulonephritis involves T-helper type 1 (Th1) responses leading to rapid crescent formation. As many inflammatory and immune responses in general are affected by histamine, we examined the effects of histaminergic ligands on immune renal injury in the rat. Female Wistar-Kyoto rats were injected intraperitoneally with an antibody against the GBMs. Histaminergic ligands were then injected twice daily for 5 days after which renal function was assessed by proteinuria. Treatment with histamine led to significant dose-dependent reductions in proteinuria compared to the control antibody-injected group and markedly decreased the number of crescentic glomeruli and macrophage infiltration of the glomeruli. Furthermore, histamine significantly decreased the plasma concentration of interleukin-12, a Th1-type cytokine compared to the antibody-injected control animals. Dimaprit, an H(2)/H(4) agonist, mimicked the effects of histamine on proteinuria and crescent formation. Clozapine, an H(4) agonist, tended to mimic the effects of histamine, whereas an H(1), mepyramine, or an H(2) antagonist, ranitidine, did not reverse the protective effect of histamine. We suggest that histamine may alleviate renal injury in anti-GBM glomerulonephritis by suppressing the immune response.