Histamine receptor 2 blockade selectively impacts B and T cells in healthy subjects.

Histamine receptor 2 (H2R) blockade is commonly used in patients with gastric, duodenal ulcers or gastroesophageal reflux disease. Beyond the gastrointestinal tract, H2R is expressed by multiple immune cells, yet little is known about the immunomodulatory effects of such treatment. Clinical reports have associated H2R blockade with leukopenia, neutropenia, and myelosuppression, and has been shown to provide clinical benefit in certain cancer settings. To systematically assess effects of H2R blockade on key immune parameters, a single-center, single-arm clinical study was conducted in 29 healthy subjects. Subjects received daily high dose ranitidine for 6 weeks. Peripheral blood immunophenotyping and mediator analysis were performed at baseline, 3 and 6 weeks into treatment, and 12 weeks after treatment cessation. Ranitidine was well-tolerated, and no drug related adverse events were observed. Ranitidine had no effect on number of neutrophils, basophils or eosinophils. However, ranitidine decreased numbers of B cells and IL-2Rα (CD25) expressing T cells that remained lower even after treatment cessation. Reduced serum levels of IL-2 were also observed and remained low after treatment. These observations highlight a previously unrecognised immunomodulatory sustained impact of H2R blockade. Therefore, the immune impacts of H2R blockade may require greater consideration in the context of vaccination and immunotherapy.

Anti-Amoxicillin Immunoglobulin E, Histamine-2 Receptor Antagonist Therapy and Mast Cell Activation Syndrome Are Risk Factors for Amoxicillin Anaphylaxis.

BACKGROUND: ß-Lactam antibiotics (mainly amoxicillin, AX) are the drugs that most frequently induce systemic drug allergy reactions. OBJECTIVE: We attempted to identify the risk factors associated with systemic reactions to AX. METHODS: All patients who were referred to our department for suspected hypersensitivity reactions to AX over a 6-month period were evaluated for anti-AX immunoglobulin E (IgE) levels and skin-test positivity for ß-lactams. Age, sex, concomitant diseases, therapies, total IgE, serum tryptase levels and signs and symptoms suggesting mast cell activation syndrome (MCAS) were analyzed in relation to the severity of the reaction in accordance with the Mueller classification. RESULTS: Sixty-seven patients were selected: 39 with mild reactions such as cutaneous or gastrointestinal symptoms (grades I and II) and 28 with severe systemic reactions (grades III and IV). Anti-AX IgE levels and total IgE were significantly higher in severe reactions than in mild ones (p < 0.00005, p = 0.0037). Treatment with histamine-2 receptor antagonists (anti-H2) was significantly related to severe reactions (p = 0.007). No significant correlations were found between the severity of the reactions and dyslipidemia or levels of angiotensin-converting enzyme and tryptase. CONCLUSION: Anti-AX IgE levels were the most significant immunological parameter distinguishing patients who presented with severe reactions to AX and those with mild reactions. Higher values of total IgE, the use of gastroprotective drugs and signs and symptoms suggesting an MCAS significantly increased the odds ratio of having a severe reaction. The risk of serious adverse reactions to AX increased in older patients and in males, but this trend was not significant.

Opposite effects of mepyramine on JNJ 7777120-induced amelioration of experimentally induced asthma in mice in sensitization and provocation.

BACKGROUND: Histamine is detected in high concentrations in the airways during an allergic asthma response. In a murine model of allergic asthma, JNJ 7777120, an antagonist at the histamine H(4) receptor, reduces asthmatic symptoms, while the histamine H(1) receptor-selective antagonist mepyramine is virtually without effect. In the present study, we analyzed the effect of combined antagonism at the histamine H(1) and H(4) receptors in a murine asthma model in relation to the timing of their application, i.e. sensitization or provocation. METHODOLOGY/PRINCIPAL FINDINGS: Asthma was induced in mice by sensitization and provocation with ovalbumin. JNJ 7777120 and/or mepyramine were injected subcutaneously either during sensitization or during provocation, and typical asthma parameters were analyzed. JNJ 7777120, but not mepyramine, reduced serum concentrations of anti-OVA IgE, inflammatory infiltrations in lung tissue, and eosinophilia in bronchoalveolar-lavage (BAL)-fluids independently of the timing of application. Upon application of JNJ 7777120 plus mepyramine in combination during provocation, mepyramine inhibited the effects of JNJ 7777120. In contrast, when applied during sensitization, mepyramine enhanced the disease-ameliorating effects of JNJ 7777120. CONCLUSIONS/SIGNIFICANCE: Our study indicates that both histamine H(1) and H(4) receptors play important roles in the course of murine experimental asthma. Unexpectedly, the contribution of these receptors to the pathogenesis differs between the two phases, sensitization or provocation. Since in human asthma, repeated contact to the allergen is not only provocation but also a boost of sensitization, a combined pharmacological targeting of histamine H(1) and H(4) receptors could be taken into consideration as an option for the prevention of asthma and maybe other allergic diseases.

Intraoperative anaphylaxis: a case report of allergy to ranitidine.

We report the case of a 18-year old male who developed intraoperative anaphylaxis. The presence of specific IgE to ranitidine was documented This case confirms the possibility of anaphylaxis at first exposure.

Immune hemolytic anemia due to cimetidine: the first example of a cimetidine antibody.

BACKGROUND: Although there have been a few reports of immune hemolytic anemia (IHA) thought to be due to cimetidine, none of them provided proof (e.g., serologic detection of anti-cimetidine and/or repeat of IHA upon drug rechallenge). One report used cimetidine as an example of how temporal associations of drug administration and hemolytic anemia are not proof of a cause-effect relationship. STUDY DESIGN AND METHODS: A 63-year-old cancer patient developed IHA on two occasions after receiving cimetidine (with and without chemotherapy). Serologic methods included testing cimetidine-treated red blood cells (RBCs) as well as testing untreated RBCs in the presence of cimetidine. RESULTS: The patient's direct antiglobulin test was positive (C3 only) and a serum antibody to cimetidine was detected by both testing methods. An eluate from the patient's RBCs was nonreactive. Cimetidine-treated RBCs were optimally prepared at room temperature and needed to be tested on the day of preparation. CONCLUSIONS: This is the first reported case of IHA due to a cimetidine antibody where a drug-dependent antibody was demonstrated. The patient had IHA after receiving cimetidine on two separate occasions.

Pilot study--cimetidine enhances lymphocyte infiltration of human colorectal carcinoma: results of a small randomized control trial.

BACKGROUND: Cimetidine preserves postoperative immune function and inhibits the growth of some cancers. In this study, the effect of cimetidine on the local immune response to colorectal carcinoma was investigated. METHODS: Forty-two patients scheduled for elective resection of colorectal carcinoma were randomized either to receive cimetidine for 1 week perioperatively or to act as controls. A lymphocyte density of 50 cells per high-power field (approximately 50% of the tumor/tissue interface) was considered a positive response. Patient survival was determined by Kaplan-Meier life table analysis. The effects of histamine and cimetidine on normal subject lymphocyte function was determined in a mitogen-stimulated proliferation assay. RESULTS: A positive lymphocyte response was observed in 5 of 24 control carcinoma patients (21%) and 10 of 18 cimetidine-treated carcinoma patients (56%) (P = 0.03). The presence of a lymphocyte response correlated with a better survival (P = 0.02). Histamine had an inhibitory effect on lymphocyte proliferation with a median effective dose of 5 x 10(-7) M. Cimetidine antagonized this effect with a negative logarithm of the cimetidine molar concentration required to reduce the effect of histamine in half of 6.55. CONCLUSIONS: Histamine inhibits normal lymphocyte function, antagonized by cimetidine at a histamine type 2 receptor. Cimetidine increases lymphocyte infiltration of primary colorectal carcinoma, possibly by overcoming the immunosuppressive effects of high local histamine concentrations. The presence of a local lymphocyte response correlates with an improved 3-year survival.

[Immunoregulating properties of histamine H2 receptor antagonists]. / Immunoregulacyjne wlasciwosci antagonistów receptora histaminowego H2.

The clinical aspects and their possible implication in the several disease treatment have been reviewed in the context of the immunomodulatory H2-receptor antagonist action. The therapeutical possibility considering the perspectives of the application of the H2-receptor blockers has been discussed.

Adverse reactions and interactions with H2-receptor antagonists.

Histamine H2-receptor antagonists have been used in the treatment of gastrointestinal diseases for more than a decade and during this period have become one of the most commonly prescribed groups of drugs in the world. The deserved popularity of the H2-receptor antagonists reflects, in part, their therapeutic efficacy, which has revolutionised the treatment of peptic ulcer disease. An equally, or more, important reason for the widespread use of H2-receptor antagonists is their remarkably low toxicity. We have attempted, in this review, to present a detailed account of the minor and more serious adverse reactions, while emphasising the low incidence of the former and the rarity of the latter. The toxicology of the H2-receptor antagonists is discussed under two main headings: adverse effects; and drug interactions. The latter category is potentially the more significant, since the frequent use of therapy with multiple drugs may give rise to drug interactions, some of which are serious and may even be lethal. These drug interactions occur especially in the gastrointestinal tract, the liver and the kidneys. Thus, the absorption of other drugs may be altered because the H2-receptor antagonists inhibit gastric secretion--an effect illustrated by ketoconazole, the absorption of which is reduced when given in combination with cimetidine. Very important drug interactions are caused by inhibition of the hepatic microsomal enzyme cytochrome P450 by some of the H2-receptor antagonists. This effect appears to be related to the chemical structure of the individual H2-receptor antagonists and is not attributable to histamine H2-receptor blockade. For example, cimetidine is a powerful inhibitor of cytochrome P450, while the interaction of ranitidine with this system is weaker. Consequently, cimetidine reduces the metabolism of many drugs which are normally degraded by phase I reactions, leading to potentially toxic plasma concentrations of therapeutic agents such as some oral anticoagulants, beta-blockers, anticonvulsants, benzodiazepines and xanthines. Some of the H2-receptor antagonists are actively secreted by the renal tubules and may thus compete with other drugs for cationic tubular transport mechanisms, resulting in reduced urinary excretion and hence potentially toxic plasma concentrations. This type of drug interaction has been reported after administration of both cimetidine and ranitidine with procainamide or quinidine.(ABSTRACT TRUNCATED AT 400 WORDS)

Method for detection of antibody against low molecular weight antigen (hapten)--production and detection of antibody against histamine H2 receptor of antibody against histamine H2 receptor antagonist "Famotidine".

Antibodies against histamine H2-receptor antagonist "Famotidine (FAMO)", molecular weight 337, chemical name; N-sulfamoyl-3-(2-guanidinothiazol-4-ylmethylthio) propionamide, were produced by subcutaneously injecting rabbits with an albumin and FAMO conjugate covalently bound with 1-ethyl-3-(3-dimethyl-amino-propyl) carbodiimide (ECDI). Two new detection systems for antibody titration were developed and employed. In one method, the antigen FAMO was tagged to sheep red blood cells (SRBC) and analysed qualitatively by a fluorescence activated cell sorter (FACS) using a second fluorescence isothiocyanate (FITC) labeled antibody. In the other method, CH-Sepharose beads were employed in place of SRBC and Horse Radish Peroxidase (HRP) was labeled to the second antibody instead of FITC used in the former method. HRP of the immune complex was colorimetrically measured with DAB-H2O2 to analyse the fine antibody titer. These high sensitive detection methods revealed the existence of IgG type of FAMO antibody. The detection sensitive detection methods revealed the existence of IgG type of FAMO antibody. The detection sensitivity was approximately 50 to 100 times higher in the later method with HRP than in the former. Furthermore these two methods could be deemed to be a good model system for a receptor assay.

[Cell-mediated immunity after blocking of the H2 lymphocyte receptors]. / Studio dell'immunita' cellulo-mediata dopo blocco dei recettori H2 dei linfociti.

The effects of cimetidine have been evaluated in 10 normal subjects on cutaneous delayed reactions in vivo, and on E rosette forming cells in vitro, in order to define the significance of the lymphocytes H2 receptors in cell-mediated immunity. The results show the immuno-suppressive activity of histamine, but do not allow us to hypothesize an immuno-regulatory action of cimetidine.