Histamine H1 Antagonists Research Articles

Underutilization of gastrointestinal prophylaxis in high-risk chronic nonsteroidal anti-inflammatory drug users in Korea.

Background The increasing use of antithrombotic therapies in older patients has led to an increased risk of gastrointestinal (GI) bleeding in chronic nonsteroidal anti-inflammatory drug (NSAID) users. Therefore, there is a pressing need for GI prophylaxis in these high-risk patients. Objective To analyze prescribing patterns and factors associated with the use of gastroprotective agents (GPAs) among high-risk, chronic NSAID users. Setting National claims database including 20% of the total Korean population aged ≥ 65years. Method In this cross-sectional study, we identified older adults prescribed traditional NSAIDs for > 90days and classified them into high- and ultra-high-risk groups if they had one or two or more GI risk factors, respectively. Proton pump inhibitors or misoprostol prescribed for more than 80% of traditional NSAID treatment days was regarded as appropriate GI prophylaxis. Main outcome measure Prevalence and associated factors with appropriate GI prophylaxis. Results Among 69,992 chronic traditional NSAID users, 38.8% and 9.4% belonged to the high and ultra-high-risk groups; 13.2% and 19.9% received appropriate GI prophylaxis, respectively. The most frequently used GPA was histamine H2 antagonists. Multiple NSAID use, concomitant antiplatelets and anticoagulants, and prior GI ulcer history increased the likelihood of receiving appropriate GI prophylaxis. Advanced age (≥ 85years), indications other than arthritis, and neurology specialists negatively affected appropriate GI prophylaxis use. Conclusion Approximately one in five chronic NSAID users, considered ultra-high risk, are prescribed appropriate GI prophylaxis in Korea. Advanced age, indications, and specialties of the prescriber all need to be considered when selecting target populations for interventions.

A case report of sleep terrors exacerbated by cetirizine

Sleep terrors are a type of sleep disorder that is classified as parasomnias and is more common in children than in adults. Cetirizine is a histamine H1 antagonist that is US Food and Drug Administration approved for the treatment of allergic rhinitis and urticaria and has common adverse effects of drowsiness and headaches. We present a case of an adult man with a history of chronic sleep terror disorder and allergic rhinitis who developed worsening of his sleep terrors after initiation of cetirizine that subsequently resolved after discontinuing cetirizine and starting paroxetine.

Maternal Transfer of Cetirizine Into Human Milk.

Cetirizine hydrochloride is a second-generation H1 histamine antagonist with Food and Drug Administration approval for treatment of allergic rhinitis and urticaria. Currently, the Food and Drug Administration does not recommend use of cetirizine during breastfeeding, as there are insufficient studies on both the transference of cetirizine into human milk and the effects of cetirizine in infants. To determine the concentration of cetirizine in human milk, samples were analyzed using high performance liquid chromatography mass spectrometry. Based on calculations, relative infant dose was found to be 1.77% at 24 hr. In addition, there were no reported adverse effects seen in the infants. We suggest that transfer of cetirizine into human milk is minimal and unlikely to pose a significant risk to the breastfeeding infant. This is the first report presenting the transfer of cetirizine in human milk.

Cutaneous manifestations due to histamine H1 antagonist

Cutaneous manifestations due to histamine H1 antagonist

Infant acid suppression use is associated with the development of eosinophilic esophagitis.

Eosinophilic esophagitis (EoE) is an esophageal allergic inflammatory disorder often presenting with infant/toddler gastroesophageal reflux symptoms refractory to treatment, including acid suppression trials with histamine H2 antagonists and proton pump inhibitors. We propose to evaluate the impact of infant acid suppressant exposure in EoE. Geisinger's pediatric EoE cases were matched to controls (1:5 EoE case control ratio) using age, race, sex, and ages at other diagnoses of asthma, eczema, and environmental allergies, totaling 526 EoE cases and 2,630 controls. Comparisons between EoE cases and matched controls were tested with regard to rates of acid suppression use with H2 antagonists and PPIs during infancy. Our analyses found the use of acid suppression in infancy was positively associated with EoE: PPI (5.7% EoE cases vs. 1.6% controls; P < 0.0001), H2 antagonists (8.8% EoE cases vs. 4.5% controls; P < 0.0001). Additionally, analysis of EoE cases using acid suppression during infancy indicated a likelihood for the diagnosis with EoE at an earlier age. Early acid suppression use in infants is significantly associated with the diagnosis of EoE in childhood in this well-matched retrospective cohort study. The potential link warrants additional investigation. Our study further reinforces the evidence-based stewardship of acid suppressant use, especially in our most vulnerable populations.

Characterization of Stressed Transgenic Mice Overexpressing H2-Histamine Receptors in the Heart.

We studied transgenic mice with cardiac-specific overexpression of H2-histamine receptors (H2-TG) by using the α-myosin heavy-chain promoter. We wanted to address whether this overexpression would protect the heart against paradigmatic stressors. To this end, we studied isolated atrial preparations in an organ bath under normoxic and hypoxic conditions and after prolonged exposure to high histamine concentrations. Moreover, we assessed cardiac function using echocardiography in mice with cardiac hypertrophy due to overexpression of the catalytic subunit of PP2A (PP2A-TG) in the heart [H2-TG × PP2A-TG = double transgenic (DT)] or H2-TG with cardiac systolic failure due to treatment of mice with lipopolysaccharides (LPSs). Furthermore, the effect of ischemia and reperfusion was studied in isolated perfused hearts (Langendorff mode) of H2-TG. We detected evidence for the protective role of the overexpressed H2-histamine receptors in the contractile dysfunction of DT and isolated atrial preparations subjected to hypoxia. In contrast, we noted the detrimental role of H2-histamine receptor overexpression against ischemia (Langendorff perfusion) and LPS-induced systolic heart failure. Hence, the role of H2-histamine receptors in the heart is context-sensitive: the results differ between hypoxia (in atrium) and ischemia (perfused whole heart), as well as between genetically induced hypertrophy (DT) and toxin-induced heart failure (LPS). The underlying molecular mechanisms for the protective or detrimental roles of H2-histamine receptor overexpression in the mammalian heart remain to be elucidated. SIGNIFICANCE STATEMENT: The beneficial and detrimental effects of the cardiac effects of H2-histamine receptors in the heart under stressful conditions, here intended to mimic clinical situations, were studied. The data suggest that depending on the clinically underlying cardiac pathophysiological mechanisms, H2-histamine agonists or H2-histamine antagonists might merit further research efforts to improve clinical drug therapy.

SEASICKNESS - CURRENT STATE OF PREVENTION AND TREATMENT ISSUE

The paper describes the current state of development of seasickness as one of movement disease variants. The given type of pathology occurs when combining different types of ship’s motion (rolling and pitching). Circular, vertical and slow movements induce more pronounced and frequent signs of seasickness than linear, horizontal and quick ones. In the view of majority of researchers, the most likely is an intersensory conflict theory i.e. violation of coherent functioning of afferent body systems performing spatial orientation, statokinetic equilibrium and keeping balance. The leading role is played by the functional dysfunction of the vestibular analyzer. The classification of means of preventing and stopping of motion sickness is given, the mechanisms of their action, specific activity and side effects are described. It has been shown that currently the most effective drugs are M-cholinergic antagonists (scopolamine hydrobromide) and H1-histamine antagonists of the 1st generation (dimenhydrinate, diphenhydramine, cyclizine, meclizine, promethazine, etc.). Of the antipsychotics and blockers of D2receptors, prochlorperazine and metoclopramide are recommended. It is also worth to use prokinetics (domperidone, cisapride, renzapride, etc.), tranquilizers (barbiturates, benzodiazepines), sleeping pills and local anesthetics. Particular attention is paid to combination drugs, consisting of antiemetic and psychostimulating drugs, designed to maintain working capacity under the influence of seasickness factors on the body. Non-pharmacological means of preventing seasickness and alleviating its symptoms are described. The main directions of improving the system of measures aimed at maintaining efficiency in the presence of symptoms of seasickness are determined.

Cinnamaldehyde elicits itch behavior via TRPV1 and TRPV4 but not TRPA1.

Introduction:Cinnamaldehyde (CA) elicits itch sensation in humans. We investigated if CA elicits scratching behavior in mice and determined the roles for TRPV1, TRPA1, and TRPV4.Materials and Methods:Scratching behavior elicited by intradermal injection of CA was assessed in wildtype (WT) mice and knockout (KO) mice lacking TRPV1, TRPA1, TRPV4, or deficient in mast cells. We also assessed scratching and wet dog shakes elicited by low-threshold mechanical stimulation of skin treated topically with CA or vehicle. Using calcium imaging we tested if CA activates dorsal root ganglion (DRG) neurons of each genotype.Results:Intradermal cheek injection of CA elicited dose-dependent hindlimb scratch bouts, with fewer forelimb wipes and facial groom bouts that were not dose-dependent. CA elicited significantly fewer scratch bouts in TRPV1 and TRPV4 KO mice, but not TRPA1KOs, compared with WTs. There were no sex differences across genotypes. The histamine H1 antagonist cetirizine did not affect CA-evoked scratching, which was normal in mast cell deficient mice, indicating lack of histamine involvement. Scores for alloknesis were significantly greater following topical application of CA compared with vehicle. Post-CA alloknesis scores were significantly higher in TRPV4KOs of both sexes and in female TRPV1 and TRPA1KOs, compared with WTs. Low threshold mechanical stimuli also elicited significantly more wet dog shakes in mice treated topically with 20% CA, with significantly fewer in TRPV1, TRPA1, and TRPV4KOs compared with WTs. In calcium imaging studies, CA excited 24% of WT DRG cells, significantly fewer (11.5%) in cells from TRPV4KOs, and none in TRPA1KOs. Responses of cells of all genotypes exhibited significant sensitization to repeated CA stimulation. Sensitization was significantly enhanced by IL-4, which itself excited 16% of WT DRG cells and none from TRPA1KOs.Discussion:The results indicate that TRPA1 is dispensable for CA-evoked scratching, which depends partly on TRPV1 and TRPV4.

Evaluation of target attainment of oral posaconazole suspension in immunocompromised children.

Posaconazole is a broad-spectrum antifungal that is not licensed for use in children <13 years of age. Despite this and by necessity, it is used extensively in paediatric hospitals for prophylaxis of invasive fungal disease. To determine whether initial prophylactic dosing recommendations attain a posaconazole plasma concentration of ≥700 ng/mL in immunocompromised children <13 years of age. We performed a retrospective study of immunocompromised children <13 years of age receiving posaconazole suspension prophylaxis at a starting dose of 5 mg/kg every 8 h for ≥7 days and who had a posaconazole concentration measured after ≥7 days. Posaconazole plasma concentrations and rate of breakthrough infection were recorded. A total of 70 patients were included with a median age of 5 years (range 3 months to 12 years). The mean posaconazole plasma concentration was 783.4 ng/mL (IQR 428.3-980 ng/mL) and the percentage of patients with a posaconazole plasma concentration ≥700ng/mL was 47.9%. Patients who were on a proton pump inhibitor, a histamine H2 antagonist or metoclopramide, had mucositis or were enterally fed had a lower posaconazole plasma concentration compared with patients without these co-administered drugs/mucositis/enteral feeding (542.3 versus 1069.8 ng/mL; P<0.001). The breakthrough invasive fungal infection rate was 4.3% (3/70). The studied 5 mg/kg posaconazole suspension every 8 h resulted in target concentrations in only 47.9% of patients and further studies looking at newer posaconazole formulations are needed.

PGI56 EVALUATION OF MORTALITY ASSOCIATED WITH PROTON PUMP INHIBITORS AND H2 BLOCKERS: A REAL WORLD EVIDENCE STUDY

The aim of this analysis was to estimate all-cause mortality among patients taking proton pump inhibitors (PPIs) and histamine H2 antagonists (H2 blockers). Patients identified through a federated network of electronic medical records were required to have taken PPIs or H2 blockers. Among these two cohorts, patients were required to have two records of these treatments recorded in their medical history at least three months apart. Patients treated with PPIs were matched 1-to-1 with patients treated with H2 blockers, using a greedy-nearest-neighbor algorithm. The risk of mortality was measured in the one year, five years, and ten years following the index treatment. All criteria were defined using ICD9/10, CPT, and RxNorm terminology. Kaplan-Meier curves and risk ratios (95% CI) were used to compare groups. The mean age was 54.4 ± 18.8 (N=1,455,638) and 46.6 ± 22.7 (N=496,538) among PPI- and H2 blocker-treated patients. In the matched analysis (N=448,446), H2 blocker patients were 0.089 (0.778,0.841), 0.8 (0.785,0.815), and 0.799 (0.786,0.812) more likely to die than PPI patients in the one year, five years, and ten years following treatment. The survival probability was 0.25%, 1.34%, and 2.35% higher in PPI-treated patients than in H2-treated patients in the one year, five years, and ten years following treatment (all with p<0.05). Taking H2 blockers is associated with a small increased risk of mortality. This burden is observed in patients with and without an indication for PPI or H2 blocker use. PPIs were not associated with an increased risk of death, in contrast to other studies. This difference may be due to a broader and less selective patient population, or use of different controls.

Histamine H2 antagonists for functional dyspepsia: A protocol for a systematic review and meta-analysis.

Functional dyspepsia (FD) is a prevalent gastrointestinal disorder. Histamine H2 antagonists (H2RAs) are the pharmacological treatment option for FD, but no potent evidence has been found for the efficacy of these drugs in the condition. Therefore, this systematic review protocol aims to examine the efficacy and safety of H2RAs in the treatment of FD. We will perform a systematic search in the following electronic databases: the Cochrane Central Register of Controlled Trials (to October 2019), MEDLINE (OvidSP; to October 2019), EMBASE (OvidSP; to October 2019). Only randomized clinical trials (RCTs) comparing any H2RA with placebo for the treatment of FD will be included. The primary outcome will be an improvement in global symptoms of dyspepsia. Study selection, data extraction, and study quality will be performed by 2 independent reviewers. Dichotomous data will be presented as a risk ratio (RR) with 95% confidence intervals (CI), and continuous data as mean difference (MD) or standardized MD (SMD) with 95% CI. RevMan v.5.3 software will be used for all statistical analyses. This study will provide a high-quality synthesis to examine the role of H2RAs in FD as reflected by the improvement of global symptoms of dyspepsia, quality of life scores, and adverse events. This systematic review will provide updated evidence to judge whether H2RAs are of benefit in FD.

Structural and clinical impact of anti-allergy agents: An overview.

Allergic disorders are markedly rising in industrialized countries. The identification of compounds that trigger the immunoglobulin E (IgE)-dependent allergic reaction remain the means to improve the quality of life by limiting patient's exposure to critical allergens. Information concerning the treatment and onset of allergic disorders including atopic dermatitis, allergic rhinitis, and bronchial asthma has been provided by the research over the past decade. Recent studies also indicated that allergic inflammation is associated closely with their exacerbation and progression and indeed is the basic pathophysiology of allergic diseases. As a result of immunological and molecular biological studies our understanding of the mechanism of allergic inflammation with regard to therapeutic agents has improved. While much effort has been paid to developing a new anti-allergic agent, the allergic disease has yet to be completely conquered. The more extensive research will allow the development of new therapeutics to combat allergic diseases. Currently, with respect to mechanism of action anti-allergy drugs are classified into five types including histamine H1 antagonists, leukotriene antagonists, Th2 cytokine inhibitors, thromboxane A2 inhibitors and mediator-release inhibitors. The use of two or more anti-allergy agents together is not acknowledged at present, but this will be the subject of research in the future because with different mechanisms of action anti-allergy agents used at the same time will theoretically increase their effects. This review article focuses on anti-allergy agents highlighting their applications, clinical trials and recent advancement on drugs.

The assessment and management of insomnia: an update

Insomnia poses significant challenges to public health. It is a common condition associated with marked impairment in function and quality of life, psychiatric and physical morbidity, and accidents. As such, it is important that effective treatment is provided in clinical practice. To this end, this paper reviews critical aspects of the assessment of insomnia and the available treatment options. These options include both non-medication treatments, most notably cognitive behavioral therapy for insomnia, and a variety of pharmacologic therapies such as benzodiazepines, "z-drugs", melatonin receptor agonists, selective histamine H1 antagonists, orexin antagonists, antidepressants, antipsychotics, anticonvulsants, and non-selective antihistamines. A review of the available research indicates that rigorous double-blind, randomized, controlled trials are lacking for some of the most commonly administered insomnia therapies. However, there are an array of interventions which have been demonstrated to have therapeutic effects in insomnia in trials with the above features, and whose risk/benefit profiles have been well characterized. These interventions can form the basis for systematic, evidence-based treatment of insomnia in clinical practice. We review this evidence base and highlight areas where more studies are needed, with the aim of providing a resource for improving the clinical management of the many patients with insomnia.

A Concise and Efficient Synthesis of an Impurity, N-Desmethyl Alcaftadine from Alcaftadine: An H1 Antagonist

Herein, a simple approach for the synthesis of N-desmethyl alcaftadine, an H1 histamine antagonist in solid state and its structure is presented. The reactions were performed under mild and metal free conditions at reflux temperature within a range of 65-70 ºC and the desired product N-desmethyl alcaftadine was obtained in high purity with good yield (96.42 %). It was detected by ultra-high-performance liquid chromatography (UHPLC).

Acute and chronic interactive treatments of serotonin 5HT2C and dopamine D1 receptor systems for decreasing nicotine self-administration in female rats

A variety of neural systems are involved in the brain bases of tobacco addiction. Animal models of nicotine addiction have helped identify a variety of interacting neural systems involved in the pathophysiology of tobacco addiction. We and others have found that drug treatments affecting many of those neurotransmitter systems significantly decrease nicotine self-administration. These treatments include dopamine D1 receptor antagonist, histamine H1 antagonist, serotonin 5HT2C agonist, glutamate NMDA antagonist, nicotinic cholinergic α4β2 partial agonist and nicotinic cholinergic α3β4 antagonist acting drugs. It may be the case that combining treatments that affect different neural systems underlying addiction may be more efficacious than single drug treatment. In the current study, we tested the interactions of the D1 antagonist SCH-23390 and the serotonin 5HT2c agonist lorcaserin, both of which we have previously shown to significantly reduce nicotine self-administration. In the acute interactions study, both SCH-23390 and lorcaserin significantly reduced nicotine self-administration when given alone and had additive effects when given in combination. In the chronic study, each drug alone caused a significant decrease in nicotine self-administration. No additive effect was seen in combination because SCH-23390 given alone chronically was already highly effective. Chronic administration of the combination was not seen to significantly prolong reduced nicotine self-administration into the post-treatment period. This research shows that unlike lorcaserin and SCH-23390 interactions when given acutely, when given chronically in combination they do not potentiate or prolong each other's effects in reducing nicotine self-administration.

Processing of NMR and MS metabolomics data using chemometrics methods: a global tool for fungi biotransformation reactions monitoring.

Biotransformation constitutes an important aspect of the drug discovery process, to mimic human metabolism of active principal ingredient but also to generate new chemical entities. Several microorganisms such as fungi are well adapted to transform drug, whether at the stage of screening or for large-scale production. Due to the high chemical complexity of the biotransformation media, it seems attractive to develop new analytical strategies in order to guarantee an adequate monitoring and optimize the production of targeted metabolites or drug candidates. The model designed for this purpose concerns the biotransformation of a potential histamine H3 antagonist (S38093) in order to produce phase I metabolites. MS, NMR and chemometrics tools were used to monitor biotransformation reactions. First, a screening of eleven filamentous fungi was carried out by UHPLC-UV-MS and principal component analysis to select the best candidates. Subsequently, MS (tR, m/z) and NMR (1H, JRES) fingerprints associated with Consensus OPLS-DA multiblock approach were used to better understand the bioreaction mechanisms in terms of nutrient consumption and hydroxylated metabolites production. Then an experimental design was set up to optimize the production conditions (pH, kinetic) of these target metabolites. This study demonstrates how NMR and MS acquisitions combined with chemometric methods offer an innovative analytical strategy to have a grasp of functionalization mechanisms, and identify metabolites and other compounds (amino acids, nutrients, etc.) in complex biotransformation mixtures.

Effect of clemastine fumarate on TLR4/PI3K/Akt signaling pathway during hypoxia-reoxygenation in rat cardiomyocytes

Objective To evaluate the effect of clemastine fumarate on Toll-like receptor 4/phosphatidylinositol-3-kinase/serine-threonine kinase (TLR4/PI3K/Akt) signaling pathway during hypoxia-reoxygenation(H/R) in rat cardiomyocytes. Methods H9C2 cells of rats cultured in vitro were seeded in culture wells or dishes at a density of 1×105 cells/ml and divided into 3 groups (n=11 each) by using a random number table method: control group (group C), H/R group and clemastine fumarate group (CF group). Cardiomyocytes were exposed to 5% CO2-95% N2 in a low-glucose DMEM medium at 37℃ for 4 h followed by 4 h reoxygenation.At 4 h of reoxygenation, the cell viability was detected by CCK-8 assay, the ultrastructure was observed with a transmission electron microscope, the expression of TLR4, PI3K, phosphorylated Akt (p-Akt) and caspase-3 was detected by Western blot, and the expression of TLR4, PI3K and caspase-3 was detected by immunofluorescence. Results Compared with group C, the cell viability was significantly decreased, the expression of TLR4 and caspase-3 was up-regulated, and the expression of PI3K and p-Akt was down-regulated in group H/R (P<0.05). Compared with group H/R, the cell viability was significantly increased, the expression of TLR4 and caspase-3 was down-regulated, the expression of PI3K and p-Akt was up-regulated (P<0.05), and the mitochondrial damage was significantly attenuated in group CF. Conclusion The mechanism by which clemastine fumarate alleviates H/R injury to rat cardiomyocytes may be related to inhibiting TLR4 expression and activating PI3K/Akt signaling pathway. Key words: Histamine H1 antagonists; Myocardial reperfusion injury; Toll-like receptor 4; Phosphatidylinositol 3-kinases; Protein-serine-threonine kinases

The problem with treating sinusitis against the background of allergic rhinitis

Both allergic rhinitis (AR) and sinusitis are widespread diseases that significantly worsen the patient’s quality of life, lead to significant financial costs and are associated with a huge health burden. When treating any AS, it is necessary to follow three basic principles: address the cause of the disease; eradicate the pathogen; restore drainage of sinuses, aerate and restore CO. The efficacy and speed in the treatment of sinusitis, which arose against the background of allergic inflammation, are comparable to those in the use of oral GCS (Ib level, persuasion scale A). The H1-histamine receptor blocker and competitive histamine antagonist ebastine is one of the most effective and safe latest-generation antihistamine.

Influence of oral magnesium-containing supplement and antacid administration on hypomagnesemia induced by panitumumab.

Hypomagnesemia is a common side effect of panitumumab. The effect of magnesium-containing supplement as a laxative and concomitant antacid (proton pump inhibitor and histamine H2 antagonist) administration on panitumumab-induced hypomagnesemia was retrospectively investigated. Patients with advanced or recurrent colorectal cancer who received panitumumab were included in this study. Serum magnesium levels were extracted from the electronic medical records of 1753 administrations in 221 patients who received panitumumab. Serum magnesium levels in patients with or without oral magnesium-containing supplement and antacid treatment were compared using analysis of covariance as the number of panitumumab administration up to 16 times for covariates. The mean serum magnesium levels were significantly decreased with increasing number of panitumumab administrations (2.13mg/dL at 1st vs. 1.55mg/dL at 16th, p < 0.001). The use of oral magnesium-containing supplement significantly inhibited the decline in mean serum magnesium level (1.98mg/dL vs. 1.78mg/dL, p < 0.001). However, antacid use in patients receiving oral magnesium-containing supplement significantly decreased the effectiveness of the magnesium supplement on serum magnesium level (2.02mg/dL vs. 1.93mg/dL, p < 0.05). The use of oral magnesium-containing supplement might function as magnesium supplement based on the finding that use of oral magnesium-containing supplement during panitumumab administration decreased hypomagnesemia. However, combination of antacid decreased the supplemental effect of oral magnesium on hypomagnesemia. These results suggest the possibility that use of antacids during anti-EGFR antibody administration may promote hypomagnesemia.

Topical application of L-carnosine to skeletal muscle excites the sympathetic nerve innervating the contralateral skeletal muscle in rats.

We previously obtained evidence suggesting that physical exercise increases the release of L-carnosine (CAR) from muscles and that CAR affects autonomic neurotransmission and physiological phenomena in rats. It has also been reported that exercise elicits an increase in activity of the sympathetic nerve innervating the skeletal muscle. Therefore, in this study, we investigated the effect of CAR application, onto the surface of the right femoral muscle, on activity of the sympathetic nerve innervating the left femoral muscle, in urethane-anesthetized rats. Topical application of 10pg (44.2fmol) of CAR increased either skeletal muscle sympathetic nerve activity (skeletal muscle-SNA) or skeletal muscle blood flow (skeletal muscle-BF) of the contralateral skeletal muscle. Furthermore, thioperamide, a histamine H3-antagonist, inhibited the increase in skeletal muscle-SNA, and butoxamine, a β2-antagonist, abolished the increase in skeletal muscle-BF caused by topical application of CAR. The present results suggest that CAR released from muscles during physical exercise might affect skeletal muscle-SNA and skeletal muscle-BF on the opposite side of the body via a CAR evoked effect in muscles.