Study on the antipruritic mechanism of Zanthoxylum bungeanum and Zanthoxylum schinifolium volatile oil on chronic eczema based on H1R and PAR-2 mediated GRPR pathway

Objective: To observe the antipruritic effect and mechanism of the volatile oil of Zanthoxylum bungeanum and Zanthoxylum schinifolium on chronic eczema to provide data support for clinical application and new drug development of Zanthoxylum bungeanum and Zanthoxylum schinifolium. Methods: The model of chronic eczema was established by using 2-dinitrochlorobenzene (DNCB), and the composition and content of volatile oil in Zanthoxylum schinifolium and Zanthoxylum bungeanum was determined by gas chromatography-mass spectrometry (GC-MS). The antipruritic effect by (EASI) score of eczema area and severity index and scratching times was then evaluated. Then, the contents of histamine, gastrin-releasing peptide (GRP), interleukin-4 (IL-4), and immunoglobulin E (IgE) in serum of rats was determined by enzyme-linked immunosorbent assay (ELISA). The tissue morphology was observed by HE staining. The expressions of H1R, PAR-2, TRPV1, TRPA1, and GRPR was then detected by immunohistochem-istry, Western blot, and QRT-PCR.Results: The results revealed that there were differences in the composition of volatile oil between Zanthoxylum bungeanum and Zanthoxylum schinifolium. Compared to the model group, the medium-dose group of Zanthoxylum bungeanum and Zanthoxylum schinifolium group significantly increased the difference of EASI score and scratching times, significantly decreased the concentrations of IL-4, IgE, GRP, and histamine, and significantly decreased the expression levels of H1R, PAR-2, TRPV1, and GRPR. The degree of inhibition on the patho-logical manifestations of chronic eczema was evident. There was no significant difference in antipruritic effect between the two groups. The expression of TRPA1 was inconsistent at the protein and gene level, which needs to be further researched (AU)

Intracerebellar microinjection of histaminergic compounds on locomotor and exploratory behaviors in mice.

The neural histaminergic system innervates the cerebellum, with a high density of fibers in the vermis and flocculus. The cerebellum participates in motor functions, but the role of the histaminergic system in this function is unclear. In the present study, we investigated the effects of intracerebellar histamine injections and H1, H2 and H3 receptor antagonist injections (chlorpheniramine, ranitidine, and thioperamide, respectively) and H4 receptor agonist (VUF-8430) on locomotor and exploratory behaviors in mice. The cerebellar vermis of male mice was implanted with guide cannula. After three days of recovery,the animals received microinjections of saline or histamine (experiment1), saline or chlorpheniramine (experiment 2), saline or ranitidine(experiment 3), saline or thioperamide (experiment 4), and saline or VUF-8430 (experiment 5) in different concentrations. Five minutes postinjection,the open field test was performed. The data were analyzed using one-way ANOVA and Duncan's post hoc test. The microinjections of histamine, ranitidine or thioperamide did not lead any behavioral effects at the used doses. In contrast, animals that received chlorpheniramine at the highest dose (0.16 nmol) and VUF-8430 at the highest dose (1.48 nmol)were more active in the open field apparatus, with an increase in the number of crossed quadrants, number of rearings and time spent in the central area of the arena, suggesting that chlorpheniramine and VUF-8430 modulates locomotor and exploratory behaviors in mice.

Intracerebroventricular injection of histamine induces the hypothalamic-pituitary-gonadal axis activation in male rats.

Brain histamine holds a key position in the regulation of behavioral states, biological rhythms, body weight, energy metabolism, thermoregulation, fluid balance, stress and reproduction in female animals. However, it is not clear whether central histamine exerts any effect on hypothalamic-pituitary-testicular in male rats and if so, the involvement of type of central histamine receptors. The current study was designed to determine the effect of centrally administrated histamine on plasma gonadotropin hormone-releasing hormone (GnRH), luteinizing hormone (LH), follicle stimulating hormone (FSH) and testosterone level, and sperm parameters, and to show the mediation of the central histaminergic H1, H2 and H3/H4 receptors on histamine-evoked hormonal and sperm parameters' effects. Studies were performed in male Sprague-Dawley rats. A total of 50 or 100 nmol doses of histamine were injected intracerebroventricularly (icv). 100 nmol dose of histamine significantly caused increases in plasma GnRH, LH, FSH and testosterone levels of animals, but not 50 nmol dose of histamine. Moreover, central pretreatment with chlorpheniramine, histaminergic H1 receptor antagonist (100 nmol), ranitidine and histaminergic H2 receptor antagonist (100 nmol) completely prevented histamine evoked increase in plasma GnRH, LH, FSH and testosterone levels, while thioperamide, histaminergic H3/H4 receptor antagonist (100 nmol) pretreatment failed to reverse sex hormones responses to histamine. Both central histamine treatment alone and central histamine treatment after central histaminergic receptors antagonists' pretreatments did not alter any sperm parameters in rats. In conclusion, our findings show that centrally administered histamine increases plasma GnRH, LH, FSH and testosterone levels of conscious male rats without change any sperm parameters. Moreover, according to our findings, central histaminergic H1, and H2 receptors mediate these histamine-induced effects.

Novel Treatment Strategies Using TiO2-Nanowired Delivery of Histaminergic Drugs and Antibodies to Tau With Cerebrolysin for Superior Neuroprotection in the Pathophysiology of Alzheimer's Disease.

More than 5.5 million Americans of all ages are suffering from Alzheimer's disease (AD) till today for which no suitable therapy has been developed so far. Thus, there is an urgent need to explore novel therapeutic measures to contain brain pathology in AD. The hallmark of AD includes amyloid-beta peptide (AßP) deposition and phosphorylation of tau in AD brain. Recent evidences also suggest a marked decrease in neurotrophic factors in AD. Thus, exogenous supplement of neurotrophic factors could be one of the possible ways for AD therapy. Human postmortem brain in AD shows alterations in histamine receptors as well, indicating an involvement of the amine in AD-induced brain pathology. In this review, we focused on role of histamine 3 and 4 receptor-modulating drugs in the pathophysiology of AD. Moreover, antibodies to histamine and tau appear to be also beneficial in reducing brain pathology, blood-brain barrier breakdown, and edema formation in AD. Interestingly, TiO2-nanowired delivery of cerebrolysin-a balanced composition of several neurotrophic factors attenuated AßP deposition and reduced tau phosphorylation in AD brain leading to neuroprotection. Coadministration of cerebrolysin with histamine antibodies or tau antibodies has further enhanced neuroprotection in AD. These novel observations strongly suggest a role of nanomedicine in AD that requires further investigation.

Bottom-Up versus Top-Down Induction of Sleep by Zolpidem Acting on Histaminergic and Neocortex Neurons.

Zolpidem, a GABAA receptor-positive modulator, is the gold-standard drug for treating insomnia. Zolpidem prolongs IPSCs to decrease sleep latency and increase sleep time, effects that depend on α2 and/or α3 subunit-containing receptors. Compared with natural NREM sleep, zolpidem also decreases the EEG power, an effect that depends on α1 subunit-containing receptors, and which may make zolpidem-induced sleep less optimal. In this paper, we investigate whether zolpidem needs to potentiate only particular GABAergic pathways to induce sleep without reducing EEG power. Mice with a knock-in F77I mutation in the GABAA receptor γ2 subunit gene are zolpidem-insensitive. Using these mice, GABAA receptors in the frontal motor neocortex and hypothalamic (tuberomammillary nucleus) histaminergic-neurons of γ2I77 mice were made selectively sensitive to zolpidem by genetically swapping the γ2I77 subunits with γ2F77 subunits. When histamine neurons were made selectively zolpidem-sensitive, systemic administration of zolpidem shortened sleep latency and increased sleep time. But in contrast to the effect of zolpidem on wild-type mice, the power in the EEG spectra of NREM sleep was not decreased, suggesting that these EEG power-reducing effects of zolpidem do not depend on reduced histamine release. Selective potentiation of GABAA receptors in the frontal cortex by systemic zolpidem administration also reduced sleep latency, but less so than for histamine neurons. These results could help with the design of new sedatives that induce a more natural sleep. SIGNIFICANCE STATEMENT: Many people who find it hard to get to sleep take sedatives. Zolpidem (Ambien) is the most widely prescribed "sleeping pill." It makes the inhibitory neurotransmitter GABA work better at its receptors throughout the brain. The sleep induced by zolpidem does not resemble natural sleep because it produces a lower power in the brain waves that occur while we are sleeping. We show using mouse genetics that zolpidem only needs to work on specific parts and cell types of the brain, including histamine neurons in the hypothalamus, to induce sleep but without reducing the power of the sleep. This knowledge could help in the design of sleeping pills that induce a more natural sleep.

Seven-day ethanol administration influence on the rat brain histaminergic neurons.

The purpose of the study is to clarify the effect of 7 days of ethanol administration upon brain histaminergic neurons in rats. Male Wistar rats were injected intraperitoneally (i.p.) with 20% ethanol/saline (0.85% NaCl) daily, over 7 days, whereas control rats were given saline. The animals were decapitated 24 h after the 7th injection and samples of hypothalamus were prepared for light and electron microscopy, accompanied by morphometry to examine the histaminergic neurons. It was found that ethanol administration gradually decreased the duration of alcohol-induced sleep and decreased the total amount of histaminergic neurons and the amount of histologically normal neurons, but increased the amount of hypochromic neurons and shadow cells. The histaminergic neuron bodies and nuclei decreased in size. The ultrastructural changes in histaminergic neurons demonstrated activation of their nuclear apparatus, both destruction or hypertrophy and hyperplasia of organelles, especially lysosomes. The histochemical examination revealed the activation of lactate dehydrogenase and acid phosphatase, and inhibition of NADH-, NADPhH, and succinate dehydrogenases. Following 7 days of ethanol administration, histaminergic neurons exhibit the structural signs of hyperactivity, which can be related to neuronal adaptation to the actions of ethanol, and increased behavioral tolerance to ethanol.

Histamine and histamine intolerance.

Histamine intolerance results from a disequilibrium of accumulated histamine and the capacity for histamine degradation. Histamine is a biogenic amine that occurs to various degrees in many foods. In healthy persons, dietary histamine can be rapidly detoxified by amine oxidases, whereas persons with low amine oxidase activity are at risk of histamine toxicity. Diamine oxidase (DAO) is the main enzyme for the metabolism of ingested histamine. It has been proposed that DAO, when functioning as a secretory protein, may be responsible for scavenging extracellular histamine after mediator release. Conversely, histamine N-methyltransferase, the other important enzyme inactivating histamine, is a cytosolic protein that can convert histamine only in the intracellular space of cells. An impaired histamine degradation based on reduced DAO activity and the resulting histamine excess may cause numerous symptoms mimicking an allergic reaction. The ingestion of histamine-rich food or of alcohol or drugs that release histamine or block DAO may provoke diarrhea, headache, rhinoconjunctival symptoms, asthma, hypotension, arrhythmia, urticaria, pruritus, flushing, and other conditions in patients with histamine intolerance. Symptoms can be reduced by a histamine-free diet or be eliminated by antihistamines. However, because of the multifaceted nature of the symptoms, the existence of histamine intolerance has been underestimated, and further studies based on double-blind, placebo-controlled provocations are needed. In patients in whom the abovementioned symptoms are triggered by the corresponding substances and who have a negative diagnosis of allergy or internal disorders, histamine intolerance should be considered as an underlying pathomechanism.

Decreased response rates by the combination of histamine and IL-2 in melphalan-based isolated limb perfusion.

Histamine (Hi) combined to melphalan in a rat experimental model of isolated limb perfusion (ILP) for lower limb soft tissue sarcoma, resulted in overall response rates (OR) of 66%. Likewise, ILP with interleukin-2 (IL-2) resulted in OR of 67%, when combined to melphalan, in the same experimental model. In systemic immunotherapy, the combination of IL-2 and Hi has been used for solid tumor treatment based on immunomodulatory effects. In this study, we used our well-established ILP experimental model to evaluate whether the synergistic effect between the two drugs seen in the systemic setting, could further improve response rates in a loco-regional setting. Histological evaluation was done directly and 24 h after ILP. Melphalan uptake by tumor and muscle were measured. Hi and IL-2 together, combined to melphalan in the ILP led to OR of only 28%. Histology of tumors demonstrated partial loss of Hi-induced hemorrhagic effect when IL-2 was present. Melphalan accumulation in the tumor when both Hi and IL-2 were added (3.1-fold) was very similar to accumulation with Hi only (2.8-fold), or IL-2 only (3.5-fold) combined to melphalan. In vitro there was no synergy between the drugs. In conclusion there was a negative synergistic effect between IL-2 and Hi in the regional setting.

Interactive effect of histamine and prostaglandin D2 on nasal allergic symptoms in rats.

This study was undertaken to investigate the interactive effect of histamine and prostaglandin D(2) in nasal allergic symptoms in rats. The intranasal application of histamine at doses lower than 10 mumol/site caused no sneezing or nasal rubbing. In addition, prostaglandin D(2) also showed no significant increase in these responses, even at a dose of 10 nmol/site. On the other hand, the simultaneous instillation of histamine and prostaglandin D(2) resulted in a 1000 times more potent effect in inducing nasal symptoms than the administration of histamine alone. Thus, prostaglandin D(2) enhanced the actions of histamine in inducing sneezing and nasal rubbing in a dose-dependent manner, and significant effects were observed at doses higher than 1 nmol/site. The responses induced by the simultaneous application of histamine and prostaglandin D(2) were inhibited by chlorpheniramine, cyproheptadine, BW A868C and ramatroban. Chlorpheniramine and cyproheptadine showed the dose-related inhibition of nasal symptoms induced by the combined administration of histamine (10 nmol) and prostaglandin D(2) (10 nmol), but the effect of cyproheptadine was relatively weak compared with chlorpheniramine. Moreover, BW A868C and ramatroban also showed the inhibition of nasal symptoms induced by the simultaneous administration of histamine and prostaglandin D(2) in a dose-dependent manner. BW A868C was more potent in inhibiting the nasal symptoms than ramatroban. These results clearly indicate that prostaglandin D(2) showed a synergistic effect on sneezing and nasal rubbing induced by histamine in rats, and its effect occurred through both prostaglandin D(2) and CRTH2 (chemoattractant receptor-homologous molecule expressed on TH2 cells) receptors.

Dalhousie dyspnea scales: Pictorial scales to measure dyspnea during induced bronchoconstriction.

The aim of this study was to validate our Dalhousie Dyspnea Scales in children referred for histamine bronchoprovocation challenge. Seventy-four children rated their dyspnea after each FEV(1) measurement following inhalation of doubling histamine concentrations from 0.125 to 8.0 mg/ml by the standard tidal breathing method. Serial FEV(1) and dyspnea rating using the Dalhousie Dyspnea Scales were recorded and Kendall's tau was computed for dyspnea rating versus fall in FEV(1). Subjects were split into those with positive (DeltaFEV(1) >or= 20% with PC(20)

Short-term alternating temperature enhances histamine-induced itch: a biphasic stimulus model.

Itch is the major symptom of many allergic or inflammatory skin diseases; yet it is still difficult to measure objectively. Human studies on the physiology and pathophysiology of the itch sensation (e.g. functional magnetic resonance imaging studies) have been hampered by the lack of an efferent and manageable "on-off" stimulus. Here, a short-term temperature-modulated human histamine itch model is presented. In nine healthy right-handed male volunteers (age 29+/-2.6 years), 1% histamine dihydrochloride was used in the skin prick model as standard itch stimulus on the right forearm with subsequent thermal modulation of the target skin area using a Medoc TSA II NeuroSensory Analyzer thermode. Modulation occurred in rapid alternating order from 32 degrees C (neutral) to 25 degrees C (slight cold) and vice versa; each temperature block lasted 20 seconds. Subjective itch ratings were recorded using a computerized visual analog scale (VAS) and - for qualitative assessment - the Eppendorf Itch Questionnaire (EIQ). All subjects reported localized itch sensations without pain; mean VAS itch intensity was 50.6+/-3.5% during the 25 degrees C blocks and 33.8+/-3.9% during the 32 degrees C blocks (P<0.0001). Also, mean EIQ ratings were significantly higher related to the 25 degrees C blocks. In spite of the common knowledge that intensive cold can inhibit itch sensation, a reproducible, significant enhancement of histamine-induced itch by short-term moderate temperature decrease could be shown. This effect might be explained by peripheral and central adaptation processes triggered by alternating afferent activity patterns and might be used - owing to its "on/off" characteristics-in future itch physiology studies such as functional magnetic resonance imaging.

Comparison between effects of intravenous and nebulized histamine in guinea pigs: correlation between changes in respiratory mechanics and exhaled nitric oxide.

Nitric oxide (NO) is a marker of airway inflammation in humans, despite not having effects on basal bronchial tone. Inhibition of NO synthesis can lead to enhanced airway reactivity in humans and it is therefore of importance to understand how bronchial provocation can affect endogenous NO. Presently, we have studied the role of exhaled nitric oxide in airway reactivity by measuring changes in pulmonary mechanics in response to histamine in anaesthetized guinea pigs. Two groups were challenged i.v. and four groups were challenged by aerosol at different doses. One of the i.v. and one of the aerosol groups received an inhibitor of NO synthesis, N(omega)-nitro-L-arginine methyl ester (L-NAME), to reduce endogenous production of NO before histamine challenge. All animals with intact NO production showed a decrease in exhaled nitric oxide after challenge. There were positive correlations between the peak in exhaled nitric oxide and pulmonary resistance, and between the decrease in exhaled nitric oxide and lung compliance. L-NAME pretreatment increased the reactivity to aerosolized histamine but not to i.v. histamine. We conclude that the different ways of administration elicit different response patterns of exhaled nitric oxide, resistance, and compliance, even when compared at similar insufflation pressure changes. The effects of L-NAME suggest that, although different mechanisms might be responsible for the changes in pulmonary mechanics, inhibition of endogenous NO enhances decrements in pulmonary function when histamine is administered in an aerosol. The close relationship between changes in exhaled nitric oxide and changes in lung compliance and pulmonary resistance merits further studies on the relationship between NO and airway reactivity.

Effect of inhaled histamine on airway epithelial cell swelling in ozone-exposed Guinea pigs.

BACKGROUND: It has been reported that histamine stimulates ion channels on airway epithelial cells and induces changes in osmolarity and the ion composition of the periciliary field of airway epithelia. OBJECTIVE: To investigate the effect of inhaled histamine on epithelial cell swelling, we studied the role of airway epithelial cells under histamine inhalation challenge in an animal model of airway inflammation using ozone exposure. METHOD: After exposure to 3.0 ppm ozone for 2 h, guinea pigs were anesthetized and tracheostomized, and then, lung resistance (R(L)) was measured. Histamine inhalation challenge and histological examination were performed. RESULT: The values of R(L) before histamine inhalation in the control group and the ozone-exposed group were 0.26 +/- 0.11 and 0.45 +/- 0.34 cm H(2)O/s, respectively. R(L) increased significantly after histamine inhalation both in the control and the ozone-exposed groups. The threshold of histamine (PC(200)) in the ozone-exposed group was significantly lower than that in the control group. A significant swelling of the epithelial cells after histamine inhalation was observed both in the control and the ozone-exposed groups, with a greater increase in the ozone-exposed group compared with the control group. However, no change in wall thickness was observed in the histamine/antihistamine or the ozone/histamine/antihistamine group. CONCLUSION: Our results suggest the possibility that the airway epithelial cell swelling plays a role in the increase in R(L) after histamine inhalation, especially in the presence of airway inflammation.

Effects of intracerebroventricular administration of ultra low doses of histaminergic drugs on morphine state-dependent memory of passive avoidance in mice.

The effects of intracerebroventricular (i.c.v.) administration of ultra low doses (ULDs) of histamine, clobenpropit and pyrilamine are studied on morphine state-dependent (STD) memory in mice. Although pre-test administration of different doses of histamine and clobenpropit showed no effect on impairment of memory induced by pre-training morphine, when the above drugs were co-administered with morphine, they inhibited the restoration of memory by morphine. These effects were opposite to microgram doses of the same drugs.

Intracerebroventricular effects of histaminergic agents on morphine-induced anxiolysis in the elevated plus-maze in rats.

Some reports indicate that morphine can induce anxiolytic effects both in animal and in man. It has also been reported that histaminergic system can interfere with some pharmacological effects of morphine. The effects of histaminergic agents on morphine-induced anxiolysis in rats, using elevated plus-maze were investigated in the present study. Intraperitoneal injection of morphine (3, 6 and 9 mg/kg) induced antianxiety effects. Intracerebroventricular administration of histamine at the doses of (5, 10 and 20 microg/rat) also increased anxiety-related behaviours. Intracerebroventricular injection of pyrilamine, a H1 receptor antagonist (25, 50 and 100 microg/rat), increased anxiety whereas injection of ranitidine, a H2 receptor antagonist (5, 10 and 20 microg/rat) at the same site, decreased anxiety. Therefore, it seems that histamine induces anxiogenic response through activation of H2 receptors, while the response of H1 blocker may be due to release of histamine. We also evaluated the interactions between morphine and histaminergic agents. Our data show that histamine (10 microg/rat), pyrilamine (50 microg/rat) and ranitidine (5 microg/rat) did not alter the response induced by different doses of morphine (3, 6 and 9 mg/kg). Similarly, a single dose of morphine did not alter the response induced by different doses of histamine (5, 10 and 20 microg/rat), pyrilamine (25, 50 and 100 microg/rat) or ranitidine (5, 10 and 20 microg/rat). In conclusion, the histaminergic system plays an important role in the modulation of anxiety, although in our experiments, no interaction was found between the effects of histaminergic agents and morphine on anxiety-related indices in the elevated plus-maze. This may imply that morphine-induced anxiolysis probably is independent of the histaminergic system.

Histamine combined with melphalan in isolated limb perfusion for the treatment of locally advanced soft tissue sarcomas: preclinical studies in rats.

PURPOSE: To evaluate the potential benefit of histamine combined with melphalan in the isolated limb perfusion (ILP) as an alternative to TNF-alfa and melphalan combination, for the treatment of irresectable soft tissue sarcomas of the limbs in Brown Norway (BN) rats. METHODS: 20 BN rats had small fragments of syngeneic BN-175 fibrosarcoma inserted on the right hind limb. In 7-10 days the tumor reached a median diameter of 12-15 mm and they were randomly divided in four groups (sham, melphalan, histamine and escalating doses of histamine combined to melphalan) being submitted to experimental ILP for 30 minutes. Tumors were measured daily with a caliper and the volume was calculated. RESULTS: Response curves showed a significant effect of the combination of histamine 200 mg/mL with melphalan, with 66% overall response, including 33% complete responses (p< 0.01). There were no systemic collateral effects and locally only mild temporary edema was observed for some animals treated with histamine. CONCLUSION: Histamine combined with melphalan had a promising effect in the ILP warranting future studies to better explore the mechanism of action as well as its potential use in organ perfusion.

Histamine combined with melphalan in isolated limb perfusion for the treatment of locally advanced soft tissue sarcomas: preclinical studies in rats

OBJETIVO: Avaliar o potencial benéfico da histamina combinada ao melfalano, na perfusão de membro isolado (PMI), como alternativa à combinacão TNF-alfa mais melfalano, no tratamento de sarcomas de partes moles irressecaveis em extremidades, em ratos de linhagem Brown Norway (BN). MÉTODOS: 20 ratos BN foram submetidos a implantacão de fragmentos de fibrosarcoma singênico BN-175 na pata traseira direita. Em cerca de 7-10 dias o tumor atingiu um diâmetro médio de 12-15 mm e foram aleatóriamente divididos em quatro grupos (controle, melfalano,histamina em doses progessivas combinada ao melfalano e histamina) sendo submetidos a PMI experimental por 30 minutos. Os tumores foram então medidos diariamente com o uso de paquímetro e o volume tumoral calculado. RESULTADOS: As curvas de resposta mostram um efeito significativo da combinacão de Histamina na concentracão de 200 mg/mL ao melfalano, com 66% de resposta global incluindo 33% de respostas completas (p < 0.01). Não houve efeitos colaterais sistêmicos e localmente apenas edema leve e transitório nos animais tratados com histamine. CONCLUSAO: A histamina em combinacão com o melfalano apresenta um efeito promissor na PMI garantindo maiores investigacões do seu mecanismo de acão e do seu potencial uso na perfusão de órgãos.

A comparison of the effects of an alpha-agonist, an anti-muscarinic agent and placebo on intranasal histamine challenge in allergic rhinitis.

Autonomic receptors play a part in the physiology and pathology of the nasal mucosa. The effect of an alpha-agonist and an anti-muscarinic agent on histamine-challenge was examined on patients with perennial allergic rhinitis. Nine patients received saline, oxitropium bromide 0.075%, or xylometazoline hydrochloride 0.1% in a double-blind fashion. Sequential challenge with increasing doses of histamine were given and resistance changes, sneezes and volume and content of secretion measured. Histamine challenge produced dose-related increases in nasal resistance (P < 0.0001), lavage fluid volume (P < 0.01) and total protein (P < 0.01). Following xylometazoline, histamine produced little increase in resistance compared with saline and oxitropium bromide (P < 0.0001). The latter reduced the dose-related increase in resistance (P < 0.01) and nasal lavage fluid volume (P = 0.0007) and total protein (P = 0.023) seen with saline. These results confirm the importance of alpha-adrenergic and muscarinic receptors in the human nasal mucosa and suggest mechanisms of action for these drugs in perennial allergic rhinitis.

Variables in allergy skin testing.

Allergy skin testing for immediate hypersensitivity is affected by a number of factors, some under the control of and others not controllable by the operator. Uncontrollable factors include the patient's age, chronobiological variation, and variation in reactivity between different parts of the body. Controllable factors include medications the patient is using, the quality of the allergy extract employed, the distance between test sites, the choice of prick or intradermal technique, and in the case of percutaneous testing, the device that is used. Considering the importance of the information that is generated by skin testing, and the major therapeutic commitments often resulting, more attention should be given to the techniques employed. It is suggested that operator performance can and should be assessed by relatively simple tests.