The role of histamine in the acute inflammatory responses to intradermal platelet activating factor.

1. The role of histamine in PAF-induced acute inflammatory responses (flare and weal) in the skin has been evaluated in a series of three separate studies. 2. Terfenadine, a potent H1-selective histamine antagonist virtually abolished the flare response and significantly inhibited the weal response. 3. Histamine depletion in the skin using compound 48/80 resulted in similar effects on the flare and weal response. Two consecutive daily injections of compound 48/80 were found to deplete comprehensively skin sites of histamine and the ability of skin to respond to PAF was completely restored within 2 weeks of compound 48/80 treatment. 4. Intradermally injected PAF was associated with acute rises in plasma histamine in blood drawn from a draining vein with peak concentrations occurring within 5 min of injection. 5. No difference in PAF-induced flare and weal response was found between atopic and non-atopic subjects and this was reflected in the peak plasma histamine results. A significantly higher baseline plasma histamine was found in the atopic group, however, when compared with the non atopic group. 6. It is concluded that histamine has an important role in the acute inflammatory responses to intradermally injected PAF, although there does appear to be a significant direct vascular component in the PAF-induced weal response.     

Effects of selective histamine receptor antagonists on skin responses to intradermal bradykinin in healthy volunteers.

The effects of chlorpheniramine and cimetidine on the cutaneous responses to intradermal injections of bradykinin were investigated in a randomized, double-blind, placebo-controlled, cross-over study. Chlorpheniramine significantly attenuated the increase in cutaneous blood flow and erythema induced by bradykinin but not the weal response. Cimetidine was without influence on these parameters and the effects of the combined therapy of chlorpheniramine and cimetidine were not significantly different from those due to chlorpheniramine alone. These results suggest that the cutaneous vasodilator effect of bradykinin is in part due to histamine release acting on histamine H1-receptors.     

Platelet activating factor and the responses of rat isolated stomach strip to prostaglandin E2

Abstract— The effect of platelet activating factor (PAF) on contractions evoked by acetylcholine, 5-hydroxytryptamine (5-HT) and prostaglandin E₂ (PGE₂) was studied in-vitro on rat stomach strip. Addition of PAF to the organ bath increased PGE- but not 5-HT- or acetylcholine-evoked responses. The effect of PAF was unaffected by atropine, methysergide or indomethacin, but prevented by a specific PAF receptor antagonist BN 52021. The data support a specific interaction between PAF and PGE₂ on rat stomach strip.     

Bronchopulmonary responses to prostaglandin F2alpha, histamine and acetylcholine in the dog.

This investigation compared quantitatively the effects of prostaglandin F2alpha, histamine and acetylcholine on pulmonary airway resistance and dynamic lung compliance in the spontaneously breathing, anesthetized dog. Airway responses were evaluated by computer analysis before and after pharmacological blockade by either atropine or propranolol. In a dose range of 1.0-10.0 mug/kg i.v., prostaglandin F2alpha was the most potent bronchoconstrictor studied. At the highest dose, prostaglandin F2alpha increased airway resistance 153.3% and decreased lung compliance 55.4% from basal levels. Similar doses of either histamine or acetylcholine produced much less effect. Atropine significantly reduced the bronchopulmonary responses evoked by histamine, acetylcholine and prostaglandin F2alpha. Propranolol did not inhibit any of the respiratory effects of those bronchoconstrictors analyzed. The bronchopulmonary effects of prostaglandin F2alpha and histamine appear to be augmented by cholinergic stimuli.     

Modulation of in vitro immune reactions by platelet activating factor and a platelet activating factor antagonist

Platelet activating factor (PAF) was found to suppress primary and secondary mixed lymphocyte reactions and BN52021, a naturally occurring PAF antagonist, blocked PAF-mediated suppression and enhanced the mixed lymphocyte reactions. The effect of delayed addition of PAF or BN52021 24 h or later after the initiation of cultures reduced the suppressive and enhancing effects, respectively. The removal of the antagonist BN52021 from mixed lymphocyte cultures up to 72 h after their initiation also was found to eliminate the potentiating effect of this antagonist. The continuous presence of PAF in mixed lymphocyte cultures used to generate cytotoxic lymphocytes suppressed the generation of effector cells while the addition of BN52021 elicited an enhanced level of cell-mediated cytotoxicity in such cultures. BN52021 enhanced the cytotoxic activity in such cultures irrespective of the presence of exogenous interleukin-2, suggesting that the antagonist-mediated enhancement is not due to the enhanced production of interleukin-2 by cells in the mixed cultures. The experiments reported here provide evidence for a role of PAF in modulating the complex interactions that take place in the initiation of cellular immune reactions. Furthermore, the results of these experiments indicate that the immunoregulatory action of PAF can be modulated by an antagonist that exerts its action independently of the production of the lymphocyte growth factor, interleukin-2.     

The effects of histamine administered in fish samples to healthy volunteers.

The effects of histamine administered in samples of fish to eight healthy volunteers (4 females and 4 males), aged 21-30 years, were studied. The subjects were given 0, 45 and 90 mg of histamine that had been metabolized from histidine by photobacteria in the fish and 90 mg of histamine added to fresh fish, for breakfast. The subjects were observed during 6 h after breakfast. Special attention was paid to clinical symptoms, blood pressure and ECG. The pH of the gastric contents was recorded continuously from 5 min before to 6 h after the meal. Blood samples to measure the histamine concentration were taken at intervals during 24 h after breakfast. Two of the subjects showed effects (facial flushing, headache) that could be attributed to the ingestion of histamine. No significant changes were observed in the blood pressure and ECG. The pH of the gastric fluids did not decrease significantly. The histamine concentration in plasma correlated closely with the histamine dose ingested (p < 0.001, r = 0.996). The Cmax of the dose of 90 mg did not differ statistically significant from the Cmax of the dose of 90 mg histamine added to unspoiled fish.     

Effects of REV 5901, a 5-lipoxygenase inhibitor and leukotriene antagonist, on pulmonary responses to platelet activating factor in the guinea-pig.

1. The effects of REV 5901 on the platelet activating factor (Paf)-induced (a) bronchoconstriction, (b) contraction of lung parenchymal strips and (c) increased airways responsiveness to histamine, were assessed in the guinea-pig. REV 5901 is a 5-lipoxygenase inhibitor and competitive peptidoleukotriene antagonist which does not inhibit multiple forms of phosphodiesterase. 2. In urethane/pentobarbitone anaesthetized animals, REV 5901 (10 or 30 mg kg-1, i.v.) substantially inhibited the bronchoconstriction, measured as changes in airways resistance (RL) and dynamic lung compliance (Cdyn), induced by leukotriene D4 (2.5 micrograms kg-1, i.v.) but did not attenuate that induced by Paf (50 ng kg-1, i.v.). 3. Paf contracted the lung parenchymal strip in a concentration-dependent manner. REV 5901 (25 microM) neither altered the magnitude of the contractions nor the tissue sensitivity to Paf. The sustained contraction induced by Paf was not affected when REV 5901 was added after the response had reached a plateau. 4. Contractions of parenchymal strips to Paf (50 nM) were prevented by pretreatment with the competitive Paf antagonists, SRI 63441 and WEB 2086. Also WEB 2086, but not SRI 63441, reversed established Paf-induced contractions and relaxed parenchymal strips from intrinsic tone in the absence of Paf. 5. Paf (20 ng kg-1, i.v.) caused an acute increase in airways responsiveness to histamine (4-12 micrograms kg-1, i.v.) which was attenuated by REV 5901 at 10 mg kg-1, i.v. and abolished by 30 mg kg-1, i.v.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cardiovascular responses to metipranolol and timolol eyedrops in healthy volunteers.

1. Intraocular pressure and cardiovascular responses to metipranolol 0.1% and 0.3% and timolol 0.25% eyedrops were measured in a balanced single dose placebo-controlled crossover study in eight healthy volunteers aged 34-58 years. 2. Timolol 0.25% and metipranolol 0.3% reduced intraocular pressure throughout the 6 h period of observation to a similar extent. Metipranolol 0.1% was marginally less effective, significantly reducing pressure up to 4 h only. 3. No drug treatment significantly altered resting heart rate or blood pressure. Timolol 0.25% significantly reduced exercise tachycardia (P less than 0.05), an effect which was not shown by metipranolol 0.1 or 0.3%. Exertional pain in the legs occurred more frequently after timolol 0.25% and metipranolol 0.3% than after metipranolol 0.1% or placebo eyedrops. 4. Octan-1-ol/pH 7.4 buffer distribution coefficients at 37 degrees C were found to be: metipranolol 5.19, timolol 0.84, indicating that metipranolol has an approximately 6-fold greater lipid solubility. 5. It is concluded that, by comparison with timolol, metipranolol in eyedrop concentrations up to 0.3%, despite its greater lipid solubility, reaches concentrations in the systemic circulation which are less likely to affect the heart.     

Comparative efficacy of bilastine,desloratadine and rupatadine in the suppression of wheal and flare response induced by intradermal histamine in healthy volunteers

Objective: To compare the peripheral antihistaminic activity of bilastine, rupatadine and desloratadine in inhibiting the histamine-induced wheal and flare (W&;F) response.

Research design and methods: Twenty-four healthy volunteers aged 18–40 years participated in this crossover, randomized, double-blind, placebo-controlled clinical study. Subjects received single doses of bilastine 20?mg, desloratadine 5?mg, rupatadine 10?mg and placebo. W&;F responses induced by intradermal injection of histamine 5?μg were evaluated before treatment (basal value) and at 0.5, 1, 2, 4, 6, 9, 12 and 24?hours after treatment. Fifteen minutes after histamine injection, W&;F surface areas (cm²) were quantified using the Visitrak System. Itching sensation was evaluated using a 100?mm visual analog scale.

EudraCT number: 2015-000790-13.

Main outcome measures: The primary outcome measure was the percentage reduction in W&;F areas after each active treatment compared with corresponding basal values.

Results: Bilastine induced the greatest inhibition in wheal area and was significantly superior to desloratadine and rupatadine from 1 to 12?hours (both p?p?p?p?Conclusions: Bilastine 20?mg induced significantly greater inhibition of the W&;F response compared with desloratadine 5?mg and rupatadine 10?mg throughout the 24?hour study period, and had the fastest onset of action. Only bilastine significantly reduced itching sensation versus placebo.     

Increased airways responsiveness to histamine induced by platelet activating factor in the guinea-pig: possible role of lipoxygenase metabolites

In anaesthetized guinea-pigs pretreated with propranolol (1 mg/kg, i.v.), platelet activating factor (Paf, 0.02 micrograms/kg, i.v.) caused an acute increase in airways response to histamine (0.5-3.0 micrograms/kg, i.v.) measured as intratracheal pressure. Treatment with the cyclooxygenase inhibitors, aspirin (10 mg/kg, i.v.) or indomethacin (5 mg/kg, i.v.), enhanced the magnitude and duration of this effect but a combined lipoxygenase/cyclooxygenase inhibitor, BW 755C (20 mg/kg, i.v.), prevented the increase in responsiveness. In aspirin treated animals, a putative lipoxygenase inhibitor NDGA (10 mg/kg, i.v.). or atropine methyl nitrate (1 mg/kg, i.v.) or bilateral vagotomy reduced the magnitude of Paf-induced increased histamine responses but did not prevent the effect. Bronchoconstriction induced by Paf was variably influenced by the drug treatments. These data suggest that Paf causes an acute increase in airways responsiveness to histamine in the guinea-pig through a mechanism that may, in part, be dependant on the release of lipoxygenase metabolites.     

The effect of MK-0524, a prostaglandin D2 receptor antagonist, on prostaglandin D2-induced nasal airway obstruction in healthy volunteers

Introduction Nasal congestion in allergic rhinitis results from tissue edema and vasodilatation in the nasal mucosa. Of the mediators released by mast cells in response to allergens, prostaglandin (PG) D₂ is regarded as the most potent inducer of nasal congestion. Intranasal administration of PGD₂ reproduces the nasal blockade experienced by patients with seasonal allergic rhinitis (SAR) via its action on the PGD₂ (DP) receptor to induce nasal vasodilatation. Intranasal challenge with PGD₂ can be a useful tool for evaluating DP-receptor antagonists. Objective The main purpose of this study was to examine the ability of MK-0524, a DP receptor antagonist in development for the treatment of SAR, to block PGD₂ induced nasal congestion in healthy volunteers. Methods To this end, a double-blind, placebo-controlled, randomized, 3-period study was performed in 15 healthy subjects. During each period, subjects received MK-0524 25 mg, MK-0524 100 mg or placebo qd for 3 days. Twenty-four hours following the last dose, nasal provocations with PGD₂ were performed to determine the PD₇₅, which is the intranasal dose of PGD₂ that provokes a 75% increase in baseline total nasal airway resistance as performed by active anterior rhinomanometry. Results Following treatment with MK-0524, the PD₇₅ (mean±SD) was significantly shifted from 15.8 ± 18.3 μg/nostril during the placebo period to more than 512 μg/nostril both following the 25- and 100-mg (maximum challenge dose tested) dose regimen. Conclusion Whether this >45 fold increase in PD₇₅ will induce a clinically meaningful effect of MK-0524 will require clinical study in participants with SAR.     

Dose proportional pharmacokinetics of alprostadil (prostaglandin E1) in healthy volunteers following intravenous infusion.

Prostaglandin E1 (PGE1) (30, 60, 120 micrograms) was administered by intravenous infusion over a 120 min period in an open, three way randomized, cross-over study to 12 healthy male volunteers. For the evaluation of PGE1, PGE0 and 15-keto-PGE0, blood samples were drawn prior to, during and after the infusion. Analytical measurements were performed by gas chromatography/negative ion chemical ionization triple stage quadruple mass spectrometry, a highly specific and sensitive GC/MS/MS-method. During intravenous infusion of 30, 60 and 120 micrograms PGE1, endogenous plasma PGE1 concentrations increased from 1.7 +/- 0.8 to 4.2 +/- 1.1, 6.7 +/- 1.0 and 11.0 +/- 1.9 pg ml-1 respectively. PGE0 plasma concentrations increased from endogenous levels of 1.3 +/- 1.0 pg ml-1 to 7.6 +/- 2.1, 14.1 +/- 3.7 and 28.0 +/- 3.0 pg ml-1 respectively, whilst 15-keto-PGE0 plasma concentrations increased from endogenous levels of 10.2 +/- 13.9 pg ml-1 to 99.3 +/- 27.9, 190.4 +/- 52.5 and 357.2 +/- 72.6 pg ml-1 respectively. Within the dose range of 30-120 micrograms PGE1 2 h-1 there was a linear increase of Cmax and AUC with the dose. The results of the analysis of variance after baseline and dose-correction show a 90% confidence interval in the bioequivalence acceptance range of 80 to 125%.     

Subjective,behavioral and physiological responses to intravenous meperidine in healthy volunteers

Meperidine is a mu opiate agonist that is frequently used to treat pain. We examined in healthy volunteers (N=10) the effects of intravenous meperidine (0, 0.25, 0.5, and 1.0 mg/kg) on mood and psychomotor performance. A randomized, placebo-controlled, crossover design was used in which subjects were injected with meperidine or saline in a double-blind fashion. Subjects completed several subjective effects questionnaires commonly used in abuse liability testing studies before drug injection and at periodic intervals for up to 5 h after drug injection. Subjects also completed several psychomotor tests. Meperidine produced a constellation of subjective effects in a dose-related fashion, including increases in ratings of “sedated,” “coasting or spaced out” and “feel drug effect” ratings. Many of the drug's subjective effects persisted up to 4 or 5 h after administration of the 1.0 mg/kg dose. Drug liking ratings assessed on a visual analog scale were increased after meperidine injection in about half of the subjects (P=0.09). Eye-hand coordination was affected slightly by meperidine but other indices of psychomotor functioning were unaffected. Miosis increased in a dose-related fashion. Other physiological parameters, such as vital signs, were not affected by meperidine. We conclude that meperidine in healthy volunteers has robust and long-lasting effects on mood, but may have weaker effects on psychomotor performance.     

The effects of a selective 5-HT2 receptor antagonist (ICI 170,809) on platelet aggregation and pupillary responses in healthy volunteers.

1. ICI 170,809 (2-(2-dimethylamino-2-methylpropylthio)-3-phenylquinoline hydrochloride) is a potent 5-hydroxytryptamine (5-HT) type 2 postsynaptic receptor antagonist. 2. Effects of ICI 170,809 as single oral doses (3, 7, 15 and 30 mg) or placebo were studied on the duration of antagonism for the ex vivo platelet aggregatory response to 5-HT and to the pupillary light constrictor response in eight healthy male volunteers. 3. Pupillary dark adapted responses to a 0.5 s light stimulus were measured using a portable infrared pupillometer, for up to 24 h after dosing. 4. The in vitro platelet 5-HT aggregation response was reduced by ICI 170,809, with depression of the dose-response curve to 5-HT at all concentrations of 5-HT and with no evidence for a parallel shift. 5. The ex vivo platelet 5-HT response demonstrated a dose related significant (P less than 0.02) decrease in aggregation reaching a maximum at 2 h after dosing with the effect persisting for at least 8 h after dosing with the 7 and 15 mg doses. 6. Resting pupil diameter (RPD), and light induced pupillary responses in the dark adapted pupil, showed a significant (P less than 0.01) dose related reduction with significant (P less than 0.05) effects still present with the 15 and 30 mg doses at 8 h after dosing. 7. We conclude that, changes in both ex vivo platelet aggregation to 5-HT and dark adapted pupil size, are significantly correlated (P less than 0.0001) with log plasma concentrations (ng ml-1) of ICI 170,809, enabling the assessment of 5-HT2-receptor antagonism in man.     

Inhibitions of histamine release and prostaglandin E2 synthesis by mangosteen,a Thai medicinal plant

The fruit hull of mangosteen, Garcinia mangostana L. has been used as a Thai indigenous medicine for many years. However, its mechanism of action as a medicine has not been elucidated. The present study was undertaken to examine the effects of mangosteen extracts (100% ethanol, 70% ethanol, 40% ethanol and water) on histamine release and prostaglandin E2 synthesis. We found that the 40% ethanol extract of mangosteen inhibited IgE-mediated histamine release from RBL-2H3 cells with greater potency than the water extract of Rubus suavissimus that has been used as an anti-allergy crude drug in Japan. All extracts of mangosteen potently inhibited A23187-induced prostaglandin E2 synthesis in C6 rat glioma cells, while the water extract of Rubus suavissimus had no effect. The 40% ethanol extract of mangosteen inhibited the prostaglandin E2 synthesis in a concentration-dependent manner with relatively lower concentrations than the histamine release. In addition, passive cutaneous anaphylaxis (PCA) reactions in rats were significantly inhibited by this ethanol extract as well as by the water extract of Rubus suavissimus. These results suggest that the 40% ethanol extract of mangosteen has potent inhibitory activities of both histamine release and prostaglandin E2 synthesis.     

Protective effects of a platelet activating factor (PAF) antagonist and its combined treatment with prostaglandin (PG) E1 in traumatic shock

We have investigated the role of platelet activating factor (PAF) in the pathogenesis of a murine model of traumatic shock using CV-6209, a specific antagonist of PAF. CV-6209, at a dose of 1 mg/kg (i.v.) given after trauma, significantly improved survival rate at 150 min and overall survival time. Furthermore, the plasma accumulation of the lysosomal hydrolase, cathepsin D, and a cardiotoxic peptide, myocardial depressant factor (MDF), were also attenuated by CV-6209 in traumatic shock. Combined treatment employing low doses of CV-6209 [0.2 mg/kg, i.v. and prostaglandin (PG) E1, 0.8 microgram/kg/min] in this shock model was also examined. CV-6209 (0.2 mg/kg) or PGE1 (0.8 microgram/kg/min) alone at these doses showed only minimal effects on survival, or plasma cathepsin D or MDF activities. However, combined treatment with CV-6209 (0.2 mg/kg, i.v.) and PGE1 (0.8 microgram/kg/min) significantly improved survival rate at 150 min, overall survival time, and decreased the accumulation of plasma MDF. These results suggest that PAF may play an important pathophysiologic role in traumatic shock in rats. Moreover, combination therapy using a PAF antagonist and PGE1 may be useful for the treatment of traumatic shock.     

Leukotriene B4 and prostaglandin E2 mediate the inflammatory response of rabbit skin to intradermal arachidonic acid.

1. Acute inflammation was induced in rabbit skin by intradermal injection of arachidonic acid. 2. Inflammation was assessed by the local accumulation of intravenously-injected 125I-serum albumin (plasma extravasation) and histologically (polymorphonuclear leucocyte, PMNL infiltration). 3. Leukotriene B4 (LTB4) and prostaglandin E2 (PGE2) were extracted from skin and fractionated using C18 mini-columns. They were quantitated by specific radioimmunoassays and authenticated by reversed-phase high performance liquid chromatography analysis. 4. Maximally elevated levels of LTB4 and PGE2 were detected in skin 5 min after arachidonic acid injection. At subsequent times the eicosanoid content of the skin decreased. 5. The decrease in the eicosanoid content of the skin was due to rapid clearance (t 1/2 approximately 5 min) via the microvasculature and not a consequence of metabolism. 6. The concentration of LTB4 and PGE2 measured in inflamed skin was sufficient to account for the plasma extravasation and PMNL infiltration induced by arachidonic acid. The model therefore is useful for evaluating the anti-inflammatory efficacy of inhibitors of arachidonic acid metabolism including 5-lipoxygenase inhibitors. 7. The consequences of the rapid clearance of LTB4 from inflammatory sites are discussed with respect to its measurement in inflammatory disease and its role as an acute inflammatory mediator.     

Role of orexin and prostaglandin E(2) in activating histaminergic neurotransmission

Although the molecular mechanisms underlying the control of sleep have been extensively studied in the past, relatively little attention has been paid to the regulatory mechanisms involved in the maintenance and control of wakefulness until today. In this article, recent developments leading to our better understanding of the arousal system will be reviewed with the main emphasis on three messengers: histamine, prostaglandin E(2) and orexin. The results reported herein may provide new insights into the molecular mechanisms of sleep-wake regulation and may lead to the development of new anti-sleep drugs as well as new hypnotic agents.