Derivation of Pluripotent Stem Cells with In Vivo Embryonic and Extraembryonic Potency.

Of all known cultured stem cell types, pluripotent stem cells (PSCs) sit atop the landscape of developmental potency and are characterized by their ability to generate all cell types of an adult organism. However, PSCs show limited contribution to the extraembryonic placental tissues in vivo. Here, we show that a chemical cocktail enables the derivation of stem cells with unique functional and molecular features from mice and humans, designated as extended pluripotent stem (EPS) cells, which are capable of chimerizing both embryonic and extraembryonic tissues. Notably, a single mouse EPS cell shows widespread chimeric contribution to both embryonic and extraembryonic lineages in vivo and permits generating single-EPS-cell-derived mice by tetraploid complementation. Furthermore, human EPS cells exhibit interspecies chimeric competency in mouse conceptuses. Our findings constitute a first step toward capturing pluripotent stem cells with extraembryonic developmental potentials in culture and open new avenues for basic and translational research. VIDEO ABSTRACT.

Etv5 safeguards trophoblast stem cells differentiation from mouse EPSCs by regulating fibroblast growth factor receptor 2.

Previous studies have demonstrated that transcription factor Etv5 plays an important role in the segregation between epiblast and primitive endoderm at the second fate decision of early embryo. However, it remains elusive whether Etv5 functions in the segregation between inner cell mass and trophectoderm at the first cell fate decision. In this study, we firstly generated Etv5 knockout mouse embryonic stem cells (mESCs) by CRISPR/Cas9, then converted them into extended potential stem cells (EPSCs) by culturing the cells in small molecule cocktail medium LCDM (LIF, CHIR99021, (S)-(+)-dimethindene maleate, minocycline hydrochloride), and finally investigated their differentiation efficiency of trophoblast stem cells (TSCs). The results showed that Etv5 knockout significantly decreased the efficiency of TSCs (CDX2+) differentiated from EPSCs. In addition, Etv5 knockout resulted in higher incidence of the differentiated cells with tetraploid and octoploid than that from wild type. Mechanistically, Etv5 was activated by extracellular-signal-regulated kinase (ERK) signaling pathway; in turn, Etv5 had a positive feedback on the expression of fibroblast growth factor receptor 2 (FGFR2) which lies upstream of ERK. Etv5 knockout decreased the expression of FGFR2, whose binding with fibroblast growth factor 4 was essentially needed for TSCs differentiation. Collectively, the findings in this study suggest that Etv5 is required to safeguard the TSCs differentiation by regulating FGFR2 and provide new clues to understand the specification of trophectoderm in vivo.

The potential of dimetindene maleate inducing resistance to blast fungus Magnaporthe oryzae through activating the salicylic acid signaling pathway in rice plants.

BACKGROUND: Rice blast disease (Magnaporthe oryzae) is considered the most destructive rice disease all over the world. Dimetindene maleate is used in medication against allergic reactions in humans. Dimetindene maleate used to induce systemic acquired resistance (SAR) in rice (Oryza sativa L.) in order to protect rice plants from blast disease. RESULTS: Dimetindene maleate was not effective against fungus linear growth in vitro. In glasshouse conditions, dimetindene maleate significantly improved resistance at 25, 50, 125, 250, 500 and 1000 mg L-1 concentrations. Leaf blast severity reached 14.18% on plants treated with the most effective concentration of 125 mg L-1 compared with control plants. In field conditions during both seasons (2016 and 2017), 125 mg L-1 dimetindene maleate decreased the disease severity to 1.1% and 2.7%, respectively, after 30 days of treatment. Also, grain yield was increased to 13.27 and 12.90 t ha-1 in 2016 and 2017 seasons, respectively. Moreover, dimetindene maleate induces some of the indicators for salicylic acid and jasmonic acid pathways via gene expression. These genes include OsWRKY45, OsNPR1, AOS2, JAMYB and PBZ1 (OsPR10), recording 15.14-, 16.47-, 5.3-, 5.37- and 5.1-fold changes, respectively, 12-h postinoculation. CONCLUSION: The results overview investigated the effectiveness of dimetindene maleate for increasing rice resistance to blast disease through inducing SAR in rice plants under glasshouse and field conditions, which could be through the SA defense pathway by expression of genes (OsWRKY45 and OsNPR1). © 2021 Society of Chemical Industry.

Permeability alterations after surgical trauma in normal rabbit peritoneum.

BACKGROUND: To investigate whether surgical trauma in a rabbit adhesion formation model and the administration of normal saline (N/S), icodextrin (ID) and/or dimetindene maleate (DM) changes the permeability of the normal rabbit parietal peritoneum. MATERIALS AND METHODS: A total of 45 female rabbits were operated on for adhesion formation and were euthanized 10 days later. In some rabbits, ID or N/S was instilled intraabdominally during operation, whereas in others DM was infused intravenously. In others, ID plus DM or no agent was used. Specimens were obtained postoperatively and were mounted between Ussing chambers. Amiloride was used to investigate Na(+) channels. Transmesothelial resistance (R(TM)) was determined as a permeability indicator. RESULTS: Amiloride increased the R(TM) of both surfaces. Surgical trauma increased R(TM) and partially inhibited the effect of amiloride. ID and N/S increased R(TM) and inhibited the effect of amiloride. Use of DM did not change R(TM) and did not inhibit the effect of amiloride. Use of ID plus DM slightly increased R(TM), but the effect of amiloride was blocked. CONCLUSIONS: Surgical trauma impairs the permeability of the normal rabbit parietal peritoneum. ID or N/S surmounted this effect, but DM did not, suggesting that surgical trauma is a diffuse process. Antiadhesion measures influence peritoneal physiology.

Analytical method for simultaneously measuring ex vivo drug receptor occupancy and dissociation rate: application to (R)-dimethindene occupancy of central histamine H1 receptors.

We introduce a novel experimental method to determine both the extent of ex vivo receptor occupancy of administered compound and its dissociation rate constant (k4). [Here, we reference k4 as the rate of offset of unlabeled ligand in convention with Motulsky and Mahan (1)]. We derived a kinetic rate equation based on the dissociation rate constant for an unlabeled compound competing for the same site as a labeled compound and describe a model to simulate fractional occupancy. To validate our model, we performed in vitro kinetics and ex vivo occupancy experiments in rat cortex with varying concentrations of (R)-dimethindene, a sedating antihistamine. Brain tissue was removed at various times post oral administration, and histamine H1 receptor ligand [3H]-doxepin binding to homogenates from drug-treated or vehicle-treated rats was measured at multiple time points at room temperature. Fractional occupancy and k4 for (R)-dimethindene binding to H1 receptors were calculated by using our proposed model. Rats dosed with 30 and 60 mg/kg (R)-dimethindene showed 42% and 67% occupancy of central H1 receptors, respectively. These results were comparable to occupancy data determined by equilibrium radioligand binding. In addition, drug k4 rate determined by using our ex vivo method was equivalent to k4 determined by in vitro competition kinetics (dissociation half-life t(1/2) approximately 30 min). The outlined method can be used to assess, by simulation and experiment, occupancy for compounds based on dissociation rate constants and contributes to current efforts in drug optimization to profile antagonist efficacy in terms of its kinetic drug-target binding parameters. Data described by the method may be analyzed with commercially available software. Suggested fitting procedures are given in the appendix.

The basophil activation test in the diagnosis of allergy: technical issues and critical factors.

BACKGROUND: The basophil activation test (BAT) is a widely validated and reliable tool especially for the diagnosis of hymenoptera venom allergy. Nevertheless, several pitfalls have to be considered and outcomes may differ because of diverse in-house protocols and commercially available kits. We aimed to identify the factors that may influence results of the CD63-based BAT. METHODS: Basophil responses to monoclonal anti-IgE (clone E124.2.8) and bee and wasp venom were determined by BAT based on CD63. The effect of stimulating factors such as, IL-3, cytochalasin B and prewarming of the samples was investigated. Furthermore, we compared two different flow cytometer systems and evaluated the influence of storage time, different staining protocols and anti-allergic drugs on the test results. RESULTS: Interleukin-3 enhanced the reactivity of basophils at 300 pM, but not at 75 and 150 pM. Prewarming of samples and reagents did not affect basophil reactivity. CD63 expression assayed after storage time of up to 48 h showed that basophil reactivity already started to decline after 4 h. Basophils stained with HLA-DR-PC5 and CD123-PE antibodies gated as HLA-DR(neg)/CD123(pos) cells showed the highest reactivity. No effect on test outcomes was observed at therapeutic doses of dimetindene and desloratadine. Finally, slight differences in the percentage of activated basophils, depending on the cytometer system used, were found. CONCLUSION: Basophil activation test should be performed as early as possible after taking the blood sample, preferably within 4 h. In contrast to the skin test, BAT can be performed in patients undergoing treatment with antihistamines. For reasons of multiple influencing factors, BAT should be performed only at validated laboratories.

Structure-activity relationships of dimethindene derivatives as new M2-selective muscarinic receptor antagonists.

A series of 2,3-disubstituted indenes, which are analogues of the widely used histamine H(1) receptor antagonist dimethindene, have been synthesized and studied as muscarinic and histamine receptor antagonists. The affinities of these compounds for the five human muscarinic receptor subtypes (M(1)-M(5)) and for human histamine H(1) receptors were determined in radioligand binding studies using membranes from transfected Chinese hamster ovary (CHO) cells and [(3)H]N-methylscopolamine ([(3)H]NMS). The results demonstrate that the diisopropyl analogue 19 has a similar high affinity as (S)-dimethindene at M(2) receptors ((S)-dimethindene: pK(i) = 7.52; (-)-19: pK(i) = 7.37) with an improved selectivity pattern ((S)-dimethindene: M(2)/M(1) = 6-fold, M(2)/M(3) = 5-fold, M(2)/M(4) = 10-fold, M(2)/M(5) = 25-fold; (-)-19: M(2)/M(1) = 36-fold, M(2)/M(3) = 96-fold, M(2)/M(4) = 42-fold, M(2)/M(5) = 275-fold). In addition, compound (-)-19 showed 35-fold lower affinity at histamine H(1) receptors (pK(i) = 5.61) than (S)-dimethindene (pK(i) = 7.16). Another interesting compound is the fluoroethyl derivative 20 (pK(i)/M(2) = 7.49), which also exhibits a higher M(2) selectivity (M(2)/M(1) = 19-fold; M(2)/M(3) = 22-fold; M(2)/M(4) = 13-fold; M(2)/M(5) = 62-fold) than (S)-dimethindene. Unfortunately, compound 20 also shows a high affinity for histamine H(1) receptors (pK(i) = 8.14). The compound with the highest affinity for M(2) receptors (pK(i) = 7.91), the dimethylaminomethylene analogue 31, displayed only a small preference for M(2) receptors. In conclusion, compound (-)-19 might be useful to test the hypothesis that blockade of muscarinic M(2) receptors in the brain is a viable mechanism by which to produce improved cognition. This second-generation dimethindene analogue might also be the starting point for the development of M(2)-selective muscarinic antagonists useful for quantifying M(2) receptors in the central nervous system with positron emission tomography imaging.

Sedation and histamine H1-receptor antagonism: studies in man with the enantiomers of chlorpheniramine and dimethindene.

1. The effects of 10 mg (+)- and (-)-chlorpheniramine and 5 mg (+)- and (-)-dimethindene on daytime sleep latencies, digit symbol substitution and subjective assessments of mood and well-being were studied in 6 healthy young adult humans. Each subject also took 5 mg triprolidine hydrochloride as an active control and two placebos. 2. Daytime sleep latencies were reduced with triprolidine, (+)-chlorpheniramine and (-)-dimethindene, and subjects also reported that they felt more sleepy after (+)-chlorpheniramine and (-)-dimethindene. Performance on digit symbol substitution was impaired with (+)-chlorpheniramine. 3. Changes in measures with (-)-chlorpheniramine and (+)-dimethindene were not different from changes with placebo. 4. In the present study, changes in measures of drowsiness and performance were limited to the enantiomers with high affinity for the histamine H1-receptor. These findings strongly suggest that sedation can arise from H1-receptor antagonism alone, and provide further support for the belief that the histaminergic system is concerned with the regulation of alertness in man.

Influence of the histaminergic system on opiate-induced neurosecretion and behaviour.

The influence of the histaminergic system on fentanyl (Fe)-induced growth hormone (GH) and prolactin (PRL) release as well as on Fe-induced increase of noradrenaline (NA) plasma levels has been studied in male volunteers. These volunteers received, according to a randomized block design, different pretreatments: the H1-antagonist dimethindene (Di) (0.1 mg/kg i.v.), or the H2-antagonist cimetidine (Ci)(5 mg/kg i.v.), or a combination of dimethindene and cimetidine (Di + Ci), or saline. The PRL increase caused by Fe (0.2 mg/70 kg) was not altered by pretreatment with the H1-antagonist Di, the H2-antagonist Ci, or the combination of both. The increase of NA plasma levels after Fe also was not modified by the histamine antagonists. In contrast, the maximum GH increase after Fe was blunted by the combination of Ci and Di, but not by either Ci or Di alone. These results suggest an involvement of the histaminergic system in opiate-induced GH-release.

Effect of H1-antagonism on cardiovascular, pulmonary, and immunological dysfunction in porcine endotoxic shock.

The definite role of histamine in early hyperdynamic septic shock is not yet clear. Therefore a randomized, controlled, blind trial was performed to investigate the effect of the H1-antagonist dimethindene in hyperdynamic porcine shock. Lipopolysaccharide (LPS) infusion (5 micrograms/kg/h) in anesthetized pigs (n = 6) in the control-group induced a hyperdynamic shock state with a decrease in mean arterial blood pressure, and systemic vascular resistance (SVR), and an increase in mean arterial pulmonary pressure and pulmonary vascular resistance (PVR). In the verum group (n = 6) dimethindene (2 mg/kg) administered 15 min before LPS application prevented the decrease in SVR significantly (p < .05) and ameliorated the increase in MPAP and PVR. The impairment in pulmonary function, as measured by the oxygenation ratio (PaO2/FiO2) in LPS-treated animals, was reduced by the H1-antagonist (p = .01). Tissue oxygenation was ameliorated by the H1-antagonist treatment, as demonstrated by plasma lactate levels and base excess values (p < .05, control group versus dimethindene group). The increase in tumor necrosis factor alpha by LPS infusion was not influenced by H1-antagonist pretreatment. The early decrease in SVR did not correlate with an enhanced nitric oxide formation, as measured by nitrate/nitrite plasma levels.

Administration of H1 and H2 antagonists for chemoprophylaxis: a double-blind, placebo-controlled study in healthy volunteers.

A double-blind, placebo-controlled trial was performed to establish the duration of action of antihistamines and their ability to attenuate the adverse affects associated with histamine release. Thirty volunteers were assigned randomly to receive either placebo or a combination of the H1 blocker dimetindene maleate (0.1 mg/kg) and the H2 blocker cimetidine (5 mg/kg). A bolus dose of histamine (450 ng/kg) was given 15 minutes after antihistamine or placebo treatment and repeated after 2, 4, and 6 hours. Cardiovascular variables, plasma histamine levels, cutaneous manifestations, and objective and subjective signs and symptoms associated with histamine release were determined before and after each histamine injection. Although many of the signs of histamine release, including erythema and metallic taste, could be attenuated effectively for 6 hours with antihistamine treatment, the protection against histamine-induced flush and headache diminished after 2 hours. Statistically significant protection against histamine-mediated tachycardia persisted for only 2 hours. Antihistamine treatment significantly reduced the increase in plasma histamine levels after the first histamine injection but did not alter the levels after subsequent histamine injections. The currently recommended administration regimen for prophylaxis with antihistamines is insufficient to prevent histamine-mediated side effects, and additional doses may be required after 4 hours to achieve appropriate chemoprophylaxis.

The (S)-(+)-enantiomer of dimethindene: a novel M2-selective muscarinic receptor antagonist.

The present study was designed to determine to determine the in vitro affinity profile of (R)-(-)-dimethindene and (S)-(+)-dimethindene at muscarinic receptor subtypes using both functional and binding assays. In addition, the racemate was investigated in functional studies. The functional muscarinic receptors studied were putative M1 receptors in rabbit vas deferens and rat duodenum, M2 receptors in guinea-pig left atria and rabbit vas deferens, as well as M3 receptors in guinea-pig ileum and trachea. Furthermore, the histamine H1 antagonism by (R)-(-)- and (S)-(+)-dimethindene has been examined in guinea-pig ileum. Muscarinic binding selectivity was assessed in homogenates from human neuroblastoma NB-OF 1 cells (M1), rat heart (M2), pancreas (3) and striatum (M4). The results demonstrate that (S)-(+)-dimethindene is a potent M2-selective muscarinic receptor antagonist (pA2 = 7.86/7.74; pKi = 7.78) with lower affinities for the muscarinic M1 (pA2 = 6.83/6.36; pKi = 7.08), the M3 (pA2 = 6.92/6.96; pKi = 6.70) and the M4 receptors (pKi = 7.00), respectively. The (S)-(+)-enantiomer was more potent (up to 41-fold) than the (R)-(-)-enantiomer in all muscarinic assays. In contrast, the stereoselectivity was inverse at histamine H1 receptors, the (R)-(-)-enantiomer being the eutomer (pA2 = 9.42; pA2/(S)-isomer = 7.48). In conclusion, (S)-(+)-dimethindene is a useful tool to investigate muscarinic receptor heterogeneity. In addition, this lipophilic compound might become the starting point for the development of M2-selective muscarinic receptor antagonists useful as diagnostic tools for quantifying muscarinic M2 receptors in the central nervous system with positron emission tomography imaging, and to test the hypothesis that muscarinic M2 receptor antagonists show beneficial effects in the treatment of cognitive disorders.

The role of histamine H1 receptors in the thermoregulatory effect of morphine in mice.

Morphine is known to release histamine from mast cells and increase the turnover of neuronal histamine. It is also known that histamine receptors mediate some of the morphine effects. The contribution of histamine H1 and H2 receptors to the thermoregulatory effect of morphine in mice was investigated in the present experiments. Morphine produced a hypothermic effect, especially at the dose of 10 mg/kg. Although the histamine H1 receptor antagonist, dimethindene (0.1 mg/kg, i.p.), attenuated the hypothermic effect of morphine (10 mg/kg), a histamine H2 receptor antagonist, ranitidine (100 mg/kg, i.p.), had no effect. These results suggest that the hypothermic effect of morphine in mice is mediated, at least partly, through histamine H1 receptors.

Acetylcholine mediation of the contractile response to histamine in human bladder detrusor muscle.

In Krebs solution, histamine evokes in human bladder detrusor muscle strips a dose-dependent contractile response which consists of two pharmacologically distinct responses: a high-sensitivity response evoked at 0.4-2 microM histamine, which is potentiated by neostigmine (0.1 microM) or blocked by atropine (0.1 microM) or ranitidine (1 microM); a low-sensitivity response evoked at 4-40 microM histamine and blocked by dimethindene or diphenhydramine. These findings suggest that the contractile response to low doses of histamine is mediated by acetylcholine released from a site proximal to the muscle. This effect of histamine seems to be mediated by a site which is insensitive to the H1 antagonists dimethindene and diphenhydramine but blocked by the H2 antagonist ranitidine.

Action of dimethindene on the electrophysiological and mechanical properties of atrial and ventricular myocardium of guinea-pig.

The effect of dimethindene (DMI) on transmembrane potentials and contractile force was studied in atrial and ventricular myocardium of guinea-pigs. DMI reduced the maximum rate of depolarization (Vmax) without changing the resting potential in both preparations. In ventricular myocardium, DMI shortened the action potential duration and exerted a negative inotropic effect. In atrial muscle, the drug prolonged the action potential duration and induced a positive inotropic effect which could be antagonized with neither the alpha-blocker phentolamine, nor the beta-blocker pindolol, H1-blocker mepyramine and H2-blocker cimetidine. DMI had no effect on the slow action potentials induced by caffeine in K+-depolarized myocardial preparations. The drug consistently shifted the sodium inactivation curve to more negative membrane potentials. The results suggest that DMI has a quinidine-like membrane-stabilizing property, which may be due to its fast Na+ channel blocking activity. The differential inotropic action of the drug in atrial and ventricular myocardium is discussed.

Blockage of the fast sodium current by dimethindene in frog auricular fibres.

The effect of dimethindene (DMI) on action potential and fast inward Na current (INa) of frog atrial fibres was studied using double sucrose gap voltage-clamp technique. DMI reduced the amplitude and maximum rate of rise of the action potentials without altering the resting membrane potential. The drug inhibited the fast Na conductance in a concentration-dependent manner, without changing the reversal potential. The shape of the current-voltage curve along the voltage axis remained unchanged in the presence of DMI. The time to peak of the INa was not significantly altered by the drug whereas the rate of the INa inactivation (tau h) was slowed. DMI shifted the steady-state inactivation curve of INa (h infinity) to more negative potentials, and increased the reactivation time constant of the sodium system (tau r). The inhibition of INa was use-dependent. The results suggest that DMI interacts with the inactivation mechanism of the sodium channel of the frog myocardium, and explain its favourable antiarrhythmic activity.

Electrophysiological characterization of histamine receptor subtypes in mammalian heart preparations.

Histamine-induced electrophysiological effects have been investigated in guinea-pig left atria, papillary muscles and rabbit AV-nodal preparations by means of intracellular recording of action potentials, slow responses in the presence of 27 mmol/l (K+)o and voltage clamp experiments. Differentiation of the H-receptor subtypes was performed by the use of the H2-selective agonists dimaprit and impromidine and the H1- and H2-selective antagonists dimetindene and cimetidine, respectively. The following results were obtained: Histamine and the H2-agonists dimaprit and impromidine show similar actions on electrophysiological parameters of ventricular myocardium. Histamine at concentrations less than 1 mumol/l leads to a small increase in APD30 and APD90, but to a marked decrease at concentrations greater than or equal to 1 mumol/l, whereas Vmax, resting potential and amplitude remain nearly unchanged. The effects on ADP are completely blocked by cimetidine and not changed by dimetindene. Changes in action potential may be explained by an increased in slow inward current and outward currents as shown by voltage clamp experiments. In left atria histamine increases APD30 and APD90, whereas there is only a minor increase in amplitude with no changes in Vmax and resting potential. These effects are completely reversed by the H1-antagonist dimetindene but not by cimetidine. IBMX decreases APD90 and does not potentiate the action of histamine. Vmax of slow responses is increased in left atria by stimulation of H1-receptors and in papillary muscles by stimulation of H2-receptors. The results suggest that stimulation of atrial H1-receptors directly causes an increase in Ca-channel conductance.(ABSTRACT TRUNCATED AT 250 WORDS)

The design and pharmacology of novel selective muscarinic agonists and antagonists.

The muscarinic pharmacology of C1-methyl-substituted chiral compounds related to McN-A-343 and of (R)- and (S)-dimethindene has been studied. Among the McN-A-343 analogues, the (S)-enantiomers were more potent and had higher affinity than the (R)-isomers. The quaternary compound (S)-BN 228 was found to be the most potent M1-selective agonist known today (pEC50: M1/rabbit vas deferens = 7.83; M2/guinea-pig atria = 6.35; M3/guinea-pig ileum = 6.29). In both the atria and ileum the tertiary carbamate, (S)-4-F-MePyMcN, was a competitive antagonist (pA2 value = 7.39 and 6.82, respectively). In contrast, in rabbit vas deferens (S)-4-F-MePyMcN was a potent partial agonist (pEC50 = 7.22; apparent efficacy = 0.83). These results indicate that (S)-4-F-MePyMcN might be a useful tool to study M1 receptor-mediated effects involved in central cholinergic function. (S)-Dimethindene was a potent M2-selective antagonist (pA2 = 7.86/atria; pKi = 7.8/rat heart) with lower affinities for the M1 (pA2 = 6.36/rat duodenum; pKi = 7.1/NB-OK 1 cells), M3 (pA2 = 6.92/guinea-pig ileum; pKi = 6.7/rat pancreas) and M4 receptors (pKi = 7.0/rat striatum). It was more potent (up to 41-fold) than the (R)-isomer. In contrast, the stereoselectivity was inverse at ileal H1 receptors (pA2: (R)-isomer = 9.42; (S)-isomer = 7.48). Thus, (S)-dimethindene could be a valuable agent to test the hypothesis that M2 antagonists show beneficial effects in the treatment of cognitive disorders. It might also become the starting point for the development of diagnostic tools for quantifying M2 receptors in the CNS with PET imaging.

Effect-kinetic characterization of dimethindene maleate following oral administration (Fenistil, Tropfen).

Dimethindene maleate is a well known H1-receptor antagonist with strong affinity to the H1-receptor. In order to evaluate the time course of its activity, dimethindene maleate was investigated in a histamine provocation model in man. Eight healthy male volunteers were treated either with 4 mg dimethindene maleate using a commercially available solution (Fenistile, Tropfen) or an identically appearing placebo solution (po) following a double-blind, crossover study design. Intracutaneous histamine injections were administered at -1, 2, 5, 14, 17, 20, 23, 26 and 29 h following drug administration. Areas of flares and weals were measured 5, 10, 20, and 30 min following histamine provocation. A strong inhibition of the development of flares and weals was observed to be more pronounced in flares than in weals. Baseline adjusted areas under the curve differ statistically significantly following verum and placebo treatment conditions (P = 0.0028). According to the time schedule of the study maximal effects were observed at time point 5 h. The mean residence times of the inhibitory effects were calculated to be congruent to 13 h compared to the mean residence times of dimethindene blood levels of approximately 8 h indicating a non-linear relationship between blood level and effect.

Histamine H3 receptor-mediated inhibition of noradrenaline release in the human brain.

Stimulation-evoked 3H-noradrenaline release in human cerebrocortical slices was inhibited by histamine (in a manner sensitive to clobenpropit) and by imetit, suggesting H3 receptor-mediated inhibition of noradrenaline release in human brain.