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PubMed1991

Investigation of the antihistaminic action of dimethindene maleate (Fenistil) and its optical isomers.

Dimethindene maleate (DM) (= Fenistil) is a potent antihistamine with a prolonged duration of action. On the histamine-stimulated guinea-pig ileum DM has a pA2 of 9.3 but produces a very marked depression of the maximum response at 10(-8) M. DM has no effect on H2 receptors nor on H3 receptors, and is not a calcium channel blocker. Muscarinic receptors (carbachol-stimulated ileum) were only influenced (competitively) at 10(-7) M or above, suggesting that the non-competitive effects described above could be due to a specific reaction with the histamine H1 receptor. As non-specific effects, such as membrane-stabilisation, would normally be seen with both isomers equally, we studied the effects of the optical isomers of DM. The (-) isomer had a profile identical to that of DM, but was slightly more potent. The (+) isomer was some 30 times less potent (results confirmed by binding studies). However in contrast to DM and the (-) isomer, the (+) isomer showed a "classical" antagonism, pA2 = 7.7, with no evidence of non-competitive effects. Thus the more active (-) isomer of DM has a potent, non-competitive H1 histamine antagonist effect. The relevance of these findings to DM's clinical profile is discussed.

Animals↗
PubMed1994

Effects of antihistaminics on experimental brain edema.

Histamine has potent effects on cerebral blood vessels which include increased permeability and dilatation. Since its concentrations are found to be increased in brain tissue in different experimental models of brain injury, histamine may act as a mediator of secondary brain damage. Using the cold-lesion model of vasogenic brain edema the effects of application of antihistaminics were studied in rats. Neither mepyramine, an H1 receptor blocker nor zolantidine, an H2 blocker provided any decrease in brain swelling or water content. Experiments with application of dexamethasone yielded a small non-significant decrease of edema while the amino-steroid U74389F did not reduce swelling. The results indicate that histamine is obviously not involved in mediating cold lesion-induced brain edema. Furthermore, generation of lipid peroxides after activation of phospholipase A2 also appears not to have a significant influence on edema in the present study.

Animals↗
PubMed1987

Antihistaminics enhance morphine-, but not amphetamine- and scopolamine-induced hyperactivity in mice.

Three histamine H1-receptor antagonists, chlorpheniramine, diphenhydramine and tripelennamine, were tested alone or in combination with morphine, amphetamine and scopolamine on locomotor activity in mice. All three antihistaminics, at some dosage levels, enhanced morphine-induced hyperactivity, but did not change or even reduce locomotor stimulation induced by amphetamine and scopolamine. The results suggest that H1-blocking agents may specifically interact, though not necessarily directly, with opiate mechanisms in producing behavioural effects.

Animals↗
PubMed1987

Initial nociceptive sensitization in carrageenin-induced rat paw inflammation is dependent on amine autacoid mechanisms: electrophysiological and behavioural evidence obtained with a quaternary antihistamine, thiazinamium.

We have studied the ability of a quaternary antihistamine, thiazinamium, to inhibit the nociceptive sensitization that occurs early, during the first hour, following intraplantar injection of the polysaccharide carrageenin in the rat. Parallel studies were performed with an electrophysiological model (changes in responsiveness of ventro-basal thalamic cells driven by noxious stimulation of the paws), and a behavioural test (changes in threshold stimulus necessary to elicit vocalization by gradually increased pressure to the paws). When thiazinamium was given intravenously 10 min before carrageenin, no sensitization due to inflammation was found in either test. By contrast, when thiazinamium was administered 20 min after carrageenin, there was a clear sensitization in both tests that did not differ from that found in animals not treated with the antagonist. Paw oedema was also slightly decreased by pretreatment with thiazinamium. These results suggests that early inflammatory sensitization of peripheral nociceptors is mainly dependent on an initial release of histamine (and/or serotonin, since thiazinamium could also have some antiserotoninergic activity).

Animals↗
PubMed1983

Early stages of chemically induced liver carcinogenesis by oral administration of the antihistaminic methapyrilene hydrochloride.

The antihistaminic drug methapyrilene hydrochloride, which induces liver tumors in rats, was administrated orally to female Wistar rats. The animals were killed after 21, 38, 77, 119, 181, and 196 days. The activities of adenosine-5-triphosphatase (ATPase) and gamma-glutamyltranspeptidase (gamma-GT) in the liver were investigated histochemically. At 21 days, a homogeneous decrease of ATPase activity as well as a slight increase of gamma-GT activity was found in the periportal zone. Additionally, after 38 days hepatocellular foci with reappearance of gamma-GT occurred mainly in the periportal zone. After 119 days, foci with increased gamma-GT activity as well as a significant reduction of ATPase activity could be observed predominantly in the periportal region. The size and number of these putative preneoplastic foci were increased according to the time of administration of methapyrilene hydrochloride. After 181 days of methapyrilene hydrochloride treatment three of five animals developed hyperplastic nodules with corresponding alterations of enzyme activities. Methapyrilene hydrochloride-a carcinogen with an unknown mechanism of reaction-produces preneoplastic changes that are analogous to the well known preneoplastic lesions in the liver observed after administration of other carcinogenic agents.

Adenosine Triphosphatases↗
PubMed1989

Effects of a sedative and of a non-sedative H1-antihistamine on the event-related potential (ERP) in normal volunteers.

Measurements of the amplitude and latency of the P3b component of the event-related potential (ERP), simple reaction time (SRT) and four psychomotor tests (VAS, DSST, DSp and CFF) were made on 12 male subjects (aged 19-24 years) 1.0-1.5 and 4.0-4.5 h after single oral doses of triprolidine (7.5 mg), terfenadine (60 mg) and placebo. Neither triprolidine nor terfenadine changed P3b amplitude or latency although VAS, CFF and DSST scores were significantly altered by triprolidine at 1.0-1.5 h after dosage. These results suggest that the P3b is too robust to reflect the mild sedative properties of an H1-receptor antihistamine, or that H1-receptors are not involved in P3b generation.

Adult↗
PubMed1988

The influence of antihistamines on human performance.

We have studied the effects of three antihistamines on task performance in two separate experiments. Healthy subjects were tested at weekly intervals in a double-blind, Latin square design. In Experiment I the subjects were treated orally with loratadine 10 mg, clemastine 1 mg, terfenadine 60 mg, or placebo. In Experiment II 5 mg diazepam was given orally with each of the four treatments used in Experiment I. In both experiments subjects' performance was evaluated in reaction time and tracking tasks after treatment. In both experiments, the tracking task initially was performed alone and then simultaneously with a continuous memory task; the subject also graded their mental status on visual analogue rating scales. In both experiments task performance was not generally impaired after treatment with loratadine or terfenadine. The concomitant administration of diazepam in Experiment II appeared not to affect subjects' performance. However, clemastine caused a decay in subjects' performance in both Experiments I and II, but only on the tracking task. At the conclusion of both experiments, sleepiness was reported by more subjects when treated with clemastine than when treated with loratadine, terfenadine, or placebo.

Administration, Oral↗
PubMed1987

Antihistamine activity and central effects of WAL 801 CL in man.

The tolerability and antihistaminic activity of WAL801 CL, a new, peripherally acting H1-receptor antagonist, have been evaluated in a double-blind, placebo-controlled, within-subject cross-over study. WAL801 CL 8 mg b.d. was given to 10 healthy volunteers for 15 days. It resulted in a distinct reduction in histamine wheal size and a decreased bronchoconstrictor response to histamine inhalation. No cardiovascular side effects were observed. Transient and slight fatigue was observed in 3 subjects. Psychological tests, such as simple visual reaction time, critical flicker fusion frequency and mood self rating scale, showed that WAL801 CL had no sedative side effects and that it did not alter psychomotor performance.

Adult↗
PubMed1992

Lack of pharmacodynamic and pharmacokinetic interactions of the antihistamine ebastine with ethanol in healthy subjects.

We have given 12 healthy subjects the H1-antihistamine ebastine (20 mg) or placebo in a double-blind, crossover study for one week each. The subjects were tested for drug effects on Day 6 of each period, and for interactions of ebastine with ethanol (0.8 g.kg-1) on Day 7. On both days, the testing runs were done at baseline and at 2, 4, and 6 h after the drug. Performance was evaluated both objectively (digit symbol substitution, flicker fusion, Madox wing, nystagmus, simulated driving, body balance) and subjectively (visual analogue scales) and with questionnaires. Venous blood samples were taken daily during maintenance and during each test run for assay of plasma carebastine. Blood ethanol concentrations were assayed with an Alcolmeter in the breath and directly in the blood. Plasma carebastine concentration reached a steady-state from Day 3 on; the mean concentrations in the morning were 92 micrograms.l-1 on Day 6 and 104 micrograms.l-1 on Day 7. The rise in plasma carebastine after an extra 20 mg of ebastine was accelerated but not increased by ethanol. Ebastine did not impair performance objectively or subjectively. It slightly improved body balance and reduced errors during simple tracking at 4 h. Blood ethanol concentrations peaked (mean 0.76 g.l-1) at 1.5 h after ethanol intake. Ethanol impaired performance in most objective tests and produced clumsiness, muzziness, and mental slowness, but little drowsiness. Ebastine neither modified the blood ethanol concentrations nor increased the effects of ethanol.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1979

Inhibition of diamine oxidase by antihistaminic agents and related drugs.

Various drugs were tested as inhibitors of diamine oxidase on the basis of chemical relationships to the enzyme substrates. It was found that serotonine tryptamine and phenformin are good competitive inhibitors while cimetidine and pheniprazine are non-competitive inhibitors. Other antihistaminic drugs like promethazine are less powerful inhibitors.

Amine Oxidase (Copper-Containing)↗
PubMed1984

H2-antihistaminics. 20. Structure-activity relationships in H2-receptor antagonists containing a 4-pyrimidone moiety.

In a series of 5,6-substituted 4- pyrimidones 1 a-v the H2-antihistaminic activity was determined (guinea-pig atrium) and lipophilicity data are given in form of Rmo -values. The influence of different substituents at position 5 or 6 of a pyrimidone moiety has been studied. Quantitative structure-activity analyses showed the importance of lipophilicity for drug activity. Additionally other physicochemical substituent-properties may play a major role.

Animals↗
PubMed1985

Dual effect of antihistamines on rat peritoneal mast cells: induction and inhibition of histamine release.

A variety of H1- and H2-receptor agonists and antagonists are shown to have a dual effect on isolated rat peritoneal mast cells. At high concentrations the drugs induce histamine release while at low concentrations they inhibit the secretion of the amine evoked by antigen. These effects do not appear to be directly related. The ability of the H1-antagonists to inhibit histamine release does not appear to correlate in simple fashion with their recorded pA2 values as measured on the guinea pig ileum, suggesting that the effect is not mediated through H1-receptors. These results are discussed in terms of the clinical utility of antihistaminic drugs.

Anaphylaxis↗
PubMed1993

Influence of epithelial removal on the antihistaminic activity of azelastine in the guinea-pig airway smooth muscles.

The influence of epithelial removal on the antihistaminic activity of azelastine in the guinea-pig isolated cervical trachea and main bronchus was examined. In both preparations with an intact epithelium, histamine produced a concentration-dependent contraction, but its potency (pD2) and contractility (Emax) were significantly higher in the main bronchus than in the cervical trachea. Epithelial removal from these preparations significantly increased the pD2 values in both tracheal and bronchial preparation, while the Emax value was significantly increased only in the cervical trachea. When these preparations were pretreated with azelastine (20 or 200 nM), concentration-response curves for histamine shifted downward, but were not influenced by the presence of an intact epithelium. Neither concentration of azelastine significantly modified the contractile responsiveness of tracheal and bronchial preparations to carbachol or neurokinin A. These results indicate that azelastine selectively antagonizes the histamine-induced contraction of the guinea-pig airway smooth muscles with or without an intact epithelium.

Animals↗
PubMed1986

Effects of antihistamines on isolated mast cells from the rat, guinea pig and man.

The effects of a range of antihistamines and related compounds on mast cells from a number of different locations have been investigated. The drugs had a dual action on all the cell types examined: at high concentrations they induced histamine release while at low concentrations they inhibited the secretion of the amine evoked by antigen. The relative potencies of the various compounds in both evoking and preventing histamine release varied from one mast cell to another. In total, these studies then further emphasise the functional heterogeneity of mast cells from different locations.

Anaphylaxis↗
PubMed1994

Effect of the antihistaminic drug Bromadryl on ex vivo platelet functions during gestation in rats.

The effect of the antihistaminic drug Bromadryl on stimulated platelet aggregation was studied in pregnant rats. Bromadryl was administered orally in doses 1, 5 and 10 mg/kg from day 2 to day 19 of gestation. On day 20 of gestation blood samples were taken and the aggregation of platelets was measured after stimulation with 9 different concentrations of ADP in the concentration range 0.2 to 100 mumol/l. During gestation, platelet aggregation was significantly increased in comparison to non-pregnant controls. This was indicated in pregnant rats by the increased maximum amplitude of the aggregation curve as well as by the decreased mean effective concentration of ADP. The treatment of dams with Bromadryl during pregnancy resulted in decreased platelet aggregation. The dose-dependent inhibitory effect of the drug was more pronounced at higher stimulus concentrations. The presented results confirmed the antiplatelet activity of Bromadryl observed previously in vitro.

Adenosine Diphosphate↗
PubMed1988

The effect of a new antihistamine drug, Loderix (EGIS-2062), on stimulus-evoked histamine release from rat peritoneal mast cells.

The ability of a new, non-sedative antihistamine drug, Loderix (EGIS-2062), to inhibit stimulus-evoked histamine release from rat peritoneal mast cells has been investigated and compared with that of ketotifen (Zaditen). At low concentrations Loderix preincubated with the cells for 10 min prior to the addition of various stimulants (immune aggregates, ionophore A23187 and compound 48/80) produced a concentration-dependent inhibition of histamine release, while at high concentrations it induced the release of histamine. The IC50 values were calculated as 0.2, 15 and 50 microM by using immune aggregate, (rat IgG2 alpha + anti rat IgG) calcium ionophore and 48/80 as stimulants, respectively. At the IC50 level Loderix was more effective than Zaditen (100 times more effective when immune aggregate and 4 times when 48/80 were used for stimulation). Both drugs had a dual effect on mast cells. The morphological observations confirmed the pharmacological action of the drugs, showing also that the histamine release at high concentrations is due to their cytotoxic effect.

Animals↗
PubMed1988

Teratological and cytogenetical evaluation of two antihistamines (pipethiadene and pizotifen maleate) in mice.

The teratogenic and cytogenetic effects of two drugs with antihistamine properties, Pipethiadene and Pizotifen maleate, were investigated. Three groups of pregnant mice were treated daily with oral doses (0.24, 0.6 and 1.2 mg/kg) of these drugs from day 4 to day 16 of gestation. The following parameters were investigated: reproductive health of the dams, external, skeletal and visceral malformations of fetuses and frequencies of micronuclei and chromosome aberrations in bone marrow cells of dams. Oral administration of Pipethiadene or Pizotifen maleate produced no teratogenic effects. No elevation was observed in the frequencies of micronuclei and chromosome aberrations. However, the significant reduction of fetal weight after all doses of Pipethiadene or Pizotifen maleate was found to correlate well with the decreased values of the mitotic indices of bone marrow cells of mice, suggesting a potential embryotoxic effect of the tested substances.

Animals↗