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PubMed2006

The antioxidative and antihistaminic effect of Nigella sativa and its major constituent, thymoquinone on ethanol-induced gastric mucosal damage.

The aim of this study was to assess the possible protective effects of Nigella sativa (NS) and its constituent, thymoquinone (TQ) on ethanol-induced gastric mucosal damage in an experimental model. Forty male rats aged four months were divided into four groups (each group containing ten animals); the control group received physiologic saline (10 ml kg(-1)) and the ethanol group had taken 1 ml (per rat) absolute alcohol by gavage. The third and fourth groups also received NS (500 mg kg(-1)) and TQ (10 mg kg(-1)) by gavage 1 h before alcohol administration, respectively. Both drugs (NS and TQ) could protect the gastric mucosa against the injurious effect of absolute alcohol and promote ulcer healing as evidenced from the ulcer index values. Gastric damage was confirmed histomorphometrically by significant increases in the number of mast cells (MC) and gastric erosions in ethanol treated rats. The NS treatment significantly decreased the number of MC and reduced the area of gastric erosions. Likewise, TQ treatment was also able to reduce the number of MC and the gravity of gastric mucosal lesions, but to lesser extent compared to NS. Gastric tissue histamine levels and myeloperoxidase activities were found to be increased in ethanol treated rats, and NS or TQ treatment reversed these increases. Results obtained from this study suggest that both drugs, particularly NS could partly protect gastric mucosa from acute alcohol-induced mucosal injury, and these gastroprotective effects could be due to their antiperoxidative, antioxidant and antihistaminic effects.

Animals↗

PubMed2006

Stimulating effects of the antihistamine fexofenadine: testing the dopamine transporter hypothesis.

RATIONALE: First- and second-generation antihistamines are known to produce different degrees of sedation. However, a few studies have shown that the H1-antagonist fexofenadine produces mild stimulating effects. One hypothesis suggests that this is due to fexofenadine producing an increase in dopamine levels by blocking the dopamine transporter. OBJECTIVE: In this study, it was investigated whether a high dose of fexofenadine blocks the dopamine transporter in the striatum. In addition, the effect of fexofenadine on cognitive performance and motor impulsivity was investigated. METHODS: Sixteen healthy subjects were given either placebo or fexofenadine 360 mg. The binding potential of N-w-fluoropropyl-2beta-carbomethoxy-3beta-[4-iodophenyl] nortropane ([123I]FP-CIT) was measured using single-photon emission computed tomography (SPECT). Cognitive performance was measured in 40 subjects (20 placebo, 20 fexofenadine) using a digit symbol substitution test (DSST) and a stop signal task. In addition, subjective and physiological effects of fexofenadine were observed. RESULTS: The SPECT data demonstrated that there was no difference in the binding potential of FP-CIT at the dopamine transporter in the striatum between the placebo- and fexofenadine-treated subjects. The behavioral results showed that fexofenadine improved performance on the DSST at T (max) of the drug. Fexofenadine did not affect motor impulsivity, subjective experience, or physiological measures. CONCLUSION: No evidence was provided to support the hypothesis that fexofenadine stimulates performance by blocking the dopamine transporter. The behavioral data suggest that a high dose of fexofenadine can stimulate performance in cognitive tasks.

Adult↗

PubMed2004

Development of an HPLC method for the identification and dosage of non-allowed substances in cosmetic products. Part I: local anaesthetics and antihistaminics.

An HPLC method with ultraviolet detection coupled with a solid-phase extraction sample clean up was developed for the analysis of five local anaesthetics and four antihistaminics in cosmetic products. The presence of these compounds in commercial cosmetic samples is fordbidden. Extracts from real samples were applied to a solid-phase extraction C18 cartridge, and the analytes were eluted with 8:2 (v/v) acetonitrile/water containing 1% trifluoroacetic acid. HPLC separation was then performed for the identification and determination of the analytes using a Purospher RP-18 column, two gradient eluting systems and a photodiode-array detector. The accuracy of the method was verified by spiking experiments on home-made cosmetic samples. The analytical recoveries were satisfactory.

Anesthetics, Local↗

PubMed2000

Metabolism of the ethanolamine-type antihistamine diphenhydramine (Benadryl) by the fungus Cunninghamella elegans.

Two strains of the filamentous fungus Cunninghamella elegans (ATCC 9245 and ATCC 36112) were grown in Sabouraud dextrose broth and screened for the ability to metabolize the ethanolamine-type antihistamine diphenhydramine. Based on the amount of parent drug recovered after 7 days incubation, both C. elegans strains metabolized approximately 74% of the diphenhydramine, 58% of this being identified as organic extractable metabolites. The organic extractable metabolites were isolated by reversed-phase high-performance liquid chromatography and identified by analyzing their mass and nuclear magnetic resonance spectra. Desorption chemical ionization mass spectrometry (DCIMS) with deuterated ammonia was used to differentiate possible isobaric diphenhydramine metabolites and to probe the mechanisms of ion formation under ammonia DCIMS conditions. C. elegans transformed diphenhydramine by demethylation, oxidation, and N-acetylation. The major metabolites observed were diphenhydramine-N-oxide (3%), N-desmethyldiphenhydramine (30%), N-acetyldidesmethyldiphenhydramine (13%), and N-acetyl-N-desmethyldiphenhydramine (12%). These compounds are known mammalian metabolites of diphenhydramine and may be useful for further toxicological studies.

Chromatography, High Pressure Liquid↗

PubMed1985

Antihistamines and highway safety.

Available evidence that antihistamine-induced impairment of human psychomotor performance constitutes a traffic hazard is reviewed against a set of criteria which could theoretically be applied to any drug or group of drugs. Two distinct classes of histamine antagonists, which act at different receptors (H1 and H2) are now available and they should be considered separately. H1-Antagonists are freely available to the public and are consumed in enormous quantities. They are a rather heterogeneous group of drugs which share the common property of antagonising some of the effects of histamine. Other effects, particularly sedation, are prominent with many of the older members of the group and these drugs can be shown to impair performance in laboratory tasks and to interact additively with alcohol and other central nervous system depressant drugs. Despite this potential for impairment of driving ability, they are seldom suggested as causative factors in traffic crashes. This may, of course, be due to inadequacy of reportage. A number of new histamine H1-antagonists have been developed recently which only gain limited access to the central nervous system and appear to be less likely to cause impairment of performance skills. Histamine H2-antagonists have a much more restricted and closely supervised use in medicine and of the two agents currently available (cimetidine and ranitidine), only cimetidine appears to pose traffic safety problems largely because of its ability to interfere with the metabolism of other drugs which depress the central nervous system. Appropriate prescribing should eliminate this problem.(ABSTRACT TRUNCATED AT 250 WORDS)

Automobile Driving↗

PubMed1976

Effect of antihistamines and chlorpromazine on the calcium-induced hyperpolarization of the Amphiuma red cell membrane.

1. It has previously been demonstrated that an increase in extracellular Ca2+ conce-tratio- induces a trandient increase in K+ permeability and associated hyperpolarization of the red cell membrane of the giant salamander, Amphiuma meand. This phenomenon is analogous to the Ca2+-induced KCl loss observed in ATP-depleted human red cells and red cell ghosts. 2. Histamine, which enhances the Ca2+-induced K+ loss from depleted human red cells, is without effect on this Ca2+-induced hyperpolarization of Amphiuma red cells. 3. Promethazine (10 muM) and mepyramine (1 mM), which inhibit the Ca2+-induced K+ loss in depleted human red cells, also block the Ca2+-related hyperpolarization of Amphiuma erythrocytes. 4. Chlorpromazine (25 muM), despite being a weak antihistamine, is equally effective in blocking the Ca2+-induced hyperpolarization of Amphiuma red cells. 5. Ionophore A23187 causes a large and sustained Ca2+/K+-dependent hyperpolarization even in the presence of normal (1.8 mM) concentrations of Ca2+. This hyperpolarization is relatively insensitive to chlorpromazine and promethazine. 6. The inhibition of the Ca2+-induced hyperpolarization of the Amphiuma red cell membrane by chlorpromazine and promethazine may berelated to their properties as local anaesthetics.

Animals↗

PubMed1980

Histamine H1-receptors labeled in vivo: antidepressant and antihistamine interactions.

3H-Mepyramine labels specific histamine H1-receptors in brains of mice after intravenous injection. The potencies of H1-antihistamines in reducing 3H-mepyramine binding in vivo correspond to their pharmacological activities and show parallels with their affinities for 3H-mepyramine binding sites in isolated brain membranes. Several antidepressants are potent in competing for 3H-mepyramine binding in vivo as well as in vitro.

Animals↗

PubMed1986

Selective displacement of [3H]mepyramine from peripheral vs. central nervous system receptors by loratadine, a non-sedating antihistamine.

Displacement of [3H]mepyramine binding was compared in membranes from guinea-pig lung vs. cerebral cortex as a measure of affinity for peripheral vs. central nervous system (CNS) histamine receptors. Loratadine, a new non-sedating antihistamine, was found to be the only compound tested which was selective for lung (Ki = 35 nM) vs. cortex (Ki = 118 nM). This difference is statistically significant (P less than 0.05) whereas there was no significant (P greater than 0.05) difference in the Kis between the 2 tissues for terfenadine, astemizole, mequitazine or chlorpheniramine. It is concluded from these and other studies that the lack of significant sedative effects shown with loratadine is due to its poor penetration into the CNS and selectivity for peripheral histamine receptors.

Aminopyridines↗

PubMed1987

Two populations of neurotensin binding sites in murine brain: discrimination by the antihistamine levocabastine reveals markedly different radioautographic distribution.

Monoiodo-[125I-Tyr3]neurotensin (NT) bound to a high affinity, low capacity binding component and a lower affinity, high capacity component in rat brain synaptic membranes. The antihistamine H1 agent levocabastine, which bears no structural relationship to NT, selectively and totally inhibited NT binding to its low affinity binding sites. The IC50 for levocabastine was 7 nM. Lowering the temperature of the binding assay from 25 to 4 degrees C markedly reduced the affinity of the high affinity NT binding site but did not affect the ability of levocabastine to discriminate between high and low affinity NT binding sites in rat brain membranes and tissue sections. Radioautographic studies of [125I-Tyr3]NT binding to rat brain tissue sections in the absence and presence of levocabastine revealed markedly different regional distributions of the two NT binding components. The levocabastine-sensitive NT binding site was present in membranes from rat and mouse brain but absent from rabbit brain membranes and from human brain tissue sections. It was also absent from mouse neuroblastoma N1E115 and human colonic adenocarcinoma HT29 cell membranes, two cell lines which have previously been shown to possess NT receptors functionally coupled to intracellular second messenger-generating systems. These findings are discussed in the light of the known properties of the high and low affinity NT binding sites in rat brain.

Animals↗

PubMed1995

Cross-generalization between a cocaine cue and two antihistamines.

Rats were trained to discriminate between 10 mg/kg cocaine and saline injections under a fixed ratio 10 schedule of food-motivated lever press responding. Once stimulus control was achieved, reinforced test sessions were conducted to assess the degree of generalization of a wide range of cocaine doses and the cross-generalization between the cocaine training stimulus and two over-the-counter antihistaminic drugs, diphenhydramine and doxylamine, when administered with saline or in drug combinations. Cocaine produced a dose-dependent generalization to the 10 mg/kg training stimulus. Cocaine also produced mild rate-increasing effects at low test doses and response rate suppression at higher doses. Both diphenhydramine and doxylamine produced a partial generalization to the 10 mg/kg cocaine training stimulus. Drug mixtures produced complete cross-generalization with the training cue.

Animals↗

PubMed1996

Cutaneous antihistaminic action of cetirizine and dose-related EEG concomitants of sedation in man.

The cutaneous antihistaminic action (prick test; 1:100, 1:200 and 1:1000) and neuropsychological and electroencephalographic (EEG) concomitants of sedation following the histamine H1 receptor antagonist cetirizine (10- and 20-mg acute oral doses) and chlorpheniramine, 4 mg, were investigated in a cross-over, placebo-controlled study in healthy male volunteers (age 23-29 years). With an average Cmax of cetirizine of 697.0 ng/ml (10 mg) and 1000.2 ng/ml (20 mg), the diameter of histamine-induced skin weals was reduced by 24.0-74.9% depending on histamine concentration and with no dose dependence for cetirizine. Placebo and chlorpheniramine were ineffective. Behavioral or neuropsychological signs of sedation were never observed. An increase of the 6.5-14.5 Hz EEG power, with anterior scalp preponderance, was observed after chlorpheniramine or cetirizine 20 mg. This effect of cetirizine was accounted for by a substantial increase of power in the 6.5-8.0 Hz frequency subsegment and is regarded, for these experimental conditions, as an established early EEG indication of mild sedation (vigilance 'state A'). No EEG effects were observed after placebo or cetirizine at the 10 mg dose. The existence of some histaminergic (H1) specificity of the mechanisms modulating vigilance and of a threshold dose of cetirizine for sedative action is suggested.

Administration, Oral↗

PubMed1995

Investigation of the stereoselective metabolism of the chiral H1-antihistaminic drug terfenadine by high-performance liquid chromatography.

The enantiomers of the racemic H1-antihistaminic drug terfenadine (1) have been resolved by fractional crystallization of the diastereomeric salts with optically active 2-chlorotartranilic acid. The enantiomeric excess of both terfenadine enantiomers was determined using an achiral and a chiral HPLC system after formation of diastereomers with S-(+)-naphthylethylisocyanate. To investigate the metabolism of terfenadine after oral administration, an achiral HPLC system, equipped with a conventional reversed-phase column, was used to quantify the main metabolite MDL 16.455 (2) in human serum and urine. The determination of the enantiomeric composition of 2 was achieved using an Ultron ES-OVM column as chiral stationary phase. Metabolite 2, extracted from human blood plasma, was found to be enriched in the R-enantiomer, but was excreted in urine as racemate. The results of a study including six volunteers are presented.

Chromatography, High Pressure Liquid↗

PubMed1996

Quantitative structure-retention relationships in the examination of the topography of the binding site of antihistamine drugs on alpha 1-acid glycoprotein.

Quantitative relationships between the structure of antihistamine drugs (AHD) and their retention on an alpha 1-acid glycoprotein (AGP) HPLC column (QSRR) were studied in order to identify characteristic structural features of the binding site for AHD on AGP. The hydrophobicity of AHD was determined by HPLC on an immobilized artificial membrane (IAM) column. A highly significant QSRR equation was obtained which describes the retention of AHD on AGP in terms of the chromatographically determined hydrophobicity parameter, electron excess charge on the aliphatic nitrogen and a molecular size descriptor. The topography of the AHD-binding site on AGP was suggested to be a conical pocket with lipophilic regions at the mouth of the receptor and an anionic region close to the spike of the cone. Protonated aliphatic nitrogen is supposed to guide a drug molecule towards the anionic region of the binding site. Hydrophobic aryl moieties provide anchoring of the molecule in the lipophilic regions of the binding site. Steric hindrance prevents the molecule from plunging into the binding site.

Binding Sites↗

PubMed1992

The suppression of olfactory bulbectomy-induced muricide by antidepressants and antihistamines via histamine H1 receptor blocking.

The effects of antidepressants [(+)-oxaprotiline, (-)-oxaprotiline, imipramine, maprotiline, and trazodone] and antihistamines (mepyramine, dimethindene, ketotifen, methapyrilene, and antazoline) on muricidal behaviour in olfactory bulbectomized rats were investigated. All drugs except for dimethindene, which only minimally passes across the blood-brain barrier, suppressed muricide. The drugs which have high affinity for histamine H1 receptor showed potent suppressive effect on muricide. It is suggested that the central histaminergic system is involved via H1 receptors in the expression of muricide in olfactory bulbectomized rats.

Aggression↗

PubMed1983

An enhancing effect of the antihistaminic drug methapyrilene on rat liver carcinogenesis by previously administered N-2-fluorenylacetamide.

The effect on hepatocarcinogenesis of sequential administration of the antihistaminic drug methapyrilene (MP) or the typical liver tumor promoter, phenobarbital (PB), each given after the genotoxic liver carcinogen, N-2-fluorenylacetamide (FAA) was studied. An initial exposure to 0.02% of FAA in the diet for 8 weeks was used to produce hepatocellular altered foci. Rats maintained for an additional 24 weeks on basal diet developed a low incidence of liver neoplasms. MP at 500 and 1000 ppm in the diet for 24 weeks after FAA increased the frequency of altered foci at early stages and liver neoplasms later, as did PB. Neither MP nor PB alone produced neoplasms, but MP alone produced a significant incidence of altered foci. Therefore, the results provide evidence for a promoting action of MP, but additional effects may be involved in its carcinogenicity.

2-Acetylaminofluorene↗

PubMed1984

Neoplastic conversion in rat liver by the antihistamine methapyrilene demonstrated by a sequential syncarcinogenic effect with N-2-fluorenylacetamide.

A study was performed to determine whether the enhancing effect of the antihistamine methapyrilene (MP) in rat liver carcinogenesis represents promotion or syncarcinogenesis . The effect on hepatocarcinogenicity induced by N-2-fluorenylacetamide (FAA) of sequential administration of MP given either before or after FAA was studied in comparison with diethylnitrosamine (DEN) also given either before or after FAA. MP in either sequence with FAA enhanced liver carcinogenicity as did DEN. Moreover, MP by itself induced liver altered foci, albeit at a high dose for a prolonged interval. A single liver neoplasm occurred with exposure to MP alone. These findings suggest that MP produces neoplastic conversion of liver cells which can be summated with the genotoxic effect of FAA to produce syncarcinogenesis .

2-Acetylaminofluorene↗

PubMed1988

Loratadine, an antihistamine, blocks antigen-and ionophore-induced leukotriene release from human lung in vitro.

Some H1-antihistamines possess anti-allergic properties, and inhibit the immunological release of mediators including histamine and sulfiopeptide-leukotrienes (slow reacting substance of anaphylaxis) from lung. The effects of the antihistiamine loratadine, SCH29851, on the release of leukotrienes and histamine from human lung fragments were measured, using the calcium ionophore A23187 and an extract of antigen from Dermatophagoides pteronyssinus, house dust mite, (with passively sensitized lung) as releasing agents. Loratadine (1-20 microM) inhibited the release of leukotrienes in a concentration-dependent manner when release was induced by calcium ionophore from lung specimens from 8 subjects, and also when release was induced by antigen from lung specimens from 7 subjects. Histamine release was unaffected by these concentrations of loratadine in both types of experiment.

Antigens↗

PubMed1982

Further analysis of the specificity of a novel animal model of depression--effects of an antihistaminic, antipsychotic and anxiolytic compound.

In previous papers we reported that chronic stress elicited reductions in selected forms of open field activity resembled endogenomorphic depression upon behavioral, motivational, neuroendocrine, and neuropharmacological grounds. In particular, the loss of acute stress elicited activity proved to be exclusively reversible by antidepressant treatments. Insofar as clinically ineffective compounds were tested, the deficit proved refractory to treatment, further suggesting the model reflected just those processes which were disrupted in depression. A number of ineffective compounds are known to yield false positives upon other related tests, but have yet to be examined in the present model. Three such compounds, an antihistamine (tripelennamine), a neuroleptic (haloperidol), and an anxiolytic (oxazepam) were examined for their behavioral and neuroendocrine effects. Although other stress related phenomena were replicated, none of the above compounds was effective in restoring the activation deficit or in eliminating the endocrine abnormality. This suggests the depression model is relatively selective pharmacologically and not critically dependent upon receptor blocking properties of the above drugs.

Animals↗