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PubMed1993

AOA's current trends in pharmacology and therapeutics histamine and antihistamine agents.

BACKGROUND: Drugs that selectively block the H-1 subtype of histamine receptors are known as classical antihistamines. METHODS: These agents are used for the symptomatic relief of allergies and colds and because they act in a manner similar to atropine, and are often used for their anticholinergic effects. They are readily available as prescription and over-the-counter medications and it is likely that the practicing optometrist will encounter these drugs in their patient population. RESULTS: Antihistamines produces several common ocular side effects that include blurred vision, diplopia, mydriasis, and decreased lacrimation. CONCLUSIONS: This article reviews the physiology of histamine as it relates to the pharmacology of antihistamines, the mechanism of action, and adverse effects associated with the classical antihistamines.

Contraindications↗
PubMedDate not supplied

Effects of E-4716, a new antihistaminic with antiallergic properties, on chemical mediators induction of immunologic reactions.

The effects of E-4716 on chemical mediators were compared with those of classical antihistaminics and other second generation (nonsedating) drugs normally used in the therapy of allergic reactions, such as astemizole, terfenadine and ebastine, in a series of in vitro and in vivo tests. In vitro, antihistaminic activity was demonstrated in a test on isolated organs and a binding test on histamine receptors, with no anticholinergic activity observed. A high antihistaminic activity was also shown in in vivo tests on chemical mediators release by compound 48/80, histamine-induced bronchospasm in anesthetized guinea pigs and histamine-induced cutaneous reaction in beagle dogs. The antiallergic activity was studied in passive cutaneous anaphylaxis test using ovalbumin antibodies. Astemizole and E-4716 had similar activities with ED50 values of 0.8 and 0.5 mg/kg, respectively, whereas terfenadine (ED50 = 4.5) was less active. E-4716 also inhibited the vascular permeability response in histamine-stimulated conjunctivitis model after topical ocular administration (ED50 = 0.002, 0.0002, 0.015 and 1.2% at 30 min and 6, 12 and 24 h, respectively). E-4716 had a high and selective antihistaminic and antiallergic activity by all routes of administration (oral, i.v., i.p., topical ocular and inhalation). These results, combined with its low toxicity and lack of central effects, indicate that E-4716 has excellent potential for therapeutic use.

Administration, Inhalation↗
PubMed2006

A structure-activity relationship study of compounds with antihistamine activity.

A structure-activity relationship (SAR) analysis of H(1)-, H(2)- and H(3)-antihistamine activity was carried out and chromatographic data of 2-[2-(phenylamino)thiazol-4-yl]ethanamine, 2-(2-benzyl-4-thiazolyl)ethanamine, 2-(2-benzhydrylthiazol4-yl)ethanamine, 2-(1-piperazinyl- and 2-(hexahydro-1H-1,4-diazepin-1-yl)benzothiazole, 2-(1-piperazinyl)benzothiazole, 2-[4-(1-alkyl)piperidinyl]benzothiazole, 2-(N,N',N'-dimethylalkyl-1,2-ethanediamino)benzothiazole, 2[1-(4-aminopiperidinyl)]benzothiazole, 2-[2-phenyl-4-thiazolyl]ethanamine derivatives and selected H(1)- and H(2)-antihistamine drugs were obtained. NP TLC and RP2 TLC plates (silica gel NP 60F(254) and silica gel RP2 60F(254) silanized precoated), impregnated with a solution of aspartic acid (L-Asp) and a solution of an analogue of aspartic acid (propionic acid), were used in two developing solvents as H(1)-, H(2)- and H(3)-antihistaminic interaction models. The lipophilicity data of the examined compounds were obtained and used in the SAR assay. Biochromatographic tests using TLC plates impregnated with solutions of asparic acid or propionic acid were found to be a source of useful data for the qualitative analysis of compounds with different structures, demonstrating activity to histamine H(1)-, H(2)- and H(3)-receptors. The four presented discriminant models based on biochromatographic studies are an efficient tool in the SAR analysis for initial prediction of compound activity direction within histamine receptors.

Benzothiazoles↗
PubMed2003

P-glycoprotein influences the brain concentrations of cetirizine (Zyrtec), a second-generation non-sedating antihistamine.

Recent in vitro studies have suggested that P-glycoprotein (Pgp) and passive membrane permeability may influence the brain concentrations of non-sedating (second-generation) antihistamines. The purpose of this study was to determine the importance of Pgp-mediated efflux on the in vivo brain distribution of the non-sedating antihistamine cetirizine (Zyrtec), and the structurally related sedating (first-generation) antihistamine hydroxyzine (Atarax). In vitro MDR1-MDCKII monolayer efflux assays demonstrated that cetirizine was a Pgp substrate (B-->A/A-->B + GF120918 ratio = 5.47) with low/moderate passive permeability (PappB-->A = 56.5 nm/s). In vivo, the cetirizine brain-to-free plasma concentration ratios (0.367 to 4.30) were 2.3- to 8.7-fold higher in Pgp-deficient mice compared with wild-type mice. In contrast, hydroxyzine was not a Pgp substrate in vitro (B-->A/A-->B ratio = 0.86), had high passive permeability (PappB-->A + GF120918 = 296 nm/s), and had brain-to-free plasma concentration ratios >73 in both Pgp-deficient and wild-type mice. These studies demonstrate that Pgp-mediated efflux and passive permeability contribute to the low cetirizine brain concentrations in mice and that these properties account for the differences in the sedation side-effect profiles of cetirizine and hydroxyzine.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1984

Comparative effects of selected phenothiazine tranquilizers and antihistaminics on bacterial cells and possible interactions with antibiotics.

Evaluation of the antibacterial effect of phenothiazine antihistaminics (trimeprazine, promethazine, and fonazine) and phenothiazine tranquilizers (promazine, chlorpromazine, triflupromazine, and propiomazine) on Staphylococcus aureus showed that tranquilizers were more active [minimum inhibitory concentration (MIC) 0.5-1.6 micrograms/mL] than antihistaminics (MIC greater than 1.6 micrograms/mL). The antibacterial activity was found to correlate with both the rate of adsorption of these drugs on the bacterial cells and the surface tension of their solutions. Phenothiazine tranquilizers caused rapid and extensive leakage of potassium ions from bacterial cells, while phenothiazine antihistaminics produced relatively slower leakage of these ions. A study of the effect of the phenothiazines on the antibacterial activity of some antibiotics showed that all phenothiazines produced a synergistic effect with erythromycin and an antagonistic effect with tobramycin. Variable effects were observed with chloramphenicol, and no effect was observed with penicillin. Results were explained on the basis of structural characteristics of the phenothiazines.

Adsorption↗
PubMed1989

H1-antihistamines and calmodulin antagonists inhibit the ionophore A23187-induced eicosanoid formation by human leukocytes.

The effects of the H1-antihistamines astemizole, oxatomide and pyrilamine, of the calmodulin antagonists trifluoperazine and N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7), on the ionophore A23187 (5 mumol/l)-induced release of cysteinyl-leukotrienes (LT) and thromboxane (TX) B2 from mixed human leukocytes were investigated in comparison to those of the cyclooxygenase inhibitor indomethacin and the lipoxygenase inhibitor nordihydroguaiaretic acid (NDGA). In contrast to pyrilamine both astemizole and oxatomide inhibited the release of cysteinyl-LT and TXB2 with IC50 values between 4 and 23 mumol/l. Both astemizole and oxatomide were about twice as effective in inhibiting cysteinyl-LT release as compared to TXB2 release. Similar to astemizole and oxatomide the calmodulin antagonists trifluoperazine and W-7 inhibited the eicosanoid release. W-7 was, however, clearly less effective and in contrast to trifluoperazine no difference was observed in its potency to inhibit cysteinyl-LT or TXB2 release. The H1-antihistamines, astemizole and oxatomide as well as the calmodulin antagonists did not cause intracellular retention of the eicosanoids tested. The reference compounds indomethacin and NDGA proved to be the most potent inhibitors. The results demonstrate that the therapeutic antihistamines astemizole and oxatomide as well as the classical calmodulin antagonists trifluoperazine and W-7 are able to inhibit eicosanoid formation.

Astemizole↗
PubMed1993

Differential modification of the rewarding effects of methamphetamine and cocaine by opioids and antihistamines.

We previously reported that the reinforcing effects of opioids are enhanced in combination with antihistamines. In the present study, effects of opioids and antihistamines on the reinforcing effects of psychostimulants such as methamphetamine and cocaine were investigated by utilizing the conditioned place preference procedure in rats. The place preference induced by methamphetamine was enhanced in combination with either morphine or chlorpheniramine, which produced additive and potentiative effects, respectively. In contrast, although the preference for cocaine was also enhanced by combination with these two drugs, morphine caused a potentiative effect and chlorpheniramine an additive one. In other words, the reinforcing effect of methamphetamine was differentially enhanced by opioids and antihistamines as compared to that of cocaine. These results suggest that the mechanism of reinforcing effect of methamphetamine is different from that of cocaine, resembling rather those of opioids.

Animals↗
PubMed1996

Antihistamines and the common cold. A review and critique of the literature.

OBJECTIVE: To determine if antihistamines provided clinically significant relief from the symptoms of the common cold. METHODS: Structured literature review following standardized guidelines of primary studies published after 1975. MEASUREMENTS: Improvements in symptom scores for total symptoms and nasal symptoms over the first three days of a common cold. RESULTS: Three of five studies reporting on sneezing found a statistically significant improvement in the antihistamine group; similarly, three of seven studies reporting on nasal discharge found a statistically significant improvement with therapy. No study reported improvement in total symptom score at the level of p < .05. The validity of these findings was weakened by several flaws in the literature such as inattention to clinical significance and functional impact, inappropriate use of statistical tests, and poorly described methodology. The clinical significance of these improvements was not demonstrated. CONCLUSIONS: The primary literature offers little support for the use of antihistamines in the common cold.

Adult↗
PubMed2002

Inhibitory effects of H1-antihistamines on CYP2D6- and CYP2C9-mediated drug metabolic reactions in human liver microsomes.

OBJECTIVE: To screen the inhibitory effects of H1-antihistamines on hepatic bufuralol 1'-hydroxylation and on tolbutamide 4-methylhydroxylation in human liver microsomes. METHODS: Bufuralol 1'-hydroxylation and tolbutamide 4-methylhydroxylation were used as index reactions for CYP2D6 and CYP2C9, respectively. The metabolites of both reactions were measured using high-performance liquid chromatography and were used as indicators of whether CYP2D6 or CYP2C9 activities were inhibited or unaffected by the agents. RESULTS: All five H1-antihistamines studied showed a concentration-dependent inhibition of CYP2D6-mediated bufuralol 1'-hydroxylation with 50% inhibitory concentration (IC50) values of 32-109 microM. Cyclizine and promethazine showed inhibitory effects on tolbutamide 4-methylhydroxylation with IC20 values of 85 microM and 88 microM, respectively. Tripelennamine, chlorpheniramine, and diphenhydramine showed no inhibitory effects on CYP2C9. CONCLUSION: All five H1-antihistamines studied inhibited CYP2D6 markedly, but only cyclizine and promethazine inhibited CYP2C9 at concentrations above that usually seen in plasma. Promethazine and chlorpheniramine inhibited CYP2D6 at concentrations that are very close to their therapeutic plasma concentrations. Further studies in humans, especially in poor metabolizers of CYP2D6, will be required to confirm these findings.

Aryl Hydrocarbon Hydroxylases↗
PubMed2006

Antimuscarinic actions of antihistamines on the heart.

Antimuscarinic side-effects, which include dry mouth, tachycardia, thickening of mucus possibly sedation, of the antihistamines limited the usefulness of these drugs. The advent of newer agents has reduced the sedative effect of the antihistamine. The data presented here show that one of the newest antihistamines, desloratadine, and a first generation drug, diphenhydramine, are both competitive inhibitors of muscarinic receptor mediated slowing of the heart as measured using a Langendorff preparation. Both agents have apparent sub-micromolar affinities for the muscarinic receptor. Two other agents, cetirizine and fexofenadine, do not interact with muscarinic receptors in the heart at the concentrations used in this study. Structural similarities of the drugs suggest that substitution of a group with a high dipole moment or charge on the side chain nitrogen decreases the binding with muscarinic receptors. We conclude that of the compounds tested fexofenadine and cetirizine have little or no interaction with muscarinic receptors.

Acetylcholine↗
PubMed2002

Sedation, cognition, and antihistamines.

First-generation antihistamines are well-known to cause subjective drowsiness. A myriad of studies has also been published that suggest a clear relationship between the use of these drugs and objective performance impairment. Although not all of the tests used in these studies have been validated, the data are fairly consistent, and suggest a difference between earlier (first-generation) sedating antihistamines and the newer (second-generation) nonsedating antihistamines.

Cognition↗
PubMed1990

Direct analysis of microbial extracts containing metabolites of ethylenediamine-type antihistamines via high-performance liquid chromatography-thermospray mass spectrometry.

The utility of high-performance liquid chromatography-thermospray mass spectrometry (HPLC-TSMS) for the characterization of the ethylenediamine-type antihistamines, pyrilamine, methapyrilene, tripelennamine, and thenyldiamine, and their methylene chloride-extractable microbial metabolites from a biological matrix is demonstrated. Typically, the [M + H]+ ion was detected as the base peak in the TS mass spectra of these compounds. The ethylenediamine-type antihistamine metabolites were detected in an extract of a fungal culture grown in the presence of 5 mg of the antihistamine. A detection limit of 200 ng was observed for the HPLC-TSMS analysis of pyrilamine.

Chromatography, High Pressure Liquid↗
PubMed1987

Effects of thiazinamium chloride and other antihistamines on phosphatidylcholine secretion in rat type II pneumocyte cultures.

Thiazinamium chloride (TCl) stimulated phosphatidylcholine secretion in cultures of adult rat type II pneumocytes in a concentration-dependent manner in the range 10(-9)-10(-6) M. At the optimal concentration, secretion was stimulated by 46% which is approximately half the stimulatory effect of the beta-agonists terbutaline and isoproterenol. TCl did not increase the rate of choline incorporation into cellular phosphatidylcholine or of lactate dehydrogenase release so its effect on secretion was not secondary to phosphatidylcholine synthesis or cell injury. Since TCl has antihistaminic properties, we examined the effects of other antihistamines. The H-1 antagonists promethazine, which is structurally similar to thiazinamium, and pyrilamine, which has a different structure, also stimulated secretion but the H-2 antagonist, cimetidine, did not. The effects of TCl and pyrilamine were additive to those of terbutaline, suggesting that the mechanisms of action of the antihistamines and the beta-agonist were different. Although we were unable to demonstrate an inhibitory effect of histamine itself on either basal or terbutaline-stimulated phosphatidylcholine secretion, it is possible that histamine plays a regulatory role in lung surfactant secretion.

Animals↗
PubMed1983

Inhibition of histamine-induced nasal symptoms by the H1 antihistamine chlorpheniramine maleate: demonstration of topical effect.

To study whether a histamine H1 receptor antagonist inhibits allergic rhinitis symptoms by a peripheral or a central mode of action 21 normal volunteers were challenged with 500 micrograms histamine chloride in the right nasal cavity on four occasions after bilateral pretreatment with an H1 antihistamine spray and a placebo spray in various combinations. The H1 antihistamine (chlorpheniramine maleate, 0.5 mg) significantly inhibited histamine-induced tickling (P less than 0.01), sneezing (P = 0.01) and discharge (P less than 0.01), but only when it was given on the same side as histamine. This is highly suggestive of a local effect on sensory nerve endings, which prompts further studies on the topical use of antihistamines in the nose.

Administration, Intranasal↗
PubMed1980

Antihistamine effect on synaptosomal uptake of serotonin, norepinephrine and dopamine.

The nature and specificity of the effect of histamine H1- and H2-receptor antagonists on the uptake of serotonin (5HT), norepinephrine (NE) and dopamine (DA) were studied in rat forebrain synaptosomes. Low concentrations (0.05-0.50 microM) of the H1-antagonist, pyrilamine, competitively inhibited 5HT uptake (Ki = 0.09 microM), had little effect on NE uptake and no effect on DA uptake. At the same concentrations, two other H1 antihistamines, promethazine and diphenhydramine, and two H2-antihistamines, metiamide and cimetidine, had no effect on 5HT or DA uptake. Diphenhydramine had a small inhibitory effect on NE uptake. It is concluded that at low concentrations, pyrilamine is a relatively selective and potent competitive inhibitor of 5HT uptake, an action which is uncharacteristic of several other antihistamines.

Animals↗
PubMed1983

Desensitization of the isolated guinea pig ileum to antihistaminic agents.

Guinea pig ileum developed in vitro a progressive desensitization to the antihistaminic agents mepyramine and benadryl. This desensitization had uncommon characteristics: (1) at the 6.5-9 h period of the experiments, it consisted only of a decreased rate of action of the drugs (1.66 fold and 2 fold increases in the 2 min Kb value of mepyramine and benadryl respectively), without variation in the equilibrium Kb values; (2) it was not a drug effect since control strips (strips exposed to the first dose of antihistaminic agent after 5.5 h in vitro) also showed a decreased rate of action of the drugs (1.58 fold and 1.6 fold increases in the 2 min Kb value of mepyramine and benadryl respectively), without variation in the Kbe values. The desensitization also did not depend on the bathing medium or on the amount of available histamine receptors. The only explanation of the desensitization is a slowing in the antihistaminic agent-receptor reaction either in its access stage or less probably in its interaction stage.

Animals↗
PubMed1992

Interference of antihistamines and anti-allergic drugs with antigen-induced paw edema in boosted and unboosted mice.

The protective effects of two antihistamines and two anti-allergic drugs against anaphylactic paw edema were studied in immunized animals that had or had not received a booster injection of antigen. The injection of 1 or 10 micrograms/paw ovalbumin induced acute paw edema of similar intensity in both groups. The antihistamine meclizine and the mixed anti histamine/anti-5-HT antagonist cyproheptadine reduced the anaphylactic reaction by 55 and 84% respectively, in non-boosted animals and were less effective against edema induced by 1 microgram antigen in boosted animals. The effectiveness of these drugs was also reduced when boosted mice were challenged with 10 micrograms antigen, where meclizine and cyproheptadine inhibited edema by 31 and 59%, respectively. The anti-allergic compounds ketotifen and azelastine, although effective against allergic inflammation in non-boosted mice, had a reduced or no effect in boosted mice. Our results suggest that allergic edema is less sensitive to antihistamine and anti-allergic drugs in boosted mice, which may be accounted for by an increased role of other mediators.

Analysis of Variance↗
PubMed1991

Determination of antihistamines in pharmaceuticals by capillary electrophoresis.

Capillary electrophoresis with on-column UV detection at 214 nm was used to separate a group of nine antihistamines. All these compounds were satisfactorily separated within ca. 6 min using a mixed carrier system containing sodium dodecyl sulphate with beta-cyclodextrin and tetrabutylammonium hydrogensulphate as modifiers. The application of the method to the determination of the amount of antihistamines present in commercial pharmaceutical samples was demonstrated. In addition, the migration behaviour of the antihistamines in the mixed carrier system was examined.

Capillary Action↗