Mepyramine Research Articles

Electrophysiological and mechanical characteristics of histamine receptors in smooth muscle cells of the guinea-pig ileum

To elucidate the role of the histamine receptor in functions related to intestinal motility, we investigated the effects of histamine and its antagonists on electrical and mechanical activities in longitudinal and circular layers of the terminal region of the guinea-pig ileum. Histamine hyperpolarized the membrane in the circular smooth muscle cells by increasing the permeability of K + and it transiently inhibited generation of the spike while resting tone was elevated. Cimetidine (CIM) inhibited the hyperpolarization and relaxation induced by histamine while mepyramine (MEP) inhibited the contraction but did not affect the histamine-induced hyperpolarization. In the presence of CIM, histamine did not depolarize the membrane but did lower the threshold potential required for generation of the spike potential, increased the appearance of the spike and enhanced the phasic contraction. Histamine, in 20 mM K + solution, hyperpolarized the membrane and produced a biphasic response, an initial relaxation and a subsequently generated contraction, in a concentration-dependent manner. In the longitudinal smooth muscle cells, histamine depolarized the membrane, and enhanced both generation of the spike and the contraction. MEP (0.1 μM) but not CIM (1 μM) blocked the histamine-induced responses. CIM at a higher concentration (10 μM) enhanced the histamine-induced contraction, while histamine did not relax the tissue precontracted by 20 mM K + These results indicate that the circular muscle cells have both H 1 and H 2 receptors while the longitudinal muscle cells have the H 1 receptor. The excitatory responses induced by activation of the H 1 receptor in smooth muscle cells differ in these layers.

Methapyrilene is a genotoxic carcinogen: Studies on methapyrilene and pyrilamine in the L5178Y/TK +/− mouse lymphoma assay

Methapyrilene (MP), a sedating antihistamine, is a potent rat hepatocarcinogen which has been thought to be non-genotoxic on the basis of the negative results in a small number of short-term mutagenicity tests. The present studies show that MP is a moderately active mutagen in the L5178Y/TK +/− → TK −/− mouse lymphoma assay (MLA) in the presence of Aroclor-induced rat-liver S9, and that it induces predominantly small-colony thymidine kinase-deficient (TK −/−) mutants of demonstrated chromosomal origin. 10 of 12 small colony TK −/− mutants analyzed by banded karyotype (230-band level of resolution) show aberrations to chromosome 11b, the known location of the single functional TK gene in these cells. The observed aberrations from nine of the mutants included insertions, deletions and translocations while the tenth mutant had highly rearranged, multiple copies of chromosome 11 segments. By varying the concentrations of the S9 protein and cofactors it was shown that our standard S9 composition was close to optimum for activating MP to a mutagen. The activity and stability of various lots of S9 prepared in-house or purchased from a contract laboratory revealed significant differences. The ability of 2 lots of in-house S9 to activate a standard concentration of MP increased rapidly over the first 4 weeks of liquid nitrogen storage then declined slowly over the next 16 weeks. Three separate lots of purchased S9 were essentially inactive for the first 2 weeks of liquid nitrogen storage then increased in activity thereafter; these were the only occasions in which MP was not mutagenic in our hands. The mutagenic activity of pyrilamine (PYR), a structurally related antihistamine which is far less carcinogenic in rats, but easily detected in short-term tests as being genotoxic, was also investigated in the MLA. PYR was slightly less mutagenic than MP over a comparable range of concentrations, and also induced predominantly small-colony mutants. These studies fail to adequately explain the great carcinogenic differences between these two compounds, but are consistent with the potent hepatocarcinogenicity of MP resulting through a mutagenic mechanism.

Effects of complement fragments on pulmonary and vascular smooth muscle.

Effects of complement fragments on pulmonary and vascular smooth muscle.

Dsc Screening for Drug-Drug Interactions in Poly Pharmaceuticals Intended for the Alleviation of the Symptoms of Colds and Flu. II.

AbstractDSC screening for drug-drug interactions of a polypharmaceutical capsule dosage form containing salicylaminde, ascorbic acid, pyrilamine maleate and phenylephrine hydrochloride was performed. The results show the following:1. Ascorbic acid is incompatible with salicylamide, pyrilamine maleate and pheynylephrine hydrochloride.2. Salicylamide is incompatible with ascorbic acid, pyrilamine maleate and phenylephrine hydrochloride.3. Pyrilamine maleate is incompatible with ascorbic acid, salicylamide and phenylephrine hydrochloride.4. Phenylephrine hydrochloride is incompatible with salicylamide, pyrilamine maleate and ascorbic acid.

Dsc Screening for Drug-Excipient and Excipient Excipient Interactions in Polypharmaceuticals Intended for the Alleviation of the Symptoms of Colds and FLU. III

DSC screening for drug-excipient interactions of a polypharmaceutical capsule dosage form containing salicylamide, ascorbic acid, pyrilamine maleate, phenylephrine hydrochloride, lactose, colloidal silicon dioxide and sodium starch glycolate was performed.

The effect of protamine sulfate on gastric acid secretion and histamine release.

１. Gastric acid secretion (GAS) of rats was dose-dependently increased by intravenous injection of 10-40 mg/kg protamine sulfate (PS). The frequency of occurrence vs. total acid output induced by each injection of PS (20 mg/kg) reavealed a statistical lognormal distribution in 65 rats. ２. Treatment with pyrilamine (5mg/kg, i.p.) or diphenhydramine (5 mg/kg, i.p.) 30 min before the injection of PS failed to inhibit the protamineinduced gastric secretion (PIGAS). However, atropine (5 mg/kg), cromolyn sodium (10mg/kg, i.p.) of cimetidine (2 mg/kg, i.p.) inhibited this effect. ３. Acid secretion and histamine-release from isolated bullfrog gastric mucosal preparations were measured in vitro by a recording pH stat and fluorometric asay. PS (2×10-4g/ml)increased GAS and histamine-release in a mucosal solution and serosal solution respectively. After the spontaneous secretion was decreased by treatment with cimetidine (1×10-4g/ml)and washed with serosal solution. Further application of PS restored acid secretion and histamine-release. ４. It is concluded that PS induces histamine-release (both in vivo and in vitro) from histamine-containing cells, basophil leucocytes and mast cells, and thereafter stimulates the acid secretion from parietal cells.

Assay of mixtures of chlorpheniramine maleate, pyrilamine meleate and phenylpropanolamine hydrochloride in cold-allergy tablets by difference spectrophotometry

Mixtures of chlorpheniramine maleate (CPM) and phenylpropanolamine hydrochloride (PPA), with and without pyrilamine maleate (PRM), are assayed by u.v. difference spectrophotometry without prior separation. The spectra for CPM and PRM in solutions at pH 1 and pH 6 show differences whereas the spectra for PPA remain the same at pH 1 and 6. For PPA, quantitation is based on the spectral change on oxidation to benzaldehyde with metaperiodate; this oxidation does not affect CPM and PRM. Calibration plots are linear for 6.7–99.9 μg ml−1 CPM (r = 0.9992), 12.7–50.6 μg ml−1 PRM (r = 0.9997) and 25–115.3 μg ml−1 PPA (r = 0.9980) in the presence of one another. Average recoveries (± RSD) from simulated PPA/CPM tablets were: PPA, 98.4 ± 0.4% (without PRM, n = 3), 99.8 ± 0.4% (with PRM, n = 5); CPM, 99.3 ± 0.6% (without PRM, n = 3), 99.2 ± 0.4% (with PRM, n = 5); and PRM, 99.5 ± 0.2% (in PPA/CPM/PRM tablets, n = 5). The method was successfully applied to commercial cold-allergy tablets containing these compounds.

Effects of histamine and related compounds on thyrotropin secretion in rats.

The effects of histamine (HA) and related compounds on thyrotropin-releasing hormone (TRH) and thyrotropin (TSH) secretion in rats were studied. Histidine (1.0 g/kg), HA (5.0 mg/kg) or histamine antagonists mepyramine (MP) (100 mg/kg) or famotidine (FA) (5.0 mg/kg) were injected intraperitoneally, and the rats were decapitated at various intervals after the injection. The hypothalamic immunoreactive TRH (ir-TRH) content increased significantly after histidine or HA injection, decreased significantly after FA injection, but was not changed by MP. The plasma ir-TRH concentration did not change significantly after injection of these drugs. The plasma TSH levels decreased significantly in a dose-related manner after histidine or HA injection and increased significantly in a dose-related manner after FA injection. The plasma thyroid hormone levels showed no changes. In the FA-pretreated group, the inhibitory effect of histidine or HA on TSH levels was prevented, but not in the MP-pretreated group. The plasma ir-TRH and TSH responses to cold were inhibited by histidine or HA and enhanced by FA. The plasma TSH response to TRH was inhibited by histidine or HA and enhanced by FA. The inactivation of TRH immunoreactivity by hypothalamus or plasma in vitro after histidine, HA, MP or FA was not different from that of the control. These findings suggest that histamine may act both on the hypothalamus and the pituitary to inhibit TRH and TSH release, and that its effects may be mediated via H2-receptor.

Histaminergic stimulation of prolactin secretion mediated via H1- or H2-receptors: dependence on routes of administration.

Controversy exists regarding the involvement of H1- or H2-receptors in the PRL-releasing activity of histamine (HA). This could be due to differences in the route of administration of HA and histaminergic compounds. Therefore, we studied the effect on PRL secretion of HA and HA-agonists infused intracerebroventricularly (ICV) or systemically (IA) either alone or in combination with HA-antagonists in male rats. HA administered ICV as well as IA stimulated PRL secretion dose dependently. The stimulatory effect of ICV-infused HA was blocked by the H2-receptor antagonist cimetidine (CIM) and mimicked by the H2-receptor agonists 4-methylhistamine (4-MeHA) and dimaprit (DIM). In contrast, the H1-receptor antagonist mepyramine (MEP) enhanced the PRL-releasing effect of HA while the H1-receptor agonist 2-thiazolylethylamine (2-TEA) had no significant effect. The stimulatory effect of IA-infused HA was blocked by the H1-receptor antagonist MEP and mimicked by the H1-receptor agonist 2-TEA, whereas the H2-receptor antagonist CIM enhanced the PRL-stimulatory effect of HA and the H2-receptor agonist DIM was without effect. 4-MeHA stimulated PRL secretion, but this effect was unrelated to stimulation of H2-receptors. The effect of ICV administered HA was unaffected by IA infused antagonists and the effect of IA administered HA was not altered by ICV infused antagonists. HA had no effect on the PRL release from isolated adenohypophyses, and HA did not stimulate PRL secretion in pituitary stalk-sectioned rats following IA infusion. The findings indicate that HA administered ICV exerts its PRL releasing activity via H2-receptors while HA administered IA stimulates PRL secretion via H1-receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of a fish-oil-enriched diet on pulmonary mechanics during anaphylaxis.

The pulmonary mechanical responses observed after antigen challenge in 2 groups of sensitized, mepyramine-treated, mechanically ventilated guinea pigs were compared: one group was fed a diet rich in fish oil and the other a control diet enriched with beef tallow. The lung tissue of animals fed a fish-oil-enriched diet for 9 to 10 wk incorporated eicosapentaenoic acid (EPA) and docosahexaenoic acid, which constituted 8 to 9% of the total fatty acid content, whereas these alternative fatty acids constituted less than 1% of total fatty acid content of the lung tissue of animals receiving a diet supplemented with beef tallow. With mepyramine pretreatment, animals receiving a fish oil diet exhibited a significantly greater decrease in dynamic compliance from 1.5 through 4.5 min after antigen challenge than did animals receiving a beef fat diet, whereas the decrements in pulmonary conductance were comparable. The combination of indomethacin and mepyramine markedly augmented the antigen-induced decrease in pulmonary mechanics in animals receiving a beef fat diet but not in those receiving a fish oil diet, such that the overall responses of the 2 groups were similar. These findings indicate that the fish oil diet and the indomethacin pretreatment of animals receiving the beef fat diet each facilitates the nonhistamine-mediated bronchoconstrictor response in pulmonary anaphylaxis.

Unusual Effects of Histamine Antagonists on Canine Nasal Blood Vessels

This paper documents some of the lesser-known effects of antihistamines on nasal blood vessel smooth muscle. An in vitro muscle tension detecting technique was utilized. Three different H1 receptor antagonists (pyrilamine maleate, chlorpheniramine maleate, promethazine hydrochloride), and the H2 antagonist metiamide were used. Besides their basic antihistaminic effect, H1 antagonists (classical antihistamines) induced a contraction, enhanced norepinephrine- and epinephrine-induced contractions, and relaxed the sustained contraction induced by methoxamine hydrochloride or high concentrations of potassium. Although these effects were quite similar to those induced by histamine, the mechanism of each effect was apparently different. Metiamide did not produce these effects except for the relaxation of the sustained contraction. The actions of histamine antagonists seem to be much more complicated than expected.

Liquid Chromatographic Determination of Organic Nitrogenous Bases in Dosage Forms: A Progress Report

A liquid chromatographic (LC) method has been developed as a general procedure for the assay of the salts of organic nitrogenous bases in a variety of dosage forms. The method uses a nitrile-bonded reverse phase column, a methanol-0.003M ammonium acetate (90 + 10) mobile phase, and photometric detection at 254 nm. The sample is dissolved in the mobile phase and an aliquot is injected through a 20 microL injection loop. Average recovery values for duplicate assays were chlorpheniramine maleate injection 97.8%, chlorpheniramine maleate tablets 99.1%, cyclizine hydrochloride tablets 100.0%, doxylamine succinate tablets 103.3%, mesoridazine besylate tablets 100.4%, pentazocine hydrochloride tablets 103.0%, promethazine hydrochloride injection 98.4%, protriptyline hydrochloride tablets 101.2%, pyrilamine maleate tablets 97.8%, pyrimethamine tablets 100.0%, tripelennamine citrate elixir 100.0%, and tripelennamine hydrochloride tablets 97.2%. Results by this method were in good agreement with those obtained by the USP XX method. This study, which is being continued, will be expanded to include additional drugs.

Trace analysis of the antihistamines methapyrilene hydrochloride, pyrilamine maleate and triprolidine hydrochloride monohydrate in animal feed, human urine and wastewater by high-performance liquid chromatography and gas chromatography with nitrogen—phosphorus detection

Toxicological evaluation of the antihistamines methapyrilene hydrochloride, pyrilamine maleate, and triprolidine hydrochloride monohydrate using methapyrilene hydrochloride as the positive indicator was investigated as part of a structure—activity relationship study in rats and mice. Prerequisites for the toxicological tests were the development of analytical procedures to certify the dose, homogeneity and stability of the drugs in animal feed and to monitor human urine for possible exposure and to ensure removal of the test agents from wastewater prior to its discharge into the environment. A high-performance liquid chromatographic (HPLC) system was developed using a fluorescence detector for the determination of methapyrilene hydrochloride and pyrilamine maleate in feed at levels as low as 100 ng/g and in human urine as low as 1 ng/g. An HPLC—UV procedure was developed for the determination of triprolidine hydrochloride monohydrate in feed at levels as low as 10 μ/g. Data concerning p-values, extraction efficiencies from feed and stability experiments in feed are presented for these antihistamines. A gas chromatographic procedure using a nitrogen—phosphorus detector was also developed for determining the three antihistamines in admixture in wastewater at levels as low as 10 ng/g.

Chronic toxicity tests of pyrilamine maleate and methapyrilene hydrochloride in F344 rats

Methapyrilene hydrochloride was administered at levels of 125 or 250 ppm in the diet to groups of male and female F344 rats. The closely analogous antihistaminic drug pyrilamine, as the maleate, was given at 2000 ppm in the diet or at 2 g/litre drinking-water to groups of male and female F344 rats. Almost all of the rats given the higher dose of methapyrilene had either carcinomas or neoplastic nodules of the liver, whereas at 125 ppm 40% of the rats had neoplastic nodules in the liver. Among the 20 male and 20 female rats treated with pyrilamine maleate mixed into the diet, two males and two females had hepatocellular carcinomas and, in addition, five males and eight females had neoplastic nodules in the liver. The incidence of liver neoplasms in the rats given pyrilamine in the drinking-water did not differ from that in the untreated controls, of which five males and three females had neoplastic nodules in the liver.

Bioasssays of smooth muscle contracting agents in cotton mill dust and bract extracts: Arachidonic acid metabolites as possible mediators of the acute byssinotic reaction

Byssinosis is an occupational respiratory disease contracted by cotton mill workers who inhale cotton mill dust. The acute byssinotic reaction is characterized by a drop in the 1-sec forced expiratory volume (FEV 1.0) on Monday following a weekend's absence from work. This physiological reaction is the result of the contraction of bronchial smooth muscle, which causes narrowing of small airways. An isolated tissue bath technique was used to assay smooth muscle contractions induced by cotton dust extract (CDE) and cotton bract extract (CBE). CBE-induced contractions of rat stomach smooth muscle were blocked (82%) by 100 ng/ml methysergide (blocks 5-hydroxytryptamine (5HT) 100%); CDE was not significantly blocked by methysergide (13%). CDE-induced contractions were blocked (100%) by 25 μg/ml indomethacin and 100 μg/ml salicylic acid (blocks prostaglandin F 2α (PGF 2α) 100%). The portion of CBE contracting ability not blocked by methysergide was blocked totally by indomethacin. Blocking agents ineffective against CDE or CBE include atropine (acetylcholine blocker), pyrilamine maleate and diphenhydramine (histamine blockers), imidazole and 7-(1-imidazolyl)heptanoic acid (7IHA) (thromboxane blockers), and carboxypeptidase B 2 (kinin blocker). The data suggest that cotton bract contains 5HT, which is responsible for a majority of the CBE-induced contraction and a minority of the CDE-induced contraction. The data also suggest that cotton dust and bract contain a substance which causes the release of PGF 2α which in turn causes the contraction of smooth muscle. This substance is responsible for a majority of the CDE-induced and a minority of the CBE-induced contractions. Radioimmunoassay (RIA) confirmed PGF 2α release from rat fundal smooth muscle when exposed to CDE and CBE. Increased synthesis and release of arachidonic acid metabolites might be a major mechanism in the bronchoconstriction observed in the acute byssinotic reaction.

Inhibition of bone resorption in tissue culture by H1-receptor antagonists.

Mouse bone culture studies show that several representative H1-receptor antagonists, promethazine hydrochloride, pyrilamine maleate, tripelennamine hydrochloride, and diphenhydramine hydrochloride, inhibit parathyroid extract-stimulated bone resorption. The H2-receptor antagonists, metiamide and cimetidine, are ineffective. In view of the finding that histamine and histamine agonists did not stimulate bone resorption, it is unlikely that histamine receptors are involved in mediating parathyroid extract-stimulated bone resorption. Because H1-receptor antagonists bind to phospholipids and have been shown to influence membrane structure and function, it is suggested that they inhibit bone resorption by a mechanism that depends on their membrane-stabilizing effect.

Constrictor effect of cotton bract extract on isolated canine airways.

Tissue bath techniques were used to examine the effects of cotton bract extract (CBE) on isolated canine airways. The CBE elicited strong contractions that were abolished by the 5-hydroxytryptamine (5-HT) antagonist, methysergide (3 x 10(-6) M), but were only slightly affected by atropine (5 x 10(-7) M) and pyrilamine (3 x 10(-6) M) Desensitization to repeated exposures to CBE was not observed, and maximal contractions were equal in force to those produced by supramaximal electrical stimulation (15 V, 25 Hz, 0.5 ms pulse duration). Responses to exogenous 5-HT were qualitatively and quantitatively similar to those produced by CBE. Partial purification of CBE by Amicon ultrafiltration yielded a bronchoactive fraction containing low molecular weight compounds (less than 500). Analysis of the 5-HT concentration in this fraction by high-pressure liquid chromatography, fluorescence, and column chromatography indicated that the amount of 5-HT present accounted for only 8 to 25% of the smooth-muscle-contracting activity of CBE. We conclude that cotton bracts contain a potent 5-HT receptor agonist that appears to be distinct from 5-HT.

Measurement of canine gastric vascular permeability to plasma proteins in the normal and protein-losing states

An isolated segment of the greater curvature of a dog's stomach was perfused at constant flow through a single cannulated artery with donor blood containing 131I-albumin, 125I-fibrinogen, and papaverine. Perfusion pressure was 30–50 mmHg, and venous pressure was set at 15 mmHg. Venous blood was collected in 1-min samples for 60 min. Filtration of fluid and loss of labeled proteins were calculated as the difference between measured arterial inflow and venous outflow. Permeability-surface area products (PS) were calculated for the proteins, and reflection coefficients (σ) were calculated from solute flux and filtration. Intraarterial infusion of histamine (1.6–1.9 μg · ml−1) increased filtration and PS and decreased σ for albumin but not fibrinogen. When protein-losing was established by topical irrigation with 10 mM dithiothreitol in neutral solution, filtration and PS increased, and σ for albumin but not fibrinogen decreased. Irrigation of the mucosa with 10 mM salicylic acid in 100 mN HCl caused bleeding that was quantitated by addition of 51Cr-erythrocytes to perfusing blood. Filtration and PS increased, and σ for albumin but not fibrinogen decreased. Hematocrit of blood lost remained low during extensive mucosal damage. Effects of histamine infusion were attenuated or abolished by cimetidine (4 mg · kg−1 loading, 1.4 mg · kg−1 · h−1 continuous infusion) or by pyrilamine maleate (5 mg · kg−1 bolus injection at beginning of irrigation, repeated at 40–50 min). Pyrilamine attenuated or abolished effects of topical dithiothreitol or salicylic acid. We conclude that during protein loss caused by dithiothreitol or salicylic acid, histamine released within the mucosa causes increased vascular permeability for plasma proteins.

GlC Analysis of Menthol, Phenol, Benzocaine, and Pyrilamine Maleate in Aerosol Spray Lotion

A GLC method is presented for the quantitative determination of menthol, phenol, benzocaine, and pyrilamine maleate. The propellent was exhausted from a pressurized can, and an aliquot of the alcoholic base was weighed. After the addition of the internal standard diluted with chloroform, 1 μl of the mixture was injected in the chromatograph with a flame-ionization detector and a glass column packed with 2.5% OV-225. Average recoveries, were 100.3 ± 1.4, 100.0 ± 1.4, 101.3 ± 1.5, and 101.5 ± 1.5% for menthol, phenol, benzocaine, and pyrilamine maleate, respectively.

Characterization of DNA repair elicited by carcinogens and drugs in the hepatocyte primary culture/DNA repair test.

The autoradiographic unscheduled DNA synthesis measured in the hepatocyte primary culture/DNA repair test after exposure to chemical carcinogens was characterized. In order to document that this synthesis was occurring in nonreplicated DNA, density labeled, replicated DNA was separated from nonreplicated DNA by cesium chloride gradient centrifugation. Incorporation of [3H] thymidine into nonreplicated DNA was detected after exposure of hepatocytes to methyl methanesulfonate, an activation independent carcinogen, or N-2-acetylaminofluorene, an activation-dependent carcinogen, but not with fluorene, a noncarcinogen. N-4-Acetylaminofluorene, a mutagenic compound of uncertain carcinogenicity, also caused DNA repair. Both the autoradiographic assay and density gradient centrifugation detected incorporation of [3H] thymidine into DNA from the same hepatocyte preparation. By using density gradient centrifugation, DNA repair was detected in hepatocytes following exposure to the antihistamines pyrilamine maleate and tripelennamine HCl. Methapyrilene failed to elicit repair. Thus this study (1) verifies that the unscheduled DNA synthesis seen in the hepatocyte primary culture/DNA repair test after carcinogen exposure in DNA repair And (2) confirms the induction of DNA repair by pyrilamine maleate and tripelennamine HCl but not by methapyrilene.