Rocastine (AHR-11325), a rapid acting, nonsedating antihistamine

Rocastine [AHR-11325, 2-[2-(dimethylamino)ethyl]-2,3-dihydro-4-methylpyrido-[3,2-f]-1,4- oxazepine-5(4H)-thione (E)-2-butenedioate)] is a rapid-acting, potent, nonsedating antihistamine. In guinea pigs challenged with a lethal dose of histamine, rocastine is as effective [based on 1 hr. oral, protective dose (PD50S)] as brompheniramine, chlorpheniramine, pyrilamine, and promethazine and superior to astemizole, diphenhydramine, terfenadine, and oxatomide. Rocastine has a faster onset of action than does terfenadine; rocastine being as effective with a 15 min pretreatment time (PD50 = 0.13 mg/kg) as it is with a 1 hr pretreatment time (PD50 = 0.12 mg/kg), while the 15 min PD50 of terfenadine (PD50 = 44.0 mg/kg) is 22 times greater than the 1 hr PD50 (PD50 = 1.93 mg/kg). Against aerosolized histamine, rocastine was 7.12 x, 2.63 x, and equipotent to pyrilamine in preventing histamine-induced prostration at pretreatment times of 1,3, and 6 hr, respectively. Rocastine protected guinea pigs from collapse induced by aerosolized antigen; rocastine was approximately 36 x more potent (based on 1 hr PD50) than diphenhydramine and as potent as oxatomide and terfenadine. Rocastine did not alter the EEG of cats at doses in vast excess (150x) of its antihistaminic dose nor did it potentiate yohimbine toxicity in mice. Further, rocastine possesses no anticholinergic, antiadrenergic, or antiserotonergic properties in vitro. Rocastine is a selective, nonsedating, H1-antagonist with a rapid onset of action.     

A study on the mechanism of the antiasthmatic effect of labetalol on experimental histamine-induced asthma

The effect of labetalol (alpha- and beta- adrenoceptor blocking agent) on the respiratory organs of guinea pig was investigated in vivo and in vitro. The asthmatic symptoms which were induced by inhalation of histamine were relieved by pretreatment with labetalol (1-5 mg/kg, i.p.) in most cases. Propranolol, on the contrary, aggravated distinctly the histamine-induced asthma, although phentolamine and diphenhydramine relieved the asthma. Experiments carried out in vitro showed that labetalol relaxed the tonus of isolated tracheal preparation, shifting the histamine dose-response curve to the right and downward. The down shifting by labetalol was dose-dependent and much more sensitive than that by papaverine, and it disappeared after pretreatment of propranolol. Thus, it was considered that labetalol exerted a relaxing action on the tracheal preparation by a beta 2-adrenoceptor partial agonist action (intrinsic sympathomimetic activity, ISA). Since labetalol in high concentration also shifted the histamine dose-response curve parallel to the right as seen with phentolamine or diphenhydramine, it was considered that labetalol exerted not only an alpha-blocking action but also an antihistaminic action.     

Inhibitory activity of terfenadine on histamine-induced skin wheals in man

Summary The inhibitory effect of orally administered terfenadine on the area of histamine-induced skin wheals was studied by single dose and multiple dose trials in 12 normal male volunteers. Single doses of 20, 60 and 200 mg of terfenadine produced dose-dependent decreases in histamine wheal area that reached a maximum by the fourth hour after dosing. The 60 and 200 mg doses blocked almost 90% of histamine whealing, and significant reduction of the wheal area persisted for 8 h. During the multiple dose trial histamine whealing was markedly inhibited after the fifth and sixth dose of terfenadine 20, 40 or 60 mg every 8 h and of 60 mg every 12 h. On the last three dosage schedules inhibition persisted for at least 12 h after the final dose. Inhibition of histamine-induced skin whealing appears to be a quantitative index of the time course of histamine H₁-receptor antagonist action.     

Interactions of chlorpheniramine ethanol combinations: acute toxicity and antihistaminic activity

Significant toxicologic and pharmacologic interactions occurred between chlorpheniramine maleate and 25% $\text{v}\text{v}$ ethanol at several dosage combinations. Conditions of both independence and antagonism of acute toxicity were observed in LD50 determinations of chlorpheniramine-ethanol combinations in mice, and confirmed expected results based on the toxicologic pattern of the agents when administered singly. Enhancement of the antihistaminic action of chlorpheniramine by ethanol was demonstrated during histamine-aerosol challenge studies in guinea pigs.     

Pharmacologic analysis of LY188695 (KB-2413), 1-(2-ethoxyethyl)-2-(4-methyl-1-homopiperazinyl)-benzimidazole difumarate, a potent histamine1 receptor antagonist

LY188695 was evaluated both in vitro and in vivo in the guinea pig to determine its pharmacologic profile. The compound antagonized histamine-induced contractions of ileum, aorta, and trachea with pKB values of 9.9, 9.9, and 9.2 respectively. In the lung parenchymal strip, LY188695 caused a rightward shift of the histamine concentration-response curve with a reduction in the maximal response at all antagonist concentrations tested. The reason for this effect is unknown, but it was not due to a nonspecific depressant action of the compound on the parenchyma. Selectivity was shown by its inactivity against leukotriene D4, bradykinin, prostaglandin F2 alpha, acetylcholine, norepinephrine, and serotonin on various guinea pig and rat smooth muscles. Similarly, H2 receptor-mediated relaxation of the rat uterus was unaltered by LY188695. Increases in total pulmonary impedance caused by i.v. histamine to anesthetized guinea pigs were reduced by as little as 3 micrograms/kg given orally 1 hour prior to histamine challenge. In this system, LY188695 was 15 times more potent than chlorpheniramine and 100 times more potent than terfenadine. Similar responses elicited by acetylcholine were not antagonized by LY188695. A duration of action greater than 4 hours was observed in this model. Ovalbumin given i.v. to sensitized guinea pigs increased total pulmonary impedance which was markedly decreased after oral administration of 30 or 100 micrograms/kg LY188695. These results indicate that LY188695 is a very potent antagonist of H1-mediated responses and suggest that this agent might be useful in disease states characterized by an overproduction of histamine.     

Preclinical pharmacology of desloratadine, a selective and nonsedating histamine H1 receptor antagonist. 1st communication: receptor selectivity, antihistaminic activity, and antiallergenic effects

Desloratadine (descarboethoxyloratadine, CAS 100643-71-8) is an active metabolite of loratadine (CAS 79794-75-5) that exhibits qualitatively similar pharmacodynamic activity with a relative oral potency in animals 2.5-4 times greater than loratadine. Its antihistaminic effect lasts 24 h. Desloratadine was shown to be a selective H1 antagonist with more potent antihistaminic activity in vitro than either loratadine or terfenadine (CAS 50679-08-8), as indicated by its displacement of 3H-mepyramine from H1 receptors in rat brain, guinea pig brain, and guinea pig lung, and by its antagonism of histamine-induced contractions of guinea pig ileum. Antihistaminic activity and anitallergic effects also were observed in vivo. After oral administration, desloratadine was 2.5 to 4 times more potent than loratadine in protecting against histamine-induced lethality in the guinea pig and paw edema in the mouse; after topical administration, it was almost 10 times more potent in antagonizing histamine-induced increases in nasal microvascular permeability in the guinea pig. Histamine-induced changes in pulmonary resistance and compliance were also prevented by oral administration of desloratadine and loratadine in the monkey. An oral antiallergic effect was demonstrated by important reductions of acute bronchospasm in the allergic monkey and potent inhibition of allergic cough in the guinea pig. These preclinical studies provide evidence that desloratadine is an antihistaminic agent with a greater potency than loratadine and, together with results from numerous published studies, suggest an antiallergic effect of desloratadine.     

Nonsedating histamine H1-receptor antagonists

The chemistry, pharmacology, pharmacokinetics, clinical efficacy, adverse effects, and dosages of the nonsedating histamine H1-receptor antagonists terfenadine, astemizole, loratadine, and acrivastine are reviewed. Terfenadine and astemizole are chemically unrelated to histamine H1-receptor antagonists such as diphenhydramine and chlorpheniramine. Loratadine is structurally related to the antihistamine azatadine, and acrivastine is a side-chain-reduced metabolite of the antihistamine triprolidine. Like other histamine H1-receptor antagonists, they competitively block histamine receptor sites rather than inhibiting histamine release. All four drugs have relatively long half-lives and are rapidly absorbed after oral administration. Terfenadine, astemizole, and loratadine are metabolized extensively in the liver; terfenadine and astemizole are both 97% protein bound. Terfenadine 60 mg twice daily has been shown to be as effective as conventional antihistamines for the treatment of seasonal allergic rhinitis. In clinical trials, astemizole 10 mg daily was comparable to or better than chlorpheniramine for treatment of chronic rhinitis. Both terfenadine and astemizole were effective for treatment of chronic urticaria. For treatment of seasonal allergic rhinitis, loratadine combined with pseudoephedrine may be preferable to triprolidine-pseudoephedrine and acrivastine-pseudoephedrine combinations that require more frequent dosing. Acrivastine must be administered more frequently than the other nonsedating antihistamines. None of these four agents impairs psychomotor activity. Infrequently reported adverse effects include dry mouth, skin reactions, and weight gain. The absence of substantial sedative effects and the less-frequent dosing schedules make these agents good alternatives to the classic antihistamines for treatment of seasonal and chronic rhinitis and chronic urticaria.     

Pharmacologic evaluation of loratadine (SCH 29851), chlorpheniramine and placebo

Summary The antihistaminic effect of loratadine (160 mg) was compared in twenty-four normal male volunteers to chlorpheniramine maleate (4 mg) and placebo in a double blinded 3-way cross-over study of latin square design. After receiving single oral doses of each medication, the wheal response to serial 0.1 ml intradermal histamine (2 µg) and saline (control) injections were recorded over a 24-h period. The calculated wheal areas were compared to baseline measurements. The results were analyzed by analysis of variance. Loratadine exhibited a more pronounced inhibition of histamine wheal formation than placebo or chlorpheniramine maleate (p<0.003). In contrast to chlorpheniramine maleate which had a duration of action of only 3 h, loratadine inhibited the response for the entire observation period between 1 and 24 h post-dose. Although sedation was observed less frequently with loratadine (Placebo,n=2; chlorpheniramine,n=3; and loratadine,n=1), the relative incidence were not statistically significant.     

The effects of stimulants and inhibitors of histamine receptors on acid secretion from guinea pig gastric fundus

Two selective H₂ receptor stimulants (5-methyl-N-methylhistamine and dimaprit) so far never tested in isolated gastric preparations, were found to be strong stimulants of acid secretion from the guinea pig isolated gastric fundus. Although some differences were observed in the cumulative dose-response curves for these two agonists, the peak responses obtained were not significantly different from the maximum response to histamine. Cimetidine produced parallel displacement of the dose-response curves to the right with the maximum response unchanged, suggesting competitive antagonism on H₂ receptors. The dose-response curve for histamine was not affected by the simultaneous administration of an H₁ receptor agonist, 2(2-aminoethyl)thiazole, or of an H₁ receptor antagonist, pyrilamine. This indicates that the action of histamine on the isolated guinea pig gastric fundus is associated exclusively with H₂ receptor stimulation.     

Decreased Schultz-Dale Reaction in Airways from Sensitized Guinea Pigs Treated with Threshold Concentrations of Egg Albumin in Vivo

Abstract: Treatment of egg albumin sensitized guinea pigs with repeated concentrations of egg albumin changed the Schultz-Dale response. The dose-response curve of egg albumin on the trachea was shifted to the right. Both the amount of SRS-A and histamine released by antigen exposure from sensitized or desensitized guinea pig lungs were almost similar. Regarding the number of H₁-receptors in an isolated membrane fraction from the lungs of sensitized and desensitized guinea pigs, no significant differences was observed. On the contrary, the receptor-response to SRS-A was found to be decreased in desensitized trachea in comparison with sensitized trachea. The treatment of guinea pigs with repeated threshold concentrations of histamine did not change the contractile response neither to histamine nor to egg albumin. The decreased Schultz-Dale response after repeated egg albumin treatment in vivo might depend on desensitization of a hypothetical SRS-A receptor.     

Pharmacological and clinical properties of cetirizine hydrochloride

A number of reports have characterized cetirizine as a potent histamine H1-receptor antagonist possessing inhibitory effects on eosinophil chemotaxis. In clinical pharmacological tests, cetirizine markedly reduced wheal and flare responses induced by histamines. The inhibition was fast onset, potent and long-lasting. A single clinical dose of cetirizine was more potent in inhibiting wheal response than other antihistamines such as terfenadine, loratadine, epinastine and ebastine. Cetirizine also inhibited eosinophil chemotaxis in vitro at a concentration easily attained after a clinical dose of 10 mg. Eosinophil infiltration into a site challenged with allergen in vivo was also inhibited. Potent antihistaminic effects of cetirizine afforded fast and strong relief from histamine-induced symptoms such as sneezing and rhinorrhoea in allergic rhinitis and itchy sensation in idiopathic chronic urticaria. Inhibitory effect of cetirizine on eosinophil chemotaxis may alleviate minimal persistent inflammation due to faintly but repeated intake of allergen. Such anti-inflammatory properties of cetirizine may be beneficial in reducing hypersensitivity to normalize the upper respiratory tract and eosinophil-related skin inflammation.     

Effect of terfenadine and ranitidine on histamine and suxamethonium wheals

Summary The effects of the H-1 receptor blocker terfenadine and the H-2 receptor blocker ranitidine have been experimentally tested in wheals induced with histamine and suxamethonium chloride.Ranitidine alone in the standard and a four-fold higher dose did not notably reduce the size of the wheal and flare as compared to placebo. As expected, both parameters were markedly reduced by the H-1 antihistamine terfenadine in full and half-dosage. A combination of the two drugs both in standard and modified dosage resulted in the greatest reduction in the wheal and flare.Histamine and suxamethonium-induced wheals reacted in a similar manner to the antihistamines.     

特非那丁治疗荨麻疹和过敏性鼻炎的多中心双盲试验384例

对760名患有急、慢性荨麻疹,季节性或常年性过敏性鼻炎患者进行临床试验。分特非那丁组(384例)、扑尔敏组(131例)、安慰剂组(245例)。特非那丁和扑尔敏的剂量分别为60mg或4mg,bid,连用1wk。特非那丁组86.7％患者症状有不同程度的改善,而扑尔敏组为74.8％,安慰剂组为23.7％,特非那丁的效果明显优于安慰剂(P<0.01)。其嗜睡的发生率与安慰剂相似,但扑尔敏嗜睡发生率34.4％,显著高于特非那丁(P<0.01)。     

Synthesis and antihistaminic activity of 3H-benzo [4,5] thieno [2,3-d][1,2,3] triazin-4-ones

In the present study the antihistaminic activity of tricyclic benzothieno 1,2,3-triazine derivatives namely CP-3 (3-(phenyl)-5,6,7,8-tetrahydro,3H-benzo[4,5] thieno [2,3-d][1,2,3] triazin-4-one), CP-5 (3-(3-methyl phenyl)-5,6,7,8-tetrahydro,3H-benzo[4,5] thieno [2,3-d][1,2,3] triazin-4-one) and CP-8 (3-(4-chloro phenyl)-5,6,7,8-tetrahydro,3H-benzo[4,5] thieno [2,3-d][1,2,3] triazin-4-one) were evaluated using in vitro (isolated guinea pig ileum) and in vivo (bronchodilator activity in guinea pigs) models and the sedative potential of the test compounds were evaluated using actophotometer in mice. In in vitro antihistaminic study, the CP-3, CP-5, CP-8 and chlorpheniramine maleate (CPM) have shown a rightward shift in concentration response curve (CRC) of histamine with a change in EC₅₀ values of histamine in all the four tissue preparations. The slope obtained in the schild plot indicated that CP-5, CP-8 and CPM were competitive in nature for H₁-receptors. However, CP-3 has shown non-competitive antagonism. In in vivo antihistaminic study, the CP-3, CP-5, CP-8 and CPM have shown mean increase in exposition time against histamine challenge compared to control group (p < 0.001). All the test drugs (10 mg/kg) and CPM (2 mg/kg) have offered a significant (p < 0.001) protection against preconvulsive dyspnoea (PCD) compared to control. In conclusion, all the test drugs have shown very good antihistaminic activity and the test drugs have very little sedative action compared to CPM.     

Evaluation of terfenadine and ketoconazole-induced QT prolongation in conscious telemetered guinea pigs

Terfenadine and ketoconazole are the most widely used positive reference agents in non-clinical cardiac repolarization safety studies. The aim of the present study was to evaluate the effects of terfenadine, ketoconazole and their combination on QT prolongation using conscious guinea pigs. Conscious telemetered guinea pigs were orally administered terfenadine (50 mg/kg), ketoconazole (200 mg/kg) or a combination of the two, and effects on QT were recorded using a telemetry system. The QT correction was carried out with Bazett's formula to eliminate confounding effect of HR. Neither terfenadine nor ketoconazole produced any effect on the RR and QT intervals, QRS complex or heart rate (HR). However, a combination of terfenadine and ketoconazole significantly prolonged the RR and QT intervals and decreased HR in a time-dependent manner. This study demonstrated that the combination of terfenadine and ketoconazole produces QT prolongation in conscious telemetered guinea pigs.     

In vitro and in vivo studies of the non-sedating antihistamine epinastine

Epinastine (3-amino-9,13b-dihydro-1H-dibenz [c,f]imidazo[1,5-a]azepine hydrochloride, WAL 801 CL) was tested in vitro and in vivo in comparison with other H1-receptor antagonists. In the guinea pig ileum and in receptor binding studies the test substance showed a high affinity to H1-receptors. The following rank order was determined: WAL 801 CL greater than astemizole greater than terfenadine. These results were confirmed in vivo. The studies were carried out with oral and intravenous administration of WAL 801 CL to assess the inhibition of histamine-induced reactions in the skin or the lung of rats, dogs and guinea pigs. 10- to 100fold antihistaminic doses of WAL 801 CL showed no effect on the sleeping-waking behaviour of cats. From this and other results it is suggested that the compound does not penetrate in the central nervous system. The action pattern of WAL 801 CL as a non-sedating antihistamine corresponds more to that of terfenadine than that of ketotifen.     

Antagonism of vasodepressor and gastric secretory responses to histamine by the H2-receptor antagonists, ranitidine and cimetidine, in the anaesthetized dog.

1 The new H2-receptor antagonist, ranitidine, has been compared with cimetidine as an inhibitor of gastric acid secretion in the anaesthetized dog. 2 Both ranitidine and cimetidine given intravenously inhibited histamine-induced gastric secretion in a dose-related manner. Ranitidine was 4.2 times more potent than cimetidine when given as an intravenous infusion and 9.6 times more potent as an intravenous bolus dose. 3 In a separate series of experiments, ranitidine was compared with cimetidine as an antagonist of vasodepressor responses to histamine. Mepyramine alone displaced the histamine dose-response curve to the right. After a maximally effective dose of mepyramine, further displacement could be achieved with ranitidine and cimetidine, ranitidine being 19.2 times more potent than cimetidine. 4 Ranitidine alone has no effect on vasodepressor response curves to histamine, acetylcholine or (-)-isoprenaline or on vasopressor response curves to phenylephrine. 5 These results indicate that displacement of the histamine dose-response curve after mepyramine blockade by ranitidine and cimetidine is due to selective H2-receptor antagonism.     

Inhibitory Effect of Nigella sativa on Histamine (H1) Receptors of Isolated Guinea Pig Tracheal Chains

In a previous study, the relaxant and anticholinergic (functional antagonism) effects of Nigella sativa have been demonstrated on guinea pig tracheal chains. To elucidate the other mechanisms responsible for this relaxant effect, the inhibitory effect of this plant on histamine H 1 receptors was examined in this study. The antihistaminic effects of aqueous and macerated extracts, 5nM chlorpheniramine, and saline were tested by performing the cumulative log concentrationresponse curves of histamine induced contraction of isolated guinea pig tracheal chains incubated with three different conditions including: 1) 1.4µM indomethacin, 2) indomethacin, 1µM propranolol, and 10 nM atropine, and 3) indomethacin and propranolol (for each group n = 8). The results showed clear parallel rightward shifts in histamine-response curves obtained in the presence of macerated extract in group 1 and aqueous extract in group 2 experiments compared with the curves obtained in the presence of saline. The EC 50 (effective concentration of histamine causing 50% of maximum response) obtained in the presence of extracts, and chlorpheniramine in all three sets of experiments were significantly higher than that of saline (P &lt; 0.05 to p = 0.002), but maximum response to histamine obtained in the presence of extracts were lower (P &lt; 0.01 to P &lt; 0.001). However, the maximum response obtained in the presence of aqueous extract in group 2 experiments compared to the other two sets of experiments was improved. These results indicated a competitive antagonistic effect of Nigella sativa at histamine H 1 receptors.     

Therapeutic effect of <Emphasis Type="Italic">Linum usitatissimum</Emphasis> (flaxseed/linseed) fixed oil on acute and chronic arthritic models in albino rats

The aim of the study was to evaluate the antiulcer activity of Linum usitatissimum fixed oil against aspirin-, indomethacin-, ethanol-, reserpine-, serotonin- and stress-induced gastric ulceration in rats and histamine-induced gastric ulceration in guinea pigs. Attempts were also made to evaluate the in vitro anticholinergic and antihistaminic activity and in vivo antisecretary and antiulcer activity of oil following pylorus ligation in rats. L. usitatissimum fixed oil exhibited significant antiulcer activity against different ulcerogens in experimental animal models. The fixed oil significantly inhibited acetylcholine- and histamine-induced contraction of guinea pig and rat ileums, respectively, suggesting its anticholinergic and antihistaminic activity. The oil also exhibited significant inhibitory effect on gastric secretion/total acidity and aspirin-induced gastric ulceration in pylorus-ligated rats. The lipoxygenase inhibitory, histamine antagonistic and antisecretory (anticholinergic) effects of the oil could probably have contributed towards antiulcer activity. L. usitatissimum fixed oil may be considered to be a drug of natural origin which possesses significant antiulcer activity. The present observation is the first experimental data showing antiulcer activity of L. usitatissimum fixed oil.     

Studies on the H2-receptor antagonism of MK-208 in isolated rabbit gastric glands

Using isolated rabbit gastric glands, the H2-receptor antagonist MK-208 was investigated with respect to its effects on [14C]aminopyrine uptake as an index of gastric acid secretion. In addition to shifting the histamine concentration-response curve to the right in a parallel fashion, the antagonism produced by MK-208 was reversible, contrary to that previously seen in the guinea pig atria. These observations suggest that the H2-receptors responsible for mediating gastric secretion in the rabbit and the chronotropic response in guinea pig atria are different.