Optically active analogues of ebastine: Synthesis and effect of chirality on their antihistaminic and antimuscarinic activity

A series of optically active analogues of the H₁-antihistamine ebastine, with chiral center(s) at the benzhydryl and/or phenylbutyl part of the molecule, have been synthesized. Their in vitro antihistaminic and antimuscarinic activities were investigated, along with a molecular modelling study. It was found that introduction of the benzhydryl chiral center yielded significant stereoselectivity for both antihistaminic and antimuscarinic activities. The steric preferences of the benzhydryl chiral center for antihistaminic and antimuscarinic actions were mirror images of each other. The (?)-isomer of 4-methylebastine ( 6d ) showed more than 10-fold higher in vitro antihistaminic potency than ebastine. Meanwhile the selectivity of 6d for histamine H₁-receptors was also increased by more than 20 times in comparison with ebastine. The chirality at the phenylbutyl part of the molecule does not significantly alter the antihistaminic or antimuscarinic activity of the compounds although the (S)-isomers showed slightly but unanimously higher antihistaminic activity than the (R)-isomers. These results have been discussed with existing stereoselectivity data of antihistamines and an asymmetric pharmacophore model for H₁-antagonists has been described. © 1994 Wiley-Liss, Inc.     

Histamine-liberating effect of antihistaminics on the isolated rat mast cells]

Research Allergological Laboratory of the USSR Academy of Medical Sciences and Laboratory of Pharmacology, S. Ordzhonikidze Research Chemico-Pharmaceutical Institute, Moscow. Among the tested new antihistaminic drugs (quinuclidine derivatives) quinuclidyl-3-(O-tolyl) carbinol possessed histamine releasing action (HRA) on the isolated rat mast cells. In used concentrations (up to 0.4 mmol) all phenothiazines (promethazine, phenethazine, chlorpromazine, methylene blue) had HRA. There was no correlation between the HRA and the antihistaminic activity of the tested drugs. Histamine release induced by antihistaminic drugs and a steep dose-response curve, was produced at low temperature and was not inhibited under conditions of inhibition of energy-dependent stage of 48/80-induced histamine release. It was concluded that the tested antihistaminic drugs which had HRA were non-selective histamine releasers.     

Bioinorganic study on [Fe(promethazine)2H2O Cl]2+ complex

The coordination chemistry of iron (III) is the environment of an antihistaminic drug, promethazine has been explained to include a low spin, six-coordinate complex [Fe(Prometha)2(H2O) Cl] Cl2. Metaldrug interaction in vitro in aqueous KCl phase was studied polarographically at physiological pH and temperature. On the basis of elemental, magnetic, conductometric, IR, UV-visible, NMR spectroscopic analysis it is concluded that in solid phase two promethazine molecules with their N,N donor sites encompass the metal. Mass spectral study on the complex confirms that one of the three chlorides is involved in the coordination. The respective changes in the antihistaminic activity of the drug as a result of complexation has been determined and a possible mechanism is suggested.     

组胺拮抗剂对小鼠ATP-敏感性钾离子通道的影响

目的观察比较3种组胺拮抗剂对缺血性心肌细胞的ATP-敏感性钾离子通道中的影响。方法利用急性酶解法分离小鼠心室肌细胞。结果组胺拮抗剂pyrilamine、chlorpheniramine及diphenhydramine均可抑制ATP-敏感性钾离子通道的活性,抑制程度为pyrilamine〉chlorpheniramine〉diphenhydramine。组胺对KATP通道活性无影响。结论第一代的组胺拮抗剂（pyrilamine、chlorpheniramine及diphenhydramine）对KATP通道活性有抑制作用,其抑制作用与膜上H1受体无关。     

Syntheses and evaluation of amidinobenzofuran derivatives as tryptase inhibitors

We report the syntheses and evaluation of amidinobenzofuran derivatives as tryptase inhibitors. Among the compounds we evaluated, 1,5-Bis[4-(5-amidinobenzofuran-2-ylcarbonyl)piperazinylca rbonylmethoxy]cyclooctane 26 (AY0068) was found to be a selective and potent non-peptide inhibitor. 26 was effective in PCA reaction in rats without showing antihistaminic activity.     

Antihistamine, anticholinergic and cardiovascular effects of 2-substituted-4-phenylquinoline derivatives

Eleven new derivatives of 4-phenylquinoline, having various substituents at the 2-position of the quinoline ring, were previously synthesized. The antidepressant activities of these derivatives were demonstrated by their antagonism to reserpine-induced hypothermia in mice. The ED50 values were found to be in the range of 12-42 mg/kg (imipramine is 21.0 mg/kg). In the present work, comparative studies of the effects of these new drugs on the cholinergic and histaminergic (H1) systems, as well as their effects on the cardiovascular system, are presented. Both imipramine and trazodone were utilized as standards representing typical and atypical antidepressant drugs, respectively. All these new compounds have very low antihistaminic (H1) activities, as compared to imipramine. In addition, a clear cut separation of the antidepressant activity from the antihistaminic (H1) activity was observed. These compounds have weak anticholinergic (atropine-like properties) activity as compared to imipramine, using the isolated guinea-pig ileum. Animal studies of the cardiac toxicity of these compounds showed reduced lethality for some of them as compared to imipramine. Arrhythmias commonly associated with imipramine were absent for most of these compounds. The effects of these compounds on the heart conduction were determined by electrocardiographic studies. Although some of these compounds do not interfere with heart conduction, as compared to imipramine most were inferior to trazodone. Correlation between the pharmacological activities and structural modifications of these derivatives has also been observed.     

Clinical evaluation of cetirizine

Efficiency of cetirizine--a new antihistaminic agent--was evaluated in 61 patients with seasonal rhinitis in placebo-controlled double-blind trial. Patients were randomly divided into subgroups. Cetirizine significantly inhibited the symptoms of allergic rhinitis and conjunctivitis. Adverse reactions were similar to those of placebo. Increased clinical efficiency but also an increase in adverse reaction incidence were noted when the drug was administered in the evening and not in the morning. High efficacy of placebo is worth mentioning. Therefore, antihistaminic agents should be tested in placebo-controlled double-blind trials.     

MEDICAL PROGRESS: Histamine and the Antihistaminic Drugs

The tissues affected by histamine and anaphylactic reactions are identical. Epinephrine antagonizes the action of histamine by acting on effector cells in a direction opposite to that of histamine. The so-called antihistaminic drugs block rather than antagonize the action of histamine. The injection into the human body of epinephrine or certain antihistaminic substances provokes the release of histamine and thereby produces a rise in the histamine blood level.There is a remarkable conformity of potency of antihistaminics as determined by Dale experiments and by histamine intoxication experiments in the intact guinea pig. Neoantergan, Pyribenzamine and Histadyl are usually superior to other compounds when potency is assayed by these methods.All antihistaminics provide similar protection again animal anaphylaxis. Larger doses are necessary to protect against anaphylaxis than against histamine intoxication.The differences in potency as determined by Dale experiments and histamine experiments in animals are not found in clinical use. One compound is not generally superior to all others in the treatment of any one or several allergic disorders.The antihistaminic drugs are beneficial in the symptomatic treatment of allergic rhinitis, acute urticaria and angioneurotic edema, and mild non-infective bronchial asthma. Their effectiveness in the management of moderately severe and severe non-infective bronchial bronchial asthma; infective bronchial asthma; migraine; atopic dermatitis (disseminated neurodermatitis), and pruritus of skin disorders other than acute urticaria and angioneurotic edema, is not worthy of particular commendation.The size of the dose of any antihistaminic substance influences the incidence of but not the type of side-effect that may accompany its usage. The quality of side effects varies according to the drug, although there is an individuality of response for each patient which must be reckoned with. In selecting an antihistaminic compound it is necessary to consider the percentage of cases in which side effects occur, as well as the percentage of good results. Optimal results are obtained by employing combinations of compounds and changing from one to the other as the case demands.     

Histamine and the antihistaminic drugs

The tissues affected by histamine and anaphylactic reactions are identical. Epinephrine antagonizes the action of histamine by acting on effector cells in a direction opposite to that of histamine. The so-called antihistaminic drugs block rather than antagonize the action of histamine. The injection into the human body of epinephrine or certain antihistaminic substances provokes the release of histamine and thereby produces a rise in the histamine blood level. There is a remarkable conformity of potency of antihistaminics as determined by Dale experiments and by histamine intoxication experiments in the intact guinea pig. Neoantergan, Pyribenzamine and Histadyl are usually superior to other compounds when potency is assayed by these methods. All antihistaminics provide similar protection again animal anaphylaxis. Larger doses are necessary to protect against anaphylaxis than against histamine intoxication. The differences in potency as determined by Dale experiments and histamine experiments in animals are not found in clinical use. One compound is not generally superior to all others in the treatment of any one or several allergic disorders. The antihistaminic drugs are beneficial in the symptomatic treatment of allergic rhinitis, acute urticaria and angioneurotic edema, and mild non-infective bronchial asthma. Their effectiveness in the management of moderately severe and severe non-infective bronchial bronchial asthma; infective bronchial asthma; migraine; atopic dermatitis (disseminated neurodermatitis), and pruritus of skin disorders other than acute urticaria and angioneurotic edema, is not worthy of particular commendation. The size of the dose of any antihistaminic substance influences the incidence of but not the type of side-effect that may accompany its usage. The quality of side effects varies according to the drug, although there is an individuality of response for each patient which must be reckoned with. In selecting an antihistaminic compound it is necessary to consider the percentage of cases in which side effects occur, as well as the percentage of good results. Optimal results are obtained by employing combinations of compounds and changing from one to the other as the case demands.     

Anti-inflammatory, analgesic and antipyretic activities of Linum usitatissimum L. (flaxseed/linseed) fixed oil

The fixed oil of L. usitatissimum (flaxseed/linseed) inhibited PGE2-, leukotriene-, histamine- and bradykinin-induced inflammation. The oil also inhibited arachidonic acid-induced inflammation, suggesting its capacity to inhibit both cyclooxygenase and lipoxygenase pathways of arachidonate metabolism. In tail immersion model, the oil raised the pain threshold to a lesser extent than morphine but showed excellent peripherally acting, analgesic activity comparable to aspirin, against acetic acid-induced writhing in mouse. In typhoid paratyphoid A/B vaccine-induced pyrexia, the oil showed antipyretic activity comparable to aspirin. The oil contains 57.38% alpha-linolenic acid. Dual inhibition of arachidonic acid metabolism, antihistaminic and antibradykinin activities of the oil could account for the biological activity and the active principle could be alpha-linolenic acid an omega-3 (18:3, n-3) fatty acid.     

Antimycobacterial and H1-antihistaminic activity of 2-substituted piperidine derivatives

2-Substituted derivatives of the antihistaminic agents Bamipine, Diphenylpyraline and of their 1-phenyl analogues were tested for their antimycobacterial and H(1)-antagonistic activities. They are strong H1-receptor antagonists and also inhibit the growth of mycobacterials with a maximum MIC of 6.25 microg/mL against Mycobacterium tuberculosis H(37)Rv. H1-receptor antagonistic potency was slightly decreased by substitution in ring position 2 and distinctly diminished by N-aryl substitution. The antimycobacterial potency of Diphenylpyraline was in general increased by substitution in ring position 2, whereas only a few Bamipine derivatives showed markedly improved activity. A correlation between the two activities was not detected for those compounds.     

Effects of histamine and H1 and H2-receptor antagonists on wet-dog-shake episodes in rats induced with tranylcypromine and 5-methoxytryptamine

Intraperitoneally administered tranylcypromine and 5-methoxytryptamine induced in rats the so called wet-dogs-shake behaviour. Histamine injected intraventricularly had no effect on the number or episodes of this behaviour during the first 40 minutes of observation. On the other hand, dimaprit in doses of 5 micrograms/rat injected also intraventricularly increased the number of these episodes. Thenalidine and antazoline--antagonists of the H1-receptor, and cimetidine and ranitidine--antagonists of the H2-receptor, decreased the number of these episodes proportionally to the injected dose. Similar effects were obtained after cimetidine injection into the lateral ventricle. In the light of these observations it may be supposed that these antihistaminic agents exert an inhibitory effect not only on the histaminergic system but decrease indirectly also the activity of the serotoninergic system.     

Effect of antihistaminic preparations on gastric secretion in rats

Experiments were made to study the influence of a new antihistaminic drug phencarol [(quinuclidyl-3) diphenylcarbinol hydrochloride] on gastric secretion in rats. Unlike the blockers of H1-histamine receptors (diphenhydramine, omeril, pyrilamine, and cyproheptadine), phencarol reduces secretion and the content of free hydrochloric acid in the gastric contents. The antacid activity of the drug is similar to that of the H2-receptor blocker, cimetidine. However, phencarol differs from the latter drug in the mechanism of action. The antacid action of phencarol is likely to be the result of its activation effect on diamine oxidase, which leads to a decrease in the content of active histamine in the tissues and diminution of its supply to H2-histamine receptors that control gastric secretion.     

ANTIHISTAMINE IN THE PREVENTION OF SERUM REACTION FOLLOWING INJECTION OF TETANUS ANTITOXIN

Of 100 patients given tetanus antitoxin, 56 were given an antihistaminic drug in oral doses of 50 mg. daily for ten days following injection. The other 44 were not given antihistamine. The incidence of serum reaction in the former group was 3.6 per cent; in the latter, 20.4 per cent.     

Physicochemical and biological properties of an extracellular serine protease of Aeromonas sobria

Previously, we cloned a protease gene of Aeromonas sobria, determined its nucleotide sequence and established a method of purifying its product. In this study, we examined the properties of the purified protease. The protease was temperature-labile and had an optimal pH of 7.5. Metallo-protease inhibitors and a cysteine protease inhibitor did not block the proteolytic activity of the enzyme. The treatment with reagents to modify sulfhydryl group did not reduce the activity. But, serine protease inhibitors did, showing that it was a serine protease. Subsequently, we examined the ability of the protease to enhance vascular permeability in dorsal skin. The protease showed activity and the reaction was inhibited by a simultaneously injected antihistaminic agent. Histopathological examination showed that mast cells appeared around the site where the protease was injected. These findings show that the vascular permeability-enhancing effect of the protease is due to histamine released at the site. Furthermore, we found that a soybean trypsin inhibitor (Kunitz) did not block the proteolytic action of the protease in vitro, but inhibited its vascular permeability-enhancing activity in skin. This suggests that a trypsin-like protease from skin mediates the activity of the protease to enhance its vascular permeability.     

Experimental investigations on action of antihistaminic nasal solutions; a preliminary report

The effect of antihistaminic drugs in the form of solutions for nasal instillation on the mucous membranes of rabbits was investigated. So far as histologic observations would indicate, Antistine(R)-Privine(R) was the most harmful and caused almost complete necrosis throughout the entire nasal area. Pyribenzamine(R) was the least harmful. Allergan(R) caused more damage than did Pyribenzamine in the nasal mucosa of rabbits, but considerably less than Antistine-Privine.Clinically, the author has observed Antistine-Privine to be extremely irritating when employed as a topical application for symptomatic relief of nasal allergic disease. Pyribenzamine has caused considerable pain and discomfort in patients and has been least effective for relief of nasal congestion since it does not contain a vasoconstrictive agent. Allergan has not been observed by the author to be irritating to any degree in patients with nasal allergic disease unaccompanied by acute infection, and it has been noted to be the least irritating of these three antihistaminic solutions in nasal allergic disease complicated by infection.     

EXPERIMENTAL INVESTIGATIONS ON ACTION OF ANTIHISTAMINIC NASAL SOLUTION—A Preliminary Report

The effect of antihistaminic drugs in the form of solutions for nasal instillation on the mucous membranes of rabbits was investigated. So far as histologic observations would indicate, Antistine®-Privine® was the most harmful and caused almost complete necrosis throughout the entire nasal area. Pyribenzamine® was the least harmful. Allergan® caused more damage than did Pyribenzamine in the nasal mucosa of rabbits, but considerably less than Antistine-Privine.Clinically, the author has observed Antistine-Privine to be extremely irritating when employed as a topical application for symptomatic relief of nasal allergic disease. Pyribenzamine has caused considerable pain and discomfort in patients and has been least effective for relief of nasal congestion since it does not contain a vasoconstrictive agent. Allergan has not been observed by the author to be irritating to any degree in patients with nasal allergic disease unaccompanied by acute infection, and it has been noted to be the least irritating of these three antihistaminic solutions in nasal allergic disease complicated by infection.     

Selective inhibition of brain Na,K-ATPase by drugs

The effect of drugs from the class of cardiac (methyldigoxin, verapamil, propranolol), antiepileptic (carbamazepine), sedative (diazepam) and antihistaminic (promethazine) drugs on Na,K-ATPase activity of plasma membranes was studied in rat brain synaptosomes. Methyldigoxin in a concentration of 0.1 mmol/l inhibits enzyme activity by 80 %. Verapamil, propranolol and promethazine in concentrations of 20, 20 and 2 mmol/l respectively, entirely inhibit the ATPase activity. Carbamazepine and diazepam in concentrations of 0.02-60 mmol/l have no effect on the activity of this enzyme. According to the drug concentrations that inhibit 50 % of enzyme activity (IC(50)), the potency can be listed in the following order: methyldigoxin promethazine verapamil ? propranolol. From the inhibition of commercially available purified Na,K-ATPase isolated from porcine cerebral cortex in the presence of chosen drugs, as well as from kinetic studies on synaptosomal plasma membranes, it may be concluded that the drugs inhibit enzyme activity, partly by acting directly on the enzyme proteins. Propranolol, verapamil and promethazine inhibitions acted in an uncompetitive manner. The results suggest that these three drugs may contribute to neurological dysfunctions and indicate the necessity to take into consideration the side effects of the investigated drugs during the treatment of various pathological conditions.     

Okicamelliaside, an extraordinarily potent anti-degranulation glucoside isolated from leaves of Camellia japonica

Guided by anti-degranulation assays, we isolated from leaves of Camellia japonica an ellagic acid glucoside named okicamelliaside. The structure was elucidated as 3,4-dioxoloellagic acid 4'-O-β-D-glucopyranoside by spectroscopic and chemical methods. Okicamelliaside was 12,000 times more potent than the antihistaminic drug, ketotifen fumarate, in inhibiting the degranulation of RBL-2H3 cells.     

A review of the tolerability and safety of levocabastine eye drops and nasal spray. Implications for patient management

Levocabastine is a highly potent and selective H(1)-receptor antagonist specifically developed for topical administration by ocular and nasal routes. The clinical effects of levocabastine occur rapidly and are predominantly due to local antihistaminic effects at the site of application. Clinically, levocabastine is well tolerated with an adverse effect profile comparable with that of sodium cromoglycate and placebo. As might be expected from the route of drug administration, local irritation is the most frequent adverse event seen with levocabastine eye drops and nasal spray with an incidence comparable with that in placebo-treated controls. Intranasal application of levocabastine has been shown to have no adverse effect on ciliary activity both in vitro and in vivo, while ocular administration has not been shown to have any significant or consistent adverse effect in both animal and human studies. At therapeutic doses, levocabastine appears to be devoid of significant systemic activity producing no apparent effects on cardiovascular, psychomotor and cognitive function. Since levocabastine undergoes little hepatic metabolism, and only low plasma levels of the drug are attained following topical administration, drug interactions are unlikely.