H2 antihistamines augment antigen-induced histamine release from human basophils in vitro

H2 antihistamines, including cimetidine, burimamide, metiamide, and tiotidine, consistently augmented antigen-induced histamine release from human basophils in vitro when control histamine release was less than 20% of total. This effect was specific to the H2-receptor blocking activity of these drugs: equivalent degrees of receptor blockade by four different H2 antihistamines resulted in equipotent enhancement; H1-receptor antagonists did not alter histamine release; and aminoguanidine and amodiaquine, agents that inhibit histamine metabolism but do not block H2 receptors, did not enhance histamine release. Cimetidine did not enhance release when present a) when basophils were "activated" but did not release histamine ("first stage"), or b) when basophils were no longer susceptible to histamine inhibition ("second stage"). Thus, H2 antagonists enhanced histamine release by blocking the capacity of released histamine to act on H2 receptors to inhibit release. Because it is likely that only small percentages of histamine are released in vivo, it is possible that H2 antihistamines amplify the inflammatory process by blocking the inhibitory effects of the released histamine.     

In-Silico Pharmacodynamics

Adverse effects are exhibited by most drugs in current clinical practice, the causes for which are often not known. In this post genomic era, bioinformatics has the potential to address several issues in understanding the mechanism of drug action and in designing improved drugs. This study describes the analysis of the possible pharmacodynamic behaviour of antihistamines blocking the histamine H(2) receptor (H(2)-antihistamines), by adopting the basic tenets of a systems biology approach. The different components that could form an appropriate sub-system are identified, thus providing a system landscape. Docking and analysis of the chosen antihistamines into each of these components resulted in identifying histamine N-methyl transferase (HNMT) as a potential unintended target for H(2)-antihistamines. Correlation with experimental data available from the literature indicates the inhibition of HNMT to be a possible cause for the adverse effects exhibited by these drugs. Implications for design of safer H(2)-antihistamines are discussed. The method reported here has the potential for application as a general strategy in understanding drug effects.     

Histamine (H2) receptor-adenylate cyclase system in pig skin (epidermis).

Histamine activated adenylate cyclase in pig skin (epidermal) slices, resulting in the accumulation of cyclic AMP. This effect was highly potentiated by the addition of cyclic AMP-phosphodiesterase inhibitors (theophylline, papaverine). A specific H2 receptor inhibitor (metiamide) inhibited the effect of histamine completely, while other antihistamines (diphenhydramine, acetophenazine, perphenazine, fluphenazine, promethazine) inhibited the effect of histamine to various lesser degrees. It has been shown that both epinephrine and prostaglandin E stimulate epidermal adenylate cyclase. Our data using specific blocking agents indicate that histamine, epinephrine and prostaglandin E2 act independently on the epidermal adenylate cyclase system.     

Histamine (H2) receptor-adenylate cyclase system in pig skin (epidermis)

Histamine activated adenylate cyclase in pig skin (epidermal) slices, resulting in the accumulation of cyclic AMP. This effect was highly potentiated by the addition of cyclic AMP-phosphodiesterase inhibitors (theophylline, papaverine). A specific H₂ receptor inhibitor (metiamide) inhibited the effect of histamine completely, while other antihistamines (diphenhydramine, acetophenazine, perphenazine, fluphenazine, promethazine) inhibited the effect of histamine to various lesser degrees. It has been shown that both epinephrine and prostaglandin E stimulate epidermal adenylate cyclase. Our data using specific blocking agents indicate that histamine, epinephrine and prostaglandin E₂ act independently on the epidermal adenylate cyclase system.     

Roles of histamine in regulation of arousal and cognition: functional neuroimaging of histamine H1 receptors in human brain

Brain histamine is involved in a wide range of physiological functions such as regulation of the sleep-wake cycle, arousal, cognition, and memory mainly through interactions with histamine H1 receptors (H1Rs). Neurons producing histamine, histaminergic neurons, are exclusively located in the posterior hypothalamus and transmit histamine to almost all regions of the brain. Histamine H1 antagonists, or antihistamines, often prescribed for treatment of allergic disorders, sometimes induce sleepiness and cognitive deficits. It is understood that the mechanism of such CNS side effects is that antihistamine blocks H1Rs in the brain. The purpose of the present study was to compare the CNS side effects of different antihistamines.Subjective sleepiness was measured using the Stanford Sleepiness Scale (SSS) and psychomotor performance was examined by a tachistoscope testing system in healthy, young, Japanese volunteers (16 males, 20-28 yrs.) before and after oral administration of antihistamines such as fexofenadine (FEX) and cetirizine (CET). Additionally, H1R occupancy by antihistamines was examined by PET with 11C-doxepin in 8 volunteers.The results of SSS and psychomotor tests demonstrated that FEX tended to be less sedative than CET though the difference was not statistically significant. PET measurements revealed that no H1Rs in the cerebral cortex were occupied by FEX while about 30% of H1Rs were occupied by CET. In summary, it was confirmed that histamine and H1Rs are involved in maintaining arousal and cognition in humans, and that the severity of clinical symptoms is correlated to the amount of antihistamine that penetrated into the brain.     

Effects of antihistamines on the cardiopulmonary changes due to canine anaphylaxis

Histamine has long been considered to be an important chemical mediator in the pathogenesis of immediate hypersensitivity reactions. We evaluated the efficacy of antihistamines to determine the physiological role of histamine in canine anaphylaxis. Either a saline vehicle (control group), an H1 antihistamine (chlorpheniramine, 10 mg/kg), or this H1 antihistamine and an H2 antihistamine (cimetidine, 30 mg/kg) was administered to three separate groups of anesthetized dogs (n = 8). Cardiopulmonary responses and plasma histamine levels were measured after the separate intravenous injection of Ascaris suum antigen and histamine. Results were analyzed only from the animals demonstrating physiological responses or histamine release after antigen injection. In the control group, antigen produced a 43 +/- 15% (mean +/- SE) decrease in mean arterial blood pressure, a 34 +/- 13% fall in cardiac output, and a 19 +/- 9% decrease in lung compliance, whereas pulmonary vascular resistance increased 161 +/- 87% and airway resistance rose 114 +/- 66%. Similar physiological abnormalities were observed with histamine shock. However, peak plasma histamine levels were, in most cases, greater after histamine injection than after antigen injection. An H1 antihistamine alone or in combination with an H2 antihistamine did not alter the physiological changes associated with systemic anaphylaxis. In contrast, the combined use of H1 and H2 antihistamines prevented the cardiopulmonary responses associated with the intravenous administration of histamine.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of histamine and histamine blockers on the ovulatory process in the vitro perfused rabbit ovary

An increase in the content of histamine in the ovary following luteinizing hormone (LH) release and the inhibition of ovulation in the rabbit by antihistamines suggest that histamine may be involved in the ovulatory process. The effects of various doses of histamine and antihistamines on ovulation were investigated using the in vitro perfused rabbit ovary system. Histamine (100 ng/ml) added to the perfusate at hourly intervals induced ovulation, although at a rate below that observed following human chorionic gonadotropin (hCG) administration. Cimetidine (10 micrograms/ml), an H2 blocker, inhibited histamine-induced ovulation, while the H1 blocker, chlorpheniramine (66.7 micrograms/ml), failed to do so. Neither cimetidine nor chlorpheniramine was able to block ovulation following hCG (50 IU). In all experimental groups in which histamine was used to induce ovulation, both extruded ova and follicular oocytes remained in an immature stage and displayed little evidence of degeneration. In contrast, a high percentage of ova exposed to hCG were mature. Ovarian edema was increased in ovaries in which ovulation occurred, regardless of treatment. A linear correlation was noted between ovulatory efficiency and degree of ovarian edema. Histamine may be an intermediary in the mechanism of follicular rupture, but does not support ovum maturation. However, the inability of H1 and H2 antagonists to block hCG-induced ovulation raises questions regarding the role of histamine in the physiologic process of ovulation.     

Mechanism of action of antipruritic drugs.

Astemizole and terfenadine, two potent non-sedative H1 antihistamines, had no effect on itch measured objectively as nocturnal scratching and subjectively on a 10 cm line. Trimeprazine, however, a more sedative but less potent H1 antihistamine, was antipruritic, as was nitrazepam, a sedative benzodiazepine. We concluded (a) that antipruritic drugs act centrally by a property related to sedation; (b) H1 receptor antagonists have a peripheral antipruritic action only when itch is due to histamine release, as in the wealing disorders. Thus the new nonsedative H1 antihistamines have no place in the treatment of itch from other causes.     

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。     

A pharmacologic analysis of the action of platelet-activating factor in the induction of hindpaw edema in the rat

Platelet-activating factor (PAF), a phospholipid product of neutrophils, alveolar macrophages, monocytes, and platelets and an important mediator of inflammatory reactions, was studied for its ability to evoke hindpaw edema in the rat. PAF caused edema, peaking at 1 hr and gradually declining over the next 2 hr. The H1 and H2 antihistamines, mepyramine and cimetidine, the serotonin/histamine antagonist, cyproheptadine, and the serotonin antagonist, methysergide, were ineffective in reducing PAF-induced paw edema. Indomethacin, acetylsalicylic acid, and dexamethasone did not inhibit the peak edematous response but significant reduction was noted with only dexamethasone at 3 hr. Prazosin and propranolol did not prevent PAF-induced edema, whereas, yohimbine, phentolamine, rauwolscine, verapamil and theophylline partially inhibited edema. Clonidine and guanfacine did not induce edema when injected into the rat hindpaw. These results suggest that PAF elicits edema at vascular sites of the rat hindpaw which are partially dependent on extracellular Ca2+ movement, are not due to alpha-1 or alpha-2-adrenoreceptor stimulation, histamine, serotonin, or prostaglandin activity, and demonstrates variable sensitivities to agents blocking Ca2+ entry. Inhibition of specific PAF-sensitive receptors await the discovery of specific PAF antagonists.     

The action of agonists and antagonists at the histamine H1 receptor and receptor protection studies in guinea pig ileum

We have examined the ability of histamine and the competitive reversible antihistamines to protect the histamine H1 receptor against alkylation with the 2-haloalkylamines, phenoxybenzamine and SY-14. In isolated guinea pig ileum these irreversible antagonists produce a parallel shift in the dose-response curve to histamine with retention of the maximum response if they are used at concentrations less than about 10(-6)M. Treatment with these 2-haloalkylamines in the presence of a high concentration of histamine did not alter the blocking activity. Thus histamine appears to be unable to protect its own receptor against irreversible blockade. The competitive reversible antagonists, on the other hand, did provide effective protection against irreversible blockade. It is likely that the competitive reversible H1 receptor antagonists have at least some part of their attachment site in common with irreversible antagonists of the 2-haloalkylamine type, while the inability of histamine to provide self-protection suggests that its primary attachment site is different from that of the antagonists.     

A pharmacologic analysis of the action of platelet-activating factor in the induction of hindpaw edema in the rat

Platelet-activating factor (PAF), a phospholipid product of neutrophils, alveolar macrophages, monocytes, and platelets and an important mediator of inflammatory reactions, was studied for its ability to evoke hindpaw edema in the rat. PAF caused edema, peaking at 1 hr and gradually declining over the next 2 hr. The H₁ and H₂ antihistamines, mepyramine and cimetidine, the serotonin/histamine antagonists, cyrpoheptadine, and the serotonin antagonist, methysergide, were ineffective in reducing PAF-induced paw edema. Indomethacin, acetylsalicylic acid, and dexamethasone did not inhibit the peak edematous response but significant reduction was noted with only dexamethasone at 3 hr. Prazosin and propranolol did not prevent PAF-induced edema, whereas, yohimbine, phentolamine, rauwolscine, verapamil and theophylline partially inihibited edema. Clonidine and guanfacine did not induce edema when injected into the rat hindpaw. These results suggest that PAF elicits edema at₂₊ vascular sites of the rat hindpaw which are partially dependent on extracellular Ca movement, are not due to -1 or -2,-adrenoreceptor stimulation, histamine, serotonin, of photaglandin activity, and demonstrates variable sensitivities to agents blocking Ca²⁺ entry. Inhibition of specific PAF-sensitive receptors await the discovery of specific PAF antagonists.     

Inflammation and the mechanism of action of anti-inflammatory drugs

Inflammation is caused by release of chemicals from tissues and migrating cells. Most strongly implicated are the prostaglandins (PGs), leukotrienes (LTs), histamine, bradykinin, and, more recently, platelet-activating factor (PAF) and interleukin-1. Evidence for their involvement comes from studies with competitive antagonists for their receptors and inhibitors of their synthesis. H1 histamine antagonists are effective for hay fever and some skin allergies such as urticaria, which indicates the importance of histamine in these conditions. Symptoms of rheumatoid arthritis are alleviated by the aspirinlike anti-inflammatory drugs, which inhibit the cyclo-oxygenase enzyme and reduce synthesis of prostanoids. Corticosteroids prevent the formation of both PGs and LTs by causing the release of lipocortin, which by inhibition of phospholipase A2 reduces arachidonic acid release. They suppress the inflammation of rheumatoid arthritis and asthma. Currently, high doses of nonsedating H1 antihistamines and PAF antagonists are being tested for the treatment of allergic asthma.     

Histamine H1-Receptor Binding Sites in Guinea Pig Brain Membranes: Regulation of Agonist Interactions by Guanine Nucleotides and Cations

Abstract: Agonist, but not antagonist, interactions with histamine H₂-receptors labeled by [³H]mepyramine are regulated selectively by sodium, divalent cations, and guanine nucleotides. Sodium decreases the affinity of histamine and the agonist 2-amino-ethylpyridine for [³H]mepyramine sites in guinea pig brain membranes up to 10-fold. The effect of sodium is exerted to a lesser extent by lithium, while potassium and rubidium are much weaker. Guanine nucleotides also decrease the affinity of histamine for H₁ binding sites about twofold. GTP and its nonmetabolized analogue GMP-PNP as well as GDP exert similar effects, while GMP, ATP, ADP, and AMP are inactive. The effects of GTP and sodium on histamine interactions with H₁-receptors are additive. By contrast, certain divalent cations enhance the potency of histamine at H₁-receptors. Manganese is most potent, while magnesium is almost as active as manganese and calcium is essentially inactive. Sodium, divalent cations, and guanine nucleotides have negligible effects on the interactions of antihistamines with H₁-receptors.     

Prolonged effect of an H1-receptor blocker antihistamine on the histamine content of white blood cells and mast cells

Hormonal imprinting usually takes place perinatally at the first encounter between the developing receptor and its target hormone, determining the future binding capacity of the receptor for life. Molecules similar to a hormone can cause faulty imprinting also with life-long consequences. Hormone production of the imprinted cell is also durably influenced. In cytogenic organs imprinting can also be provoked in adulthood. At present the effect of a single terfenadine treatment in adult rats on the histamine content of peritoneal cells (lymphocytes, mast cells and the monocyte-macrophage-granulocyte group), white blood cells (lymphocytes, granulocytes, monocytes) and thymic lymphocytes was studied 3 weeks after treatment to clarify the effect of prolonged treatment with an antihistamine in adulthood.The cells were studied by flow cytometric analysis. Peritoneal mast cells contained significantly more and thymic lymphocytes significantly less histamine than controls. In the other cells the differences were not significant. The results support earlier observations on the effect of antihistamines on mast cell histamine release (inhibition) and call attention to the fact that this effect is durable (hormonal imprinting provoked in adults).     

Utilization of protein intrinsic disorder knowledge in structural proteomics

Intrinsically disordered proteins (IDPs) and proteins with long disordered regions are highly abundant in various proteomes. Despite their lack of well-defined ordered structure, these proteins and regions are frequently involved in crucial biological processes. Although in recent years these proteins have attracted the attention of many researchers, IDPs represent a significant challenge for structural characterization since these proteins can impact many of the processes in the structure determination pipeline. Here we investigate the effects of IDPs on the structure determination process and the utility of disorder prediction in selecting and improving proteins for structural characterization. Examination of the extent of intrinsic disorder in existing crystal structures found that relatively few protein crystal structures contain extensive regions of intrinsic disorder. Although intrinsic disorder is not the only cause of crystallization failures and many structured proteins cannot be crystallized, filtering out highly disordered proteins from structure-determination target lists is still likely to be cost effective. Therefore it is desirable to avoid highly disordered proteins from structure-determination target lists and we show that disorder prediction can be applied effectively to enrich structure determination pipelines with proteins more likely to yield crystal structures. For structural investigation of specific proteins, disorder prediction can be used to improve targets for structure determination. Finally, a framework for considering intrinsic disorder in the structure determination pipeline is proposed.     

Interaction of active compounds from Aegle marmelos CORREA with histamine-1 receptor

The aim of this study is to determine the affinity of six active compounds of Aegle Marmelos Correa, they are (E, R)-Marmin, skimmianine, (S)-aegeline, aurapten, zeorin, and dustanin as antihistamines in histamine H1 receptor in comparison to cetirizin, diphenhydramine and chlorpheniramine as ligands comparison. Previously, in the in vitro study marmin obviously antagonized the histamine H1 receptor in a competitive manner. Methods: molecular docking to determine the interaction of ligand binding to its receptor. Lower docking score indicates more stable binding to that protein. Results: Marmin, skimmianine, aegeline, aurapten, zeorin, and dustanin were potential to develop as antihistamine agents, especially as histamine H1 receptor antagonists by interacting with amino acid residues, Asp107, Lys179, Lys191, Asn198, and Trp428 of histamine H1 receptor. Conclusions: Based on molecular docking, Amino acid residues involved in ligand protein interactions were Asp107, Lys179, Lys191, Asn198, and Trp428.     

The relationship between prostaglandin release and lung c-AMP levels during anaphylaxis in the guinea-pig.

A four-fold transient rise in c-AMP levels was seen when sensitized guinea-pig lungs were challenged with antigen in vitro. This rise in c-AMP also occurred in vivo and was shown to be due to release of Prostaglandin E2. This conclusion is supported by the finding that inhibitors of prostaglandin synthesis (Indomethacin and Poly phloretin phosphate) prevent the rise in c-AMP while neither ICI 74, 917, an inhibitor of histamine release, nor antihistamines had any effect on the c-AMP levels.     

HETEROGENEITY OF HISTAMINE Hi-RECEPTORS: SPECIES VARIATIONS IN [3H]MEPYRAMINE BINDING OF BRAIN MEMBRANES

[³H]Mepyramine binds with high affinity to membranes from brain of human, rat, guinea-pig, rabbit and mouse with drug specificity indicating an association with histamine H₁receptors. Considerable species differences occur in the affinity of [³H]mepyramine, with guinea-pig and human having 34 times greater affinity than rat, mouse or rabbit. The greater affinity of [³H]mepyramine in guinea-pig than in rat is attributable both to faster association and slower dissociation rates in guinea-pig. Species differences in affinity for H₁ receptor sites occur for some antihistamines but not for others. Some tricyclic antidepressant and neuroleptic drugs are extremely potent inhibitors of [³H]mepyramine binding, exceeding in potency any H₁ antihistamines examined. The tricyclic antidepressant doxepin and the neuroleptic clozapine are the most potent of all drugs examined in competing for [³H]mepyramine binding. The regional distribution of specific [³H]mepyramine binding differs considerably in the various species examined.     

Proteomic analyses of the shrimp white spot syndrome virus

White spot syndrome virus (WSSV), a unique member within the virus family Nimaviridae, is the most notorious aquatic virus infecting shrimp and other crustaceans and has caused enormous economic losses in the shrimp farming industry worldwide. Therefore, a comprehensive understanding of WSSV morphogenesis, structural proteins, and replication is essential for developing prevention measures of this serious parasite. The viral genome is approximately 300kb and contains more than 180 open reading frames (ORF). However, most of proteins encoded by these ORF have not been characterized. Due to the importance of WSSV structural proteins in the composition of the virion structure, infection process and interaction with host cells, knowledge of structural proteins is essential to understanding WSSV entry and infection as well as for exploring effective prevention measures. This review article summarizes mainly current investigations on WSSV structural proteins including the relative quantities, localization, function and protein-protein interactions. Traditional proteomic studies of 1D or 2D gel electrophoresis separations and mass spectrometry (MS) followed by database searches have identified a total of 39 structural proteins. Shotgun proteomics and iTRAQ were initiated to identify more structural proteins. To date, it is estimated that WSSV is assembled by at least 59 structural proteins, among them 35 are defined as the envelope fraction (including tegument proteins) and 9 as nucleocapsid proteins. Furthermore, the interaction within several major structural proteins has also been investigated. This identitification and characterization of WSSV protein components should help in the understanding of the viral assembly process and elucidate the roles of several major structural proteins.