Frontiers in Clinical Drug Research - Anti-Allergy Agents: Volume 3

Developing the Perfect Antihistamine for Use in Allergic Conditions: A Voyage in H1 Selectivity

Diana R. Cundell*, Kathryn E. Mickle

Division of Health Professions, College of Science, Health and the Liberal Arts, Philadelphia University, 4201, Henry Avenue, Philadelphia, PA 19144, USA

Abstract

Histamine is a potent chemical mast cell and basophil messenger able to stimulate vasodilatation, gastrointestinal, respiratory and cardiac muscle contractions.At least four types of histamine receptors exist with varying physiological effects including vasodilatation, gastric acid secretion, brain chemistry and the cardiovascular system. Pharmacological antagonists are in common usage to at least two types of these receptors, H1 and H2; H1 being the classical antihistamine used in allergic conditions and H2 antagonism primarily associated with the prevention of gastric acid secretions. The first use of antihistamines to treat allergies was made over seventy years ago and these agents have undergone many chemical derivations since in order to maximize their H1 selectivity. In order to fully understand the underlying biochemistry of allergic disease, physiological roles of mast cells and basophils will be discussed together with a review of the mechanism through which histamine stimulates the H1 receptor. This chapter will delve into the history of the discovery of histamine, development of the antihistamines and the different pharmacological generations of drugs that have occurred since. Finally, we will conclude with a discussion of the new H1antihistamines currently under development together with potential future directions for this class of pharmaceuticals.

Keywords: Combinatorial chemistry, Drug repurposing, H1, Histamine, Mast cells, Metabolomics, Urticaria and Rhinoconjunctivitis.

* Corresponding author Diana R. Cundell: Division of Health Professions, College of Science, Health and the Liberal Arts, Philadelphia University, 4201, Henry Avenue, Philadelphia, PA 19144, USA; Tel: 215-951-2664; Fax: 215-951-6812; Email: Cundelld@philau.edu

INTRODUCTION

The biological importance of histamine in allergic and anaphylactic reactions, as well as its physiologic effects on the gastrointestinal system, was first established over 100 years ago [1-6]. Anaphylaxis was first described in 1902 by Richet and Portier and was a frightening phenomenon in which guinea pigs suffered sudden death when repeatedly injected to apparently harmless sera from horses [1].

Richet and Portier [1] later extended their studies of anaphylaxis to investigate the effects of Portuguese Man-of-War jellyfish toxin, which was known to produce severe skin wheals on contact. Repeated exposure of guinea pigs to this toxin resulted in dramatic and typically fatal reactivity in the animals, which Richet termed anaphylaxis [1].Given that the jellyfish was also associated with human allergic reactions this also represents the first association between allergies and anaphylactic shock. Anaphylaxis was the name given to this phenomenon of sudden death in order to distinguish it from the prophylaxis typically seen when sera or antitoxins from immunized animals were used as vaccines or in the treatment of infectious diseases [2]. The next major connection between anaphylaxis and allergy was to come only three years later from studies of Von Pirquet and Schick [2, 3] of the disease they named serum sickness. Von Pirquet and Schick studied scarlet fever patients in a local clinic who had been treated with horse serum and then developed a fever, enlarged glands, and an itchy rash between 1 and 2 weeks later [2, 3]. In some patients, a second exposure to the animal serum then resulted in death [2, 3]. Von Pirquet and Schick [2, 3] realized that the reactivity they were seeing was similar to that previously described by Richet and Portier and that this was human anaphylaxis. Von Pirquet and Schick [2, 3] called their phenomenon allergy and suggested that it required at least two exposures to a substance in which the first made the body hyper-reactive for a second exposure.

With a connection made between allergy and anaphylaxis, it only remained for an understanding of the pathophysiology behind the conditions to be elucidated [4]. Studies by Schultz [4] of guinea pigs sensitized with horse serum demonstrated that addition of the serum generated a prolonged contraction of the smooth muscle. These studies were extended by first Barger and Dale [5] and later Dale and Laidlaw [6] who in 1910 demonstrated that the catecholamine administered to guinea pigs produced smooth muscle contraction, bronchoconstriction and stimulated cardiac muscle contraction; all hallmarks of anaphylactic shock. To this day, anaphylaxis is treated in an emergency room situation using at least two methods which antagonize histaminic effects; injection of epinephrine and administration of high doses of antihistamines [7].

Spurred by the biological importance of histamine, research institutes and pharmaceutical industries began the search for clinically useful antagonists. The first of these was 2-isopropyl-5-methyl phenoxyethyl diethylamine (929F) an ethanolamine, which was synthesized in 1933 by Fourneu and Bovet of the Pasteur Institute [8]. During the next decade several antihistamines were successfully launched including antergan (N1Ndimethyl-N1-benzyl-N-phenyl-ethylenediamine) [9], diphenhydramine [10] and phenergan (promethazine) [11]. The discovery of promethazine was particularly important, since its potent sedating effects led Rhone-Poulenc to modify the antihistamine into chlorpromazine (Thorazine) for usage in psychiatric medicine [11]. Although, in the 1940s pharmacologists did not appreciate that human histamine receptors have at least four variants (H1-H4) with separate effects [12], sedation was an issue for the development of many early anti-allergic antihistamines [13].

Indeed it was not until 1966, that anti-allergic antihistamines were given the name H1 antagonists, with H2 antagonists being those which stimulated gastric acid secretion and prevented smooth muscle contraction [14]. Histamine was already understood to control gastric acid secretion in the mid-1950s [15] but most conventional anti-allergic antihistamines of the time, being primarily H1 in nature, had no effects on the gastrointestinal tract [16]. In 1963, Dr. James Black working with Dr. James Paget at Smith, Kline and French launched a program to see whether the catecholamine bound to a different kind of receptor whose modulation would have great potential in the treatment of ulcers and reflux disease [16]. Studies to develop these other antihistamines began by using bioassays of isolated animal smooth muscle, chiefly guinea pig atrium and rat uterus as well as in vivo studies of directly stimulated rat gastric acid secretion [16]. An intelligent approach to designing a new agent was used, which was to modify the structure of histamine itself and through the discovery of 4-methylhistamine the ground work was finally laid to support the concept of a second class of receptor [16]. Modification of these assays by another team member, Dr. Mike Parsons, led to the discovery of the first active H2 antagonist metiamide in 1973 [16]. Side effects of metiamide soon led to its withdrawal, but replacement of the thiourea group with cyanoguanidine produced the first powerful H2 antagonist; cimetidine [16]. Cimetidine was launched in 1976 as the drug Tagamet™ and this therapeutic still stands today as a landmark acid-blocking medication [16]. It also illustrates the importance of intelligent drug design over accidental discovery, which would prove the undoing of some H1 antagonists as will be seen later in this chapter.

Since the 1970s a greater understanding of histamine receptors combined with elucidation of the mechanism by which tissue mast cells and circulating basophils release histamine has produced more selective second generation H1 anti-allergic pharmaceutical agents [13]. Antihistamines are now sold around the world as over the counter and prescription medications for the treatment of allergies, particularly rhinitis, conjunctivitis and urticaria [17]. These pharmaceuticals are big business as evidenced by the $14.7 billion in sales for 2015 predicted in the United States alone [18]. Given the importance of the current H1 market and the lengthy history behind its success, this chapter will now seek to detail the processes of medicinal chemistry and pharmacology that have brought us to this point. For the reader to fully understand the interaction between histamine and the body, this chapter begins with a discussion of the cellular origins of histamine, together with its role in the pathophysiology of rhinitis, conjunctivitis and urticaria. This is followed by a discussion of the historical development of H1 agents, proceeding through first and second generation antihistamines. Finally, future directions of H1 antagonists currently in clinical trials and the potential for other new combined anti-allergic therapeutics containing selective non-H1 histamine antagonists will be analyzed.

Pharmacology of Histamine

Histamine is produced in the body through the actions of the enzyme L-histidine decarboxylase on the amino acid histidine [13]. The catecholamine displays a very short half life of less than one minute [19] but has effects for between 5 and 70 minutes after exposure [20, 21]. Studies have estimated that in the absence of disease or allergy human baseline circulating levels of histamine are low, being of the order of 0.3-1.0 ng/ml of blood [22]. However, for the mediator to produce its pro-inflammatory effects on respiratory, skin, ocular, gastrointestinal, and central nervous system organs circulating levels need to be much higher [23, 24]. Skin itching (pruritis) is associated with histamine levels of the order of 3-5 ng/ml and bronchial smooth muscle contraction occurs at 7-12 ng/ml [23]. Histamine has other pro-inflammatory effects at these locations including stimulation of mucus secretion and vasodilatation, which have been shown to occur at micromolar (µM) [23] and nanogram levels [24], respectively.

Clearly to elicit reactivity in patients with allergies circulating histamine levels need to be elevated in these patients. Studies have shown that allergic individuals also seem to be more reactive to the mediator, termed histamine intolerance [23]. Indeed, Mainz and Novak [23] recently produced an excellent review of the literature detailing mechanisms behind histamine intolerance and underline two key components to the condition; impaired histamine clearance from the circulation and affected tissues combined with increased levels of histamine produced by over-reactive cells.

Histamine metabolism is known to occur through two main enzymatic processes; diamine oxidase (DAO) and histamine N-methyl transferase [HNMT or HNT in some reference works] [23]. As reviewed by Mainz and Novak [23], which enzyme system is activated appears to be associated with the tissue location and source of histamine. Of the two enzymes, it appears that HNT plays a primary role in allergy-based reactions [23]. HNMT is able to metabolize histamine only in intracellular spaces i.e. in organ/tissue based responses [25] and is manufactured in a number of tissues particularly the kidney, liver [26] and brain [27]. Studies by Yamauchi and colleagues [28] using isolated human bronchial epithelium were able to demonstrate that in the case of this particular location histamine metabolism occurred solely through HNMT, since an antagonist of DAO was without effect [28].

Interestingly, research data is now accumulating to suggest that histamine intolerance, such as occurs in allergies, may be as a result of genetically-inherited faulty HNMT activity [29, 30]. Studies by Preuss and colleagues [29] identified two common allelic variants of HNMT. HNMT with high enzymatic activity, was associated with a tyrosine amino acid in position 105 (Thr105 form), but this was replaced with an isoleucine (Ile105 form), which significantly reduced the activity [29]. Further studies by Horton and colleagues [30], determined that the Ile105 variant showed little difference in overall had a 1.3-1.8 fold increase in enzymatic Km, i.e. required more substrate to produce the same level as product as the Thr105 variant [30]. Studies by Preuss and colleagues [29], have suggested that the Thr105 variant of HNMT appears more common. In their study of 114 human kidney samples, only 10% or 11 subjects possessed the Ile105 form. Further evidence of the role of faulty HNMT in disease was provided by Yan and colleagues [31] in their studies of Caucasian asthmatic patients. These authors compared DNA samples from 237 healthy controls with those of 192 asthmatic patients for the presence of the two genetic isoforms of the HNMT enzyme [31]. They observed a significant increase in the incidence of Ile105 in the asthmatic group (27/192 individuals) compared with control subjects (19/327) (p<0.01) [31]. Thus one component of histamine intolerance is likely to be provided through one or more variants of HNMT, which allow elevated levels of histamine to prevail resulting in symptoms. As a footnote, it is also important to add at this point that some H1 antihistamines, including the early diphenhydramine, are also potent HNMT blockers [32].

Cellular Sources of Histamine and Mechanisms of Release

Early studies on the cellular origins of histamine were able to identify a single major cell as primary sources of the mediator; the tissue based mast cell [33, 34]. In ground breaking studies conducted in 1952 and 1953, Riley and West [33, 34] made several observations identifying mast cells as a major tissue source of histamine. First, using compounds that caused histamine release (liberators), Riley and West [33, 34] demonstrated that selective damage occurred to tissue mast cells isolated from rats [33]. Second, they documented that various animals possessed these cells including rats, pigs and oxen and all were able to release the catecholamine [34]. Third, they noted that some tissues had histamine levels which could not be explained by their mast cell levels, thus providing the base for further investigations on histamine-containing cells [33, 34]. Types of cells now known to generate histamine are many and each has different mechanisms used to trigger the release of the catecholamine, as outlined in Table 1 [33-47].

Table 1 Cellular histamine sources and their release mechanisms.

Abbreviations used in the Table: Ag = antigens to which the patient was previously sensitized, FcεR1 = high affinity receptor for IgE, FcγR1-RIII = receptors for IgG, GABA = Gamma-aminobutyric acid, IgE = immunoglobulin E, LPS = lipopolysaccharide.

Amounts of histamine produced by each cell also vary [46]. Human mast cells and basophils contain the most histamine with 1.0-3.0 pg/cell and 1.0 pg/cell, respectively. However, most recently neutrophils have also been shown to play a role in histamine generation [46]. Studies by Alcañiz and colleagues, using human neutrophils have demonstrated that these cells are able to release histamine via an immunoglobulin E (IgE)-mediated mechanism in sensitized, allergic individuals [46]. Neutrophils contain less histamine than mast cells and basophils (0.29 pg/cell) and the studies of Alcañiz and colleagues [46] suggest that only around one half of the available catecholamine is released following immunological challenge. These cells may, however, still be important in situations/tissues where mast cells are lacking or present in low numbers [46].

Mast cells may also increase the survival of the normally short lived circulatory neutrophil by releasing growth and anti-apoptotic factors [46, 48]. Indeed, several studies have observed that programmed cell death and removal of neutrophils is decreased in asthma patients [48, 49]. Neutrophils are also very responsive to chemoattractants released by mast cells, so they are likely to be very prevalent in the milieu of inflammation and allergic reactions [50]. Thus there appears to be a strong relationship between these cells, which in turn connects neutrophils to allergic responses in ways that may have not as yet been fully appreciated.

The currently available research suggests that there are several mechanisms through which histamine is released from cells [33-47], but the overarching theme for many is via stimulation or cross-linking of the high affinity occupied receptors for immunoglobulin E (IgE) or FcεR1 [33, 34, 44, 46]. For mast cells, allergen-induced release of histamine is the best understood and is outlined in Fig. (1) [33, 34, 44, 46].

Fig. (1))

Allergenic mechanisms of histamine release from mast cells.

Following initial exposure (sensitization) to allergens local B lymphocytes respond by the secretion of IgE, which then becomes attached to local mast cells [51]. Once the allergen is encountered for a second time (provocation), the release of mast cell mediators proceeds through a sequence of events initiated by specific antigen binding to two or more molecules of FcεR1 on the mast cell surface [39]. This is followed by a series of protein kinase associations and phosphorylation events [39], which culminate in the generation of the intracellular messenger inositol triphosphate (IP3) [39], release of stored intracellular calcium [38] and release of granules containing histamine [37-39]. A secondary mechanism by which mast cells release histamine has been termed FcεR1-independent [34, 40-43]. Studies have shown that degranulation of mast cells occurs through a G-protein stimulated mechanism, which does not involve either calcium mobilization or IP3 production [40, 41]. Several compounds have been shown to produce mast cell degranulation including substance P, venoms and peptidoglycan from bacteria [38], as well as compound 48/40 [40, 41] and the ionophore A23187 [42].

In contrast, activation of mast cells through non-FcεR1 mechanisms may not result in the generation of histamine but instead of other mast cell mediators chiefly the cytokines tumor necrosis factor alpha (TNF) and interleukin 6 (IL-6) [38]. Recently reviewed by Theoharides and colleagues [38], mast cells behave differently in inflammatory situations than in allergic conditions. During inflammation the cells undergo what is described as a piecemeal or more selective release of mediators, which typically does not include histamine [38]. Since mast cells possess more than 50 types of receptors including those for the inflammatory complement components (anaphylatoxins) C3a and C5a they are now believed to play a role in many inflammatory processes [38]. Their responses to infectious components such as bacterial lipopylsaccharide (LPS) differ from other cells in which the lipid may release histamine through FcεR1-dependent mechanisms [43]. Given that this molecule is a primary component of the gram negative bacterial membrane [44] and is released during infectious disease, this latter observation also underlines the dual nature of the mast cell in health and disease. The next section of this chapter will discuss the locations in which histamine plays a key role, focusing in allergies, involving the nose, skin and conjunctiva.

It is important for the reader to be aware that histamine is not the only product released by mast cells upon degranulation but since it released immediately its effects are felt first [51]. Additional molecules are then generated by mobilization of phospholipids in the mast cell membrane to produce the powerful leukotriene (LT), thromboxane (TX) and prostaglandin (PG) molecules whose effects are of longer duration [51]. These molecules have the capacity to recruit inflammatory cells such as neutrophils and macrophages into the area [51]. In addition, they induce these cells to release cytokines such as interleukins 1 (IL-1) and tumor necrosis factor-α (TNF-α), which can modulate cellular adhesion, phagocytosis and induce tissue injury [51].

Mast Cells and the Inflammatory Environment

Work begun in the 1960s suggested that macrophages were at the hub of directing both acute and chronic inflammation but it has become clear during the past three decades that mast cells also play a major role [52-54].

Acute inflammation is typically the response to a foreign/tumor insult and has long been shown to pivot on the initial phagocytic macrophage type that is present [53]. M1 macrophages generate pro-inflammatory molecules including interleukin-12 (IL-12) which aids in the production of T helper cells (Th1) [53]. Th1 cells are classic helper cells which are maintained by stimulation from local dendritic (antigen-presenting; APC) macrophages and are able to elicit the stimulation of production of antibodies from activated B lymphocytes and effector T cytotoxic cells [52, 53]. Th1 further promote the activation of T cytotoxic cells, which are anti-viral and anti-tumor, through the generation of the cytokines IL-2 and tumor necrosis factor alpha (TNF-α) [54]. This pro-inflammatory environment is associated with rapid and effective clearance of the threat, accompanied with a return to health [52-54]. Chronic inflammation is seen in both autoimmune disease, allergies and tumor development and is believed to involve different macrophage and T helper cell populations [52-54]. M2 macrophages differ from their M1 counterparts in that they generate immunosuppressive cytokines including IL-4, IL-10 and IL-6 which prevent T-cytotoxic cell activation [52-54]. The presence of a second subset of helper cells termed Th2, adds to the complement of immunosuppressive cytokines in the environment [52-54]. Finally, the replacement of APC with immature myeloid suppressor cells (MDSC) further perpetuates the inflammatory milieu as these cells can initiatiate the production of T regulator cells able to suppress inflammation, via IL-10 and tumor growth factor beta (TGFß) secretion, and further inhibit specific anti-tumor immunity [55].

More recently researchers have suggested that there may be several varieties of M2 macrophages or that the arbitrary division of cells into M1 and M2 may just represent more of a cellular plasticity as influenced by their microenvironment [53]. Khatami has also suggested more of a Yin and Yang approach to examining how foreign or tumor materials are removed from the body and they support this with their ground breaking studies of mast cells begun in the 1980s [52].

Khatami and colleagues investigated the cellular progression in acute and chronic conjunctivally-associated guinea pig lymphoid tissues (CALTs) when these were challenged with either antigens such as coupled ovalbumin, infectious worms or tumor-inducing agents [52]. As for other researchers of allergy, they observed a classic, initial acute inflammation, which occurred in the ocular tissue nine days after initial challenge, and was characterized by classic type I hypersensitivity reactions involving mast cell degranulation through FcεR1-dependent mechanisms [52, 56]. Tears from the animals contained elevated histamine levels and also phospholipid membrane-derived prostaglandins [52, 56]. Taken together these studies suggested that both pre-formed mediators e.g. histamine together with the de novo synthesis of arachidonic acid mediators had occurred in the guinea pig ocular mast cells [52, 56, 57].

Arachidonic acid can generate highly inflammatory mediators through either cyclooxygenase or lipoxygenase enzyme pathways [41, 58]. The lipoxygenase pathway results in the generation of several important so-called Cys leukotrienes (LTs) (LTC4, D4 and E4) which have various pro-inflammatory effects, most notably increasing mucus secretion and smooth muscle constriction [41, 58]. Activation of the cyclooxygenase pathway of arachidonic acid metabolism results in the generation of the pro-inflammatory mediator PGE2, but how much is present depends on how stressed the cells become [58]. Under non-stressed conditions, cells accumulate little PGE2 but when cells continue to be stimulated, this leads to the appearance of first the cyclooxygenase-1 (COX-1) enzyme, and then later COX-2, which has been associated with persistent inflammation and disease [58]. This pathway also leads to the production of thromboxane (TX) TXA2, which produces smooth muscle contraction, induces platelet aggregation and causes serotonin release [58]. The effects of all these lipid mediators last far longer than histamine and are more potent [58].

What set Khatami and colleagues’ research [52, 56, 59] apart was that they took the phenomenon of the allergic response a stage further in that they continued to repeatedly challenge the animals for a further 12-30 months. They observed two other responses which they termed intermediate and chronic phases [52, 56, 59]. Intermediate responses typically occurred after 2 months of sensitization and challenge and were associated with a different inflammatory milieu characterized by tissue swelling and enlargement of individual cells, exhaustion of functional mast cells, eosinophilia in the subepithelium and new growth of blood vessels [52, 56, 59]. When the authors used a classic mast cell degranulating agent (48/80) on the eyes of desensitized animals at this stage there was little reaction [52, 56, 59]. In contrast, histamine produced a classic mast cell activation and type 1 allergic response as seen in the initial acute phase of inflammation [52, 56, 59]. Khatami and colleagues [52, 56, 59] realized that these results indicated the mast cells had become non-functional i.e. were exhausted whereas histamine receptors had continued capabilities.

In the chronic phase response, which occurred more than a year after the ocular challenges had begun, Khatami and colleagues observed the induction of neoplastic-like tissue in the guinea pigs [52, 56, 60]. These nodular lymphoid lesions were more than five times larger than in unchallenged animals and were characterized by new blood vessel growth (angiogenesis), expansion of lymphoid tissue containing secondary lymphocyte follicles, activated macrophages and swollen goblet cells [52, 56, 60]. Khatami and colleagues noted that the mast cells recovered from these tissues were either completely or partially degranulated (leaky) and were the first to make a connection between the mast cell, chronic inflammation and tumorigenesis [52, 56, 60]. In this later situation, mast cell degranulation was occurring via an FcεR1-independent mechanism and that these cells were consistently releasing low levels of histamine and recruiting cells such as eosinophils and macrophages to sites of neoplastic tissue [52, 56, 60]. As was previously described, these macrophages behave in M2 fashion or may be tumor associated macrophages (TAMs), whose role is to allow the tumor’s escape as well as to stimulate new blood vessel growth to feed the growing neoplastic tissue [55].

Since these studies it has been suggested that, like macrophages, mast cells may also exhibit a duality in function that ranges from rapid and acute inflammatory reactions to chronic disease [52, 59]. They certainly seem to accumulate at tumor sites and are associated with poor patient outcomes in several neoplasias including Hodgkin’s lymphoma [61], gastric [62] colorectal [63], hepatic [64] and pancreatic cancers [65]. Mast cells also generate IL-8, which is an angiogenesis factor and stimulates tumor division (mitogen) [66]. There is also evidence that histamine from mast cells can induce proliferation of tumors such as melanoma through stimulation of H1 receptors and suppress immune surveillance through the stimulation of H2 receptors [66, 67]. Studies by Nielsen and colleagues [68] have shown that the use of the H2 antagonist ranitidine is effective in prolonging the survival of patients with colorectal cancer. Parshad and colleagues [69] suggested that administering a second H2 antagonist, famotidine, for 10-14 days pre-operatively was able to enhance the accumulation of anti-tumor lymphocytes in patients with breast cancer. A third study by Bowrey and colleagues [70] using the classic H2 antagonist cimetidine pre-operatively for a similar time period found no protective effects in breast cancer patients. There is also evidence that some H1 antagonists, most notably loratadine and astemizole can promote the growth of melanoma in animals although this has not been implicated for humans [71].

Understanding the mast cell-tumor phenomenon is further complicated by the fact that some tumors are negatively or unaffected by the presence of mast cells [66, 72]. For example, patients with breast cancer who have high numbers of mast cells in local axillary lymph nodes seem to fare better than those without [66]. A study by Tinge and colleagues [72] found no correlation between high or low levels of mast cells in patients with esophageal cancer. For those tumors in which mast cell modulation is involved it would seem that use of either histamine or leukotriene antagonists might have potential benefits. Indeed, the single study that has been done on the use of aspirin (which blocks the mast cell lipoxygenase pathway) in reducing the risk of pancreatic cancer did yield positive results [73]. This large six year study of over 900 patients and matched healthy subjects is the first of its kind to support the importance of approaching tumor intervention the way that allergic disease is managed [73]. Although not directly the subject of this monograph, it may also suggest a possible new venue for antihistamines, especially the more selective variants of the future.

Histamine and Body Tissues; Antihistamines for the Treatment of Allergies

Histamine has potent effects on a number of tissues and organs in the body, especially in areas where mast cells predominate such as the skin, and mucosa of the nasal cavity and respiratory tract [46]. In the digestive system, histamine is stored in enterochromaffin cells and is involved in the secretion of gastric acid from local parietal cells in the stomach [36]. The catecholamine is also generated by tuberomamillary neurons in the brain, where it has potent effects on wakefulness and memory [45]. Primary tissues affected by histamine and its effects on them are summarized in Table 2.

Table 2 Effects of histamine on select body locations.

Histamine has also recently been shown to produce sensitization of the nerve endings associated with pain and itch [81]. Studies by Akayima and colleagues [80], using male C57BL/6 mice, demonstrated that histamine plays a role in both acute and chronic skin itch through activation of a protease-activated receptor 2 (PAR-2) pathway [81]. These results may have implications for usage of antihistamines in many other diseases including atopic dermatitis and