Current Medicinal Chemistry - Anti-Inflammatory & Anti-Allergy Agents - Volume 4, Issue 5, 2005

Antihistamines are among the most commonly prescribed drugs in the world. They are widely used in the treatment of conditions such as urticaria and angioedema, seasonal and perennial rhinoconjunctivitis, and pruritic diseases occurring in children and adults. The first generation antihistamines are still widely available and in use today since their first introduction more than 50 years ago. As these drugs have considerable sedative effects that can interfere with the quality of life of patients, the second generation antihistamines were introduced as nonsedating alternatives. However, some of them have shown rare but lethal cardiotoxic side effects. The third generation antihistamines are metabolites of the earlier drugs with favourable pharmacokinetic properties, and few adverse events. This special issue of the journal deals with advances in the development of the new antihistamines, mechanism of action of the old and new antihistamines, their use in different allergic and nonallergic conditions, principals of antihistamine use in children and pregnancy, the systemic and cutaneous adverse reactions of antihistamines as well as their adverse effects on skin tests. Antihistamines seem to be the mainstay of therapy of many allergic conditions in the future, too. The considerable evolution of new antihistamines is promising, and the improvement in their clinical benefit / risk ratio will improve the quality of life of patients.

H1 antihistamines are widely used in the treatment of allergic disorders. The CNS depressant and antimuscarinic effects of the first generation compounds limited their use in allergic disorders, and the second generation compounds were developed to reduce or eliminate these effects. However, the use of the first second generation H1 antihistamines, terfenadine and astemizole, under certain circumstances, was associated with adverse cardiac effects, which were occasionally fatal and they were withdrawn from the market. This review examines the pharmacokinetics of the second generation antihistamines and the impact of the pharmacokinetic properties on their efficacy and safety, particularly with regard to their effects on the central nervous and cardiovascular systems and their potential for interactions with concomitantly administered drugs and dietary components.

Antihistamines have an important role in dermatology. In order to understand how antihistamines work, effects of histamine should be examined first. Histamine was first defined in 1920s and was shown to take part in the pathogenesis of diseases such as urticaria, anaphylaxis, asthma, and allergic rhinitis. The main goal in the treatment of urticaria and other diseases related to histamine is to keep this powerful mediator's effects under control. So many antihistamines have been presented to the market since 1942 and still, new compounds are being developed. For years, antihistamines have been categorized as first, second and third generation. In this text, a review of the action mechanism of antihistamines and the new antihistamines will be presented.

Allergic rhinitis is a common disease worldwide and antihistamines remain the mainstay of pharmacotherapy for allergic rhinitis. Histamine is one of main mediators involved in the disease pathophysiology. The primary mechanism of antihistamine action is believed to be competitive antagonism of histamine receptors, specifically the H1-receptors. These receptors are present on nerve endings, smooth muscles, and glandular cells. However, H1- antagonism may not be their sole mechanism of action. Antihistamines have been used in two forms; oral and topical, in the management of allergic rhinitis. The use of the first-generation oral antihistamines (chlorpheniramine, diphenhydramine, promethazine, tripolidine, clemastine, and tripelennamine) is considerably limited by their sedative and anticholinergic effects. The secondgeneration antihistamines (acrivastine, astemizole, azelastine, cetirizine, ebastine, fexofenadine, loratadine, mizolastine, and terfenadine) are effective in reducing nasal symptoms, and have no sedative effects. However, terfenadine, astemizole and recently, loratadine, have been found to cause prolongation of the QT interval on electrocardiogram, and can increase the risk for development of potentially lethal ventricular tachyarrhythmias, or torsades de pointes. The next-generation antihistamines (fexofenadine, desloratadine, tecastemizole, and levocetirizine) are typically the structurally modified, active metabolites or isomers of second-generation antihistamines. These agents retain the non-sedating properties of second- generation antihistamines while eliminating or limiting the cardiac risks. Topical antihistamines (azelastine and levocabastine), delivered by nasal spray, avoid or minimize systemic adverse effects. They have a rapid onset of action (less than 15 min) at low drug dosage, but their action is limited to the treated organ.

Approximately 20% of the general population have allergic symptoms of various forms. One third of these people have also ocular symptoms. Some forms of ocular allergy can cause severe symptoms and result in significant ocular morbidity. Allergic ocular disease consists of allergic conjunctivitis (including seasonal hay fever and perennial allergic rhinoconjunctivitis and acute anaphylaxis), giant papillary conjunctivitis (including vernalis, atopic keratoconjunctivitis and contact lens induced conjunctivitis), contact dermatokeratoconjunctivitis and microbioallergic disease. Histamine is the most prominent mediator in allergic ocular disease and causes increased vasopermeability, vasodilation, and bronchoconstriction, mediated through histamine receptors. Both H1 and H2 receptors have been identified on the ocular surface. Oral H1-receptor blockers can be given to relieve symptoms in the allergic ocular disease, but side effects such as sedation and systemic anticholinergic reactions are possible. Newer oral antihistamines such as astemizole and terfenadine supposedly have lesser side effects. Topical H1-receptor blocking antihistamine drugs are now available. Levocabastine is an agent with proven efficacy. There are no topical H2-receptor antagonists presently available for ocular use, but such agents have theoretic potential, especially in combination with an H1-receptor blocker

Antihistamines can be used in various disorders of dermatology. They are the mainstay of pharmacological therapy used in the management of urticaria and angioedema. They are also important in the management of atopic dermatitis, mastocytosis, eosinophilic disorders, contact dermatitis and flushing. Pruritus associated with other conditions such as lichen planus, pityriasis rosea, lichen simplex chronicus, dermatomyositis, amyloidosis, nummular dermatitis, exfoliative dermatitis, prurigo gravidarum, herpes gestationis, pruritic urticarial papules and plaques of pregnancy, erythema annulare centrifugum and erythema gyratum repens may also be relieved by antihistamines. Sedative antihistamines may help patients to reduce pruritus in scabies, prurigo nodularis, pruritus ani, lichen sclerosus and Grover disease. In bedbug, spider, human flea, bee, wasp, hornet or mosquito bites and in autosensitization dermatitis besides topical antipruritic agents, systemic antihistamines can be used against pruritus. Also, antihistamines may relieve pruritus in infestations, sponge dermatitis or cercarial dermatitis and can be used in varicella infection. Antihistamines are often helpful for relieving pruritus in exanthematous reactions to medications. Pruritus secondary to underlying medical disorders or of an idiopathic nature may also be relieved by these antihistamines, although controlled trials do not exist.

H1 antihistamines are first line drugs in the treatment of allergic rhinitis and chronic idiopathic urticaria and widely used in children as well as in adults. Although first-generation antihistamines are effective in relieving allergic symptoms, they are not preferred because of their sedative side effects. The earliest "second generation" antihistamines, terfenadine and astemizole, non-sedating alternatives to the first generation counterparts are not commonly used due to their potential arythmogenic effects. The newer second-generation antihistamines such as loratadine, fexofenadine, mizolastine, ebastine, cetirizine, levocetirizine and desloratadine have been shown to be efficacious and well tolerated with additional anti-inflammatory effects and lacking cardiotoxic potential activity in adults. The early treatment of atopic children study, the long term clinical trial with cetirizine of infants with atopic dermatitis demonstrated that cetirizine delayed the onset of asthma in patients sensitized to grass pollen or house dust mite; and also reduced the duration and the amount of topical steroids used in the treatment of atopic dermatitis. In the Preventia I study, which was designed to evaluate the efficacy of loratadine in reducing the number of respiratory infections in young children at risk of recurrent infections, loratadine was not found to be significantly different from placebo. Both drugs were found to have a similar safety profile to that of placebo confirming their long-term use in infants and children. Pediatric formulation of desloratadine, which has favorable effect on nasal congestion, is marketed worldwide now. The effectiveness of new antihistamines in the treatment of urticaria in pediatric age group is based on extrapolation of adult studies performed in this area. Further studies with new antihistamines are needed for their evidence-based use in children with urticaria and atopic dermatitis.

Antihistamines are already among the most frequently used pharmaceutical compounds and with the predictable increase of the prevalence of atopic disease, even more patients are expected to use them in future. Though the common belief on their safety has existed since some decades, they, including the over the counter ones, might potentially bear serious side effects. Thus , the following article focuses on the adverse effects of antihistamines by summarizing the current data mainly on central nervous system and cardiovascular side effects. Meanwhile, less common side effects, and important issues like their use in pregnancy and lactation are also included. Updated information is provided on drug interactions and overdose situations along with their management. As a finalstep, pitfalls in choosing suitable antihistamine/ s in special circumstances to avoid adverse effects are also covered.

Allergy skin tests are the best and most reliable method of diagnosing allergies. Medications may influence the interpretation of skin testing. Antihistamines interfere with prick and intradermal skin tests, while they do not suppress patch tests. Some other medications also have influence on allergy skin tests. It's important to know the suppression mechanism and the duration of the inhibitory effect of these drugs on the skin test to get correct interpretation, which would be a valuable guide in allergen identification and avoidance in treatment of allergies. Allergic diseases are common and bothering medical problems in pregnant patients. It's generally recommended to avoid all medications during pregnancy, if possible. But sometimes antihistamines are needed to be used in the treatment of allergic diseases regarding the benefit/risk ratio. In such cases, antihistamines should be carefully chosen. Considering the animal and human data available, chlorpheniramine seems to be the antihistamine to choose with the least risk.

Cutaneous adverse reactions to systemic antihistamines are rare but an important finding. The reaction may vary from an eczematous eruption as the most frequent type, to rare but severe reactions such as urticaria / angioedema, erythema multiforme / Stevens-Johnson syndrome or Lyell syndrome. This is a review of the reported types of cutaneous adverse reactions due to systemically administered old and new antihistamines.

PPAR-γ (peroxisome proliferator activated receptor gamma) mediates ligand-dependent transcriptional activation and repression. PPAR-γ was shown to be directly activated by naturally occurring fatty acids and several synthetic compounds such as thiazolidinediones (TZDs), agonists of PPAR-γ. TZDs are used in the first place as orally active antidiabetic agents in the treatment of type 2 diabetes. Lately, it has been implicated that TZDs might also serve as regulators of inflammatory diseases. TZDs inhibit the production of monocyte inflammatory cytokines such as RANTES, TNF-α, IL-6 and IL-1β in vitro and reduce plasma concentrations of TNF-α, sICAM-1, MCP-1, CRP and PAI-1 in vivo. TZDs can also stimulate the secretion of IL-6, IL-8 and CSF-1 in a cultured human endometrial cell line (EM42), which suggested a role of PPAR-γ in the pathogenesis of endometriosis. Although TZDs are not currently in clinical use as anti-inflammatory drugs, more recent observations were done to show that TZDs act as anti-inflammatory substances in several diseases. TZDs have anti-inflammatory, antiatherogenic and anti-oxidative stress effects reducing the incidence and severity of atherosclerosis and can reduce blood pressure. TZDs may be of therapeutic benefits in patients with Alzheimer's disease (AD) based on convergent findings that insulin also plays a role in aspects of CNS function. It has been confirmed that TZDs can prevent progressive cavitation by limiting inflammation subsequent secondary damage after CNS trauma in vivo and in vitro. TZDs can also prevent experimental autoimmune encephalomyelitis. The beneficial effects of TZDs in some autoimmune or atopic diseases, such as multiple sclerosis (MS), psoriasis, atopic dermatitis and asthma, and a common chronic liver disease, nonalcoholic steatohepatitis (NASH) have been shown in several clinical trials. There are some recent data demonstrating that TZDs may have anti-inflammatory properties in animal models and in cellular systems of other diseases such as inflammatory bowel disease, arthritis, glomerulonephritis, sepsis, chronic obstructive pulmonary disease (COPD) and endometriosis. All of the above mentioned results reveal a novel potential anti-inflammatory pathway of TZDs in these diseases.

We found that compounds, which can selectively inhibit the activity of mammalian DNA polymerase λ (pol λ) in vitro, show an anti-12-O-tetradecanoylphorbol-13-acetate (TPA)-induced inflammatory effect in mice. Originally, we screened selective inhibitors for each of the mammalian DNA polymerases, and found two novel pol λ-inhibitors, phenolic compounds termed petasiphenol and curcumin (diferuloylmethane). Curcumin is known as an anti-chronic inflammatory agent and structurally quite similar to petasiphenol. The IC50 values of petasiphenol and curcumin for pol λ were 7.8 μM and 7.0 μM, respectively, and neither compound influenced any other mammalian DNA polymerases. Expectedly, petasiphenol also showed an anti-TPA-induced inflammatory effect. A relationship between the pol λ-inhibition and the anti-inflammatory activity is suggested. Therefore, we investigated whether other anti-inflammatory compounds such as terpeno benzoic acids, triterpene acids and epolactaene derivatives could be pol λ-inhibitors. Although all the compounds influenced not only several different DNA polymerase species but DNA topoisomerase II, they all most efficiently inhibited the pol λ-activity. These results unexpectedly suggest that there is a physiological relationship between pol l inhibition and anti-TPA-induced inflammation. This finding may provide insight into the molecular mechanism of TPAinduced inflammation, or neoplastic promotion.