DEVELOPMENTS: THE "DUAL-ACTING" ANTIHISTAMINES
Over the several past decades, there has been considerable interest in the development of novel antihistaminic compounds with dual mechanisms of action including H1-receptor antihistaminic action and mast cell stabilization. Currently available drugs that exhibit such dual antihistaminic actions include azelastine and ketotifen. These compounds contain the basic pharmacophore to produce relatively selective anti-histaminic action (diarylalkylamines) as well as inhibition of the release of histamine and other mediators (e.g., leukotrienes and PAP) from mast cells involved in the allergic response. In vitro studies suggest that these compounds also decrease chemotaxis and activation of eosinophils. Azelastine and ketotifen currently are indicated for the treatment of itching of the eye associated with allergic conjunctivitis. Their antiallergy actions occur within minutes after administration and may persist for up to 8 hours. The structures, chemical properties, pharmacological profiles, and dosage data for these agents are provided in the monographs that follow.
Azelastine hydrochloride, (± )-4-[(4-chlorophenyl) methyl]-2-(hexahydro-l-methyl-1H-azepin-4-yl)-l-(2H)-phthalazinone monohydrochloride (Optivar), is a white crystalline powder that is sparingly soluble in water, methanol, and propylene glycol and slightly soluble in ethanol, octanol, and glycerine. The commercial preparation is available as a 0.05% sterile ophthalmic solution for topical administration to the eyes. Each milliliter of azelastine solution contains 0.5-mg azelastine hydrochloride equivalent to 0.457 mg of azelastine base, the preservative benzalkonium chloride (0.125 mg), and inactive ingredients including disodium edetate dihydrate, hydroxypropyl-methylcellulose, sorbitol solution, sodium hydroxide, and water for injection. The solution has a pH of approximately 5.0 to 6.5 and an osmolality of approximately 271 to 312 mOsm/L.
The recommended dose of azelastine solution is 1 drop instilled into each affected eye twice a day. This drug product is for ocular administration only and not for injection or oral use. Absorption of azelastine following ocular administration is relatively low (less than 1 ng/rnL). Absorbed drug undergoes extensive oxidative N-demethyl-ation by CYP, and the parent drug and metabolite are eliminated primarily in the feces. The most frequently reported adverse reactions are transient eye burning or stinging, headaches, and bitter taste. Azelastine solution should be used with caution during pregnancy or while nursing, because its safety has not been studied under these circum-
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Hypnosis has been defined as a state of heightened suggestibility in which the subject is able to uncritically accept ideas for self-improvement and act on them appropriately. When a hypnotist hypnotizes his subject, it is known as hetero-hypnosis. When an individual puts himself into a state of hypnosis, it is known as self-hypnosis.