Olopatadine (AL-4943A; KW-4679) [(z)-11-[3-(dimethylamino)propylidene]-6, 11-dihydrodibenz[b,e]oxepine-2 acetic acid hydrochloride] is an anti-allergic agent which inhibits mast cell mediator release and possesses histamine H1 receptor antagonist activity. Studies were conducted to characterize the in vitro and in vivo pharmacological profile of this drug relevant to its topical ocular use. AL-4943A inhibits histamine release in a concentration-dependent fashion (IC50 = 559 microM) from human conjunctival mast cell preparations in vitro. Histamine release was not stimulated by AL-4943A at concentrations as high as 10 mM. In contrast, ketotifen stimulated histamine release at concentrations slightly higher than effective inhibitory concentrations. AL-4943A did not display any in vitro cyclooxygenase or 5-lipoxygenase inhibition. Topical ocular application of AL-4943A effectively inhibits antigen- and histamine-stimulated conjunctivitis in guinea pigs. Passive anaphylaxis in guinea pig conjunctiva was attenuated by AL-4943A applied 30 min prior to intravenous or topical ocular antigen challenge (ED50 values 0.0067% and 0.0170%, w/v, respectively). Antihistaminic activity in vivo was demonstrated using a model of histamine-induced vascular permeability in guinea pig conjunctiva. AL-4943A applied topically from 5 min to 24 hrs prior to histamine challenge effectively and concentration-dependently inhibited the vascular permeability response, indicating the compound has an acceptable onset and a long duration of action. Drug concentrations 5-fold greater than those effective against histamine-stimulated conjunctival responses failed to inhibit vascular permeability responses induced with either serotonin or Platelet-Activating-Factor. These data indicate that the anti-histaminic effect observed with AL-4943A is specific. These anti-allergic/antihistaminic activities of AL-4943A observed in preclinical model systems have been confirmed in clinical trials in allergic patients.

Emedastine [l-(2-ethoxyethyl)-2-(4-methyl-l-homopiperazinyl)-benzimidazole difumarate] was evaluated for topical ocular anti-histaminic activity in histamine and antigen stimulated conjunctivitis models. Concentration-dependent inhibition of histamine induced vascular permeability changes occurring in the conjunctiva was observed when the time interval between topical ocular administration and histamine challenge ranged from 1 min to 8 hr. The calculated ED50 values obtained using intervals of 1 min, 30 min, 2,4 and 8 hr were 0.0002%, 0.000035%, 0.0029%, 0.019% and 0.19%, w/v, respectively. Comparisons of relative potency 30 min post dosing between emedastine and other anti-histamines demonstrated that emedastine is equipotent to ketotifen, and 7, 7, 10, 10, 100, 357, 3333, and 5813 times more potent than brompheniramine, chlorpheniramine, clemastine, pyrilamine, levocabastine, pheniramine, diphenhydramine, and antazoline, respectively. Emedastine (0.1%) failed to significantly attenuate either serotonin or platelet-activating-factor induced vascular permeability changes indicating high selectivity for the histamine H, receptor. In a passive conjunctival anaphylaxis model in guinea pigs, significant inhibition of the allergic response was observed following topical ocular administration of emedastine 5 min or 30 min prior to antigen challenge (ED50s 0.0046% and 0.00022%, respectively). These data clearly indicate that emedastine has potential as a topical ocular anti-histamine for treating allergic conjunctivitis.

Bromfenac [2-amino-3-(4-bromobenzoyl)benzeneacetic acid sodium salt sesquihydrate] is an anti-inflammatory/analgesic agent that possesses potent topical activity in rats, guinea pigs, and mice. In rat models of acute (carrageenan paw edema) and chronic (adjuvant arthritis) inflammation, preparations of bromfenac at concentrations as low as 0.01-0.32% (0.01-0.32 mg bromfenac) produced significant anti-inflammatory activity when applied to the injected paw or to the backs of rats. In the acute paw edema test, topical bromfenac was more potent than indomethacin or hydrocortisone and about as active as triamcinolone acetonide. Bromfenac, at concentrations of 0.1-0.32%, showed topical analgesic activity in the acetylcholine-induced abdominal constriction test in mice. In this test, bromfenac was more potent than indomethacin (24.9X), more potent than ketoprofen (approximately 14.9X), and superior to piroxicam. In the guinea pig UV-erythema test, bromfenac was active (26.1X indomethacin) when applied to the UV-exposed site, but not when applied away from the site. The results suggest that bromfenac has activity topically because of a local and a systemic effect. Test results obtained with a long (4-7 hr) pretreatment time (paw edema, adjuvant arthritis, abdominal constriction) are due in great part to a systemic effect of topically applied bromfenac, while the UV-erythema test (1-hr treatment time) clearly indicates a local effect.

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Rocastine [AHR-11325, 2-[2-(dimethylamino)ethyl]-2,3-dihydro-4-methylpyrido-[3,2-f]-1,4- oxazepine-5(4H)-thione (E)-2-butenedioate)] is a rapid-acting, potent, nonsedating antihistamine. In guinea pigs challenged with a lethal dose of histamine, rocastine is as effective [based on 1 hr. oral, protective dose (PD50S)] as brompheniramine, chlorpheniramine, pyrilamine, and promethazine and superior to astemizole, diphenhydramine, terfenadine, and oxatomide. Rocastine has a faster onset of action than does terfenadine; rocastine being as effective with a 15 min pretreatment time (PD50 = 0.13 mg/kg) as it is with a 1 hr pretreatment time (PD50 = 0.12 mg/kg), while the 15 min PD50 of terfenadine (PD50 = 44.0 mg/kg) is 22 times greater than the 1 hr PD50 (PD50 = 1.93 mg/kg). Against aerosolized histamine, rocastine was 7.12 x, 2.63 x, and equipotent to pyrilamine in preventing histamine-induced prostration at pretreatment times of 1,3, and 6 hr, respectively. Rocastine protected guinea pigs from collapse induced by aerosolized antigen; rocastine was approximately 36 x more potent (based on 1 hr PD50) than diphenhydramine and as potent as oxatomide and terfenadine. Rocastine did not alter the EEG of cats at doses in vast excess (150x) of its antihistaminic dose nor did it potentiate yohimbine toxicity in mice. Further, rocastine possesses no anticholinergic, antiadrenergic, or antiserotonergic properties in vitro. Rocastine is a selective, nonsedating, H1-antagonist with a rapid onset of action.