Patricia B. Williams

Lacritin, a Novel Human Tear Glycoprotein, Promotes Sustained Basal Tearing and Is Well Tolerated

PURPOSE Lacritin is a novel human tear glycoprotein that promotes basal tear peroxidase secretion by rat lacrimal acinar cells in vitro. This study investigates whether lacritin is prosecretory when added topically to the ocular surface of normal living rabbits, and if so, what is its efficacy and tolerability versus cyclosporine and artificial tears. METHODS Purified recombinant human lacritin (1, 10, 50, or 100 μg/mL), inactive lacritin truncation mutant C-25 (10 μg/mL), cyclosporine (0.05%), or artificial tears were topically administered to eyes of normal New Zealand White rabbits either as a single dose or three times daily for 14 days with monitoring of basal tear production. Basal tearing under proparacaine anesthesia was repeatedly assessed throughout and 1 week after chronic treatment ceased. Eyes were examined weekly by slit-lamp biomicroscopy. RESULTS Lacritin acutely increased basal tearing to 30% over vehicle at 240 minutes. Three times daily treatment with 10-100 μg/mL lacritin was well tolerated. Basal tearing became progressively elevated 4, 7, and 14 days later and was 50% over baseline (50 μg/mL lacritin) 1 week after treatment had ceased. Cyclosporine elevated tearing to a similar level on days 4 and 7 but had little or no effect on day 14 and had returned to baseline 1 week after ending treatment. C-25 and artificial tears had no effect. CONCLUSIONS Lacritin acutely stimulates basal tear flow that is sustained for at least 240 minutes. Two weeks of lacritin treatment three times daily was well tolerated and progressively elevated the basal tear flow. One week after treatment ended, basal tearing was still 50% over baseline. In contrast, cyclosporine triggered mild to moderate corneal irritation and a temporary elevation in tearing.

Omalizumab: a future innovation for treatment of severe ocular allergy?

Conjunctival and corneal manifestations of atopic keratoconjunctivitis (AKC) are chronic, disabling and may be blinding. In common with other allergic diseases, such as asthma and atopic dermatitis, AKC is characterised by an allergen-induced immune response mediated through expression of IgE. The humanised monoclonal IgE antibody Xolair® (omalizumab) complexes with free circulating IgE, thereby preventing binding of IgE to FcεRI receptors on immune cells. Omalizumab effectively alleviates the signs and symptoms of asthma. Given the pivotal role of IgE in the allergic cascade, it is hypothesised that omalizumab has potential as an entirely new therapeutic approach to AKC.

Topical WIN55212-2 Alleviates Intraocular Hypertension in Rats Through a CB1 Receptor Mediated Mechanism of Action

INTRODUCTION Systemically administered cannabinoids can reduce intraocular pressure (IOP), but produce undesirable cardiovascular and central nervous system effects. In a chronic model of ocular hypertension, we examined the efficacy of acute topical administration of WIN55212-2 (WIN) in a novel commercially available vehicle and in combination with timolol. METHODS IOP was chronically elevated by the surgical ligature of vortex veins in Sprague Dawley rats. IOP was measured by using Goldmann applanation tonometry. IOP, blood pressure (BP), and heart rate (HR) were measured at baseline and 30, 60, 90, and 120 min after the topical administration of WIN 1.0%, 0.25%, 0.06%, or 0.015%, the commercially available vehicle, timolol 0.5%, or a combination of WIN and timolol. SR141716 (CB1 antagonist) or SR144528 (CB2 antagonist) was administered topically 30 min before WIN to determine receptor specificity. To determine ocular and systemic penetration, 3H WIN 55212-2 was administered topically and tissues were collected at 60 and 120 min. Ocular irritation was evaluated by slit-lamp examination (SLE) at baseline and 120 min. RESULTS WIN significantly decreased IOP in the hypertensive eye, with no BP or HR effects. SR141716 pretreatment significantly inhibited the IOP effects of WIN 1.0% in a dose-dependent manner, while SR 144528 was not as effective. No significant additive effects were observed by combining WIN (0.5% or 1.0%) with timolol 0.5%. WIN was retained in ocular tissue with a t1/2 of 80-100 min. SLE at 120 min revealed no solvent or drug-related toxic effects. CONCLUSIONS In a chronic ocular hypertensive rat model, topically applied WIN is an effective, nontoxic ocular hypotensive agent with no hemodynamic side-effects. This effect was predominantly CB1 receptor mediated, but some CB2 contribution could not be ruled out.

Confocal microscopy used as the definitive, early diagnostic method in Chandler syndrome.

Purpose: To report the early, rapid diagnosis of the Chandler variant of the iridocorneal endothelial (ICE) syndrome using confocal light microscopy. Methods: A 62-year-old man with a long history of unilateral glaucoma reported progressively blurred vision in his right eye. Examination of both eyes included visual acuity, slit-lamp examination, pneumotonometry, visual field, gonioscopy, and confocal microscopy. Results: On examination, visual acuity was 20/80 and 20/20 and the IOPs were 26 and 12. The anterior segment OD revealed 1+ inferior and axial corneal edema, while the OS was normal to biomicroscopy and posterior segment. Chandler syndrome or Fuchs endothelial dystrophy was suspected. In the affected eye, confocal light microscopy clearly showed an “epithelium-like” transformation of the corneal endothelium with irregularly shaped cells and hyperreflective nuclei, establishing the diagnosis of Chandler syndrome. Conclusions: In the presence of corneal edema or haze, corneal endothelium can be clearly visualized by confocal microscopy. “Epithelium-like” endothelial cells with highly reflective nuclei characteristic of Chandler syndrome were easily identified by confocal light microscopy to establish the diagnosis, despite the presence of corneal edema. Thus, confocal microscopy is a sensitive tool for the rapid, early diagnosis of ICE syndrome and may help distinguish among its variants.

Vasospasm contributes to monosodium glutamate-induced headache.

SYNOPSIS

Azelastine hydrochloride, a dual-acting anti-inflammatory ophthalmic solution, for treatment of allergic conjunctivitis

Over 50% of patients who seek treatment for allergies present with ocular symptoms. Our current ability to control ocular allergic symptoms is greater than ever before. Newer dual-acting topical eyedrops attack multiple facets of the allergic cascade. Azelastine has antihistaminic effects providing immediate relief, mast cell stabilization providing early-phase intervention, and inhibition of expression and activation of anti-inflammatory mediators which characterize the late phase of the immune reaction. The ophthalmic eyedrop formulation is approved for treatment of allergic conjunctivitis in adults and children aged over 3 years. In clinical trials comparing azelastine with other dual-acting eyedrops, such as levocabastine and olopatadine, azelastine was reported to be slightly less efficacious and to sting briefly upon administration. Even so, many patients experienced the full benefit of symptom relief, and preferred azelastine. As a broad-spectrum drug, azelastine offers many desirable properties for management of ocular allergies. Because it can often produce maximal effect with just twice-daily dosing, azelastine is a particularly good choice for the allergic population in whom minimizing exposure to topical products and preservatives is a key concern.

Cyclosporin as an adjunct to glaucoma filtration surgery.

Purpose:Current adjunctive therapies to glaucoma surgery have unreliable effects, are toxic, and have numerous late complications associated with their use. This study examined whether topical cyclosporin (CsA) prolongs bleb survival after glaucoma filtration surgery. Methods:Anesthetized white New Zealand rabbits underwent glaucoma filtration surgery with a drainage tube. Cyclosporin (2%), applied intraoperatively or as topical treatment following glaucoma filtration surgery, was compared with intraoperative mitomycin C (MMC) and an untreated control group. Results:The bleb remained elevated for 15.1 ± 3.2 days in the untreated control group, 12.2 ± 2.1 days after intraoperative cyclosporin, and 27.5 ± 1.7 days after intraoperative mitomycin C (P< 0.001). When topical treatment with cyclosporin followed intraoperative mitomycin C, bleb survival significantly decreased to 19.2 ± 4.6 days (P= 0.003). Intraocular pressure (IOP) remained significantly reduced in the mitomycin C-treated group longer than in either the control or cyclosporine-treated groups. Conclusions:In comparison with mitomycin C, neither intraoperative nor postoperative treatment with cyclosporin was associated with a decrease in intraocular pressure or prolonged bleb survival. Contrary to the initial hypothesis, topical treatment with cyclosporin actually mitigated the beneficial effects of mitomycin C on bleb survival. Clinical implications of these findings for patients with functioning blebs deserve further study.

Efficacy of a phosphorodiamidate morpholino oligomer antisense compound in the inhibition of corneal transplant rejection in a rat cornea transplant model.

PURPOSE The cornea is one of the most commonly transplanted tissues. The morpholino-oligomer antisense compound AVI-5126 suppresses expression of proto-oncogene c-myc, a key factor in transplant rejection. AVI-5126 was evaluated in a rat cornea transplant model. METHODS Donor corneas obtained from August x Copenhagen Irish rats were stored in Optisol™ containing 1.0 or 0.5 mg/mL AVI-5126 or Optisol alone for 24 h before transplant. Recipient Lewis rats were treated topically 3x/d with TobraDex™ and with 1.0 or 0.5 mg/mL of AVI-5126 or saline with daily monitoring for rejection using a modified McDonald-Shadduck Slit Lamp Scale. Using the high-performance liquid chromatography technique, the stability of AVI-5126 (0.5 mg/mL) in Optisol was evaluated for 30 days. AVI-5126 corneal transport was measured using Ussing chamber mounted rabbit corneas. The potential ocular toxicity of AVI-5126 (0.5 mg/mL) was evaluated after 8 days of 3x/d topical application in rats and in-vitro by incubation of human corneas for 8 days. RESULTS Cornea storage in Optisol containing 1.0 mg/mL AVI-5126 plus post-transplant topical tid AVI-5126 (1.0 mg/mL) application significantly increased graft survival (7.0±1.6 days) versus 5.0±0.8 days for Optisol alone storage plus post-transplant topical tid saline application (P<0.001). After 30 days of storage, no significant degradation of AVI-5126 in Optisol was noted by high-performance liquid chromatography analysis. After 24 h, 5 μg/mL (1% of total dose) crossed the corneas mounted in Ussing chambers. Neither extended topical application of AVI-5126 to rats nor incubation of human corneas in AVI-5126 decreased endothelial cell density. CONCLUSIONS Graft rejection was significantly delayed after pretransplantation storage of graft corneas in Optisol containing AVI-5126 followed by topical application of AVI-5126 post-transplantation. AVI-5126 was well tolerated, stable, and effectively penetrated the cornea.

Web-based sharing of cutting-edge teaching strategies

Abstract. The need to implement improved teaching methods in clinical pharmacology is critically important for health care globally. This need is driven by the overwhelming amount of information currently available on appropriate drug usage, by a proliferation of new biotechnology-derived pharmacologic agents, and by an expanded prescribing authority that is being granted to health professionals who have not traditionally had this responsibility and training. This discussion emphasizes the points that (a) the technology is available to share the best teaching materials for clinical pharmacology over the Internet, (b) clinical pharmacology organizations are best positioned to facilitate this exchange of educational materials, and that (c) continued discourse about problem-based learning and other curricular approaches to teaching clinical pharmacology is essential. The currently available information on the Internet includes case studies, slide sharing for lectures, educational programs and educational software. Clinical pharmacology organizations are not only starting to organize this information, but also to review the content of these programs and continuously add new material. These organizations have also developed a powerful tool through their journals in which to present educational series on rational therapeutics and to discuss educational approaches to instruction. Teaching forums, such as those presented annually at the American College of Clinical Pharmacology Annual Meeting, are essential to encourage discussion about teaching clinical pharmacology in the broadest context of the therapeutics, the economics and the legal aspects of clinical drug use.

Evaluation of Student Achievement and Educational Outcomes

Development of problem‐solving skills is vital to professional education as is factual recall. Student mastery must be measured to document student achievement required for completion of educational requirements and professional certification. These measurements also help determine if the educational process is meeting its goal of helping students develop critical cognitive skills fortherapeutic problem solving. Testing student growth in the ability to solve problems is less understood. Stressing integration of information across disciplines to derive answers is also important. Test items should resemble the real‐world task that students are expected to master. That is really the essence of content validity, which means faculty should be biased toward presenting information that way. This article is based on a symposium presented at the annual meeting of the American College of Clinical Pharmacology in September 1996. Symposium goals were to define purposes and uses of student evaluations by type and format, including application of techniques that improve evaluation, precision, and validity. Technical applications of computer‐based learningand evaluation of problem‐solving skills are described. Actual experience with evaluation of problem solving in the curriculum is discussed. The process by which a medical school developed and implemented an evaluation system for a new problem‐based curriculum is presented, followed by a critique of the successes and problems encountered duringthe first year of implementation. Criteria that a well‐constructed evaluation program must meet are explored. The approach and philosophy of national standardized testing centers are explained.