Double-masked, placebo-controlled safety and efficacy trial of diquafosol tetrasodium (INS365) ophthalmic solution for the treatment of dry eye.

PURPOSE: To investigate the safety and efficacy of diquafosol tetrasodium, a P2Y2 receptor agonist that stimulates fluid and mucin secretion on the ocular surface, as a novel topical treatment of dry eye disease. METHODS: Subjects with dry eye (n=527) were evaluated in a randomized, double-masked, parallel-group trial comparing 24 weeks of treatment with 2 concentrations of diquafosol (1% and 2%) versus placebo instilled 4 times daily. Corneal staining, conjunctival staining, Schirmer tests, and subjective symptoms of dry eye were evaluated. Use of artificial tears was permitted as necessary. RESULTS: Subjects treated with 2% diquafosol had significantly lower corneal staining scores compared with placebo at the 6-week, primary efficacy time point (P<0.001), and superiority continued throughout the 24-week study. Reductions in corneal staining were observed as early as after 2 weeks of treatment, were maintained throughout the 24-week study, and were observed to worsen slightly (toward baseline) when diquafosol treatment was discontinued (week 25). Results for conjunctival staining were consistent with those observed for corneal staining. Schirmer scores at week 6 were significantly higher with diquafosol treatment than with placebo (P

Characterization of ocular surface symptoms from optometric practices in North America.

PURPOSE: This study characterized ocular symptoms typical of dry eye in an unselected optometric clinical population in the United States and Canada. METHODS: Self-administered dry eye questionnaires, one for non-contact lens wearers (dry eye questionnaire) and one for contact lens wearers (contact lens dry eye questionnaire), were completed at six clinical sites in North America. Both questionnaires included categoric scales to measure the prevalence, frequency, diurnal severity, and intrusiveness of nine ocular surface symptoms. The questionnaires also asked how much these ocular symptoms affected daily activities and contained questions about computer use, medications, and allergies. The examining doctors, who were masked to questionnaire responses, recorded a nondirected dry eye diagnosis for each patient, based on their own diagnostic criteria. RESULTS: The dry eye questionnaires were completed by 1,054 patients. The most common ocular symptom was discomfort, with 64% of non--contact lens wearers and 79% of contact lens wearers reporting the symptom at least infrequently. There was a diurnal increase in the intensity of many symptoms, with symptoms such as discomfort, dryness, and visual changes reported to be more intense in the evening. The 22% percent of non-contact lens wearers and 15% of contact lens wearers diagnosed with dry eye (most in the mild to moderate categories) reported symptoms at a greater frequency than those not diagnosed with dry eye. CONCLUSIONS: Our results show that symptoms of ocular irritation and visual disturbances were relatively common in this unselected clinical population. The intensity of many ocular symptoms increased late in the day, which suggested that environmental factors played a role in the etiology of the symptoms.

The contact lens and myopia progression (CLAMP) study: design and baseline data.

BACKGROUND: Although previous contact lens myopia control studies indicate that rigid contact lenses slow the progression of myopia in children, they have all suffered from limitations that challenge the significance of their results. The Contact Lens and Myopia Progression (CLAMP) Study addresses the limitations of previous studies and attempts to correct them by implementing alternative Study designs. The CLAMP study also measures all the ocular components to examine the potential mechanism of treatment effect. METHODS: Eligible children were fitted with rigid gas-permeable contact lenses and enrolled in a run-in period to determine whether they were able to adapt to rigid contact lens wear. Subjects who successfully completed the run-in period were randomly assigned to wear rigid contact lenses or soft contact lenses for the remainder of the 3-year study. The primary outcome measure will be the 3-year change in cycloplegic autorefraction; the secondary outcome measures will include the 3-year change in axial length, peripheral autorefraction, crystalline lens curvatures, corneal curvature and thickness, accommodation, and intraocular pressure, which are being measured annually. RESULTS: We examined 148 eligible subjects who participated in the run-in period. Of the 148 eligible subjects, 116 (78.4%) were able to adapt to rigid contact lens wear and were enrolled in the CLAMP Study. The mean age of the participants at the baseline visit was 10.5 years, and 59.5% were girls. At the randomization visit, the mean (+/-SD) spherical equivalent refractive error in the right eye was -2.09 +/- 0.89 D, the mean central curvature of the right cornea by videokeratography was 44.5 +/- 1.3 D, and the mean axial length of the right eye was 24.13 +/- 0.71 mm. CONCLUSIONS: Four of five children aged 8- to 11-years-old were able to adapt to rigid gas-permeable contact lens wear. The CLAMP Study aims to further clarify the effect of rigid gas-permeable contact lenses on myopia progression in children.

The thickness of the human precorneal tear film: evidence from reflection spectra.

PURPOSE: Interferometric methods have considerable potential for studying the thickness of layers of the human tear film and cornea because of their ability to make noninvasive, accurate, and rapid measurements. However, previous interferometric studies by Prydal and Danjo yielded tear thickness values near 40 and 11 microm, respectively, considerably greater than estimates made by invasive methods of 4 to 8 microm. Using a modified version of Danjo's method, interference effects from the tear film and cornea were studied, with the aim of correlation with known structure and optical properties of the cornea and hence determining the most probable value of tear film thickness. METHODS: Reflectance spectra from the human cornea were measured at normal incidence. These spectra show oscillations whose maxima correspond to constructive interference between light reflected from the air surface and from some deeper surface. The frequency of these spectral oscillations is proportional to the thickness of the layer between the air surface and the second surface. Therefore, Fourier analysis of reflectance spectra can be used to determine the thickness of layers of the tear film and cornea. In the main experiment, 36 low-resolution spectra were obtained from six normal eyes for measuring thickness up to 100 microm. Control experiments included measurements of the time course of thickness changes and high-resolution spectra for measuring thickness up to 1000 microm. RESULTS: For the main experiment, in the thickness range 1 to 100 microm, the strongest peak in the Fourier transform was near 3 microm (range, 1.5-4.7 microm) beneath the air surface. In the range 20 to 100 microm, the strongest peak was near 55 microm (range, 50-59 microm) for all 36 spectra; none were in Prydal's range near 40 microm. This 55-microm peak is consistent with a reflection from the basement membrane of the epithelium. Time course measurements after a blink show that the 3-microm peak is not an artifact. High-resolution spectra gave a peak near 510 microm, corresponding to the complete thickness of the cornea (plus tear film). This peak had a contrast similar to that of the 3-microm peak. CONCLUSIONS: These studies did not confirm Prydal's estimate of approximately 40 microm. Nor were there prominent peaks near Danjo's value of approximately 11 microm, except in cases of probable reflex tears. Because the reflection at the aqueous-mucus boundary would be expected to be weaker than that from the epithelial surface, the 3-microm peak is unlikely to correspond to the aqueous layer (rather than the complete tear film). The proposal that the 3-microm peak corresponds to a reflection from the front of the cornea is supported by the demonstration of a peak of similar contrast from the back of the cornea. Thus, the current evidence consistently supports a value of approximately 3 microm for the thickness of the human precorneal tear film.

Frequency of dry eye diagnostic test procedures used in various modes of ophthalmic practice.

PURPOSE: There are many suggested dry eye diagnostic test batteries in the literature. However, clinicians use a wide variety of dry eye diagnostic tests in clinical practice due to a number of factors, including time constraints. In addition, there has been no systematic description of the standard of care in diagnosing dry eye in the literature. The purpose of this study is to determine the type and frequency of dry eye diagnostic tests used in various modes of ophthalmic practice across a spectrum of dry eye severity. METHODS: A total of 467 patient charts (patients with a previous dry eye diagnosis) were reviewed retrospectively to determine diagnostic test frequency. In reviewing patient charts, the following tests were identified as performed or not performed: symptom assessment, fluorescein staining, tear break-up time (TBUT), Schirmer test, rose bengal staining, and "tear assessment" (including quantity and quality of the tear meniscus). RESULTS: Dry eye diagnostic tests were used in the following frequencies across all modes of practice: symptom assessment (82.8%), fluorescein staining (55.5%), TBUT (40.7%), tear assessment (22.2%), Schirmer test (8.5%), and rose bengal staining (4.9%). When the clinics are pooled, two test procedures were used with the highest frequency (38.9%). The most commonly performed two-test procedure combination was a symptom assessment combined with fluorescein staining of the cornea (43.7%). CONCLUSIONS: Symptom assessment plays a large role in the diagnosis of dry eye. The current clinical standard of care for dry eye diagnosis includes the performance of at least one test procedure in addition to a symptom assessment.

Responses of contact lens wearers to a dry eye survey.

The purpose of this study was to examine ocular symptoms that have been associated with dry eye among contact lens wearers. A dry eye questionnaire was administered at random to 83 contact lens wearers at a private practice in Toronto, Ontario. On average, the most frequent ocular symptom among those queried was dryness and the least frequent was soreness. There was a significant shift (p < 0.0001; paired t-test) toward increased symptoms in the evening compared with the morning. Blurry, changeable vision was also a frequent and noticeable symptom. However, most subjects reported that their ocular symptoms were not severe enough for them to stop work or hobbies or to remove their contact lenses. Our results show that the symptoms of ocular dryness and discomfort are relatively common among contact lens wearers, and that they worsen toward the end of the day. These findings suggest that lens care practitioners should examine their patients who wear contact lenses toward the end of the day to best identify symptomatic patients.

Symptoms of ocular irritation in patients diagnosed with dry eye.

PURPOSE: The purpose of this study was to develop a pilot survey to evaluate ocular irritation symptom frequency, severity, and impact on daily activity in patients previously diagnosed with dry eye. METHODS: Forty-five patients previously diagnosed with dry eye (ICD-9 code 375.15) completed the 17-item symptom survey. Analog-scale response questions concerning the frequency, severity, and effect on daily activity were asked for the following symptoms: dryness, scratchiness and soreness, burning and stinging, light sensitivity, blurry vision, and ocular itching. RESULTS: Dryness and soreness were the most frequently reported symptoms of ocular irritation. Although the occurrence of symptoms of ocular irritation was reported as frequent by patients diagnosed with dry eye, the symptoms had minimal to moderate impact on daily activity. CONCLUSIONS: Patient expression of the symptoms of dryness and soreness at more frequent and/or more severe levels may lend more validity to a diagnosis of dry eye.

Semisynthetic chemical modification of the antifungal lipopeptide echinocandin B (ECB): structure-activity studies of the lipophilic and geometric parameters of polyarylated acyl analogs of ECB.

Echinocandin B (ECB) is a lipopeptide composed of a complex cyclic peptide acylated at the N-terminus by linoleic acid. Enzymatic deacylation of ECB provided the peptide "nucleus" as a biologically inactive substrate from which novel ECB analogs were generated by chemical reacylation at the N-terminus. Varying the acyl group revealed that the structure and physical properties of the side chain, particularly its geometry and lipophilicity, played a pivotal role in determining the antifungal potency properties of the analog. Using CLOGP values to describe and compare the lipophilicities of the side chain fragments, it was shown that values of > 3.5 were required for expression of antifungal activity. Secondly, a linearly rigid geometry of the side chain was the most effective shape in enhancing the antifungal potency. Using these parameters as a guide, a variety of novel ECB analogs were synthesized which included arylacyl groups that incorporated biphenyl, terphenyl, tetraphenyl, and arylethynyl groups. Generally the glucan synthase inhibition by these analogs correlated well with in vitro and in vivo activities and was likewise influenced by the structure of the side chain. These structural variations resulted in enhancement of antifungal activity in both in vitro and in vivo assays. Some of these analogs, including LY303366 (14a), were effective by the oral route of administration.