CPEB4-CLOCK crosstalk during temporal lobe epilepsy.

OBJECTIVE: Posttranscriptional mechanisms are increasingly recognized as important contributors to the formation of hyperexcitable networks in epilepsy. Messenger RNA (mRNA) polyadenylation is a key regulatory mechanism governing protein expression by enhancing mRNA stability and translation. Previous studies have shown large-scale changes in mRNA polyadenylation in the hippocampus of mice during epilepsy development. The cytoplasmic polyadenylation element-binding protein CPEB4 was found to drive epilepsy-induced poly(A) tail changes, and mice lacking CPEB4 develop a more severe seizure and epilepsy phenotype. The mechanisms controlling CPEB4 function and the downstream pathways that influence the recurrence of spontaneous seizures in epilepsy remain poorly understood. METHODS: Status epilepticus was induced in wild-type and CPEB4-deficient male mice via an intra-amygdala microinjection of kainic acid. CLOCK binding to the CPEB4 promoter was analyzed via chromatin immunoprecipitation assay and melatonin levels via high-performance liquid chromatography in plasma. RESULTS: Here, we show increased binding of CLOCK to recognition sites in the CPEB4 promoter region during status epilepticus in mice and increased Cpeb4 mRNA levels in N2A cells overexpressing CLOCK. Bioinformatic analysis of CPEB4-dependent genes undergoing changes in their poly(A) tail during epilepsy found that genes involved in the regulation of circadian rhythms are particularly enriched. Clock transcripts displayed a longer poly(A) tail length in the hippocampus of mice post-status epilepticus and during epilepsy. Moreover, CLOCK expression was increased in the hippocampus in mice post-status epilepticus and during epilepsy, and in resected hippocampus and cortex of patients with drug-resistant temporal lobe epilepsy. Furthermore, CPEB4 is required for CLOCK expression after status epilepticus, with lower levels in CPEB4-deficient compared to wild-type mice. Last, CPEB4-deficient mice showed altered circadian function, including altered melatonin blood levels and altered clustering of spontaneous seizures during the day. SIGNIFICANCE: Our results reveal a new positive transcriptional-translational feedback loop involving CPEB4 and CLOCK, which may contribute to the regulation of the sleep-wake cycle during epilepsy.

Oxidative Stress in the Anterior Ocular Diseases: Diagnostic and Treatment.

The eye is a metabolically active structure, constantly exposed to solar radiations making its structure vulnerable to the high burden of reactive oxygen species (ROS), presenting many molecular interactions. The biomolecular cascade modification is caused especially in diseases of the ocular surface, cornea, conjunctiva, uvea, and lens. In fact, the injury in the anterior segment of the eye takes its origin from the perturbation of the pro-oxidant/antioxidant balance and leads to increased oxidative damage, especially when the first line of antioxidant defence weakens with age. Furthermore, oxidative stress is related to mitochondrial dysfunction, DNA damage, lipid peroxidation, protein modification, apoptosis, and inflammation, which are involved in anterior ocular disease progression such as dry eye, keratoconus, uveitis, and cataract. The different pathologies are interconnected through various mechanisms such as inflammation, oxidative stress making the diagnostics more relevant in early stages. The end point of the molecular pathway is the release of different antioxidant biomarkers offering the potential of predictive diagnostics of the pathology. In this review, we have analysed the oxidative stress and inflammatory processes in the front of the eye to provide a better understanding of the pathomechanism, the importance of biomarkers for the diagnosis of eye diseases, and the recent treatment of anterior ocular diseases.

Improvement of Soft Contact Lens Wettability After the Instillation of Hyaluronic Acid Eye Drops.

PURPOSE: To evaluate the effect of the topical instillation of hyaluronic acid eye drops with different viscosity on soft contact lens wettability and comfort. METHODS: A randomized and participant-masked study was performed, involving 20 participants (25.4±2.6 years). One eye wore hydrogel (ocufilcon D) contact lenses, and another eye wore silicone-hydrogel (somofilcon A) contact lenses. The in vivo wettability tear film surface quality (TFSQ) index and comfort were measured before and after the instillation of different eye drops: saline solution (control) and 0.1%, 0.2%, and 0.3% hyaluronic acid. RESULTS: Compared with saline solution, the instillation of 0.1%, 0.2%, and 0.3% hyaluronic acid improved the in vivo wettability of the hydrogel contact lenses by decreasing their TFSQ mean for 5, 10, and 30 min, respectively ( P <0.05). During silicone-hydrogel contact lens wear, the hyaluronic acid did not affect wettability because there were no changes in TFSQ mean ( P ≥0.05), but the 0.3% hyaluronic acid produced a decrease in comfort for the first 3 min ( P <0.05). CONCLUSIONS: The instillation of hyaluronic acid eye drops increased the in vivo wettability of the hydrogel contact lens, and the duration of this effect was directly related to its concentration and viscosity.

Efficacy of a Deep Learning Convolutional Neural Network System for Melanoma Diagnosis in a Hospital Population.

(1) Background: The purpose of this study was to evaluate the efficacy in terms of sensitivity, specificity, and accuracy of the quantusSKIN system, a new clinical tool based on deep learning, to distinguish between benign skin lesions and melanoma in a hospital population. (2) Methods: A retrospective study was performed using 232 dermoscopic images from the clinical database of the Ramón y Cajal University Hospital (Madrid, Spain). The skin lesions images, previously diagnosed as nevus (n = 177) or melanoma (n = 55), were analyzed by the quantusSKIN system, which offers a probabilistic percentage (diagnostic threshold) for melanoma diagnosis. The optimum diagnostic threshold, sensitivity, specificity, and accuracy of the quantusSKIN system to diagnose melanoma were quantified. (3) Results: The mean diagnostic threshold was statistically lower (p < 0.001) in the nevus group (27.12 ± 35.44%) compared with the melanoma group (72.50 ± 34.03%). The area under the ROC curve was 0.813. For a diagnostic threshold of 67.33%, a sensitivity of 0.691, a specificity of 0.802, and an accuracy of 0.776 were obtained. (4) Conclusions: The quantusSKIN system is proposed as a useful screening tool for melanoma detection to be incorporated in primary health care systems.

Efficacy of Artificial Tears Based on an Extract of Artemia salina Containing Dinucleotides in a Rabbit Dry Eye Model.

(1) Background: Artemia salina is a brine shrimp containing high concentrations of dinucleotides, molecules with properties for dry eye treatment. For this reason, the purpose of the study was to evaluate the effect of the artificial tears based on an extract of Artemia salina in a rabbit dry eye model. (2) Methods: A prospective and randomized study was carried out. Twenty rabbits were divided into 4 groups (n = 5, each group): healthy rabbits, dry eye rabbits, dry eye rabbits treated with hypromellose (HPMC), and dry eye rabbits treated with Artemia salina. Dry eye was induced by the topical instillation of 0.2% benzalkonium chloride. The measurements were performed before and after the treatment for 5 consecutive days. (3) Results: The topical instillation of artificial tears containing Artemia salina showed beneficial effects on tear secretion, tear break-up time, corneal staining, the density of Goblet cells, heigh of mucin cloud secreted by these cells, and mRNA levels of IL-1ß and MMP9 in conjunctival cells. Compared with the HPMC, there was a statistically significant improvement (p < 0.05) with the Artemia salina in all the variables under study, except for the conjunctival hyperemia, density of Goblet cells, and mRNA levels of IL-6. (4) Conclusions: The potential of artificial tears based on Artemia salina as a secretagogue agent for dry eye treatment was confirmed, opening the door for future clinical trials and studies to extrapolate the findings for dry eye patients.

From Oxidative Stress to Inflammation in the Posterior Ocular Diseases: Diagnosis and Treatment.

Most irreversible blindness observed with glaucoma and retina-related ocular diseases, including age-related macular degeneration and diabetic retinopathy, have their origin in the posterior segment of the eye, making their physiopathology both complex and interconnected. In addition to the age factor, these diseases share the same mechanism disorder based essentially on oxidative stress. In this context, the imbalance between the production of reactive oxygen species (ROS) mainly by mitochondria and their elimination by protective mechanisms leads to chronic inflammation. Oxidative stress and inflammation share a close pathophysiological process, appearing simultaneously and suggesting a relationship between both mechanisms. The biochemical end point of these two biological alarming systems is the release of different biomarkers that can be used in the diagnosis. Furthermore, oxidative stress, initiating in the vulnerable tissue of the posterior segment, is closely related to mitochondrial dysfunction, apoptosis, autophagy dysfunction, and inflammation, which are involved in each disease progression. In this review, we have analyzed (1) the oxidative stress and inflammatory processes in the back of the eye, (2) the importance of biomarkers, detected in systemic or ocular fluids, for the diagnosis of eye diseases based on recent studies, and (3) the treatment of posterior ocular diseases, based on long-term clinical studies.

Influence of Circadian Rhythm in the Eye: Significance of Melatonin in Glaucoma.

Circadian rhythm and the molecules involved in it, such as melanopsin and melatonin, play an important role in the eye to regulate the homeostasis and even to treat some ocular conditions. As a result, many ocular pathologies like dry eye, corneal wound healing, cataracts, myopia, retinal diseases, and glaucoma are affected by this cycle. This review will summarize the current scientific literature about the influence of circadian patterns on the eye, focusing on its relationship with increased intraocular pressure (IOP) fluctuations and glaucoma. Regarding treatments, two ways should be studied: the first one, to analyze if some treatments could improve their effect on the ocular disease when their posology is established in function of circadian patterns, and the second one, to evaluate new drugs to treat eye pathologies related to the circadian rhythm, as it has been stated with melatonin or its analogs, that not only could be used as the main treatment but as coadjutant, improving the circadian pattern or its antioxidant and antiangiogenic properties.

Comparison Between Viscous Teardrops and Saline Solution to Fill Orthokeratology Contact Lenses Before Overnight Wear.

OBJECTIVE: To compare, in terms of efficacy, the differences between the use of saline solution and a viscous artificial tear to fill the lens during the first month of orthokeratology wear. METHODS: A pilot, double-masked, crossed, randomized, and prospective study was conducted. In this study, 20 subjects (14 males and 6 females) with a mean age of 16.29±6.22 years (range, 10-26) were fitted with orthokeratology contact lenses. For the study, nonpreserved 0.9% NaCl commercial saline solution (Avizor, Madrid, Spain) and nonpreserved artificial teardrops with 0.3% of hyaluronic acid (Ocudry 0.3%; Avizor, Madrid, Spain) were used. Corneal staining, tear break up time (TBUT), topography, refraction, visual acuity, and subjective comfort and vision with the visual analog scale (score from 0 to 10, being 10 better comfort and vision) were evaluated at 1 day, 1 week, and 1 month of contact lens wear. RESULTS: The corneal staining was statistically greater in the saline group than in the Ocudry group for the first day and during 1 week of wear (P<0.05). Comfort was found to be statistically better, with Ocudry 0.3% than saline solution, being 7.17±1.94 and 6.37±1.63, for the first day, and 8.78±0.43 and 8.15±0.62 for the day 28, respectively (P<0.05). However, no differences were found for subjective vision scores, TBUT, spherical equivalent, best-corrected visual acuity and uncorrected visual acuity, and mean keratometry between groups for any visit (P>0.05). CONCLUSION: Viscous artificial tears improve the subjective comfort of patients and reduce the corneal staining, compared with saline solution during the orthokeratology lenses fitting process. However, no differences between solutions for the treatment efficacy, in vision and corneal topography, were found.

Post-lens tear turbidity and visual quality after scleral lens wear.

BACKGROUND: The aim was to evaluate the turbidity and thickness of the post-lens tear layer and its effect on visual quality in patients with keratoconus after the beginning of lens wear and before lens removal at the end of eight hours. METHODS: Twenty-six patients with keratoconus (aged 36.95 ± 8.95 years) participated voluntarily in the study. The sample was divided into two groups: patients with intrastromal corneal ring (ICRS group) and patients without ICRS (KC group). Distance visual acuity (VA), contrast sensitivity, pachymetry, post-lens tear layer height and post-lens tear layer turbidity (percentage area occupied and number of particles per mm2 ) were evaluated with optical coherence tomography before and after wearing a scleral lens. RESULTS: A significant increase of turbidity was found in all groups assessed (p < 0.05). The number of particles per square millimetre was eight times higher after scleral lens wear than at the beginning of wearing the lens for all groups. VA decreases in all groups after scleral lens wear (p < 0.001). All patients showed a statistical diminishing of contrast sensitivity after scleral lens wear (p < 0.05). A significant correlation was found for both turbidity parameters with distance VA but no correlation between turbidity and post-lens tear layer thickness at the beginning was found (p > 0.05). A strong correlation in all groups between the post-lens tear layer at the beginning and differences of tear layer thickness between two measures was also found (p < 0.05). CONCLUSION: The VA decrease during the scleral lens wearing, filled with preserved saline solution, was due to the increasing post-lens tear layer turbidity.

Signs and Symptoms of Dry Eye in Keratoconus Patients Before and After Intrastromal Corneal Rings Surgery.

PURPOSE: Based on the relationship between keratoconus and dry eye, the aim of this study was to evaluate changes in signs and symptoms of dry eye in keratoconus patients before and after intrastromal corneal ring surgery. METHODS: Fifteen keratoconus patients were enrolled in Fundación Jiménez-Díaz of Madrid and University Clinic of Optometry of the Universidad Complutense de Madrid (Madrid, Spain). Tear break up time (TBUT), Schirmer test without anesthesia, corneal staining, diadenosine tetraphosphate (Ap4A) concentration, and ocular surface disease index (OSDI) were evaluated. Impression cytology combined with laser confocal microscopy was performed to evaluate goblet cell density, mucin cloud height (MCH), and cell layer thickness (CLT). All measurements were performed before (pre) surgery, 1 month (post) and 6 months after surgery (post6m). RESULTS: We found no statistical differences in time in Schirmer test, TBUT, and corneal staining. OSDI scores were 44.96 ± 8.65, 26.30 ± 6.79, and 19.31 ± 4.28 for (pre), (post), and (post6m) surgery, respectively (p < 0.001). Impression cytology showed a decrease in cell density at (post6m) compared with presurgery (47.36 ± 35.15 cells/mm2 and 84.88 ± 32.08 cells/mm2, respectively, p = 0.04). At post6m, the MCH increased compared with presurgery values (13.97 ± 4.26 µm and 6.77 ± 2.51 µm, respectively, p < 0.001). There was a statistically significant increase in CLT in time. Ap4A tear concentrations were lower post6m than presurgery (1.02 ± 0.65 and 2.56 ± 1.10 µM, respectively, p < 0.001). CONCLUSION: Intrastromal corneal ring surgery induces changes improving dry eye symptoms but no changes were found in signs of dry eye after surgery in keratoconus patients except for the MCH that increases drastically. More studies are needed to clarify the reason of its improvement.

Ocular Surface Temperature During Scleral Lens Wearing in Patients With Keratoconus.

OBJECTIVE: To evaluate the ocular surface temperature using an infrared thermography camera before and after wearing scleral lens in patients with keratoconus and correlate these results with the tear production and stability. METHODS: A pilot, experimental, short-term study has been performed. Twenty-six patients with keratoconus (36.95±8.95 years) participated voluntarily in the study. The sample was divided into two groups: patients with intrastromal corneal ring (KC-ICRS group) and patients without ICRS (KC group). Schirmer test, tear breakup time (TBUT), and ocular surface temperature in the conjunctiva, limbus, and cornea were evaluated before and after wearing a scleral lens. RESULTS: The patients wore the scleral lenses from 6 to 9 hours with average of 7.59±0.73 hours. No significant changes in Schirmer test and TBUT were found for both groups. No temperature differences were found between the KC-ICRS and the KC groups for all zones evaluated. There was a slight, but statistically significant, increase in the inferior cornea, temporal limbus, and nasal conjunctival temperature for KC-ICRS group and temporal limbus temperature decreasing for the KC group after wearing scleral lens (P<0.05). The conjunctiva and limbus temperature was statistically higher than the central cornea for both groups before and after scleral lenses wearing (P<0.05), but no difference in the peripheral cornea was found. No statistically significant differences in the central corneal temperature were found between the groups after scleral lens wearing (P>0.05). CONCLUSION: Scleral contact lens seems not to modify the ocular surface temperature despite the presence of the tear film stagnation under the lens.

Differences in Dry Eye Questionnaire Symptoms in Two Different Modalities of Contact Lens Wear: Silicone-Hydrogel in Daily Wear Basis and Overnight Orthokeratology.

Purpose. To compare the ocular surface symptoms and signs in an adult population of silicone-hydrogel (Si-Hy) contact lens (CL) wearers with another modality of CL wear, overnight orthokeratology (OK). Materials and Methods. This was a prospective and comparative study in which 31 myopic subjects were fitted with the same Si-Hy CL and 23 underwent OK treatment for 3 months. Dry eye questionnaire (DEQ) was filled in at the beginning of the study and then after 15 days, 1 month, and 3 months using each CL modality. The tear quality was evaluated with noninvasive tear break-up time. Tear production was measured with Schirmer test. Tear samples were collected with Schirmer strips being frozen to analyze the dinucleotide diadenosine tetraphosphate (Ap4A) concentration with High-Performance Liquid Chromatography (HPLC). Results. After refitting with ortho-k, a reduction in discomfort and dryness symptoms at the end of the day (p < 0.05, χ2) was observed. No significant changes were observed in Ap4A concentration in any group. Bulbar redness, limbal redness, and conjunctival staining increased significantly in the Si-Hy group (p < 0.05, Kruskal-Wallis test). Conclusion. Discomfort and dryness symptoms at the end of the day are lower in the OK CL group than in the Si-Hy CL group.

The role of dinucleoside polyphosphates on the ocular surface and other eye structures.

Dinucleoside polyphosphates comprises a group of dinucleotides formed by two nucleosides linked by a variable number of phosphates, abbreviated NpnN (where n represents the number of phosphates). These compounds are naturally occurring substances present in tears, aqueous humour and in the retina. As the consequence of their presence, these dinucleotides contribute to many ocular physiological processes. On the ocular surface, dinucleoside polyphosphates can stimulate tear secretion, mucin release from goblet cells and they help epithelial wound healing by accelerating cell migration rate. These dinucleotides can also stimulate the presence of proteins known to protect the ocular surface against microorganisms, such as lysozyme and lactoferrin. One of the latest discoveries is the ability of some dinucleotides to facilitate the paracellular way on the cornea, therefore allowing the delivery of compounds, such as antiglaucomatous ones, more easily within the eye. The compound Ap4A has been described being abnormally elevated in patient's tears suffering of dry eye, Sjogren syndrome, congenital aniridia, or after refractive surgery, suggesting this molecule as biomarker for dry eye condition. At the intraocular level, some diadenosine polyphosphates are abnormally elevated in glaucoma patients, and this can be related to the stimulation of a P2Y2 receptor that increases the chloride efflux and water movement in the ciliary epithelium. In the retina, the dinucleotide dCp4U, has been proven to be useful to help in the recovery of retinal detachments. Altogether, dinucleoside polyphosphates are a group of compounds which present relevant physiological actions but which also can perform promising therapeutic benefits.

The influence of rigid gas permeable lens wear on the concentrations of dinucleotides in tears and the effect on dry eye signs and symptoms in keratoconus.

PURPOSE: To evaluate the signs and symptoms of dry eye and dinucleotide secretion in tears of keratoconus patients (KC) and the potential effect of rigid gas permeable (RGP) contact lens wear. METHODS: Twenty-three KC patients and forty control subjects were enrolled in this study. Signs of dry eye including tear volume, tear stability and corneal staining along with symptoms were assessed using the McMonnies questionnaire. Tears were collected using Schirmer strips, and dinucleotide concentrations in collected tears measured using high pressure liquid chromatography. Values obtained in KC and controls were compared. The effect of contact lens wear in KC was also assessed. RESULTS: KC eyes showed a significantly lower tear volume compared to controls, shorter tear break up time (TBUT), higher corneal staining and higher McMonnies dry eye questionnaire scores (p<0.05). When compared with non-wearers, KC contact lens wearers showed significantly higher symptoms, lower Schirmer and TBUT values (p<0.05). Concentration of Ap4A (0.695±0.304µM vs. 0.185±0.178µM) and Ap5A (0.132±0.128µM vs. 0.045±0.036µM) were higher in KC compared to controls (p<0.001) and only Ap4A was statistically higher in RGP wearers compared to non-wearers (0.794±0.478µM vs. 0.417±0.313µM) (p<0.05). CONCLUSION: Signs and symptoms of dry eye as well as concentrations of Ap4A and Ap5A were markedly increased in KC patients compared to controls. Moreover, Ap4A and symptoms of dry eye were statistically higher in RGP wearers compared to non-wearers. This seems to indicate that factors such as RGP contact lens wear might exacerbate the clinical condition of dry eye.

Effect of overnight orthokeratology on conjunctival goblet cells.

OBJECTIVE: To evaluate the differences between goblet cell density (GCD) and symptomatology after one month of orthokeratology lens wear. METHODS: A pilot, short-term study was conducted. Twenty-two subjects (29.7±7.0 years old) participated voluntarily in the study. Subjects were divided into two groups: habitual silicone hydrogel contact lens wearers (SiHCLW) and new contact lens wearers (NCLW). Schirmer test, tear break up time (TBUT), Ocular Surface Disease Index (OSDI) questionnaire and conjunctival impression cytology. GCD, mucin cloud height (MCH) and cell layer thickness (CLT) were measured. All measurements were performed before orthokeratology fitting and one month after fitting to assess the evolution of the changes throughout this time. RESULTS: No differences in tear volume and TBUT between groups were found (p>0.05). However, the OSDI score was statistically better after one month of orthokeratology lens wear than the baseline for the SiHCLW group (p=0.03). Regarding the goblet cell analysis, no differences were found in CLT and MCH from the baseline visit to the one month visit for the SiHCLW compared with NCLW groups (p>0.05). At baseline, the GCD in the SiHCLW group were statistically lower than NCLW group (p<0.001). There was a significant increase in GCD after orthokeratology fitting from 121±140cell/mm(2) to 254±130cell/mm(2) (p<0.001) in the SiHCLW group. CONCLUSION: Orthokeratology improves the dry eye subject symptoms and GCD after one month of wearing in SiHCLW. These results suggest that orthokeratology could be considered a good alternative for silicone hydrogel contact lens discomfort and dryness.

Short-term Effect of Scleral Lens on the Dry Eye Biomarkers in Keratoconus.

PURPOSE: To evaluate the most important signs of dry eye, such as osmolarity, inflammation, and diadenosine tetraphosphate (Ap(4)A) concentration before and after wearing scleral lenses for 8 h in keratoconus patients. METHODS: A pilot, experimental, short-term study involved 26 keratoconus patients (average age, 36.95 ± 8.95 years). They voluntarily enrolled in the study at the Optometry Clinic of the Faculty of Optics and Optometry in the University Complutense of Madrid. They were divided into two groups: patients with intrastromal corneal ring, the ICRS group, and patients without ICRS, the keratoconus (KC) group. Ocular Surface Disease Index questionnaire, the Schirmer test without anesthesia, tear break-up time, matrix metalloproteinase 9 (MMP-9) concentration, osmolarity, and Ap4A concentration were evaluated before and after wearing a scleral lens for 8 h. RESULTS: The patients wore the scleral lenses from 6 to 9 h, with a mean of 7.59 ± 0.73 h. The mean scleral lens sag for all patients was 4310 ± 166.31 µm, ranging from 4200 µm to 4800 µm. No significant changes in the Schirmer test and tear break-up time were found for either group. Ocular Surface Disease Index scores were statistically lower after wearing scleral lenses for both groups (p < 0.05). A significantly lower osmolarity and a significant rise of MMP-9 concentration after wearing scleral lenses were found in both groups (p < 0.05). Diadenosine tetraphosphate concentration was lower after wearing the scleral lens in the KC group (p < 0.05) but no significant difference was found for the ICRS group (p > 0.05). CONCLUSIONS: Short-term scleral lens wearing improves the symptomatology and some signs of dry eye, such as osmolarity and Ap4A concentration. The increase of MMP-9 concentration could be caused by tear film stagnation and use of preserved saline.

Dry Eye Treatment Based on Contact Lens Drug Delivery: A Review.

Dry eye disease affects a substantial segment of the word population with increasing frequency. It is a multifactorial disease of the ocular surface and tear film, which causes ocular discomfort, visual disturbances, and tear instability with potential damage to the cornea and conjunctiva. Because of its multifactorial etiology, the use of different pharmacological treatment for dry eye treatment has been proposed, which include anti-inflammatory molecules, lubricants or comfort agents, and secretagogues. However, in some cases these pharmacological approaches only relieve symptoms temporarily, and consequently, eye care professionals continue to have difficulties managing dry eye. To improve pharmacological therapy that allows a more efficient and long-term action, effective ocular drug delivery of the currently available drugs for dry eye treatment is required. Contact lenses are emerging as alternative ophthalmic drugs delivery systems that provide an increased residence time of the drug at the eye, thus leading to enhanced bioavailability and more convenient and efficacious therapy. In this article, we reviewed the different techniques used to prepare contact lens-based drug delivery systems and focused on articles that describe the delivery of compounds for dry eye treatment through contact lenses.

Symptoms and Signs in Rigid Gas Permeable Lens Wearers During Adaptation Period.

OBJECTIVES: To evaluate neophyte contact lens wearers' fitting to rigid gas permeable (RGP) contact lenses in terms of wearing time, tear volume, stability, corneal staining, and subjective ratings, over a 1-month period of time. METHODS: Twenty-two young healthy subjects were enrolled for wearing RGP on a daily wear basis. The participants included in this study never wore contact lenses and showed a value under 10 in McMonnies Questionnaire. Contact Lens Dry Eye Questionnaire, Visual Analog Scales, Schirmer test, tear film break-up time (BUT), and corneal staining grading were performed. Follow-up visits were scheduled at 1, 7, 15, and 28 days. RESULTS: Six subjects dropped out due to discomfort from the study before 1 month (27% of discontinuation rate). Successful RGP wearers (16 participants) achieved high levels of subjective vision and reported comfort scores of approximately 9 of 10 between 10 and 15 days. They reported wearing their lenses for an average of 10.12±2.43 hr after 1 month of wear. Conversely, unsuccessful wearers discontinued wearing the lenses after the first 10 to 15 days, showing comfort scores and wearing time significantly lower compared with the first day of wear. Schirmer test showed a significant increase at 10 days (P<0.001), and the BUT trends decreased after the first week of wear in unsuccessful group. CONCLUSIONS: Symptomatology related with dryness and discomfort, detected during the first 10 days of the adaptation, may help the clinician to predict those participants who will potentially fail to adapt to RGP lens wear.

Signs and Symptoms of Dry Eye in Keratoconus Patients: A Pilot Study.

PURPOSE: To compare signs and symptoms of dry eye in keratoconus (KC) patients versus healthy subjects. METHODS: A total of 15 KC patients (KC group, n = 15 eyes) and 16 healthy subjects (control group, 16 eyes) were enrolled in this study. The Schirmer I test with no anesthetic, tear break-up time (TBUT), corneal staining characteristics, and ocular surface disease index (OSDI) scores were evaluated for both groups. Impression cytology, combined with/scanning laser confocal microscopy (LCM), was performed to evaluate goblet cell density, mucin cloud height (MCH), and goblet cell layer thickness (CLT). Finally, tear concentrations of di-adenosine tetraphosphate (Ap4A) were assessed. Results were statistically analyzed using Shapiro-Wilk and non-parametric Wilcoxon rank sum tests. Statistical significance was set at p < 0.05. RESULTS: KC patients had lower tear volumes and greater corneal staining than did healthy subjects (p < 0.05). OSDI scores were 44.96 ± 8.65 and 17.78 ± 6.50 for the KC and control groups, respectively (p < 0.05). We found no statistically significant differences in TBUT between groups. Impression cytology revealed lower goblet cell densities in KC group patients versus control group subjects (84.88 ± 32.98 and 128.88 ± 50.60 cells/mm,(2) respectively, p < 0.05). There was a statistically significant reduction in MCH and CLT in KC group patients compared with control group subjects. Ap4A tear concentrations were higher in KC group patients than in control group subjects (2.56 ± 1.10 and 0.15 ± 0.12 µM, respectively, p < 0.05). CONCLUSIONS: The parameters evaluated in this study indicate that KC patients suffer greater symptoms of dry eye and greater tear instability, primarily due to the decreased mucin production in their tears, than do healthy patients with no KC.

Melatonin and its analog 5-methoxycarbonylamino-N-acetyltryptamine potentiate adrenergic receptor-mediated ocular hypotensive effects in rabbits: significance for combination therapy in glaucoma.

Melatonin is currently considered a promising drug for glaucoma treatment because of its ocular hypotensive and neuroprotective effects. We have investigated the effect of melatonin and its analog 5-methoxycarbonylamino-N-acetyltryptamine, 5-MCA-NAT, on ß2/α(2A)-adrenergic receptor mRNA as well as protein expression in cultured rabbit nonpigmented ciliary epithelial cells. Quantitative polymerase chain reaction and immunocytochemical assays revealed a significant ß2-adrenergic receptor downregulation as well as α(2A)-adrenergic receptor up-regulation of treated cells (P < 0.001, maximal significant effect). In addition, we have studied the effect of these drugs upon the ocular hypotensive action of a nonselective ß-adrenergic receptor (timolol) and a selective α2-adrenergic receptor agonist (brimonidine) in normotensive rabbits. Intraocular pressure (IOP) experiments showed that the administration of timolol in rabbits pretreated with melatonin or 5-MCA-NAT evoked an additional IOP reduction of 14.02% ± 5.8% or 16.75% ± 5.48% (P < 0.01) in comparison with rabbits treated with timolol alone for 24 hours. Concerning brimonidine hypotensive action, an additional IOP reduction of 29.26% ± 5.21% or 39.07% ± 5.81% (P < 0.001) was observed in rabbits pretreated with melatonin or 5-MCA-NAT when compared with animals treated with brimonidine alone for 24 hours. Additionally, a sustained potentiating effect of a single dose of 5-MCA-NAT was seen in rabbits treated with brimonidine once daily for up 4 days (extra IOP decrease of 15.57% ± 5.15%, P < 0.05, compared with brimonidine alone). These data confirm the indirect action of melatoninergic compounds on adrenergic receptors and their remarkable effect upon the ocular hypotensive action mainly of α2-adrenergic receptor agonists but also of ß-adrenergic antagonists.