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Ophthalmology Jan 2020To evaluate the efficacy and safety of topical cenegermin (recombinant human nerve growth factor) in patients with neurotrophic keratopathy. (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
To evaluate the efficacy and safety of topical cenegermin (recombinant human nerve growth factor) in patients with neurotrophic keratopathy.
DESIGN
Multicenter, randomized, double-masked, vehicle-controlled trial.
PARTICIPANTS
Patients with neurotrophic persistent epithelial defect with or without stromal thinning.
METHODS
The NGF0214 trial, conducted among 11 sites in the United States, randomized 48 patients 1:1 to cenegermin 20 μg/ml or vehicle eye drops, 6 drops daily for 8 weeks of masked treatment. Follow-up was 24 weeks. Safety was assessed in all patients who received study drug. Efficacy was assessed by intention to treat.
MAIN OUTCOME MEASURES
The primary end point was healing of the neurotrophic lesion (persistent epithelial defect or corneal ulcer) after 8 weeks of masked treatment. Masked central readers measured neurotrophic lesions in randomized clinical pictures, then assessed healing status conventionally (<0.5 mm of fluorescein staining in the greatest dimension of the lesion area) and conservatively (0-mm lesion staining and no other residual staining). Secondary variables included corneal healing at 4 weeks of masked treatment (key secondary end point), overall changes in lesion size, rates of disease progression, and changes in visual acuity and corneal sensitivity from baseline to week 8.
RESULTS
Conventional assessment of corneal healing showed statistically significant differences at week 8: compared to 7 of 24 vehicle-treated patients (29.2%), 16 of 23 cenegermin-treated patients (69.6%) achieved less than 0.5 mm of lesion staining (+40.4%; 95% confidence interval [CI], 14.2%-66.6%; P = 0.006). Conservative assessment of corneal healing also reached statistical significance at week 8: compared to 4 of 24 vehicle-treated patients (16.7%), 15 of 23 cenegermin-treated patients (65.2%) achieved 0 mm of lesion staining and no other residual staining (+48.6%; 95% CI, 24.0%-73.1%; P < 0.001). Moreover, the conservative measure of corneal healing showed statistical significance at week 4 (key secondary end point). Compared to vehicle, cenegermin-treated patients showed statistically significant reductions in lesion size and disease progression rates during masked treatment. Cenegermin was well tolerated; adverse effects were mostly local, mild, and transient.
CONCLUSIONS
Cenegermin treatment showed higher rates of corneal healing than vehicle in neurotrophic keratopathy associated with nonhealing corneal defects.
Topics: Administration, Ophthalmic; Adult; Aged; Aged, 80 and over; Cornea; Corneal Ulcer; Double-Blind Method; Epithelium, Corneal; Female; Fluorophotometry; Follow-Up Studies; Humans; Male; Middle Aged; Nerve Growth Factor; Ophthalmic Solutions; Recombinant Proteins; Treatment Outcome; Trigeminal Nerve Diseases; Visual Acuity; Wound Healing
PubMed: 31585826
DOI: 10.1016/j.ophtha.2019.08.020 -
Journal of Optometry 2015Tear exchange beneath a contact lens facilitates ongoing fluid replenishment between the ocular surface and the lens. This exchange is considerably lower during the wear... (Review)
Review
Tear exchange beneath a contact lens facilitates ongoing fluid replenishment between the ocular surface and the lens. This exchange is considerably lower during the wear of soft lenses compared with rigid lenses. As a result, the accumulation of tear film debris and metabolic by-products between the cornea and a soft contact lens increases, potentially leading to complications. Lens design innovations have been proposed, but no substantial improvement in soft lens tear exchange has been reported. Researchers have determined post-lens tear exchange using several methods, notably fluorophotometry. However, due to technological limitations, little remains known about tear hydrodynamics around the lens and, to-date, true tear exchange with contact lenses has not been shown. Further knowledge regarding tear exchange could be vital in aiding better contact lens design, with the prospect of alleviating certain adverse ocular responses. This article reviews the literature to-date on the significance, implications and measurement of tear exchange with contact lenses.
Topics: Contact Lenses, Hydrophilic; Cornea; Fluorophotometry; Humans; Models, Theoretical; Tears
PubMed: 25575892
DOI: 10.1016/j.optom.2014.12.001 -
International Journal of Pharmaceutics Jun 2022In this study, the intravitreal pharmacokinetics of nanomaterials were investigated in vivo in rats and rabbits. Impact of particle size and shape (spherical,...
In this study, the intravitreal pharmacokinetics of nanomaterials were investigated in vivo in rats and rabbits. Impact of particle size and shape (spherical, longitudinal) on ocular particle distribution and elimination was investigated with fundus camera, optical coherence tomography and ocular fluorophotometry. Differently sized particles showed prolonged ocular retention and remarkable differences in vitreal elimination, but size dependence was consistent, suggesting that other features have influence on their vitreal kinetics. We also demonstrate that liposomes are eliminated from the rabbit vitreous mainly via the anterior route. Simulation of drug concentrations after injection of intravitreal particles shows the importance of synchronized particle retention and drug release rate for efficient drug delivery. In conclusion, we provide kinetic insights in intravitreally administered nanoparticles to improve retinal drug delivery.
Topics: Animals; Drug Delivery Systems; Intravitreal Injections; Kinetics; Nanostructures; Rabbits; Rats; Retina
PubMed: 35533923
DOI: 10.1016/j.ijpharm.2022.121800 -
Pharmaceutics Dec 2021The treatment of retinal diseases by intravitreal injections requires frequent administration unless drug delivery systems with long retention and controlled release are...
The treatment of retinal diseases by intravitreal injections requires frequent administration unless drug delivery systems with long retention and controlled release are used. In this work, we focused on pullulan (≈67 kDa) conjugates of dexamethasone as therapeutic systems for intravitreal administration. The pullulan-dexamethasone conjugates self-assemble into negatively charged nanoparticles (average size 326 ± 29 nm). Intravitreal injections of pullulan and pullulan-dexamethasone were safe in mouse, rat and rabbit eyes. Fluorescently labeled pullulan particles showed prolonged retention in the vitreous and they were almost completely eliminated via aqueous humor outflow. Pullulan conjugates also distributed to the retina via Müller glial cells when tested in ex vivo retina explants and in vivo. Pharmacokinetic simulations showed that pullulan-dexamethasone conjugates may release free and active dexamethasone in the vitreous humor for over 16 days, even though a large fraction of dexamethasone may be eliminated from the eye as bound pullulan-dexamethasone. We conclude that pullulan based drug conjugates are promising intravitreal drug delivery systems as they may reduce injection frequency and deliver drugs into the retinal cells.
PubMed: 35056906
DOI: 10.3390/pharmaceutics14010012 -
Cornea Sep 2021NOV03 has a unique dual mode of action to address dry eye disease (DED) associated with meibomian gland dysfunction. SEECASE evaluated the efficacy, safety, and... (Comparative Study)
Comparative Study Randomized Controlled Trial
PURPOSE
NOV03 has a unique dual mode of action to address dry eye disease (DED) associated with meibomian gland dysfunction. SEECASE evaluated the efficacy, safety, and tolerability of NOV03 at 2 dosing regimens compared with a saline comparator in patients with DED.
METHODS
SEECASE was a prospective, multicenter, randomized, double-masked, saline-controlled clinical study. A total of 336 DED patients [tear film breakup time ≤5 seconds, abnormal meibum secretion, total corneal fluorescein staining (tCFS) score of 4 ≤ X ≤ 11 (National Eye Institute scale), Schirmer of ≥5 mm] were randomized in a 2:2:1:1 manner to NOV03 4 times daily (QID), NOV03 twice daily (BID), saline BID, and saline QID, respectively. The primary efficacy endpoint was tCFS staining at 8 weeks for both regimens. Secondary endpoints included visual analog scales and the Ocular Surface Disease Index questionnaire for symptom assessment.
RESULTS
The study met its primary endpoint, change from baseline of tCFS over control, for both dosing regimens QID and BID (P < 0.001 and P = 0.009, respectively). NOV03 also showed pronounced improvement in various symptoms. For the Eye Dryness Score, changes from baseline were statistically significant compared with those of the control at week 8 [P < 0.001 (QID) and P = 0.002 (BID)]. Benefits on tCFS and symptoms started at 2 weeks after start of treatment and were maintained over the study duration. The effects were dosing schedule dependent. NOV03 was well tolerated with instillation site reactions below 3% in both treatment regimes.
CONCLUSIONS
The SEECASE study demonstrated that NOV03 improves signs and symptoms in patients with highly symptomatic evaporative dry eye disease.
Topics: Administration, Ophthalmic; Adult; Aged; Aged, 80 and over; Double-Blind Method; Dry Eye Syndromes; Female; Fluorescein; Fluorocarbons; Fluorophotometry; Humans; Male; Meibomian Gland Dysfunction; Middle Aged; Ophthalmic Solutions; Prospective Studies; Staining and Labeling; Surveys and Questionnaires; Tears; Treatment Outcome; Visual Analog Scale; Young Adult
PubMed: 33369937
DOI: 10.1097/ICO.0000000000002622 -
Eye (London, England) Mar 2016To compare intraocular pressure (IOP) measurements obtained with Goldmann applanation tonometery (GAT), dynamic contour tonometry (DCT), tonopen (TP), and ocular... (Comparative Study)
Comparative Study
AIMS
To compare intraocular pressure (IOP) measurements obtained with Goldmann applanation tonometery (GAT), dynamic contour tonometry (DCT), tonopen (TP), and ocular response analyzer (ORA), and to determine the influence of Amsler grade and central corneal thickness (CCT) on the IOP readings in eyes with keratoconus that are classified into four groups according to the Amsler-Krumeich classification.
METHODS
All eyes with keratoconus were separated into four groups using Amsler-Krumeich classification for keratoconus. IOP was measured in 202 eyes of 202 patients with keratoconus using GAT, DCT, TP, and ORA.
RESULTS
The IOP differences revealed no significant difference among the Amsler degree in the DCT and corneal-compensated IOP (IOPcc) measurements (P>0.05 for all). There was no statistically significant difference in terms of IOP differences between GAT and IOPcc (P>0.05), TP and Goldmann-correlated measure of IOP (IOPg; P>0.05) in the Amsler I, while the IOP measurements revealed significant difference among the measurements of the four different tonometers in the Amsler II, Amsler III, and Amsler IV (P<0.05 for all).
CONCLUSIONS
There was no significant association between DCT IOP or IOPcc and CCT in eyes with keratoconus; no statistically significant difference was found between keratoconus stages and the control group in terms of the IOP analyzed with these two techniques. These two techniques may be the most stable in the measurement of IOP in different keratoconus stages. However, no IOP technique can be used interchangeably with other techniques in the follow-up of keratoconus patients.
Topics: Adult; Cornea; Corneal Pachymetry; Female; Fluorophotometry; Humans; Intraocular Pressure; Keratoconus; Male; Prospective Studies; Reproducibility of Results; Tonometry, Ocular; Young Adult
PubMed: 26634712
DOI: 10.1038/eye.2015.248 -
BMC Ophthalmology May 2016Diagnostic tests for dry eye disease (DED), including ocular surface disease index (OSDI), tear breakup time (TBUT), corneal fluorescein staining, and lissamine... (Observational Study)
Observational Study
BACKGROUND
Diagnostic tests for dry eye disease (DED), including ocular surface disease index (OSDI), tear breakup time (TBUT), corneal fluorescein staining, and lissamine staining, have great deal of variability. We investigated whether fluorophotometry correlated with previously established DED diagnostic tests and whether it could serve as a novel objective metric to evaluate DED.
METHODS
Dry eye patients who have had established signs or symptoms for at least 6 months were included in this observational study. Normal subjects with no symptoms of dry eyes served as controls. Each eye had a baseline fluorescein scan prior to any fluorescein dye. Fluorescein dye was then placed into both eyes, rinsed with saline solution, and scanned at 5, 10, 15, and 30 min. Patients were administered the following diagnostic tests to correlate with fluorophotometry: OSDI, TBUT, fluorescein, and lissamine. Standard protocols were used. P < 0.05 was considered significant.
RESULTS
Fifty eyes from 25 patients (DED = 22 eyes, 11 patients; Normal = 28 eyes, 14 patients) were included. Baseline scans of the dry eye and control groups did not show any statistical difference (p = 0.84). Fluorescein concentration of DED and normal patients showed statistical significance at all time intervals (p < 10(-5), 0.001, 0.002, 0.049 for 5, 10, 15, & 30 min respectively). Fluorophotometry values converged towards baseline as time elapsed, but both groups were still statistically different at 30 min (p < 0.01). We used four fluorophotometry scoring methods and correlated them with OSDI, TBUT, fluorescein, and lissamine along with adjusted and aggregate scores. The four scoring schemes did not show any significant correlations with the other tests, except for correlations seen with lissamine and 10 (p = 0.045, 0.034) and 15 min (p = 0.013, 0.012), and with aggregate scores and 15 min (p = 0.042, 0.017).
CONCLUSIONS
Fluorophotometry generally did not correlate with any other DED tests, even though it showed capability of differentiating between DED and normal eyes up to 30 min after fluorescein dye instillation. There may be an aspect of DED that is missed in the current regimen of DED tests and only captured with fluorophotometry. Adding fluorophotometry may be useful in screening, diagnosing, and monitoring patients with DED.
Topics: Adult; Case-Control Studies; Cornea; Diagnostic Techniques, Ophthalmological; Dry Eye Syndromes; Female; Fluorescein; Fluorophotometry; Humans; Male; Middle Aged; Permeability
PubMed: 27177442
DOI: 10.1186/s12886-016-0231-3 -
The British Journal of Ophthalmology Jul 1990
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ELife May 2022Tobacco use is the leading cause of preventable death worldwide, and relapse during abstinence remains the critical barrier to successful treatment of tobacco addiction....
Tobacco use is the leading cause of preventable death worldwide, and relapse during abstinence remains the critical barrier to successful treatment of tobacco addiction. During abstinence, environmental contexts associated with nicotine use can induce craving and contribute to relapse. The insular cortex (IC) is thought to be a critical substrate of nicotine addiction and relapse. However, its specific role in context-induced relapse of nicotine-seeking is not fully known. In this study, we report a novel rodent model of context-induced relapse to nicotine-seeking after punishment-imposed abstinence, which models self-imposed abstinence through increasing negative consequences of excessive drug use. Using the neuronal activity marker Fos we find that the anterior (aIC), but not the middle or posterior IC, shows increased activity during context-induced relapse. Combining Fos with retrograde labeling of aIC inputs, we show projections to aIC from contralateral aIC and basolateral amygdala exhibit increased activity during context-induced relapse. Next, we used fiber photometry in aIC and observed phasic increases in aIC activity around nicotine-seeking responses during self-administration, punishment, and the context-induced relapse tests. Next, we used chemogenetic inhibition in both male and female rats to determine whether activity in aIC is necessary for context-induced relapse. We found that chemogenetic inhibition of aIC decreased context-induced nicotine-seeking after either punishment- or extinction-imposed abstinence. These findings highlight the critical role nicotine-associated contexts play in promoting relapse, and they show that aIC activity is critical for this context-induced relapse following both punishment and extinction-imposed abstinence.
Topics: Animals; Extinction, Psychological; Female; Male; Nicotine; Punishment; Rats; Recurrence; Self Administration
PubMed: 35536612
DOI: 10.7554/eLife.75609 -
European Journal of Pharmaceutical... Apr 2021Rats are widely used to study ocular drug responses, whereas rabbits are the most widely used preclinical model of ocular pharmacokinetics. Despite their wide use in...
Rats are widely used to study ocular drug responses, whereas rabbits are the most widely used preclinical model of ocular pharmacokinetics. Despite their wide use in evaluation of intravitreally injected drugs, translational information about pharmacokinetics and dose scaling between rats and rabbits is missing. In this study, we investigated intravitreal pharmacokinetics in rats and rabbits using non-invasive ocular fluorophotometry. Fluorescein and fluorescently labeled molecules (dextrans) with different molecular weights (376 Da, 10, 150 and 500 kDa), were injected into the vitreous of rabbits and rats. Intravitreal concentrations of the compounds were determined and pharmacokinetic parameters were calculated. Overall, the elimination half-lives of the macromolecules in rat vitreous were 5-6 times shorter than in rabbits, and the half-lives were prolonged at increasing molecular weights. The apparent volumes of distribution for tested compounds in rats and rabbits were in the range of the anatomical vitreal volumes. In both species, anterior route of elimination was predominant for the dextrans, whereas fluorescein was mainly eliminated via posterior route. Rabbit-to-rat ratios for intravitreal clearance were in the range of 2 to 5 for dextrans. Therefore, 2-5 times higher doses are needed for similar drug exposure in rabbits than in rats. Also, the shorter half-lives of macromolecules in the rat vitreous must be taken into account in translation to rabbit and human studies. The scaling factors presented herein will augment translational drug development for eye diseases.
Topics: Animals; Eye; Fluorescein; Half-Life; Intravitreal Injections; Rabbits; Rats
PubMed: 33465477
DOI: 10.1016/j.ejps.2021.105720