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Biomaterials Science Aug 2022A reliable animal model providing chronic and persistent ocular hypertension and characteristic neurodegeneration is essential to recapitulate human glaucoma and...
A reliable animal model providing chronic and persistent ocular hypertension and characteristic neurodegeneration is essential to recapitulate human glaucoma and understand the underlying pathophysiological mechanisms behind this disease. Many approaches have been tried to establish persistently elevated intraocular pressure (IOP), while no efficient model and no systematic evaluation has been widely accepted yet. Herein, we developed a novel approach to reliably induce persistent IOP elevation using an injectable hydrogel formulated by hyperbranched macromolecular poly(ethylene glycol) (HB-PEG) and thiolated hyaluronic acid (HA-SH) under physiological conditions and established a systematic system for model evaluation. By formulation screening, an appropriate hydrogel with proper mechanical property, non-swelling profile and cytocompatibility was selected for further experiment. By intracameral injection, a persistent IOP elevation over 50% above baseline was obtained and it led to progressive retinal ganglion cell loss and ganglion cell complex thickness reduction. The evaluation of the efficacy of the model was thoroughly analyzed by whole-mounts retina immunostaining, optical coherence tomography, and hematoxylin-eosin staining for histological changes and by electroretinography for visual function changes. The N35-P50 amplitude of the pattern electroretinography and the N2-P2 amplitude of the flash visual-evoked potential were decreased, while the scotopic electroretinography showed no statistically significant changes. The -forming HB-PEG/HA-SH hydrogel system could be an appropriate strategy for developing a reliable experimental glaucoma model without any confounding factors. We expect this model would be conducive to the development of neuroprotective and neuro-regenerative therapies.
Topics: Animals; Disease Models, Animal; Glaucoma; Humans; Hydrogels; Intraocular Pressure; Ocular Hypertension; Tonometry, Ocular
PubMed: 35815806
DOI: 10.1039/d2bm00552b -
Expert Opinion on Therapeutic Patents Oct 2019: Glaucoma is a neurodegenerative disease of the eye characterized by selective retinal ganglion cell loss that provokes progressive defects in the visual field.... (Review)
Review
: Glaucoma is a neurodegenerative disease of the eye characterized by selective retinal ganglion cell loss that provokes progressive defects in the visual field. Elevated intraocular pressure (IOP) is an important contributor for the progression of glaucoma. The current therapeutic arsenal for reducing IOP includes prostaglandin analogs, β-blockers, carbonic anhydrase inhibitors, α-adrenergic agonist, miotics, rho-kinase inhibitors and combinations thereof, generally administered as eye drops. : This manuscript reviews the state of art on adrenergic modulators for treating glaucoma. Both monotherapy and fixed-drugs combinations including α-adrenergic agonists and β-blockers are discussed as well as drug delivery systems where these classes of drugs are used. The review then covers the patent literature involving adrenoceptors modulators over the period 2013-2019. : While the scientific community is moving forward novel targets and related modulators for treating glaucoma and ocular hypertension, adrenergic modulators held a prominent position in the therapy of glaucoma and related disorders. Indeed, though not embodying anymore the first-choice monotherapy, they are widely marketed worldwide ordinarily in combination with other drugs, are subjects of many studies for identifying new drug compositions and have been assessed as active ingredients in several innovative ocular drug delivery systems.
Topics: Adrenergic alpha-2 Receptor Agonists; Adrenergic beta-Antagonists; Animals; Drug Combinations; Drug Delivery Systems; Drug Design; Glaucoma; Humans; Intraocular Pressure; Ocular Hypertension; Patents as Topic
PubMed: 31486689
DOI: 10.1080/13543776.2019.1665023 -
Eye & Contact Lens Nov 2021To determine the incidence of ocular hypertension (OHT) and glaucoma in patients with acanthamoeba keratitis (AK) and to outline the risk factors for the development of...
OBJECTIVES
To determine the incidence of ocular hypertension (OHT) and glaucoma in patients with acanthamoeba keratitis (AK) and to outline the risk factors for the development of glaucoma.
METHODS
A retrospective review of patients diagnosed with AK at our institute during the period from 2000 to 2018. The main outcome measures were the incidence of OHT and glaucoma, and risk factors for the development of glaucoma.
RESULTS
Fifty-two eyes diagnosed with AK were included. The incidence of OHT and glaucoma was 51.9% and 32.7%, respectively. The mean duration from disease onset to the first attack of elevated intraocular pressure was 8.4±16.6 months. The use of corticosteroids in the treatment regimen was significantly associated with the development of glaucoma (odds ratio, 3.93; 95% confidence interval, 0.96-16.15; P=0.049). At the last follow-up visit, both patients with glaucoma and nonglaucoma patients had improved visual acuity without a difference in the mean amount of logarithm of the minimum angle of resolution acuity improvement among them (0.56±0.91 vs. 0.67±0.87, P=0.686).
CONCLUSION
Our findings confirm that OHT and glaucoma are frequent complications in AK. Patients treated with a regimen containing corticosteroids are at a higher risk; thus, they should receive close intraocular pressure monitoring.
Topics: Acanthamoeba Keratitis; Glaucoma; Humans; Incidence; Intraocular Pressure; Ocular Hypertension; Retrospective Studies; Risk Factors
PubMed: 34334725
DOI: 10.1097/ICL.0000000000000824 -
BMJ Open Aug 2023Glaucoma, a major cause of irreversible blindness, is a highly heritable human disease. Currently, the majority of the risk genes for glaucoma are unknown. We...
PURPOSE
Glaucoma, a major cause of irreversible blindness, is a highly heritable human disease. Currently, the majority of the risk genes for glaucoma are unknown. We established the Genetics of Glaucoma Study (GOGS) to identify disease genes and improve genetic prediction of glaucoma risk and response to treatment.
PARTICIPANTS
More than 5700 participants with glaucoma or a family history of glaucoma were recruited through a media campaign and the Australian Government healthcare service provider, Services Australia, making GOGS one of the largest genetic studies of glaucoma globally. The mean age of the participants was 65.30±9.36 years, and 62% were female. Participants completed a questionnaire obtaining information about their glaucoma-related medical history such as family history, glaucoma status and subtypes, surgical procedures, and prescriptions. The questionnaire also obtained information about other eye and systemic diseases. Approximately 80% of the participants provided a DNA sample and ~70% consented to data linkage to their Australian Government Medicare and Pharmaceutical Benefits Scheme schedules.
FINDINGS TO DATE
4336 GOGS participants reported that an optometrist or ophthalmologist has diagnosed them with glaucoma and 3639 participants reported having a family history of glaucoma. The vast majority of the participants (N=4393) had used at least one glaucoma-related medication; latanoprost was the most commonly prescribed drug (54% of the participants who had a glaucoma prescription). A subset of the participants reported a surgical treatment for glaucoma including a laser surgery in 2008 participants and a non-laser operation in 803 participants. Several comorbid eye and systemic diseases were also observed; the most common reports were ocular hypertension (53% of the participants), cataract (48%), hypertension (40%), nearsightedness (31%), astigmatism (22%), farsightedness (16%), diabetes (12%), sleep apnoea (11%) and migraines (10%).
FUTURE PLANS
GOGS will contribute to the global gene-mapping efforts as one of the largest genetic studies for glaucoma. We will also use GOGS to develop or validate genetic risk prediction models to stratify glaucoma risk, particularly in individuals with a family history of glaucoma, and to predict clinical outcomes (eg, which medication works better for an individual and whether glaucoma surgery is required). GOGS will also help us answer various research questions about genetic overlap and causal relationships between glaucoma and its comorbidities.
Topics: Aged; Humans; Female; Middle Aged; Male; Antihypertensive Agents; Australia; National Health Programs; Glaucoma; Ocular Hypertension; Intraocular Pressure
PubMed: 37536973
DOI: 10.1136/bmjopen-2022-068811 -
Romanian Journal of Ophthalmology 2020to describe a clinical case of ocular hypertension (OHT) in Axenfeld-Rieger Syndrome (ARS). Observational case report of a 43-year-old woman with background of OHT....
to describe a clinical case of ocular hypertension (OHT) in Axenfeld-Rieger Syndrome (ARS). Observational case report of a 43-year-old woman with background of OHT. The data was collected originally with a standardized electronic medical record. A complete ophthalmologic examination was performed. In the biomicroscopy, a posterior embryotoxon, iris atrophy with absence of crypts and irregularity of pigmentation, and discoria in OU were observed. Gonioscopy revealed an open angle with a prominent and anterior displaced Schwalbe line. Ocular fundus (OF) demonstrated small and oblique papillae, with normal neurorretinal ring. Functional tests were normal. The patient did not present systemic pathologies, so the diagnosis of Rieger anomaly was made. The IOP control was achieved with aqueous humor suppressants. Glaucoma is the main cause of visual morbidity in patients with ARS, therefore a complete periodic ophthalmological exam is a priority. :ARS = Axenfeld-Rieger Syndrome, RP = retinitis pigmentosa, IOP = Intraocular Pressure, BCVA = Best Corrected Visual Acuity, OR = right eye, OS = left eye, OU = both eyes, OF = ocular fundus, OCT = optical coherence tomography, VF = visual field, TBC = trabeculectomy.
Topics: Adult; Anterior Chamber; Anterior Eye Segment; Eye Abnormalities; Eye Diseases, Hereditary; Female; Gonioscopy; Humans; Intraocular Pressure; Ocular Hypertension
PubMed: 33367186
DOI: 10.22336/rjo.2020.70 -
Clinical & Experimental Optometry May 2022Systemic hypertension or hypertension is a very common chronic age-related disease worldwide. It is typically characterised by a sustained elevation of blood pressure,...
Systemic hypertension or hypertension is a very common chronic age-related disease worldwide. It is typically characterised by a sustained elevation of blood pressure, particularly when the systolic blood pressure and/or diastolic blood pressure are of more than 140 mmHg and 90 mmHg, respectively. If hypertension is not well controlled, it may lead to an increased risk of stroke and heart attack. It has been shown that hypertension is linked to various ocular diseases, including cataract, diabetic retinopathy, age-related macular degeneration, and glaucoma. Glaucoma is the leading cause of irreversible blindness worldwide. Primary open angle glaucoma is the most common form of the disease and is usually characterised by an increase in intraocular pressure. This condition, together with normal tension glaucoma, constitutes open angle glaucoma. Systemic hypertension has been identified as a risk factor for open angle glaucoma. It is speculated that blood pressure is involved in the pathogenesis of open angle glaucoma by altering intraocular pressure or ocular blood flow, or both. Recent evidence has shown that both extremely high and low blood pressure are associated with increased risk of open angle glaucoma. Additional pathogenic mechanisms, including increased inflammation likely to be involved in the development and progression of these two diseases, are discussed.
Topics: Blood Pressure; Glaucoma, Open-Angle; Humans; Hypertension; Intraocular Pressure; Ocular Hypertension; Tonometry, Ocular
PubMed: 34402761
DOI: 10.1080/08164622.2021.1964332 -
Expert Opinion on Investigational Drugs 2023Glaucoma is a leading cause of blindness with intraocular pressure (IOP) as the only known modifiable risk factor. Prostaglandin FP receptor agonists are the first-line... (Review)
Review
INTRODUCTION
Glaucoma is a leading cause of blindness with intraocular pressure (IOP) as the only known modifiable risk factor. Prostaglandin FP receptor agonists are the first-line medical treatment for glaucoma and ocular hypertension. Despite their efficacy, their IOP lowering effect may be insufficient requiring second agents, and poor patient compliance to medical therapy may preclude their full effect.
AREAS COVERED
This literature review examines the novel FP receptor drugs and drug delivery devices in clinical phase trials for treatment of glaucoma. Three novel drugs targeting FP receptors were identified, including latanoprostene bunod, NCX 470, and sepetaprost. Additionally, sustained drug delivery devices in early clinical phase trials included intracameral implants, punctal plugs, ocular rings, and contact lenses.
EXPERT OPINION
NO hybrid FP receptor agonists and dual FP/EP3 receptor agonists may show promise as novel medical therapies with greater efficacy than approved prostaglandin analogs in clinical use, with a similar safety profile. Alternatively, drug delivery systems may provide a similar IOP lowering effect to existing agonists but overcome issues with patient compliance and convenience. A personalized approach to drug delivery devices may be required to ensure the most appropriate fit for the patient according to the invasiveness and duration of therapy desired.
Topics: Humans; Glaucoma; Ocular Hypertension; Receptors, Prostaglandin; Intraocular Pressure; Prostaglandins, Synthetic; Antihypertensive Agents
PubMed: 37929314
DOI: 10.1080/13543784.2023.2279146 -
Retina (Philadelphia, Pa.) Jul 2021To analyze the incidence, risk factors, and time to onset of ocular hypertension (OHT) after intravitreal injections (IVI) of dexamethasone implant and to evaluate the... (Observational Study)
Observational Study
PURPOSE
To analyze the incidence, risk factors, and time to onset of ocular hypertension (OHT) after intravitreal injections (IVI) of dexamethasone implant and to evaluate the long-term cumulative probability of intraocular pressure elevation.
METHODS
Eyes of patients having received at least one dexamethasone implant IVI between October 2010 and February 2015 were included in the present study. Ocular hypertension was defined as intraocular pressure > 25 mmHg and/or an increase of 10 mmHg over the follow-up period compared with baseline intraocular pressure.
RESULTS
Four hundred ninety-four eyes were studied in 410 patients. For a total of 1,371 IVI, the incidence of OHT was 32.6% in the study eyes with a mean follow-up period of 30 months (3-62.5) and a median follow-up of 29 months. Pressure-lowering treatment was introduced for 36.9% of eyes. Topical treatment alone was sufficient to manage OHT in 97%. Young age, male sex, uveitis and retinal vein occlusion, and glaucoma treated with a double- or triple-combination topical pressure-lowering medication were found to be risk factors for OHT. The incidence of OHT did not change with an increase in the number of IVI, and there was no cumulative effect, defining by an increase of the incidence of OHT in patients after repeated IVI (P = 0.248).
CONCLUSION
This study confirmed that OHT is of moderate incidence, transient, controlled by topical treatment and provides data on the long-term cumulative probability of intraocular pressure elevation in a large cohort of eyes treated with dexamethasone implant IVI. Repeat injections of dexamethasone implant neither increase nor decrease the risk of OHT.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Child; Dexamethasone; Drug Implants; Female; Follow-Up Studies; France; Glucocorticoids; Humans; Incidence; Intraocular Pressure; Intravitreal Injections; Macular Edema; Male; Middle Aged; Ocular Hypertension; Retrospective Studies; Risk Assessment; Risk Factors; Time Factors; Young Adult
PubMed: 33315814
DOI: 10.1097/IAE.0000000000003080 -
Expert Opinion on Drug Safety Apr 2022In the last 25 years, topical prostaglandin analogues (PGAs) have emerged to become first line and first choice therapeutic options in the management of glaucoma and... (Review)
Review
INTRODUCTION
In the last 25 years, topical prostaglandin analogues (PGAs) have emerged to become first line and first choice therapeutic options in the management of glaucoma and ocular hypertension (OHT). Although the short-term efficacy and safety of PGAs has been extensively investigated, less is known about their long term safety and tolerability. This gap in current knowledge is clinically relevant, because treatment-related adverse events and long-term tolerability issues are key determinants of the overall success of long-term therapy and the final outcome of a lifelong, symptomless disease like glaucoma.
AREAS COVERED
We include selected evidence pertaining to the safety and tolerability of available and emerging PGA formulations. We also outline PGA formulations with different concentrations of the active ingredient, different preservatives, and preservative-free (PF) options.
EXPERT OPINION
Undoubtedly PGAs will continue to play a major role in the medical therapy of glaucoma and OHT. Despite extensive literature and prolonged clinical experience with these agents worldwide, a number of areas that warrant further research have been identified in the present review. Recently launched novel PGAs, or those still in development offer new opportunities and future challenges.
Topics: Antihypertensive Agents; Glaucoma; Glaucoma, Open-Angle; Humans; Intraocular Pressure; Ocular Hypertension; Ophthalmic Solutions; Prostaglandins, Synthetic
PubMed: 34666576
DOI: 10.1080/14740338.2022.1996560 -
Investigative Ophthalmology & Visual... Sep 2023Keratin 8/18 (KRT8/18), paired members of the intermediate filament family, have shown vital functions in regulating physiological activities more than supporting the...
PURPOSE
Keratin 8/18 (KRT8/18), paired members of the intermediate filament family, have shown vital functions in regulating physiological activities more than supporting the mechanic strength for cells and organelles. However, the KRT8/18 presence in retinal ganglion cells (RGCs) and functions on neuroprotection in a mouse model of acute ocular hypertension (AOH) are unknown and worthy of exploration.
METHODS
We identified the existence of KRT8/18 in normal human and mouse retinas and primary RGCs. KRT8/18 levels were detected after AOH modeling. The adeno-associated virus (AAV) system was intravitreally used for selective KRT8 knockdown in RGCs. The histological changes, the loss and dysfunction of RGCs, and the gliosis in retinas were detected. The markers of cell apoptosis and MAPK pathways were investigated.
RESULTS
KRT8/18 existed in all retinal layers and was highly expressed in RGCs, and they increased after AOH induction. The KRT8 knockdown in RGCs caused no histopathological changes and RGC loss in retinas without AOH modeling. However, after the KRT8 deficiency, AOH significantly promoted the loss of whole retina and inner retina thickness, the reduction, apoptosis, and dysfunction of RGCs, and the glial activation. Besides, downregulated Bcl-2 and upregulated cleaved-Caspase 3 were found in the AOH retinas with KRT8 knockdown, which may be caused by the increased phosphorylation level of MAPK pathways (JNK, p38, and ERK).
CONCLUSIONS
The KRT8 deficiency promoted RGC apoptosis and neurodegeneration by abnormal activation of MAPK pathways in AOH retinas. Targeting KRT8 may serve as a novel treatment for saving RCGs from glaucomatous injuries.
Topics: Animals; Humans; Mice; Apoptosis; Glaucoma; Ocular Hypertension; Retina; Retinal Ganglion Cells
PubMed: 37656477
DOI: 10.1167/iovs.64.12.1