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1.
BMJ Open Ophthalmol ; 9(1)2024 Jun 03.
Article in English | MEDLINE | ID: mdl-38830728

ABSTRACT

BACKGROUND: Unpreserved single-dose unit (SDU) eye drops are commonly used to avoid benzalkonium chloride-related toxicity. Although intended for single use, many patients report off-label repeated use of SDUs over a prolonged period. We investigated whether repeated use of dexamethasone 0.1% SDUs in the same patient increases the bacterial contamination rate. METHODS: We prospectively enrolled patients scheduled for inpatient corneal and glaucoma surgery receiving dexamethasone 0.1% SDU four times per day from the same vial. To assess contamination rates, one drop from the vial was cultured immediately after opening the SDU (t0), 10 hours later after four drop applications (t10) and 24 hours after opening without further drop applications (t24). Conjunctival swabs were taken before and after drop application. Contamination rate was assessed with a standard clinical culturing protocol without introducing a positive control. RESULTS: 110 eyes of 109 patients were evaluated. Drops collected immediately after opening the SDU (t0) were contaminated in 9/110 cultures (8.1%). At t10, 13/110 cultures were contaminated (11.8%; p=0.267) and 11/110 at t24 (10.0%; t24 vs t0; p=1.00). In 5 of 21 cases of contaminated drops at t10 and/or t24, the same isolates were cultured from the initial conjunctival swab and the SDU. In three cases, the same bacterial species was found in consecutive samples. CONCLUSION: The contamination rate of the SDU did not increase after multiple use within 24 hours. Contamination from fingertip flora was more likely than from ocular surface flora. Reuse of dexamethasone 0.1% SDU in the same patient within 24 hours appears to be safe.


Subject(s)
Dexamethasone , Glucocorticoids , Ophthalmic Solutions , Preservatives, Pharmaceutical , Humans , Dexamethasone/administration & dosage , Dexamethasone/adverse effects , Ophthalmic Solutions/adverse effects , Male , Female , Prospective Studies , Preservatives, Pharmaceutical/adverse effects , Preservatives, Pharmaceutical/administration & dosage , Aged , Middle Aged , Glucocorticoids/administration & dosage , Glucocorticoids/adverse effects , Aged, 80 and over , Adult , Drug Contamination , Glaucoma/drug therapy , Conjunctiva/microbiology , Conjunctiva/drug effects , Bacteria/drug effects , Bacteria/isolation & purification , Corneal Diseases/chemically induced
2.
Int J Mol Sci ; 25(11)2024 May 21.
Article in English | MEDLINE | ID: mdl-38891764

ABSTRACT

Glaucoma is a chronic neurodegenerative disease that poses a significant threat of irreversible blindness worldwide. Current treatments for glaucoma focus on reducing intraocular pressure (IOP), which is the only modifiable risk factor. Traditional anti-glaucomatous agents, including carbonic anhydrase inhibitors, beta-blockers, alpha-2 agonists, and prostaglandin analogs, work by either improving uveoscleral outflow or reducing aqueous humor production. Rho kinase (ROCK) inhibitors represent a novel class of anti-glaucomatous drugs that have emerged from bench to bedside in the past decade, offering multifunctional characteristics. Unlike conventional medications, ROCK inhibitors directly target the trabecular meshwork outflow pathway. This review aims to discuss the mechanism of ROCK inhibitors in reducing IOP, providing neuroprotection, and preventing fibrosis. We also highlight recent studies and clinical trials evaluating the efficacy and safety of ROCK inhibitors, compare them with other clinical anti-glaucomatous medications, and outline future prospects for ROCK inhibitors in glaucoma treatment.


Subject(s)
Glaucoma , Intraocular Pressure , Protein Kinase Inhibitors , rho-Associated Kinases , Humans , Glaucoma/drug therapy , rho-Associated Kinases/antagonists & inhibitors , rho-Associated Kinases/metabolism , Protein Kinase Inhibitors/therapeutic use , Protein Kinase Inhibitors/pharmacology , Intraocular Pressure/drug effects , Animals
3.
Drug Deliv ; 31(1): 2361168, 2024 Dec.
Article in English | MEDLINE | ID: mdl-38899440

ABSTRACT

Glaucoma is the leading cause of blindness worldwide. However, its surgical treatment, in particular via trabeculectomy, can be complicated by fibrosis. In current clinical practice, application of the drug, Mitomycin C, prevents or delays fibrosis, but can lead to additional side effects, such as bleb leakage and hypotony. Previous in silico drug screening and in vitro testing has identified the known antibiotic, josamycin, as a possible alternative antifibrotic medication with potentially fewer side effects. However, a suitable ocular delivery mechanism for the hydrophobic drug to the surgical site does not yet exist. Therefore, the focus of this paper is the development of an implantable drug delivery system for sustained delivery of josamycin after glaucoma surgery based on crosslinked γ-cyclodextrin. γ-Cyclodextrin is a commonly used solubilizer which was shown to complex with josamycin, drastically increasing the drug's solubility in aqueous solutions. A simple γ-cyclodextrin crosslinking method produced biocompatible hydrogels well-suited for implantation. The crosslinked γ - cyclodextrin retained the ability to form complexes with josamycin, resulting in a 4-fold higher drug loading efficiency when compared to linear dextran hydrogels, and prolonged drug release over 4 days.


Subject(s)
Delayed-Action Preparations , Hydrogels , Solubility , gamma-Cyclodextrins , Hydrogels/chemistry , gamma-Cyclodextrins/chemistry , Drug Liberation , Drug Delivery Systems/methods , Glaucoma/drug therapy , Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Drug Carriers/chemistry , Animals , Humans , Cross-Linking Reagents/chemistry
4.
Biomed Pharmacother ; 175: 116711, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38735082

ABSTRACT

Glaucoma, the leading cause of irreversible blindness worldwide, is characterized by neurodegeneration and neuroinflammation with retinal NAD/NADP and GSH decline. Nicotinamide adenine dinucleotide (NAD)/NAD phosphate (NADP) and glutathione (GSH) are two redox reducers in neuronal and glial metabolism. However, therapeutic strategies targeting NAD/NADP or GSH do not exert ideal effects, and the underlying mechanisms are still poorly understood. We assessed morphological changes in retinal ganglion cells (RGCs), the affected neurons in glaucoma, and Müller cells, the major glial cells in the retina, as well as the levels of phosphorylated p38 (p-p38) and Caspase-3 in glaucoma patients. We constructed a modified chronic ocular hypertensive rat model and an oxygen-glucose deprivation (OGD) cell model. After applying NADPH and N-acetylcysteine (NAC), a precursor to cysteine, the rate-limiting substrate in GSH biosynthesis, to cells, apoptosis, axonal damage and peroxidation were reduced in the RGCs of the NAC group and p-p38 levels were decreased in the RGCs of the NADPH group, while in stimulated Müller cells cultured individually or cocultured with RGCs, gliosis and p38/MAPK, rather than JNK/MAPK, activation were inhibited. The results were more synergistic in the rat model, where either NADPH or NAC showed crossover effects on inhibiting peroxidation and p38/MAPK pathway activation. Moreover, the combination of NADPH and NAC ameliorated RGC electrophysiological function and prevented Müller cell gliosis to the greatest extent. These data illustrated conjoined mechanisms in glaucomatous RGC injury and Müller cell gliosis and suggested that NADPH and NAC collaborate as a neuroprotective and anti-inflammatory combination treatment for glaucoma and other underlying human neurodegenerative diseases.


Subject(s)
Acetylcysteine , NADP , Ocular Hypertension , Rats, Sprague-Dawley , Retinal Ganglion Cells , p38 Mitogen-Activated Protein Kinases , Animals , NADP/metabolism , p38 Mitogen-Activated Protein Kinases/metabolism , Ocular Hypertension/metabolism , Ocular Hypertension/drug therapy , Ocular Hypertension/pathology , Acetylcysteine/pharmacology , Rats , Male , Retinal Ganglion Cells/drug effects , Retinal Ganglion Cells/metabolism , Retinal Ganglion Cells/pathology , Glaucoma/metabolism , Glaucoma/pathology , Glaucoma/drug therapy , Neuroinflammatory Diseases/drug therapy , Neuroinflammatory Diseases/metabolism , Humans , Ependymoglial Cells/drug effects , Ependymoglial Cells/metabolism , Ependymoglial Cells/pathology , Disease Models, Animal , MAP Kinase Signaling System/drug effects , Apoptosis/drug effects , Chronic Disease , Neuroprotective Agents/pharmacology , Cells, Cultured , Lipid Peroxidation/drug effects
5.
Invest Ophthalmol Vis Sci ; 65(5): 32, 2024 May 01.
Article in English | MEDLINE | ID: mdl-38771570

ABSTRACT

Purpose: To evaluate VEGF-C-induced lymphoproliferation in conjunction with 5-fluorouracil (5-FU) antimetabolite treatment in a rabbit glaucoma filtration surgery (GFS) model. Methods: Thirty-two rabbits underwent GFS and were assigned to four groups (n = 8 each) defined by subconjunctival drug treatment: (a) VEGF-C combined with 5-FU, (b) 5-FU, (c) VEGF-C, (d) and control. Bleb survival, bleb measurements, and IOP were evaluated over 30 days. At the end, histology and anterior segment OCT were performed on some eyes. mRNA was isolated from the remaining eyes for RT-PCR evaluation of vessel-specific markers (lymphatics, podoplanin and LYVE-1; and blood vessels, CD31). Results: Qualitatively and quantitatively, VEGF-C combined with 5-FU resulted in blebs which were posteriorly longer and wider than the other conditions: vs. 5-FU (P = 0.043 for longer, P = 0.046 for wider), vs. VEGF-C (P < 0.001, P < 0.001) and vs. control (P < 0.001, P < 0.001). After 30 days, the VEGF-C combined with 5-FU condition resulted in longer bleb survival compared with 5-FU (P = 0.025), VEGF-C (P < 0.001), and control (P < 0.001). Only the VEGF-C combined with 5-FU condition showed a negative correlation between IOP and time that was statistically significant (r = -0.533; P = 0.034). Anterior segment OCT and histology demonstrated larger blebs for the VEGF-C combined with 5-FU condition. Only conditions including VEGF-C led to increased expression of lymphatic markers (LYVE-1, P < 0.001-0.008 and podoplanin, P = 0.002-0.011). Expression of CD31 was not different between the groups (P = 0.978). Conclusions: Adding VEGF-C lymphoproliferation to standard antimetabolite treatment improved rabbit GFS success and may suggest a future strategy to improve human GFSs.


Subject(s)
Disease Models, Animal , Fluorouracil , Glaucoma , Intraocular Pressure , Trabeculectomy , Vascular Endothelial Growth Factor C , Animals , Rabbits , Fluorouracil/therapeutic use , Fluorouracil/pharmacology , Glaucoma/surgery , Glaucoma/physiopathology , Glaucoma/drug therapy , Vascular Endothelial Growth Factor C/metabolism , Trabeculectomy/methods , Intraocular Pressure/physiology , Antimetabolites/pharmacology , Antimetabolites/therapeutic use , Tomography, Optical Coherence , Conjunctiva , RNA, Messenger/genetics
7.
Vision Res ; 221: 108434, 2024 Aug.
Article in English | MEDLINE | ID: mdl-38805893

ABSTRACT

Treatment of glaucoma, the leading cause of irreversible blindness, remains challenging. The apoptotic loss of retinal ganglion cells (RGCs) in glaucoma is the pathological hallmark. Current treatments often remain suboptimal as they aim to halt RGC loss secondary to reduction of intraocular pressure. The pathophysiological targets for exploring direct neuroprotective approaches, therefore are highly relevant. Sphingolipids have emerged as significant target molecules as they are not only the structural components of various cell constituents, but they also serve as signaling molecules that regulate molecular pathways involved in cell survival and death. Investigations have shown that a critical balance among various sphingolipid species, particularly the ceramide and sphingosine-1-phosphate play a role in deciding the fate of the cell. In this review we briefly discuss the metabolic interconversion of sphingolipid species to get an insight into "sphingolipid rheostat", the dynamic balance among metabolites. Further we highlight the role of sphingolipids in the key pathophysiological mechanisms that lead to glaucomatous loss of RGCs. Lastly, we summarize the potential drug candidates that have been investigated for their neuroprotective effects in glaucoma via their effects on sphingolipid axis.


Subject(s)
Glaucoma , Neuroprotective Agents , Retinal Ganglion Cells , Sphingolipids , Humans , Glaucoma/drug therapy , Glaucoma/physiopathology , Glaucoma/metabolism , Sphingolipids/metabolism , Retinal Ganglion Cells/physiology , Neuroprotective Agents/pharmacology , Animals , Ceramides/metabolism , Apoptosis/physiology , Intraocular Pressure/physiology
8.
Exp Eye Res ; 244: 109927, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38750784

ABSTRACT

Subconjunctival fibrosis is the major cause of failure in both conventional and modern minimally invasive glaucoma surgeries (MIGSs) with subconjunctival filtration. The search for safe and effective anti-fibrotic agents is critical for improving long-term surgical outcomes. In this study, we investigated the effect of inhibiting the rapamycin-insensitive mTORC1/4E-BP1 axis on the transforming growth factor-beta 1(TGF-ß1)-induced fibrotic responses in human Tenon's fibroblasts (HTFs), as well as in a rat model of glaucoma filtration surgery (GFS). Primary cultured HTFs were treated with 3 ng/mL TGF-ß1 for 24 h, followed by treatment with 10 µM CZ415 for additional 24 h. Rapamycin (10 µM) was utilized as a control for mTORC1/4E-BP1 signaling insensitivity. The expression levels of fibrosis-associated molecules were measured using quantitative real-time PCR, Western blotting, and immunofluorescence analysis. Cell migration was assessed through the scratch wound assay. Additionally, a rat model of GFS was employed to evaluate the anti-fibrotic effect of CZ415 in vivo. Our findings indicated that both rapamycin and CZ415 treatment significantly reduced the TGF-ß1-induced cell proliferation, migration, and the expression of pro-fibrotic factors in HTFs. CZ415 also more effectively inhibited TGF-ß1-mediated collagen synthesis in HTFs compared to rapamycin. Activation of mTORC1/4E-BP signaling following TGF-ß1 exposure was highly suppressed by CZ415 but was only modestly inhibited by rapamycin. Furthermore, CZ415 was found to decrease subconjunctival collagen deposition in rats post GFS. Our results suggest that rapamycin-insensitive mTORC1/4E-BP1 signaling plays a critical role in TGF-ß1-driven collagen synthesis in HTFs. This study demonstrated that inhibition of the mTORC1/4E-BP1 axis offers superior anti-fibrotic efficacy compared to rapamycin and represents a promising target for improving the success rate of both traditional and modern GFSs.


Subject(s)
Adaptor Proteins, Signal Transducing , Fibroblasts , Fibrosis , Mechanistic Target of Rapamycin Complex 1 , Sirolimus , Tenon Capsule , Transforming Growth Factor beta1 , Animals , Transforming Growth Factor beta1/metabolism , Mechanistic Target of Rapamycin Complex 1/metabolism , Mechanistic Target of Rapamycin Complex 1/antagonists & inhibitors , Humans , Rats , Fibroblasts/metabolism , Fibroblasts/drug effects , Fibroblasts/pathology , Sirolimus/pharmacology , Fibrosis/metabolism , Tenon Capsule/metabolism , Tenon Capsule/drug effects , Cells, Cultured , Adaptor Proteins, Signal Transducing/metabolism , Adaptor Proteins, Signal Transducing/genetics , Cell Movement/drug effects , Disease Models, Animal , Blotting, Western , Rats, Sprague-Dawley , Cell Cycle Proteins/metabolism , Signal Transduction , Real-Time Polymerase Chain Reaction , Male , Glaucoma/metabolism , Glaucoma/drug therapy , Glaucoma/pathology , Immunosuppressive Agents/pharmacology
9.
Cells ; 13(9)2024 May 01.
Article in English | MEDLINE | ID: mdl-38727311

ABSTRACT

Glaucoma is a heterogeneous group of optic neuropathies characterized by a progressive degeneration of the retinal ganglion cells (RGCs), leading to irreversible vision loss. Nowadays, the traditional therapeutic approach to glaucoma consists of lowering the intraocular pressure (IOP), which does not address the neurodegenerative features of the disease. Besides animal models of glaucoma, there is a considerable need for in vitro experimental models to propose new therapeutic strategies for this ocular disease. In this study, we elucidated the pathological mechanisms leading to neuroretinal R28 cell death after exposure to glutamate and hydrogen peroxide (H2O2) in order to develop new therapeutic approaches for oxidative stress-induced retinal diseases, including glaucoma. We were able to show that glutamate and H2O2 can induce a decrease in R28 cell viability in a concentration-dependent manner. A cell viability of about 42% was found after exposure to 3 mM of glutamate and about 56% after exposure to 100 µM of H2O2 (n = 4). Label-free quantitative mass spectrometry analysis revealed differential alterations of 193 and 311 proteins in R28 cells exposed to 3 mM of glutamate and 100 µM of H2O2, respectively (FDR < 1%; p < 0.05). Bioinformatics analysis indicated that the protein changes were associated with the dysregulation of signaling pathways, which was similar to those observed in glaucoma. Thus, the proteomic alteration induced by glutamate was associated with the inhibition of the PI3K/AKT signaling pathway. On the other hand, H2O2-induced toxicity in R28 cells was linked to the activation of apoptosis signaling and the inhibition of the mTOR and ERK/MAPK signaling pathways. Furthermore, the data show a similarity in the inhibition of the EIF2 and AMPK signaling pathways and the activation of the sumoylation and WNT/ß-catenin signaling pathways in both groups. Our findings suggest that the exposure of R28 cells to glutamate and H2O2 could induce glaucoma-like neurodegenerative features and potentially provide a suitable tool for the development of new therapeutic strategies for retinal diseases.


Subject(s)
Glaucoma , Glutamic Acid , Hydrogen Peroxide , Oxidative Stress , Glaucoma/metabolism , Glaucoma/pathology , Glaucoma/drug therapy , Oxidative Stress/drug effects , Animals , Hydrogen Peroxide/pharmacology , Glutamic Acid/metabolism , Cell Survival/drug effects , Rats , Cell Line , Retinal Ganglion Cells/metabolism , Retinal Ganglion Cells/drug effects , Retinal Ganglion Cells/pathology , Signal Transduction/drug effects , Models, Biological , Humans
10.
Neuromolecular Med ; 26(1): 13, 2024 Apr 15.
Article in English | MEDLINE | ID: mdl-38619671

ABSTRACT

Normal tension glaucoma (NTG) is a progressive neurodegenerative disease in glaucoma families. Typical glaucoma develops because of increased intraocular pressure (IOP), whereas NTG develops despite normal IOP. As a subtype of open-angle glaucoma, NTG is characterized by retinal ganglion cell (RGC) degeneration, gradual loss of axons, and injury to the optic nerve. The relationship between glutamate excitotoxicity and oxidative stress has elicited great interest in NTG studies. We recently reported that suppressing collapsin response mediator protein 2 (CRMP2) phosphorylation in S522A CRMP2 mutant (CRMP2 KIKI) mice inhibited RGC death in NTG mouse models. This study evaluated the impact of the natural compounds huperzine A (HupA) and naringenin (NAR), which have therapeutic effects against glutamate excitotoxicity and oxidative stress, on inhibiting CMRP2 phosphorylation in mice intravitreally injected with N-methyl-D-aspartate (NMDA) and GLAST mutant mice. Results of the study demonstrated that HupA and NAR significantly reduced RGC degeneration and thinning of the inner retinal layer, and inhibited the elevated CRMP2 phosphorylation. These treatments protected against glutamate excitotoxicity and suppressed oxidative stress, which could provide insight into developing new effective therapeutic strategies for NTG.


Subject(s)
Alkaloids , Glaucoma, Open-Angle , Glaucoma , Low Tension Glaucoma , Neurodegenerative Diseases , Sesquiterpenes , Animals , Mice , Disease Models, Animal , Glaucoma/drug therapy , Glutamic Acid/toxicity , Phosphorylation , Retinal Ganglion Cells , Semaphorin-3A
11.
Am J Physiol Cell Physiol ; 326(5): C1505-C1519, 2024 May 01.
Article in English | MEDLINE | ID: mdl-38557355

ABSTRACT

Glaucoma is a blinding disease. Reduction of intraocular pressure (IOP) is the mainstay of treatment, but current drugs show side effects or become progressively ineffective, highlighting the need for novel compounds. We have synthesized a family of perhydro-1,4-oxazepine derivatives of digoxin, the selective inhibitor of Na,K-ATPase. The cyclobutyl derivative (DcB) displays strong selectivity for the human α2 isoform and potently reduces IOP in rabbits. These observations appeared consistent with a hypothesis that in ciliary epithelium DcB inhibits the α2 isoform of Na,K-ATPase, which is expressed strongly in nonpigmented cells, reducing aqueous humor (AH) inflow. This paper extends assessment of efficacy and mechanism of action of DcB using an ocular hypertensive nonhuman primate model (OHT-NHP) (Macaca fascicularis). In OHT-NHP, DcB potently lowers IOP, in both acute (24 h) and extended (7-10 days) settings, accompanied by increased aqueous humor flow rate (AFR). By contrast, ocular normotensive animals (ONT-NHP) are poorly responsive to DcB, if at all. The mechanism of action of DcB has been analyzed using isolated porcine ciliary epithelium and perfused enucleated eyes to study AH inflow and AH outflow facility, respectively. 1) DcB significantly stimulates AH inflow although prior addition of 8-Br-cAMP, which raises AH inflow, precludes additional effects of DcB. 2) DcB significantly increases AH outflow facility via the trabecular meshwork (TM). Taken together, the data indicate that the original hypothesis on the mechanism of action must be revised. In the OHT-NHP, and presumably other species, DcB lowers IOP by increasing AH outflow facility rather than by decreasing AH inflow.NEW & NOTEWORTHY When applied topically, a cyclobutyl derivative of digoxin (DcB) potently reduces intraocular pressure in an ocular hypertensive nonhuman primate model (Macaca fascicularis), associated with increased aqueous humor (AH) flow rate (AFR). The mechanism of action of DcB involves increased AH outflow facility as detected in enucleated perfused porcine eyes and, in parallel, increased (AH) inflow as detected in isolated porcine ciliary epithelium. DcB might have potential as a drug for the treatment of open-angle human glaucoma.


Subject(s)
Aqueous Humor , Digoxin , Intraocular Pressure , Macaca fascicularis , Ocular Hypertension , Animals , Intraocular Pressure/drug effects , Digoxin/pharmacology , Aqueous Humor/metabolism , Aqueous Humor/drug effects , Ocular Hypertension/drug therapy , Ocular Hypertension/physiopathology , Ocular Hypertension/metabolism , Disease Models, Animal , Glaucoma/drug therapy , Glaucoma/metabolism , Glaucoma/physiopathology , Rabbits , Humans , Ciliary Body/drug effects , Ciliary Body/metabolism , Sodium-Potassium-Exchanging ATPase/metabolism , Sodium-Potassium-Exchanging ATPase/antagonists & inhibitors , Male , Trabecular Meshwork/drug effects , Trabecular Meshwork/metabolism
12.
Int J Pharm ; 657: 124098, 2024 May 25.
Article in English | MEDLINE | ID: mdl-38621614

ABSTRACT

Glaucoma, the second most common cause of blindness worldwide, requires the development of new and effective treatments. This study introduces a novel controlled-release system utilizing elastin-like recombinamers (ELR) and the Supercritical Antisolvent (SAS) technique with supercritical CO2. Acetazolamide (AZM), a class IV drug with limited solubility and permeability, is successfully encapsulated in an amphiphilic ELR at three different ELR:AZM ratios, yielding up to 62 %. Scanning electron microscopy (SEM) reveals spherical microparticles that disintegrate into monodisperse nanoparticles measuring approximately 42 nm under physiological conditions. The nanoparticles, as observed via Transmission Electron Microscopy (TEM) and Atomic Force Microscopy (AFM), do not exhibit aggregates, a fact confirmed by the zeta potential displaying a value of -33 mV over a period of 30 days. Transcorneal permeation tests demonstrate a 10 % higher permeation level compared to the control solution, which increases to 30 % after 2 h. Ocular irritation tests demonstrate no adverse effects or damage. Intraocular pressure (IOP) tests conducted on hypertensive rabbits indicate greater effectiveness for all three analyzed formulations, suggesting enhanced drug bioavailability during treatment. Consequently, the combination of recombinant biopolymers and high-pressure techniques represents a promising approach for advancing glaucoma therapy, emphasizing its potential clinical significance.


Subject(s)
Acetazolamide , Elastin , Glaucoma , Intraocular Pressure , Nanoparticles , Rabbits , Animals , Acetazolamide/administration & dosage , Acetazolamide/chemistry , Acetazolamide/pharmacokinetics , Glaucoma/drug therapy , Elastin/chemistry , Intraocular Pressure/drug effects , Nanoparticles/chemistry , Delayed-Action Preparations/chemistry , Solvents/chemistry , Solubility , Male , Carbonic Anhydrase Inhibitors/administration & dosage , Carbonic Anhydrase Inhibitors/chemistry , Carbonic Anhydrase Inhibitors/pharmacokinetics , Biological Availability , Cornea/metabolism , Cornea/drug effects , Drug Compounding/methods , Permeability
13.
J Ocul Pharmacol Ther ; 40(5): 309-324, 2024 06.
Article in English | MEDLINE | ID: mdl-38603587

ABSTRACT

Purpose: Glaucoma is a complex degenerative optic neuropathy characterized by loss of retinal ganglion cells (RGCs) leading to irreversible vision loss and blindness. Solanum nigrum has been used for decades in traditional medicine system. However, no extensive studies were reported on its antiglaucoma properties. Therefore, this study was designed to investigate the neuroprotective effects of S. nigrum extract on RGC against glaucoma rat model. Methods: High performance liquid chromatography and liquid chromatography tandem mass spectrometry was used to analyze the phytochemical profile of aqueous extract of S. nigrum (AESN). In vitro, {3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide} (MTT) and H2DCFDA assays were used to determine cell viability and reactive oxygen species (ROS) production in Statens Seruminstitut Rabbit Cornea cells. In vivo, AESN was orally administered to carbomer-induced rats for 4 weeks. Intraocular pressure, antioxidant levels, and electrolytes were determined. Histopathological and immunohistochemical analysis was carried out to evaluate the neurodegeneration of RGC. Results: MTT assay showed AESN exhibited greater cell viability and minimal ROS production at 10 µg/mL. Slit lamp and funduscopy confirmed glaucomatous changes in carbomer-induced rats. Administration of AESN showed minimal peripheral corneal vascularization and restored histopathological alterations such as minimal loss of corneal epithelium and moderate narrowing of the iridocorneal angle. Immunohistochemistry analysis showed increased expression of positive BRN3A cells and decreased matrix metalloproteinase (MMP)-9 activation in retina and cornea, whereas western blot analysis revealed downregulation of extracellular matrix proteins (COL-1 and MMP-9) in AESN-treated rats compared with the diseased group rats. Conclusions: AESN protects RGC loss through remodeling of MMPs and, therefore, can be used for the development of novel neurotherapeutics for the treatment of glaucoma.


Subject(s)
Cell Survival , Disease Models, Animal , Extracellular Matrix , Glaucoma , Neuroprotective Agents , Plant Extracts , Reactive Oxygen Species , Retinal Ganglion Cells , Solanum nigrum , Animals , Retinal Ganglion Cells/drug effects , Retinal Ganglion Cells/metabolism , Retinal Ganglion Cells/pathology , Glaucoma/drug therapy , Glaucoma/pathology , Glaucoma/metabolism , Rats , Solanum nigrum/chemistry , Neuroprotective Agents/pharmacology , Plant Extracts/pharmacology , Reactive Oxygen Species/metabolism , Extracellular Matrix/drug effects , Extracellular Matrix/metabolism , Cell Survival/drug effects , Male , Rabbits , Intraocular Pressure/drug effects , Cell Death/drug effects , Rats, Sprague-Dawley
14.
J Ocul Pharmacol Ther ; 40(5): 297-308, 2024 06.
Article in English | MEDLINE | ID: mdl-38687355

ABSTRACT

Purpose: To investigate gel stent implantation with and without intraoperative sustained-release mitomycin C (MMC SR) in a rabbit model for gel stent implantation, and to examine aqueous humor outflow (AHO) postimplantation. Methods: Four groups of rabbits were included. Group 1 was untreated (control). Groups 2, 3, and 4 received the gel stent without MMC, with MMC solution (subconjunctival injection), and with MMC SR (subconjunctival injection), respectively. Intraocular pressure (IOP) and AHO were assessed via tonometry and indocyanine green-based angiography, respectively. The main efficacy measure was change in IOP from baseline. Results: Following gel stent implantation, Groups 2, 3, and 4 maintained ≥20% IOP reduction (response) for a median duration of 1 week, 6.5 weeks, and 30 weeks, respectively. Angiography showed normal aqueous humor drainage (Group 1) beginning at the perilimbal trabecular plexus and continuing posteriorly to episcleral outflow vessels. Following implantation, drainage occurred preferentially and directly into the subconjunctival bleb. Conclusions: Gel stent implantation with MMC SR was most effective in achieving sustained, long-term IOP reduction in the rabbit model, compared with implantation with or without MMC solution. Bleb presence and the postimplantation aqueous angiography results indicated redirection of the AHO to the subconjunctival vasculature and presumed lymphatics, suggesting efficient glaucoma filtration to lower IOP in this model. This rabbit model and aqueous angiography may help refine understanding of the mechanism of action of minimally invasive glaucoma surgeries and ultimately translate to improved surgical devices and procedures for patients with glaucoma.


Subject(s)
Aqueous Humor , Delayed-Action Preparations , Filtering Surgery , Intraocular Pressure , Mitomycin , Animals , Rabbits , Mitomycin/administration & dosage , Mitomycin/pharmacology , Filtering Surgery/methods , Intraocular Pressure/drug effects , Aqueous Humor/metabolism , Aqueous Humor/drug effects , Stents , Gels , Glaucoma/surgery , Glaucoma/drug therapy , Conjunctiva/surgery , Disease Models, Animal
15.
Ophthalmologie ; 121(4): 333-348, 2024 Apr.
Article in German | MEDLINE | ID: mdl-38587538

ABSTRACT

The use of ophthalmic agents during pregnancy and breastfeeding always represents an off-label use. Therefore, the use of drugs must be particularly carefully assessed with respect to the risk-benefit assessment. In this overview the literature databank of the PubMed library, pharmaceutical lists (Red List, Swiss pharmaceutical compendium), guidelines of the specialist societies the German Society of Ophthalmology (DOG), the Swiss Society of Ophthalmology (SOG), the European Glaucoma Society (EGS), the American Academy of Ophthalmology (AAO) and internet portals (embryotox, reprotox) were inspected and recommendations for the use of ophthalmic agents during pregnancy and breastfeeding were derived. More attention should be dedicated to this topic in the specialist societies.


Subject(s)
Glaucoma , Ophthalmology , Female , Humans , Pregnancy , Academies and Institutes , Glaucoma/drug therapy , Pharmaceutical Preparations , Societies, Medical , United States
16.
Int J Mol Sci ; 25(7)2024 Mar 26.
Article in English | MEDLINE | ID: mdl-38612500

ABSTRACT

Increased intraocular pressure (IOP) is the most important risk factor for glaucoma. The role of IOP fluctuation, independently from elevated IOP, has not yet been confirmed in glaucoma. We investigated the effects of IOP fluctuation itself on retinal neurodegeneration. Male rats were treated with IOP-lowering eyedrops (brinzolamide and latanoprost) on Mondays and Thursdays (in the irregular instillation group) or daily (in the regular instillation group), and saline was administered daily in the normal control group for 8 weeks. The IOP standard deviation was higher in the irregular instillation group than the regular instillation group or the control group. The degree of oxidative stress, which was analyzed by labeling superoxide, oxidative DNA damage, and nitrotyrosine, was increased in the irregular instillation group. Macroglial activation, expressed by glial fibrillary acidic protein in the optic nerve head and retina, was observed with the irregular instillation of IOP-lowering eyedrops. Microglial activation, as indicated by Iba-1, and the expression of TNF-α did not show a significant difference between the irregular instillation and control groups. Expression of cleaved caspase-3 was upregulated and the number of retinal ganglion cells (RGCs) was decreased in the irregular instillation group. Our findings indicate that IOP fluctuations could be induced by irregular instillation of IOP-lowering eyedrops and this could lead to the degeneration of RGCs, probably through increased oxidative stress and macrogliosis.


Subject(s)
Glaucoma , Intraocular Pressure , Male , Animals , Rats , Retina , Glaucoma/drug therapy , Retinal Ganglion Cells , Ophthalmic Solutions
17.
Acta Neuropathol Commun ; 12(1): 65, 2024 Apr 22.
Article in English | MEDLINE | ID: mdl-38649962

ABSTRACT

The progressive and irreversible degeneration of retinal ganglion cells (RGCs) and their axons is the major characteristic of glaucoma, a leading cause of irreversible blindness worldwide. Nicotinamide adenine dinucleotide (NAD) is a cofactor and metabolite of redox reaction critical for neuronal survival. Supplementation with nicotinamide (NAM), a precursor of NAD, can confer neuroprotective effects against glaucomatous damage caused by an age-related decline of NAD or mitochondrial dysfunction, reflecting the high metabolic activity of RGCs. However, oral supplementation of drug is relatively less efficient in terms of transmissibility to RGCs compared to direct delivery methods such as intraocular injection or delivery using subconjunctival depots. Neither method is ideal, given the risks of infection and subconjunctival scarring without novel techniques. By contrast, extracellular vesicles (EVs) have advantages as a drug delivery system with low immunogeneity and tissue interactions. We have evaluated the EV delivery of NAM as an RGC protective agent using a quantitative assessment of dendritic integrity using DiOlistics, which is confirmed to be a more sensitive measure of neuronal health in our mouse glaucoma model than the evaluation of somatic loss via the immunostaining method. NAM or NAM-loaded EVs showed a significant neuroprotective effect in the mouse retinal explant model. Furthermore, NAM-loaded EVs can penetrate the sclera once deployed in the subconjunctival space. These results confirm the feasibility of using subconjunctival injection of EVs to deliver NAM to intraocular targets.


Subject(s)
Extracellular Vesicles , Glaucoma , Mice, Inbred C57BL , Neuroprotective Agents , Niacinamide , Retinal Ganglion Cells , Animals , Extracellular Vesicles/metabolism , Extracellular Vesicles/drug effects , Retinal Ganglion Cells/drug effects , Retinal Ganglion Cells/metabolism , Niacinamide/administration & dosage , Niacinamide/pharmacology , Mice , Neuroprotective Agents/administration & dosage , Neuroprotective Agents/pharmacology , Glaucoma/metabolism , Glaucoma/drug therapy , Neuroprotection/drug effects , Sclera/metabolism , Sclera/drug effects , Drug Delivery Systems/methods , Male
18.
BMJ Open Ophthalmol ; 9(1)2024 Apr 15.
Article in English | MEDLINE | ID: mdl-38626933

ABSTRACT

BACKGROUND: Self-treatment with glaucoma medication (eye drops) has been associated with adherence challenges. Poor adherence results in worse outcomes in terms of visual field loss. OBJECTIVE: To investigate patterns in medication adherence among Danish patients with glaucoma in relation to selected predictors of adherence, long-term adherence patterns, and long-term societal economic consequences of poor adherence. METHODS AND ANALYSIS: This register-based study included 30 100 glaucoma patients followed for 10 years between 2000 and 2018. Glaucoma was identified from the Danish national registers by diagnosis of Open Angle Glaucoma and/or by redeemed prescriptions of glaucoma medication. Logistic regression models were applied to estimate patient characteristics related to medical adherence. Diagnosis-related group fees were applied to estimate healthcare costs. RESULTS: High adherence in the first year(s) of treatment was less likely among men (ORfirst year: 0.78, 95% CI: 0.75 to 0.82), younger individuals and among those with a positive Charlson Comorbidity Index (CCI) score (ORfirst year/CCI≥3: 0.71, 95% CI: 0.63 to 0.80). Adherence in the first year and in the first two years was associated with adherence in the fifth (ORfirst year: 4.55, 95% CI: 4.30 to 4.82/ORfirst two years: 6.47, 95% CI: 6.10 to 6.86) as with adherence in the 10th year with slightly lower estimates. Being medical adherent was related to higher costs related to glaucoma medication after 5 and 10 years comparing with poor adherence, whereas poor adherence was associated with a marked increase in long-term costs for hospital contacts. CONCLUSION: Increasing age, female sex and low comorbidity score are correlated with better adherence to glaucoma treatment. Adherence in the first years of treatment may be a good predictor for future adherence. In the long term, patients with poor adherence are overall more expensive to society in terms of hospital contacts.


Subject(s)
Glaucoma, Open-Angle , Glaucoma , Male , Humans , Female , Glaucoma, Open-Angle/drug therapy , Glaucoma/drug therapy , Medication Adherence , Registries , Denmark/epidemiology
19.
Comput Biol Med ; 174: 108399, 2024 May.
Article in English | MEDLINE | ID: mdl-38615461

ABSTRACT

Glaucoma is one of the leading cause of blindness worldwide. Individuals affected by glaucoma, including patients and their family members, frequently encounter a deficit in dependable support beyond the confines of clinical environments. Seeking advice via the internet can be a difficult task due to the vast amount of disorganized and unstructured material available on these sites, nevertheless. This research explores how Large Language Models (LLMs) can be leveraged to better serve medical research and benefit glaucoma patients. We introduce Xiaoqing, a Natural Language Processing (NLP) model specifically tailored for the glaucoma field, detailing its development and deployment. To evaluate its effectiveness, we conducted two forms of experiments: comparative and experiential. In the comparative analysis, we presented 22 glaucoma-related questions in simplified Chinese to three medical NLP models (Xiaoqing LLMs, HuaTuo, Ivy GPT) and two general models (ChatGPT-3.5 and ChatGPT-4), covering a range of topics from basic glaucoma knowledge to treatment, surgery, research, management standards, and patient lifestyle. Responses were assessed for informativeness and readability. The experiential experiment involved glaucoma patients and non-patients interacting with Xiaoqing, collecting and analyzing their questions and feedback on the same criteria. The findings demonstrated that Xiaoqing notably outperformed the other models in terms of informativeness and readability, suggesting that Xiaoqing is a significant advancement in the management and treatment of glaucoma in China. We also provide a Web-based version of Xiaoqing, allowing readers to directly experience its functionality. The Web-based Xiaoqing is available at https://qa.glaucoma-assistant.com//qa.


Subject(s)
Glaucoma , Humans , Glaucoma/drug therapy , Glaucoma/physiopathology , Natural Language Processing , Male , Female
20.
Biomed Pharmacother ; 174: 116538, 2024 May.
Article in English | MEDLINE | ID: mdl-38579401

ABSTRACT

Glaucoma is considered a neurodegenerative disease characterized by progressive visual field defects that may lead to blindness. Although controlling intraocular pressure (IOP) is the mainstay of glaucoma treatment, some glaucoma patients have unmet needs due to unclear pathogenic mechanisms. Recently, there has been growing evidence that neuroinflammation is a potential target for the development of novel antiglaucoma agents. In this study, we investigated the protective effects and cellular mechanisms of H7E, a novel small molecule inhibits HDAC8, using in vitro and in vivo glaucoma-like models. Importantly, H7E mitigated extracellular MMP-9 activity and MCP-1 levels in glutamate- or S100B-stimulated reactive Müller glia. In addition, H7E inhibited the upregulation of inflammation- and proliferation-related signaling pathways, particularly the ERK and JNK MAPK pathways. Under conditions of oxidative damage, H7E prevents retinal cell death and reduces extracellular glutamate released from stressed Müller glia. In a mouse model of NMDA-induced retinal degeneration, H7E alleviated functional and structural defects within the inner retina as assessed by electroretinography and optical coherence tomography. Our results demonstrated that the newly identified compound H7E protects against glaucoma damage by specifically targeting HDAC8 activity in the retina. This protective effect is attributed to the inhibition of Müller glial activation and the prevention of retinal cell death caused by oxidative stress.


Subject(s)
Ependymoglial Cells , Glaucoma , Histone Deacetylase Inhibitors , Histone Deacetylases , Mice, Inbred C57BL , Oxidative Stress , Animals , Oxidative Stress/drug effects , Glaucoma/drug therapy , Glaucoma/metabolism , Glaucoma/pathology , Histone Deacetylase Inhibitors/pharmacology , Ependymoglial Cells/drug effects , Ependymoglial Cells/metabolism , Ependymoglial Cells/pathology , Mice , Histone Deacetylases/metabolism , Retina/drug effects , Retina/metabolism , Retina/pathology , Disease Models, Animal , Neuroprotective Agents/pharmacology , Male , Retinal Degeneration/drug therapy , Retinal Degeneration/pathology , Retinal Degeneration/metabolism , Retinal Degeneration/prevention & control
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