Glaucoma is a chronic eye disease and worldwide leading cause of irreversible vision loss [1]. Glaucoma is one of leading causes of blindness and visual impairment, which is age-related and thus affects quality of life [2]. Impaired microcirculation at the level of the optic nerve head is regarded as one of the main mechanisms of pathogenesis of glaucoma and may be accelerated as a result of glaucoma surgery [3]. In addition, patients with glaucoma have been shown to have progression of visual function despite intraocular pressure (IOP) control [4]. Furthermore, although many glaucoma medications are developed, more efficient treatments need to explore to improve the symptoms of glaucoma.

Valproic acid (VPA) has been shown to improve collagen and contrast threshold sensitivities in clinical patients [5]. VPA has been widely used to human diseases, such as mood disorders, epilepsy, migraines, neuropathic pain and glaucoma [6]. Previously, VPA exerts therapeutic efficacy by regulating glutamate neurotransmissions, gamma-aminobutyric acid, pro-survival protein kinases and histone deacetylase [7]. In addition, oral VPA improves visual acuity in patients with advanced glaucoma in a prospective randomized study [8]. Furthermore, VPA has been shown to reduce muscle collagen content and renal fibrosis and cutaneous radiation syndrome [9]. However, the efficacy of single treatment of VPA is limited and needs further investigate in patients with glaucoma.

Dexamethasone (DEX) therapy has been used to reduce inflammation, improve structural complications and long-term visual loss in patients with uveitis [10]. DEX has a favorable safety profile by controlling IOP for patients with glaucoma [11]. DEX implant will rise the short-term IOP, but it is safe and acceptable in patients with glaucoma or ocular hypertension [12]. In addition, a previous study has been identified the tolerance of intravitreal DEX in patients glaucoma, and the results show that DEX is well tolerance [13]. Furthermore, DEX medical intervention can be performed in patients with glaucoma by reduction of IPO and improvement of visual acuity in patients with glaucoma [14]. However, clinical efficacy and safety profile of DEX should further analyze in patients with glaucoma.

The purpose of this study was to examine the clinical efficacy and safety profile of ophthalmologic nursing of VPA combined with DEX for patients with glaucoma. This study also prospectively examined whether combined treatment of VPA and DEX could improve the BCVA, LogMAR visual acuity, mean deviation on visual fields, and multifocal ERG and CRT on optical coherence tomography in patients with glaucoma.

Material and Methods

Study Design

This randomized, placebo-controlled 3-month clinical trials was used to analyze the treatment effects of DEX (0.7 mg/day) and/or VPA (500 mg/day) in patients with glaucoma. Patients (n = 364) with glaucoma were enrolled at Department of 2nd ophthalmology in The First Branch of Mudanjiang Medical University Affiliated Hongqi Hospital between May 2017 and July 2019. The exclusion criteria included as follow:

1. History of glaucoma;
2. Ischemic RVO;
3. Intraocular surgery or laser therapy;
4. Bacterial, fungal, viral or parasitic infection.

Inclusion criteria included as follow:

1. age >18 years;
2. intraocular pressure <16 mmHg;
3. BCVA score more than 34 letters.

The protocols in this study were approved by an Ethics Committee of The first branch of Mudanjiang Medical University Affiliated Hongqi Hospital. All patients provided written informed consent (NCT01660802).

Study Treatment

A total of 346 patients with glaucoma received placebo (n=84), VPA (n=88), DEX (n=85) or VPA-DEX (n=89) for 3 months continued therapy. Patients received study treatment and assigned to 0.7 mg of intravitreal injection of DEX by using a single-use applicator system. Type of VPA (500) therapy for glaucoma patients was oral.

Outcomes Measures

The mean change in LogMAR visual acuity from baseline during 3 months was evaluated measured using the ETDRS. The mean CRT changes for all patients were evaluated using optical coherence tomography. Key safety evaluations for each patient included biomicroscopy/ophthalmology, IOP and treatment-emergent adverse events (TEAEs). TEAEs included onset or an increase in severity or any serious adverse event after receive treatment with VPA and/or DEX. All patients were visited by investigators every 15 days from baseline.

Statistical Analysis

Data are shown as mean± standard deviation (SD) or number (%). The SPSS software (version 17.0, Chicago IL, USA) was used for statistical analysis. The baseline characteristics between the groups were compared using independent t-test, Chi-square, or Mann-Whitney U test. The median visual acuity was analyzed used the Wilcoxon Signed-rank test. A p value less than 0.05 was considered statistically significant.