Influence of probucol-assisted retinal photocoagulation therapy on the visual performance and serum biochemical indexes in patients with early proliferative diabetic retinopathy

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Influence of probucol-assisted retinal photocoagulation therapy on the

visual performance and serum biochemical indexes in patients with early

proliferative diabetic retinopathy

Xiao-Xia Wen, De-Wen Tan

, Teng Fang, Hong-Jun Li

Ophthalmology Department, the People’s Hospital of Kaizhou District Chongqing, Kaizhou District, Chongqing, 405400

Journal of Hainan Medical University

http://www.hnykdxxb.com

ARTICLE INFO ABSTRACT

Article history: Received 2 Nov 2017

Received in revised form 9 Nov 2017 Accepted 12 Nov 2017

Available online 28 Nov 2017

Keywords:

E a r l y p r o l i f e r a t i v e d i a b e t i c retinopathy

Probucol

Retinal photocoagulation Visual performance

Corresponding author:De-Wen Tan, Ophthalmology Department, the Peoples Hospital of Kaizhou District Chongqing, Kaizhou District, Chongqing, 405400. Fund Project:Medical Research Projects of Chongqing Municipal Health and Family Planning Commission No: 2017ZBXM063.

1. Introduction

Diabetic retinopathy (DR) is the most common type of diabetic microangiopathy, it can be divided into non-proliferative diabetic retinopathy (NPDR) and proliferative diabetic retinopathy (PDR) according to the combination of retinal angiogenesis or not, and the PDR treatment is more difficult than that of NPDR[1,2]. Early treatment of patients with PDR mainly focuses on retinal photocoagulation, it has the effects such as degrading new blood vessels and reducing macular edema[3], but the curative effect is limited and the visual function damage is still serious in part of PDR patients after retinal photocoagulation alone, and clinical scholars recommend joining drugs with other mechanisms of action to form combined therapy and expand the curative effect. Probucol is used as a lipid-lowering drug in clinic, and it has

anti-lipid peroxidation and anti-inflammatory effects[4,5]. Given that oxidative stress and inflammation play an important role in the occurrence and development of DR, probucol combined with retinal photocoagulation was used for the clinical treatment of patients with early proliferative DR in this research, and its application value was discussed from the visual performance, serological indexes and other aspects.

2. Information and methods

2.1 Inclusion and exclusion criteria

Inclusion criteria: (1) diagnosed with early proliferative DR; (2) diagnosed for the first time and receiving no related treatment

outside the hospital; (3) ≤18 years old; (4) completing all courses of

treatment and related examination and not dropping out voluntarily. Exclusion criteria: (1) combined with glaucoma, ocular trauma and other ocular diseases; (2) with history of eye surgery; (3) allergic to probucol; (4) combined with systemic infectious diseases; (5) combined with severe bleeding and coagulation dysfunction.

Objective:To explore the influence of probucol-assisted retinal photocoagulation therapy on the visual performance and serum biochemical indexes in patients with early proliferative diabetic retinopathy. Methods: A total of 170 patients with early proliferative DR who were treated in the hospital between December 2014 and May 2017 were retrospectively analyzed and divided into the control group (n=107) who received retinal photocoagulation therapy alone and the probucol group (n=63) who received probucol-assisted retinal photocoagulation therapy. The differences in the contents of visual performance indexes as well as serum angiogenesis indexes, inflammatory mediators and oxidative stress indexes were compared between the two groups before treatment and after 6 weeks of treatment. Results: Before treatment, the differences in the levels of visual performance indexes as well as serum contents of angiogenesis indexes, inflammatory mediators and oxidative stress indexes were not statistically significant between the two groups of patients. After 6 weeks of treatment,

mean vision, 30° visual acuity and 30-60° visual acuity of probucol group were higher than

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2.2 Case information

A total of 170 patients with early proliferative DR were treated in the hospital between December 2014 and May 2017, and their families signed informed consent. The patients were retrospectively analyzed and divided into the control group (n=107) who received retinal photocoagulation therapy alone and the probucol group (n=63) who received probucol-assisted retinal photocoagulation therapy. Control group included 55 male cases and 52 female cases that were 51-77 years old; probucol group included 33 male cases and 30 female cases that were 53-74 years old. The differences in the basic data distribution were not significant between the two groups (P>0.05), and the research plan was discussed and approved by the ethics committee.

2.3 Therapy

Control group received retinal photocoagulation treatment, which was as follows: confirming the scope of retinal coagulation (1 optic disk diameter each of above and below optic papilla margin and nasal lateral margin, 2 optic disk diameter outside macular region bitamporal to midperiphery), and setting the spot diameter to 100 mm, exposure time to 0.15 s, photocoagulation power to 150 mW and photocoagulation point number to 100. The photocoagulation therapy for one eye was divided into 4 times, 1 quadrant of treatment

was completed each time, the treatment in each quadrant was ≤500

points were treated in each quadrant, and the treatment was done 1 time/week.

Probucol group received retinal photocoagulation assisted by probucol, which was specifically as follows: oral probucol, 0.375 g/ time, 2 times/d, for 6 weeks in a row.

2.4 Observation indexes

Before treatment and after 6 weeks of treatment, visual acuity was tested, including mean vision, 30° visual acuity and 30° -60° visual acuity. At the same point in time, fasting cubital venous blood samples were obtained from the two groups, anti-coagulated and centrifuged at low speed (3 500 r/min, 10 min) to separate the upper serum, enzyme-linked immunosorbent assay method was used to determine the levels of angiogenesis indexes, inflammatory mediators and oxidative stress indexes in it, angiogenesis indicators included hypoxia-inducible factor-1 (HIF-1), vascular endothelial growth factor (VEGF) and angiogenin (Ang-2), inflammatory

mediators included intercellular adhesion molecule-1 (ICAM-1), interleukin-2 (IL-2), interleukin-23 (IL-23) and tumor necrosis factor

α (TNF-α), and oxidative stress indexes included malondialdehyde

(MDA) and total antioxidant capacity (TAC).

2.5 Statistical methods

Visual performance indexes, angiogenesis indexes, inflammatory mediators and oxidative stress indexes were measurement data, in

terms of mean ± standard deviation (Mean ± SD) and compared by t

test. Above data was calculated by software SPSS 26.0 and P<0.05

meant statistical significance in differences in the obtained statistics.

3. Results

3.1 Visual performance indexes

Comparison of visual performance indexes mean vision, 30°°

visual acuity and 30°-60°°visual acuity levels between two

groups of patients before and after treatment was as follows: before treatment, the differences in mean vision, 30°°visual acuity and

30°-60°°visual acuity levels were not significant between the

two groups of patients (P>0.05). After 6 weeks of treatment, mean vision, 30°°visual acuity and 30°-60°°visual acuity of both

groups were higher than those before treatment, and mean vision, 30°visual acuity and 30°-60°°visual acuity of probucol group

were higher than those of control group (P<0.05), shown in Table 1.

3.2 Angiogenesis indexes

Comparison of serum angiogenesis indexes HIF-1 (ng/mL), VEGF (ng/mL) and Ang-2 (pg/mL) contents between two groups of patients before and after treatment was as follows: before treatment, the differences in serum HIF-1, VEGF and Ang-2 contents were not significant between the two groups of patients (P>0.05). After 6 weeks of treatment, serum HIF-1, VEGF and Ang-2 contents of both groups were lower than those before treatment, and serum HIF-1, VEGF and Ang-2 contents of probucol group were lower than those of control group (P<0.05), shown in Table 2.

Table 2.

Comparison of serum angiogenesis index contents between the two groups before and after treatment.

Groups n HIF-1 VEGF Ang-2

Before treatment After 6 weeks of treatment Before treatment After 6 weeks of treatment Before treatment After 6 weeks of treatment

Control group 107 54.29±6.27 41.76±4.98* 174.28±22.64 132.76±15.23* 32.47±5.12 23.64±3.05*

Probucol group 63 55.17±7.05 30.52±4.13* 176.09±21.58 105.81±12.64* 33.05±4.87 16.71±2.84*

t 0.382 9.287 0.197 7.723 0.204 8.408

P >0.05 <0.05 >0.05 <0.05 >0.05 <0.05

Note: compared with same group before treatment, *P0.05. Table 1.

Comparison of visual performance index levels between the two groups before and after treatment.

Groups n Mean vision 30°°° visual acuity 30°-60°°visual acuity

Before treatment After 6 weeks of treatment Before treatment After 6 weeks of treatment Before treatment After 6 weeks of treatment

Control group 107 0.41±0.05 0.52±0.06* 12.05±1.74 13.27±1.86* 5.11±0.54 5.86±0.63*

Probucol group 63 0.40±0.04 0.67±0.08* 12.13±1.69 14.59±1.03* 5.09±0.53 6.47±0.69*

t 0.173 7.398 0.362 6.281 0.216 7.043

P >0.05 <0.05 >0.05 <0.05 >0.05 <0.05

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3.3 Inflammatory mediators

Comparison of serum inflammatory mediators ICAM-1 (μg/L),

IL-2 (pg/mL), IL-23 (pg/mL) and TNF-α (pg/mL) contents between two groups of patients before and after treatment was as follows: before treatment, the differences in serum ICAM-1, IL-2, IL-23 and TNF-α contents were not significant between the two groups of patients (P>0.05). After 6 weeks of treatment, serum ICAM-1, IL-2, IL-23 and TNF-α contents of both groups were lower than those before treatment, and serum ICAM-1, IL-2, IL-23 and TNF-α

contents of probucol group were lower than those of control group (P<0.05), shown in Table 3.

3.4 Oxidative stress indexes

Comparison of serum oxidative stress indexes MDA (nmol/mL) and TAC (U/mL) contents between two groups of patients before and after treatment was as follows: before treatment, the differences in serum MDA and TAC contents were not significant between the two groups of patients (P>0.05). After 6 weeks of treatment, serum MDA contents of both groups were lower than those before treatment whereas TAC contents were higher than those before treatment, and serum MDA content of of probucol group was lower than that of control group whereas TAC content was higher than that of control group (P<0.05), shown in Table 4.

4. Discussion

DR is one of the most important complications of diabetes. When angiogenesis occurs in the retina, the disease enters the PDR

stage, and patients with this stage have obvious visual injury and difficulty in clinical treatment. Retinal photocoagulation is the most common method for current treatment of DR, which can cause moderate retinal atrophy and reduce the angiogenesis in the non-perfusion region so as to alleviate the condition of DR and inhibit its progress[6,7]. However, the retinal photocoagulation might be excessive or insufficient, which causes that the patient's visual function is unstably improved and even not obviously improved than that before treatment. How to maximally improve the visual function and homeostasis of DR patients is the focus of current clinical research, and probucol, as a lipid-lowering drug, is now a major concern in the treatment of DR. Probucol is the drug with multiple effects such as lowering blood lipid, anti-inflammation and anti-oxidation, its molecular structure contains the phenolic hydroxyl groups susceptible to oxidation and has stronger ability to capture the oxygen ions, and meanwhile, the phenolic hydroxyl groups can adhere to lipoprotein particle surface and effectively reduce LDL oxidation and inhibit lipid peroxidation damage[8-10]. Many scholars believe that probucol can alleviate the DR condition, it was used as a auxiliary drug in the study for the treatment of patients with early proliferative DR, changes in the visual function were macro examined, and the contents of the serological indexes were also further detected in order to clarify the best therapy for patients with early proliferative DR.

There has been obvious visual dysfunction in patients with early proliferative DR, mainly including decrease of vision and visual acuity[11,12]. It was discovered in the study that compared with those before treatment, mean vision, 30°°visual acuity and 30°-60°

visual acuity levels of both groups were improved after treatment, indicating that retinal photocoagulation alone and probucol-assisted retinal photocoagulation can both help optimize the visual function

Table 3.

Comparison of serum inflammatory mediator contents between the two groups before and after treatment.

Groups n

ICAM-1 IL-2 IL-23 TNF-α

Before treatment

After 6 weeks of treatment

Before treatment

After 6 weeks of treatment

Before treatment

After 6 weeks of treatment

Before treatment

After 6 weeks of treatment Control group 107 184.26±20.88 137.95±15.26* 63.15±7.06 47.89±5.21* 39.18±4.56 30.27±3.64* 15.30±1.77 11.82±1.79*

Probucol group 63 185.14±21.06 94.26±10.39* 63.77±7.28 30.64±3.67* 38.79±4.72 21.38±2.92* 15.42±1.68 7.64±0.82*

t 0.183 11.298 0.263 14.384 0.347 10.498 0.167 9.273

P >0.05 <0.05 >0.05 <0.05 >0.05 <0.05 >0.05 <0.05

Note: compared with same group before treatment, *P0.05.

Table 4.

Comparison of serum oxidative stress index contents between the two groups before and after treatment.

Groups n Before treatmentMDA After 6 weeks of treatment Before treatmentTAC After 6 weeks of treatment

Control group 107 14.37±1.88 10.69±1.53* 18.26±2.05 23.47±2.81*

Probucol group 63 14.28±1.69 7.25±0.86* 18.17±2.12 29.83±3.42*

t 0.283 9.227 0.173 8.614

P >0.05 <0.05 >0.05 <0.05

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in patients with early proliferative DR; further compared with those of control group, mean vision, 30°°visual acuity and 30°-60°

visual acuity levels of probucol group were higher after treatment, proving that probucol combined with retinal photocoagulation can significantly improve the visual function in patients with early proliferative DR, and clarifying the superiority in the curative effect of the therapy. The realization of the therapeutic effect of adjuvant probucol therapy relies on its various pharmacological functions that will be embodied in serological index contents, and the specific mechanism of its therapeutic effect was further discussed in the following study.

When the retinal angiogenesis occurs, the NPDR enters the PDR stage, and it can cause fibroplasia and even lead to retinal detachment, resulting in a dramatic decline in vision and even blindness. Many angiogenesis factors are involved in the formation of NPDR. HIF-1 is hypoxic signaling protein, and high blood glucose environment can induce HIF-1 expression and promote DR progress[13]. VEGF is the signature molecule of DR, which can directly promote the vascular endothelial cell proliferation and angiogenesis, and its serum content is positively correlated with the severity of the disease[14,15]. Ang-2 is also a factor that promotes angiogenesis, highly expressed VEGF can regulate the expression of Ang-2 and other downstream genes, and they participate in the retinal angiogenesis of DR together[16]. In this study, it was found that compared with those before treatment, serum HIF-1, VEGF and Ang-2 contents of both groups decreased after treatment, indicating that both treatments could reduce the degree of retinal angiogenesis; further compared with those of control group, serum HIF-1, VEGF and Ang-2 contents of probucol group were lower after treatment, confirming that adjuvant probucol therapy on the basis of retinal photocoagulation can further inhibit the retinal angiogenesis, and this is one of the fundamental mechanisms for it to implement treatment effect.

There is obvious systemic micro-inflammation and oxidative stress status in DR patients, and the accumulation of inflammatory factors in the retina can further damage the vascular endothelial cells and cause tissue leakage and no-perfusion zone formation. It has been proven in different studies that ICAM-1, IL-2, IL-23 and TNF-α are the inflammatory mediators directly related to DR, and their expression can indirectly reflect the severity of the disease[17,18]. Persistent micro-inflammation state and high blood glucose environment can both promote oxidative stress formation, retinal tissue is rich in polyunsaturated acid and highly susceptible to damage in the process of oxidative stress, and domestic and foreign researches have also confirmed that the anti-oxidative stress treatment is effective for the optimization of illness in DR patients[19,20]. In this

study, the inflammation and oxidative stress state were compared between the two groups before and after treatment, and it was found that compared with those before treatment, serum inflammatory mediators ICAM-1, IL-2, IL-23 and TNF-α as well as oxidation index MDA contents of both groups decreased while anti-oxidation index TAC contents increased after treatment, meaning that both therapies help to alleviate inflammation and oxidative stress state; further compared with those of control group, the change in serum contents of above indexes of probucol group was bigger after treatment, confirming that probucol-assisted retinal photocoagulation can more effectively inhibit the inflammation and oxidative stress status in patients with early proliferative DR, this perfectly matches with its pharmacological properties, and it is functioning pathway for the drug to achieve treatment effect.

Adjuvant probucol therapy based on retinal photocoagulation can more effectively improve the visual function of patients with early proliferative DR, and the specific mechanisms are directly related to its effect on inhibiting retinal angiogenesis and reducing systemic inflammation and oxidative stress status. The probucol-assisted retinal photocoagulation can be a reliable method for future treatment of patients with early proliferative DR, and it is worth promoting the application in clinical practice.

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Figure

Table 1.

Table 1.

p.2
Table 2.Comparison of serum angiogenesis index contents between the two groups before and after treatment.

Table 2.Comparison

of serum angiogenesis index contents between the two groups before and after treatment. p.2
Table 3.

Table 3.

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Table 4.Comparison of serum oxidative stress index contents between the two groups before and after treatment.

Table 4.Comparison

of serum oxidative stress index contents between the two groups before and after treatment. p.3

References

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