Effects of Cilostazol Tablets Combined with Epalrestat

Acta Medica Mediterranea, 2019, 35: 2185

EFFECTS OF CILOSTAZOL TABLETS COMBINED WITH EPALRESTAT TABLETS ON SERUM INFLAMMATORY RESPONSE, OXIDATIVE STRESS, AND NERVE CONDUCTION VELOCITY IN ELDERLY PATIENTS WITH TYPE 2 DIABETIC PERIPHERAL NEUROPATHY

Wei Shu1, Zhangyuan Liao2, Ruicun Liu1,Tao Du1, HongweiZhu1* 1Department of functional neurosugery,Beijing Institute of Function neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, PR China - 2Department of Neurology, Tianjin Medical University General Hospita, Tianjin, PR China

ABSTRACT

Objective: To explore the effects of cilostazol tablets combined with epalrestat tablets on serum inflammatory response, oxidative stress, and nerve conduction velocity in elderly patients with peripheral neuropathy of type 2 diabetes mellitus. Methods: Ninety-six elderly patients with type 2 diabetic peripheral neuropathy received treatment in our hospital from June 2016 to March 2018 and were randomly divided into two groups: the control group and the experimental group with 48 cases in each group. Both groups were given insulin to control blood glucose, diet therapy, exercise guidance, and other routine treatment. The patients in the control group were treated with cilostazol tablets alone, and the patients in the experimental group were treated with cilostazol tablets combined with epalrestat tablets. Both of the two groups were treated continuously for eight weeks. The clinical curative effect, serum inflammatory index level (C-reactive protein (CRP), interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α)), oxidative stress index activity (malondialdehyde (MDA), total antioxidant capacity (TAOC), superoxide dismutase (SOD)), nerve conduction velocity (median nerve, common peroneal nerve motor conduction velocity (MNCV), and nerve sensory conduction velocity (SNCV)) were observed. The changes in adverse reactions were compared between the two groups. Results: After treatment, the total effective rate of the experimental group was 93.75%, and the total effective rate of the control group was 66.67%. The total effective rate of the experimental group was significantly higher than that of the control group (P<0.01). The levels of CRP, IL-6, and TNF-α in the experimental group and the control group were significantly decreased after treatment, and the experimental group was significantly better than the control group (P<0.05). After treatment, the level of MAD decreased and the level of GSH-Px and SOD increased significantly in the experimental group and the control group. The level of MAD in the experimental group was significantly lower than that of the control group, and the level of GSH-Px and SOD was significantly higher than that of the control group (P<0.05). After the treatment, the speed of the MNCV and SNCV of the median nerve and the common peroneal nerve in the experimental group and the control group were significantly elevated, and the experimental group was significantly higher than that of the control group (P<0.05). The incidence of adverse reactions in the experimental group was 2.08%, which was significantly lower than that in the control group (12.51%, P<0.05). Conclusion: The combination of cilostazol tablets and epalrestat tablets is effective in the treatment of elderly patients with type 2 DPN. It can significantly improve nerve conduction velocity, increase antioxidant stress, reduce the inflammatory reaction, control blood glucose, and have fewer adverse reactions.

Keywords: Cilostazol tablets, epalrestat tablets, elderly patients with type 2 diabetic peripheral neuropathy, inflammatory reaction, oxidative stress, nerve conduction velocity.

DOI: 10.19193/0393-6384_2019_4_342

Received November 30, 2018; Accepted February 20, 2019

Introduction mostly after the age of 35. Diabetic peripheral neuropathy (DPN) is the damage of the nervous system Diabetes mellitus (DM) is a metabolic disease caused by hyperglycaemia and the pathophysiologi- caused by a deficiency in insulin secretion or insulin cal changes caused by DM(2- 3). DPN is a microangi- dysfunction, characterised by long-term hypergly- opathy, which is one of the most common compli- caemia(1). It was divided into insulin-dependent dia- cations of T2DM, where the symptoms of the lower betes mellitus (IDDM) and type 2 diabetes mellitus limbs are more common. A previous study found (T2DM) according to the pathogenesis of diabetes. that DPN may be related to glycolipid metabolism With the improvement of people’s living standard, abnormalities, oxidative stress in the body, and in- the incidence of T2DM is increasing year by year, flammatory reactions(4). 2186 Wenjun You, Xiaojie Qin et Al

The cilostazol tablet is a new type of drug, A comparison of the basic data between the which plays an important role in anti-platelet ag- two groups of patients is shown in Table 1. (5) gregation, anti-thrombus, and vasodilation . The Sex (cases) Age Course Course BMI epalrestat tablet is a reversible non-competitive Groups n of T2DM of DPN 2 (years old) (years) (years) (kg/m ) inhibitor of aldose reductase. It can block the path- Male Female way of polyol, inhibit the level of oxidative stress, Experimental 48 58.34±3.12 28 20 8.92 ± 2.12 3.28 ± 1.51 25.24 ± 2.05 and obviously improve the nerve conduction veloc- Control 48 59.68±3.71 26 22 8.56 ± 2.31 2.97 ±1.59 25.88 ± 1.36 ity(6). The purpose of this study was to observe the 2 clinical effect of the treatment of elderly patients t/χ 1.915 0.169 0.796 0.979 1.802 with type 2 DNP by the combination of cilostazol P 0.059 0.681 0.428 0.329 0.075 and epalrestat tablets, and to further investigate the Table. 1: Comparison of the basic data between the two effect of the drug combination on serum inflamma- groups of patients. tory factors, oxidative stress response, and nerve conduction velocity. Methods Both groups of patients were given insulin to Data and methods control blood glucose, diet therapy, exercise guidance, and other routine treatment. The patients General Information in the control group were treated with cilostazol Ninety-six elderly patients with type 2 dia- tablets (Chengdu LiEr Pharmaceutical Co., Ltd., betic peripheral neuropathy received treatment in production batch number: 20156723, specifica- our hospital from June 2016 to March 2018 and tion: 50 mg*12 tablets), 50 mg each time, twice a were randomly divided into two groups: the control day. The patients in the experimental group were group and the experimental group with 48 cases in treated with cilostazol tablets combined with epal- each group. restat tablets (Shandong Dayin Marine biological Inclusion criteria included all patients that met pharmaceutical co. LTD, production batch number: the diagnostic criteria of type 2 diabetes established 20150893, specification: 50 mg*12s), 50 mg each by WHO(7); patients who had a nerve conduction time, three times a day, and was administered oral- disorder on electromyography, MNCV<45m/s, ly before meals. The patients in both groups were SNCV<40m/s; patients with good mental symp- treated continuously for eight weeks. toms, and can cooperate with the treatment; patients with the approval of the Hospital Ethics Observation indexes Committee, and patients and their families who A volume of 5 mL of fasting venous blood were informed, agreed to participate in the study, was collected from all patients in the morning be- and signed the informed consent form. fore and after treatment, and the supernatant was Exclusion criteria included patients with type 1 collected after centrifugation and stored in the re- diabetes or other diabetes; severe liver, kidney, and frigerator at -20 ℃. heart function insufficiency; patients with a history of serious drug allergy; patients suffering from severe Clinical efficacy(8) infectious diseases; pregnant or lactating patients. Obvious effect: In the control group, there were 26 males and Numbness, cooling and other clinical symp- 22 females, aged 39 to 71 years old, with an av- toms were resolved, tendon reflex was normal, erage age of 59.68±3.71 years old. The course of nerve conduction velocity increased above 5 m/s T2DM was 8.56±2.31 years, the course of DPN was or returned to normal. 2.97±1.59 years, and the body mass index (BMI) Effective: was 25.88±1.36 kg/m2. In the experimental group, The clinical symptoms and tendon reflexes there were 28 males and 20 females, aged 42 to 70 were improved, nerve conduction velocity was re- years old, with an average age of 58.24±3.12 years duced below 5 m/s; old. The course of T2DM was 8.92±2.12 years, the Ineffective: course of DPN was 3.28±1.51 years, and the body All clinical symptoms did not improve or ag- mass index (BMI) was 24.94±1.15 kg/m2. There gravate, nerve conduction velocity change was not was no significant difference in age and other basic obvious. data between the two groups (P>0.05). Effects of cilostazol tablets combined with epalrestat tablets on serum inflammatory response, oxidative stress, and... 2187

Serum inflammatory index: cantly decreased after treatment, and the experimen- The levels of C-reactive protein (CRP), in- tal group was significantly better than the control terleukin-6 (IL-6), and tumour necrosis factor-α group (P<0.05). The results are shown in Table 3. (TNF-α) were detected by enzyme-linked immu- Groups n Time CRP (mg/L) IL-6 (ng/mL) TNF-α (ng/mL) nosorbent assay (ELISA). Before 3.18±2.97 33.18±5.97 2.56±2.13 Oxidative stress index: Experimental treatment group 48 After ab 20.03±3.46ab 1.74±0.71ab The level changes of malondialdehyde (MDA) treatment 2.03±1.46 and total antioxidant capacity (TAOC) were deter- Before 3.87±2.91 35.17±5.91 2.62±1.31 Control treatment group 48 mined by the thiobarbituric acid method, and the After a a a 2.95±2.08 32.16±5.08 2.08±1.11 activity of superoxide dismutase (SOD) was de- treatment tected by the enzyme-rate method. Table. 3: Comparison of the inflammatory factors betwe- Nerve conduction velocity: en the two groups of patients (x̅±s). a The sensory nerve conduction velocity Note: P<0.05:compared with the same group before treatment; bP<0.05: compared with the control group after treatment. (SNCV) and motor nerve conduction velocity (MNCV) of the median nerve and common pero- Comparison of oxidative stress indexes be- neal nerve were measured by the nerve conduction tween the two groups of patients velocity meter. After treatment, the level of MAD decreased, Adverse reactions: and the level of GSH-Px and SOD increased sig- The adverse reactions that occurred in the two nificantly in the experimental group and the con- groups were compared. trol group. The level of MAD in the experimental group was significantly lower than that of the con- Statistical method trol group, and the level of GSH-Px and SOD was All the statistical data were analysed with the significantly higher than that of the control group SPSS22.0 software package. The measurement data (P<0.05). The results are shown in Table 4. were compared by independent sample t-test, the Groups n Time MDA SOD GSH-Px counting data were compared with the Chi-square (χ2) (nmol/mL) (IU/mL) (U/L) Before 5.68±1.44 86.22±15.81 101.54±9.82 test and the ranked data was compared by the Ridit Experimental treatment group 48 After ab 101.13± 16.57ab 148.63±8.72ab test. P<0.05 represents statistically significant results. treatment 3.04±0.88

Before 5.71±1.51 85.41±15.93 99.65±10.74 Control treatment Results group 48 After a a a treatment 4.33±0.97 92.25±15.63 111.48±7.66 Comparison of therapeutic effects between Table. 4: Comparison of oxidative stress indexes between the two groups of patients the two groups (x̅±s). Note: aP<0.05:compared with the same group before treatment; After treatment, the total effective rate of the bP<0.05: compared with the control group after treatment. experimental group was 93.75%, and the total effective rate of the control group was 66.67%. The Comparison of nerve conduction velocity be- results are shown in Table 2. tween the two groups of patients Obvious Total effective Groups n effect Effective Ineffective rate MNCV(m/s) SNCV(m/s) Groups n Time Common Common Experimental 48 28(58.33) 17(35.42) 3(6.25) 45(93.75) Median Median group nerve peroneal nerve peroneal nerve nerve Control 48 18(37.51) 14(29.17) 16(33.33) 32(66.67) Before group treatment 45.94±5.41 39.36±4.33 40.24±6.41 36.26±7.13 Experimental 48 group After 2 45.23±2.81ab 46.83±4.97ab 44.21±6.03ab χ 11.089 treatment 52.28±2.12ab Before treatment 46.34±5.61 39.07±4.41 41.37±5.98 36.19±7.81 P 0.001 Control 48 group After treatment 49.21±4.41 a 41.37±2.83 a 43.94±5.01 a 41.41±5.77 a Table. 2: Comparison of the therapeutic effects between the two groups of patients (%). Table. 5: Comparison of nerve conduction velocity Total effective rate= (Obvious effect + Effective)/n × 100%. between two groups of patients (x̅±s). Note: aP<0.05:compared with the same group before treatment; bP<0.05: compared with the control group after treatment. Comparison of the inflammatory factors between the two groups of patients After the treatment, the speed of MNCV The levels of CRP, IL-6, and TNF-α in the ex- and SNCV of the median nerve and the common perimental group and the control group were signifi- peroneal nerve in the experimental group and the 2188 Wenjun You, Xiaojie Qin et Al control group were significantly elevated, and the The results showed that the combination of the experimental group was significantly higher than two drugs was safe and effective in the treatment of that of the control group (P<0.05). The results are DPN. shown in Table 5. Studies have found that there are persistent chronic inflammatory responses in patients with DM. Comparison of adverse reactions between the An inflammatory reaction can stimulate the synthe- two groups of patients sis of vascular endothelial growth factor (VEGF), During treatment, the main side effects were increase the thickness of the micro-vessel basement nausea, vomiting, and hypoglycaemia. The inci- membrane in patients with DM, then decrease the dence of adverse reactions in the experimental blood flow of nerve tissue in patients, and seriously group was 2.08%, which was significantly lower affect the neurological function(14). CRP is an impor- than that in the control group (12.51%, P<0.05). tant inflammatory factor in the body. IL-6 can induce The results are shown in Table 6. the synthesis of CRP, leading to defence and tissue

Groups n Nausea Vomiting Hypoglycaemia Total damage, thus stimulating the gradual proteinisation

Experimental of macrophages. It has an important relationship group 48 1(2.08) 0(0.00) 0(0.00) 1(2.08) with the occurrence and development of microangi- Control group 48 3(6.25) 1(2.08) 2(4.17) 6(12.50) opathy in patients with DM. CRP can be used as an (15) 2 . χ 3.873 effective indicator of inflammation or infection TNF-α is an important proinflammatory factor, P 0.049 which can activate the release of other inflammatory Table. 6: Comparison of the adverse reactions between factors (such as IL-6), induce an inflammatory re- the two groups of patients (%). action, and induce cell apoptosis and necrosis. The results in this study showed that the inflammatory Discussion factors in the experimental group were significantly lower than those in the control group (P<0.05). It in- DPN is a kind of microvascular neuropathy dicated that the combination of cilostazol and epal- mainly characterised by sensory and neurotic symp- restat could significantly inhibit the transcription of toms. It is one of the most serious chronic compli- nuclear factors induced by inflammatory factors and cations of diabetes mellitus. The main manifestations thus play an anti-inflammatory role. are distal primary sensory neuropathy, autonomic It is reported that there is a very complex in- neuropathy, and diabetic foot(9). The pathogenesis of teraction between oxidative stress and inflammatory DPN is not clear, and it is generally thought to be re- reactions. The oxidative stress response is an impor- lated to metabolic disorders, inflammatory reactions, tant pathophysiological change in the pathogenesis of oxidative stress, and nerve factor deficiencies in pa- DPN. The imbalance between oxidation and antioxi- tients(10). At present, most of the DPN patients are dation in vivo will result in infiltration of inflammato- treated by oral administration of cilostazol tablets, but ry cells, resulting in a significant increase in oxygen the effect of single drug treatment is not ideal, so our consumption of activated neutrophils, resulting in a hospital chooses to use the combination of cilostazol large number of oxidative intermediates, resulting in tablets and epalrestat for the treatment. Cilostazol is a series of damage to the tissue(16). In this study, the a selective phosphodiester (PDEs), which can signif- improvement of antioxidant stress index in the experi- icantly inhibit platelet phosphodiesterase activity and mental group was higher than that in the control group has a strong inhibitory effect on platelet aggregation after treatment (P<0.05). These results indicated that induced by platelet aggregation inducers. Epalrestat the combined use of the two drugs could obviously is a drug with a selective inhibitory effect on aldose inhibit the activity of aldoxime reductase, increase the reductase. It is reported that Epalrestat tablets can ef- activities of Na+-K+-ATP enzyme and inositol, thus fectively inhibit the accumulation of red blood cell promoting the secretion of antioxidants and alleviat- sorbitol in patients with DPN, and improve its MNCV ing the injury degree of nerve cells. and autonomic nerve function. 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