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JKM > Volume 37(4); 2016 > Article
Jang, Kwak, and Park: The Effects and Safety of Cardiotonic Pills with Pletaal on Post-Reperfusion Syndrome of Arteriosclerotic Occlusive Disease(Pilot Study)

Abstract

Objectives

The patients who had arteriosclerotic occlusive disease were treated by reperforating procedures or vessel replacing operations. We divided them by two groups. one(control group) is treated by Pletaal(cilostazole), the other(CP group) is by Pletaal with cardiotonic pills(CP).

Methods

Control group was treated by Pletaal, CP group was treated by Pretaal with CP for 8 weeks. We primarily evaluated the outcomes by visual analogue scale(VAS) of pain, coldness, numbness, and edema, secondarily hematologic tests.

Results

Coldness, numbness and edema were reduced at both groups. In CP group, the VAS dropped more sharply than control group, but not significant. Otherwise, there was significant reduction of VAS on pain. In hematologic tests, there were no abnormal results of all items.

Conclusion

The therapy of Pletaal with CP is effective to relieve PRS specially in pain and safety on hematologic tests.

Introduction

An arteriosclerotic occlusive disease in lower limbs causes ulcer and necrosis below occlusive areas1). This disease is treated by reperforating procedures or vessel replacing operations2,3). After these treatments, Several problems such as pain, coldness, numbness and edema may occur. These problems are called post-reperfusion syndrome(PRS). To this day, Pletaal(cilostazole) is used to reduce the symptoms of PRS4,5). But the conventional therapy is not sufficient to treat PRS.
Cardiotonic Pills(CP) are the complex of herbal medicines, composed of Saliviae Miltiorrhizae Radix, Notoginseng Radix and Borneolum6). CP is uesd to treat anginapectoris, coronary arteriosclerosis, hyperlipidemia and others7,8). To evaluate the effects and safety to PRS by CP with Pletaal, we designed this study by random allocation and comparison to control group.

Objects and Methods

1. Objects

This study was approved by the IRB of Daegu catholic hospital and performed at Daegu catholic medical center.
The objects were the patients of arteriosclerotic occlusive disease treated by reperforating procedures or vessel replacing operations. We selected objects according with the inclusion and exclusion criteria and agreeing to the consent form. We divided the patients by two groups in the course of randomized allocation. One(control group) is treated by Pletaal(cilostazole), the other(CP group) is by Pletaal with CP. Control group was 14 persons(male-11, female-3), and CP group was 13 persons(male-12, female-1). the average of age was 70.21 years in control group, and 68.15 years in CP group(Table 1).

2. Methods

Control group was treated by Pletaal(100 mg) twice a day, CP group was treated by Pretaal(100 mg) twice a day with CP(10 pills) three times a day for 8 weeks.
We primarily evaluated the outcomes by visual analogue scale(VAS) of pain, coldness, numbness, and edema, secondarily hematologic tests. We evaluated the outcomes at first day, and the day of 2 weeks, 4 weeks and 8 weeks.

3. Statistical analysis

Results were expressed as the mean±standard deviation. Statistical analysis of the data was carried out by multiple comparison test. A difference from the respective control data at the level of p<0.05 was regarded as statistically significant.

Results

1. Primary endpoints

(1) Pain

The VAS of control group were 2.036 at first, 1.245 at 2 weeks later, 0.857 at 4 weeks later and 0.833 at 8 weeks later. CP group were 2.731 at first, 1.091 at 2 weeks later, 0.357 at 4 weeks later and 0.283 at 8 weeks later. CP group showed significant decrease of the VAS of pain compared with control group as p<0.05.(Table 2, Fig. 1)

(2) Coldness

The VAS of control group were 1.357 at first, 0.273 at 2 weeks later, 0.286 at 4 weeks later and 0.222 at 8 weeks later. CP group were 1.308 at first, 0.273 at 2 weeks later, 0.000 at 4 and 8 weeks later. CP group showed decrease of the VAS of coldness but not significant.(Table 2, Fig 2)

(3) Numbness

The VAS of control group were 2.75 at first, 1.073 at 2 weeks later, 1.071 at 4 weeks later and 0.778 at 8 weeks later. CP group were 3.000 at first, 0.936 at 2 weeks later, 0.529 at 4 weeks later and 0.283 at 8 weeks later. CP group showed decrease of the VAS of numbness but not significant.(Table 2, Fig 3)

(4) Edema

The VAS of control group were 0.857 at first, 0.545 at 2 weeks later, 0.386 at 4 weeks later, and 0.167 at 8 weeks later. CP group were 1.077 at first, 0.518 at 2 weeks later, 0.100 at 4 weeks later, and 0.000 at 8 weeks later. CP group showed decrease of the VAS of edema but not significant.(Table 2, Fig 4)

2. Secondary endpoints

(1) Hematologic tests

The results of hematologic tests were compared with first time and 8 weeks later. The items of hematologic tests were WBC, RBC, Hb, Hct, Platelet, PT(INR), aPTT, AST, ALT, BUN and creatinine.
The results of all groups were within normal limit and no significant changes between first time and 8 weeks later.(Table 3)

Discussion

An arteriosclerotic occlusive disease in lower limbs may cause ulcer or necrosis, in a worse case, amputation is required1,2). To treat this disease, Reperforating procedures or vessel replacing operations is commonly done3). However, the ischemia of peripheral small vessels can not be covered by procedure or operations. Because of this reason, anticoagulant therapy is commonly used after operation.
Pletaal(cilostazole) is a antiplatelet agent that is commonly used in the peripheral artery disease and can improve walking distance9). Cilostazole is selective type III phosphodiesterase inhibitor10,11). It has the effects of anticoagulaton and vasodilatation11). If there are no contraindication, Plettal is generally used after reperforating procedures.
After operations, several problems may occur such as pain, coldness, numbness and edema. Those problems are called post-reperfusion syndrome(PRS). PRS can cause walking problems and several disorders such as insomnia and depression, so it can lower the quality of patient’s life. Because the conventional therapy was not sufficient to treat PRS, we tried to carry the new type of methods.
In Korean medicine, extravasated blood causes pains and sensory problems, so the therapy of blood-activating and stasis-dispelling can kill pains and relieve sensory problems. Because pain is the major part of PRS, blood-activating and stasis-dispelling herbs may relieve the symptoms of PRS.
Before we started this clinical trial, we had evaluated the pharmacokinetics interaction between CP and Plettal in rats. The result suggests that co-administration of CP and Plettal may not cause interactions12).
To relieve PRS and improve the quality of patient’s life, we designed the integral model of Korean and western medicine. We performed clinical trial using CP with Pletaal. CP are composed of Saliviae Miltiorrhizae Radix, Notoginseng Radix and Borneolum. There were several studies about anginapectoris, neuroprotective effects, lipid-lowering effects and cerebral blood flow treated by CP68). They have effects of blood-activating, stasis-dispelling and lipid-lowering, so we thought that CP can be used for PRS.
We designed that one group(control group) is treated by only Pletaal, the other(CP group) is by Pletaal with CP. Control group is consist of 14 persons and CP group is 13 persons. We primarily evaluated the effects on relieving tht symptoms of PRS by VAS of pain, coldness, numbness and edema. We compared each group at first day, 2 weeks, 4 weeks and 8 weeks later by multiple comparison. Secondarily evaluate the safety by hematologic tests.
In the results, coldness, numbness and edema were reduced at both groups. In CP group, the VAS dropped more sharply than control group, but not significant by multiple comparison. Otherwise, there was significant reduction of VAS on pain(p<0.05) by multiple comparison. Because pain is the major part of PRS, it is meaningful that the therapy of Pletaal with CP can relieve pain significantly. I think that the blood-activating and stasis-dispelling function of Saliviae Miltiorrhizae Radix and Notoginseng Radix can significantly reduce the pain of PRS.
Otherwise in hematologic tests, we evaluated the items of WBC, RBC, Hb, Hct, Platelet, PT(INR), aPTT, AST, ALT, BUN and creatinine. In the results, all items were within normal limits. In each group there were no significant changes or abnormal signs between first day and 8 weeks later by multiple comparison. These results means that the therapy of Pletaal with CP is safe in the point of hematology. Bleeding is the major and serious problem of anticoagulant agents, so the evidences of safety on platelet, PT(INR), aPTT are remarkable.

Conclusion

From this study, the therapy of Pletaal with CP is effective to relieve PRS specially in pain and safe on hematologic tests.
Therefore it can reduce the symptoms of PRS and improve the quality of patient’s life. But this study has the limitation of pilot study by small group, so we need to do further and more trials. I think that this study will be helpful for the patients of PRS.

Acknowledgements

This study was supported by Comprehensive and Integrative Medical Institute. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

Fig. 1
Change of VAS on Pain
jkm-37-4-30f1.gif
Fig. 2
Change of VAS on Coldness
jkm-37-4-30f2.gif
Fig. 3
Change of VAS on Numbness
jkm-37-4-30f3.gif
Fig. 4
Change of VAS on Edema
jkm-37-4-30f4.gif
Table 1
Baseline Characteristics
Variable Group p-value
CP Control
Sex, n(%) Male 12(92.3) 11(78.6) 0.315
Female 1(7.7) 3(21.4)
Age, mean(SD) 68.15(9.965) 70.21(6.807) 0.533
Table 2
The Change of VAS about Primary Endpoints
Variable Group Time, mean(se) p-value
S 2W 4W 8W Time Gorup T*G
Pain CP 2.731 (0.204) 1.091 (0.222) 0.357 (0.278) 0.283 (0.3) .000* .464 .019*
Control 2.036 (0.197) 1.245 (0.222) 0.857 (0.278) 0.833 (0.245)
Coldness CP 1.308 (0.147) 0.273 (0.16) 0 (0.2) 0 (0.216) .000* .265 .832
Control 1.357 (0.141) 0.273 (0.16) 0.286 (0.2) 0.222 (0.176)
Numbness CP 3 (0.204) 0.936 (0.221) 0.529 (0.277) 0.283 (0.3) .000* .183 .284
Control 2.75 (0.196) 1.073 (0.221) 1.071 (0.277) 0.778 (0.245)
Edema CP 1.077 (0.116) 0.518 (0.126) 0.1 (0.158) 0 (0.171) .000* .511 .255
Control 0.857 (0.112) 0.545 (0.126) 0.386 (0.158) 0.167 (0.14)
Table 3
The Results of Hematologic Tests
Variable Group Time, mean(se) p-value
S 8W Time Group T*G
WBC CP 8.146 (0.728) 8.05 (1.312) .233 .847 .272
Control 9.064 (0.701) 6.74 (1.173)
RBC CP 4.086 (0.183) 4.708 (0.329) .579 .099 .060
Control 4.146 (0.176) 3.808 (0.294)
Hb CP 12.654 (0.585) 13.8 (1.055) .946 .378 .141
Control 13.136 (0.564) 11.88 (0.944)
Hct CP 37.938 (1.674) 41.875 (3.018) .894 .357 .120
Control 39.414 (1.613) 36.1 (2.7)
Platelet CP 216.231 (18.279) 270.5 (32.954) .211 .750 .380
Control 230.5 (17.615) 240 (29.475)
PT (INR) CP 1.212 (0.105) 0.995 (0.19) .945 .575 .122
Control 1.067 (0.101) 1.304 (0.17)
aPTT CP 41.723 (2.504) 39.175 (4.513) .959 .371 .435
Control 35.871 (2.413) 38.78 (4.037)
AST CP 24.462 (3.126) 17.25 (5.636) .741 .438 .186
Control 22.071 (3.013) 26.4 (5.041)
ALT CP 18.769 (3.755) 16.5 (6.769) .957 .307 .626
Control 21.571 (3.618) 24.4 (6.054)
BUN CP 16.077 (1.303) 15.65 (2.348) .952 .240 .861
Control 17.893 (1.255) 18.1 (2.1)
Creatinine CP 0.808 (0.074) 0.875 (0.133) .814 .723 .375
Control 0.936 (0.071) 0.82 (0.119)

References

1. Park SH, Youm W. Clinical Analysis of Arterial Bypass on the Atherosclerotic Occlusive Disease in Lower Extremities. Korean J Thorac Cardiovasc Surg. 1997; 30:195–199.


2. Shin YC, Kim MJ, Song CM, Ahn JB, Kim IS, Kim WS, et al. The Use of Greater Saphenous Vein in Situ Graft in Arterial Occlusive Disease of Lower Extremity. Korean J Thorac Cardiovasc Surg. 2006; 39:456–461.


3. Chung SW, Kim JW. Occlusive Complications after Lower Limb Arterial Bypass Surgery. Korean J Thorac Cardiovasc Surg. 2005; 38:152–156.


4. Falconer TM, Eikelboom JW, Hankey GJ, Norman PE. Management of pheripheral arterial disease in the elderly : focus on cilostazol. Clinical Interventions in Aging. 2008; 3:1. 17–23.
crossref

5. O’Donnell ME, Bader SA, Sharif MA, Makar RR, McEneny J, Young IS, et al. The Effects of Cilostazol on Exercise-induced Ischaemia-reperusion Injury in Patients with Peripheral Arterial Disease. Eur J Vasc Endovasc Surg. 2009; 37:326–335.
crossref

6. Jang IS, Ko CN, Lee I, Park JM, Kim SH, Kim SW. Effect of Carditonic Pills on Chest Pain and Discomfort : A Multi-center Double-blind Randomized Controlled Trial. J Korean Oriental Med. 2005; 26:2. 95–104.


7. Kwon TW, Son YS, Cho SI, Kim YK. Protective Effects of Cardiotonic Pills(CP) on Neuroglia Cells Against Oxidative Stress and the Effects on Regional Cerebral Blood Flow in Normal Rats. Kor J Herbology. 2008; 23:4. 71–79.


8. Kim HW, Kwon TW, Sun Jung, Cho SI, Kim YG, Bong SJ. Effects of Cardiotonic Pills(CP) on Serum Lipid Level in Hyperlipidemic Rats. Kor J Herbology. 2008; 23:2. 145–150.


9. O’Donnell ME, Badger SA, Sharif MA, Young IS, Bernard Lee, Soong CV. The vascular and biochemical effects of cilostazol in patients with peripheral arterial disease. J Vasc Surg. 2009; 49:1226–1234.
crossref

10. Thompson PD, Richard Zimet, Forbes WP, Peter Zhang. Meta-Analysis of Results from Eight Randomized, Placebo-Controlled Trials on the Effect of Cilostazol on Patients With Intermittent Claudication. The American Journal of Cardiology. 2002; 90:1314–1319.
crossref

11. Hiatt W, Money SR, Brass EP. Long-term safety of cilostazol in patients with peripheral artery disease : The CASTLE study. Journal of Vascular Surgery. 2008; 47:2. 330–336.
crossref

12. Kim E. Pharmacokinetics Interaction between Cardiotonic Pills and Cilostazol in Rats. Journal of Life Science. 2016; 26:1. 123–128.
crossref

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