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Clinical efficacy of different doses of lipo-prostaglandin E1 in the treatment of painful diabetic peripheral neuropathy
Journal of Diabetes and Its Complications xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Journal of Diabetes and Its Complications journal homepage: WWW.JDCJOURNAL.COM
Clinical efficacy of different doses of lipo-prostaglandin E1 in the treatment of painful diabetic peripheral neuropathy Lihua Hong a, b, Jian Zhang b, Jianguo Shen a,⁎ a b
Department of Endocrinology, The First Affiliated Hospital of Zhejiang University School of Medicine, 79# Qingchun Road, Hangzhou, Zhejiang Province, PR China 310003 Lin'an People's Hospital, 548# Yijin Road, Jincheng Town, Lin'an, Hangzhou, Zhejiang Province, PR China 311300
a r t i c l e
i n f o
Article history: Received 26 February 2015 Received in revised form 1 August 2015 Accepted 4 August 2015 Available online xxxx Keywords: Diabetes mellitus Diabetic peripheral neuropathy Lipo-prostaglandin E1 Mecobalamin Dose
a b s t r a c t Objective: To observe the clinical efficacy of different doses of alprostadil (lipo-prostaglandin E1, lipo-PGE1) in the treatment of painful diabetic peripheral neuropathy (DPN). Methods: Sixty patients with painful DPN were equally and randomly assigned into three groups. Two groups received different doses of lipo-PGE1 by intravenous drip injection (A group: low-dose lipo-PGE1; B group: high-dose lipo-PGE1) following intravenous bolus injection of mecobalamin (MeCbl, 0.5 mg once daily (QD)); the third group received MeCbl alone (C group). All patients received optimized treatment to lower blood glucose, blood pressure, and blood lipids to target levels. The efficacy of lipo-PGE1 in the three groups of patients was observed after 3 weeks of treatment. Results: The overall response rate was 90% in the B group, significantly higher than that in the A and C groups (80% and 55%, respectively; P b 0.05). During the observation period, there was no incidence of serious adverse reactions (e.g., acute heart failure, sudden drop in blood pressure, or malignant arrhythmias) in any of the three groups. Conclusions: High-dose lipo-PGE1 has better efficacy than low-dose lipo-PGE1 or MeCbl alone in the treatment of painful DPN. © 2015 Elsevier Inc. All rights reserved.
1. Introduction Diabetic peripheral neuropathy (DPN) is a common complication of type 2 diabetes mellitus. DPN can involve systemic nerve injury or necrosis, seriously affecting patients’ health and quality of life. More than 50% of diabetic patients exhibit concomitant peripheral neuropathy (Boulton et al., 2005). Early DPN manifests as sensory disturbances, with limb numbness and symptoms of hyperalgesia such as prickling, burning, and/or stabbing pain. Late DPN can affect motor nerves, leading to a reduction of muscle tension and the occurrence of limb weakness and walking difficulty (Zhao, Ma, & Peng, 2014). Although a great many methods are available for clinical treatment of DPN, few have demonstrated significant efficacy. The lack of effective therapy can lead to serious sensory loss, pain, intractable ulcers, infections, and impaired wound healing, which may eventually lead to amputation. In our hospital, alprostadil (lipo-prostaglandin E1, lipo-PGE1) was used in the treatment of DPN in addition to standardized control of blood glucose, blood pressure, and blood lipid levels, in accordance with current understanding of the multiple pathogenic mechanisms of DPN and associated physiopathological changes. Different doses of lipo-PGE1 preparation were provided with Conflicts of interest: The authors have no conflict of interest to declare. ⁎ Corresponding author. Tel.: +86 186 0651 7106. E-mail address: [email protected] (J. Shen).
the nutritive supplement, mecobalamin (MeCbl) for combination therapy of painful DPN, which achieved satisfactory clinical results. We report here the efficacy of lipo-PGE1 in the treatment of painful DPN. 2. Subjects and methods 2.1. Subjects The study recruited 60 patients who were diagnosed with painful DPN in our department from September 2012 to June 2014. The patients were stratified by age, gender, glycemic control, and severity of neuropathy. A stratified random control approach was used to assign the patients into control (C) and treatment (A and B) groups. The C group included 11 males and 9 females, aged 60–75 years old, with an average age of 63.4 ± 7.1 years; the duration of diagnosed diabetes was 8.1 ± 4.3 years and the glycosylated hemoglobin (HbA1c) level was 9.2% ± 0.8%. The A group included 8 males and 12 females, aged 60– 76 years old, with an average age of 63.9 ± 7.0 years; the duration of diagnosed diabetes was 7.9 ± 4.6 years and the HbA1c level was (9.3% ± 0.7%. The B group included 9 males and 11 females, aged 60– 77 years old, with an average age of 63.5 ± 6.9 years; the duration of diagnosed diabetes was 8.0 ± 4.5 years and the HbA1c level was 9.1% ± 0.9%. Comparison of the three groups of patients showed no significant differences (P N 0.05) in gender composition, age, duration
http://dx.doi.org/10.1016/j.jdiacomp.2015.08.001 1056-8727/$© 2015 Elsevier Inc. All rights reserved.
Please cite this article as: Hong, L., et al., Clinical efficacy of different doses of lipo-prostaglandin E1 in the treatment of painful diabetic peripheral neuropathy, Journal of Diabetes and Its Complications (2015), http://dx.doi.org/10.1016/j.jdiacomp.2015.08.001
2
L. Hong et al. / Journal of Diabetes and Its Complications xxx (2015) xxx–xxx
of diagnosed diabetes, HbA1c levels, body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), low-density lipoprotein cholesterol (LDL-c), and triglyceride (TG) levels during the treatment, confirming the comparability of the three groups (Table 1). 2.2. Inclusion criteria All three groups of patients met the following criteria: (1) the 1999 WHO diagnostic criteria for diabetes; (2) typical clinical manifestations of painful DPN; (3) neurophysiological examination of lower limb motor nerve conduction velocity (MCV) reduction: MCV b 45 m/s, and (or) sensory nerve conduction velocity (SCV) b40 m/s; (4) exclusion of nerve injures due to other causes; and (5) no heart, liver or kidney function abnormalities, and no contraindication for use of PGE1. 2.3. Treatment methods The study was approved by the Ethics Committee of ZheJiang University, and all patients gave their informed consent to participate in this study. The recruited patients were orally administered hypoglycemic agents and/or insulin to control blood glucose (target fasting glucose b 8 mmol/L, and target 2 h postprandial blood glucose b10.0 mmol/L) and lower blood pressure (target SBP/DBP b140/90 mmHg). The patients of the C group were administered mecobalamin (MeCbl) (Eisai, China; License No.: SFDA J20070063) by intravenous bolus injection (0.5 mg QD). Following MeCbl injection, the patients of the A group were administered lipo-PGE1 injection (Tide Pharmaceuticals, Beijing, China; License No.: SFDA H10980023) by intravenous drip (10 μg QD, in 100 mL of 0.9% sodium chloride; drip time, 2 h). The patients of the B group were administered 20 μg of lipo-PGE1 following MeCbl injection as performed for the A group. All three groups of patients were treated for 3 consecutive weeks. The use of painkillers and peripheral vasodilators was avoided during the observation period.
to normal levels, and increase in the EMG-nerve conduction velocity (NCV) (N5 m/s); partial response (PR): alleviation of subjective symptoms, incomplete return of the tendon reflex to normal levels, and increase in the EMG-NCV (≤ 5 m/s); and no response (NR): either no improvement or aggravation of subjective symptoms, and no improvements in the tendon reflex or EMG-NCV. Total response number ¼ CR number þ PR number; Total response rate ¼ total response number=total patient number 100%:
2.6. Statistical analysis Data were statistically analyzed using SPSS 17.5 (SPSS Inc., Chicago, IL, USA). Continuous data were expressed as mean ± standard deviation (SD). Two-sided Student t-test was performed for two-group comparison. Multi-group comparisons of continuous data were performed using analysis of variance, and ordinal data were compared using the rank-sum test. P b 0.05 and power N 0.8 were considered statistically significant. 3. Results 3.1. Comparison of clinical efficacy among three groups of patients In the C group, there were 4 cases of CR, 7 cases of PR, and 9 cases of NR, with a total response rate of 55%. In the A group, there were 7 cases of CR, 9 cases of PR, and 4 cases of NR, with a total response rate of 80%. In the B group, there were 10 cases of CR, 8 cases of PR, and 2 cases of NR, with a total response rate of 90% (Table 2). 3.2. Comparison of pre- and post-treatment MCV, SCV, and VAS changes among three groups of patients
2.4. Outcome measures Blood glucose, blood pressure, and blood lipid levels were measured in the patients before and after treatment. Additionally, clinical indicators of safe medication were monitored, including routine blood, urine, and stool tests, liver and kidney function tests, and electrocardiogram. Algesthesia and knee tendon reflex were measured and recorded by a specialist. The following clinical parameters of the patients were observed before and after treatment: fasting plasma glucose (FPG), 2 h postprandial glucose (2hPG), SBP, DBP, serum total cholesterol (T-CHOL), triglyceride (TG), high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c), and visual analogue scale (VAS). Electromyograph (EMG) was used to record the pre- and post-treatment MCV and SCV of the median and common peroneal nerves in the right medial and lateral limbs. 2.5. Efficacy evaluation Patients were assigned to the following groups: complete response, partial response or no response. Complete response (CR): disappearance of all subjective symptoms, return of the tendon reflex
The three groups of patients had no significant differences in the pre-treatment median and common peroneal nerve MCV or SCV (P N 0.05). In the C group, the post-treatment values of the median nerve MCV and SCV as well as the common peroneal nerve SCV were significantly improved compared with pre-treatment values (P b 0.05). However, no significant difference occurred in the post-treatment common peroneal nerve MCV (P N 0.05). In both the A and B groups, the post-treatment values of the median and common peroneal nerve MCV and SCV were significantly improved compared with pre-treatment values (P b 0.05). Comparison among the three groups of patients showed that: the post-treatment values of the median and common peroneal nerve MCV and SCV were significantly improved in the A and B groups relative to the C group (P b 0.05); the post-treatment median and common peroneal MCV and SCV values were also significantly improved in the B group relative to the C and A groups (P b 0.05). The pre-treatment VAS was not significantly different among the three groups of patients (P N 0.05). Compared with the pre-treatment values, the post-treatment VAS scores relatively decreased in all the three groups, showing statistically significant differences (P b 0.05). The post-treatment VAS scores also
Table 1 Comparison of general clinical data (mean ± standard deviation) before treatment. Group
Case number (n, male/female)
Age (year)
Duration of diagnosed DM (year)
HbA1c (%)
BMI
SBP (mmHg)
DBP (mmHg)
LDL-c (mmol/L)
TG (mmol/L)
Control Treatment A Treatment B
20 (11/9) 20 (8/12) 20 (9/11)
63.4 ± 7.1 63.9 ± 7.0 63.5 ± 6.9
8.1 ± 4.3 7.9 ± 4.6 8.0 ± 4.5
9.2 ± 0.8 9.3 ± 0.7 9.1 ± 0.9
23.5 ± 0.8 23.6 ± 0.7 23.4 ± 0.9
152.8 ± 10.5 154.6 ± 10.2 153.8 ± 10.6
95.5 ± 6.4 94.7 ± 6.6 95.3 ± 6.9
3.51 ± 0.60 3.42 ± 0.71 3.63 ± 0.52
2.80 ± 0.41 2.91 ± 0.52 2.82 ± 0.63
Control, mecobalamin alone; Treatment A, low-dose lipo-PGE1 plus mecobalamin; Treatment B, high-dose lipo-PGE1 plus mecobalamin; DM, diabetes mellitus; HbA1c, glycosylated hemoglobin; BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; LDL-c, low-density lipoprotein cholesterol; TG, triglyceride.
Please cite this article as: Hong, L., et al., Clinical efficacy of different doses of lipo-prostaglandin E1 in the treatment of painful diabetic peripheral neuropathy, Journal of Diabetes and Its Complications (2015), http://dx.doi.org/10.1016/j.jdiacomp.2015.08.001
L. Hong et al. / Journal of Diabetes and Its Complications xxx (2015) xxx–xxx Table 2 The therapeutic effect of lipo-prostaglandin E1 (lipo-PGE1) among three groups of patients with painful diabetic peripheral neuropathy. Group
CR (n)
PR (n)
NR (n)
Total RR (%)
Control Treatment A Treatment B
4 7 10
7 9 8
9 4 2
55 80 90
CR, complete response number; PR, partial response number; NR, no response number; and RR, response rate.
significantly differed among the three groups (P b 0.05), with the greatest decrease in the B group (Table 3). 3.3. Adverse reactions During the observation period, the C group had 1 case each of chest tightness, nausea, vomiting, bloating, diarrhea, pruritus, and mild hypoglycemia; the A group had 2 cases each of dizziness, diarrhea, and mild hypoglycemia and 1 case each of nausea, vomiting, bloating, skin rash, and pruritus; the B group had 2 cases each of nausea and diarrhea and 1 case each of dizziness, rash, and mild hypoglycemia. The above discomfort disappeared upon symptomatic treatment. Routine blood, urine, and stool test or liver and kidney function monitoring before and after treatment showed no significant abnormal changes in the three groups. Serious adverse reactions such as acute heart failure, sudden drop in blood pressure, and malignant arrhythmia were not observed. No patients withdrew from treatment. 4. Discussion The etiology and mechanism of DPN are generally believed to be associated with microvascular lesions, metabolic disorders, neurological factor decrease, and oxidative stress reactions in diabetic patients. The combined action of these factors leads to nervous system damage, injuring the sensory, motor, and autonomic nervous systems. This can exhibit in the patient as the sensation of numbness and pain, as well as motor disorders. In severe cases, lower limb gangrene may occur. At present, DPN is often treated by allowing damaged nerves to repair, thus alleviating disease symptoms and slowing disease progression. This is achieved through the strict control of blood glucose and improvement of the microcirculation to correct nerve fiber ischemia and hypoxia (Ziegler, 2007). MeCbl is methylated vitamin B12, which primarily promotes cellular synthesis of nucleic acids, proteins and lipids through methylation reactions. MeCbl especially promotes the formation of axons and myelin sheath. It can directly enter nerve cells to stimulate the synthesis of lecithin, repair the myelin sheath and enable the regeneration of damaged axonal areas, as well as promote the repair of injured nerve tissues, ultimately improving nerve conduction. Therefore, MeCbl has been widely used to repair various nerve
3
systems following injury (Liu, Wu, & Li, 2012), improve NCV, and ease the symptoms of limb pain and numbness in DPN patients. However, clinical observations have shown that the efficacy of MeCbl treatment alone is limited among DPN patients who have a longer course of disease with severe illness and severe damage to the neural structure. The major component of lipo-PGE1 is PGE1, a highly active bio-substance that not only has a significant role in vasodilation, but also inhibits platelet aggregation, reduces blood viscosity and erythrocyte aggregation, improves microcirculation, prevents atherosclerotic lipid plaque formation, and alleviates nerve damage (Bai, Zhou, & Li, 2008). Owing to its encapsulation by lipid microspheres in lipo-PGE1, PGE1 in this formulation is unlikely to be deactivated and has less stimulatory effect on local blood vessels, with fewer adverse reactions (Tong, 2011). Moreover, lipo-PGE1 possesses targeting properties for easy distribution to damaged vessel sites (Nie, Jiang, & Li, 2007) and thus can better aggregate in inflamed lesions and vessels and effectively improve the ischemic and hypoxic conditions of the nervous system. Early in the 1980s, the use of PGE1 for the treatment of peripheral arterial occlusive disease was reported overseas, achieving good efficacy (Clifford, Martin, Dieppe, Sheddon, & Baird, 1983). PGE1 has a significant and extensive role in vasodilation. Additionally, it can inhibit platelet adhesion and aggregation, prevent smooth muscle cell migration and proliferation, reduce endothelin-1 levels, and improve the blood supply. Therefore, the indication for PGE1 has been gradually extended from the treatment of chronic arterial occlusive disease to improvement in cardiovascular and microcirculatory disorders (Chen et al., 2013). Substantial clinical data also show that the use of PGE1 for DPN can improve associated symptoms and increase the NCV of the lesion. A recent study has found that PGE1 has anti-oxidative stress activity and its beneficial effect on anti-oxidative stress injury is independent from blood glucose decline (Fu et al., 2013). The present study focuses on 60 patients with painful DPN. These patients were stratified by age, gender, glycemic control, and severity of neuropathy and then assigned into the control (C) and treatment (A and B) groups by a stratified random control approach. The three groups of patients displayed no statistically significant differences in gender composition, age, duration of diagnosed diabetes, or HbA1c, BMI, blood pressure, or lipid levels (P N 0.05). All patients received optimized treatment to lower blood glucose, blood pressure, and blood lipids to specific target levels. MeCbl injection of 0.5 mg QD was administered by intravenous bolus injection as a nutritive supplement for neurons. Following MeCbl administration, the treatment groups (A and B) received a combination therapy with different doses of lipo-PGE1 for 3 weeks. The clinical efficacy was evaluated in different groups after treatment and the total response rates were 55% in the C group, 80% in the A group, and 90% in the B group. Clearly, the total response rate in the B group administered high-dose lipo-PGE1 was significantly higher than those in the other two groups. In all three groups, post-treatment VAS statistically significantly decreased
Table 3 Comparison of pre- and post-treatment MCV, SCV, and VAS among three groups of patients with painful diabetic peripheral neuropathy (mean ± standard deviation). Group
Control Treatment A Treatment B
Case number (n) Pre-T Post-T Pre-T Post-T Pre-T Post-T
20 20 20 20 20 20
MCV (m/s)
SCV (m/s)
VAS (points)
Median nerve
Common peroneal nerve
Median nerve
Common peroneal nerve
41.02 46.14 41.33 52.35 40.67 57.89
38.11 40.32 37.85 45.57 38.09 52.12
39.21 45.32 38.96 50.66 38.84 56.91
29.21 32.12 29.71 37.42 30.55 44.62
± ± ± ± ± ±
3.18 4.22⁎ 4.24 5.16⁎,⁎⁎ 4.38 4.50⁎,⁎⁎,⁎⁎⁎
± ± ± ± ± ±
4.02 4.34 3.68 4.18⁎,⁎⁎ 3.90 4.31⁎,⁎⁎,⁎⁎⁎
± ± ± ± ± ±
4.20 4.41⁎ 3.98 4.35⁎,⁎⁎ 3.72 4.20⁎,⁎⁎,⁎⁎⁎
± ± ± ± ± ±
3.31 3.89⁎ 3.20 4.16⁎,⁎⁎ 3.36 4.29⁎,⁎⁎,⁎⁎⁎
5.32 4.14 5.25 3.28 5.19 2.48
± ± ± ± ± ±
1.57 1.21⁎ 1.51 1.20⁎,⁎⁎ 1.48 1.11⁎,⁎⁎,⁎⁎⁎
Control, mecobalamin alone; Treatment A, low-dose lipo-PGE1 plus mecobalamin; Treatment B, high-dose lipo-PGE1 plus mecobalamin; Pre-T, pre-treatment; Post-T, post-treatment; MCV, motor nerve conduction velocity; SCV, sensory nerve conduction velocity; VAS, visual analogue scale; ⁎ Compared with pre-treatment data, P b0.05. ⁎⁎ Compared with control group, P b0.05. ⁎⁎⁎ Compared with treatment A, P b0.05.
Please cite this article as: Hong, L., et al., Clinical efficacy of different doses of lipo-prostaglandin E1 in the treatment of painful diabetic peripheral neuropathy, Journal of Diabetes and Its Complications (2015), http://dx.doi.org/10.1016/j.jdiacomp.2015.08.001
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L. Hong et al. / Journal of Diabetes and Its Complications xxx (2015) xxx–xxx
relative to the pre-treatment values (P b 0.05). Post-treatment VAS in the B group was significantly lower than those in the C and A groups. The analysis of EMG parameters revealed significant improvements in the post-treatment values of the median nerve MCV and SCV in both the A and B groups (P b 0.05), with the B group exhibiting significantly better improvement than the A group. Group comparisons and analysis showed that the high-dose group (20 μg of lipo-PGE1; intravenous infusion, QD) had a significantly better effect than the low-dose group (10 μg of lipo-PGE1; intravenous infusion, QD) and the C group, without increasing the incidence of clinical adverse reactions. Nie et al. (2007) performed a meta-analysis on the efficacy and adverse reactions of PGE1 therapy for diabetic DPN with data retrieved from the China Academic Journals Full-text Database (January 1994–December 2006). The results showed that PGE1 can significantly reduce the clinical symptoms of DPN patients and improve NCV. PGE1 exhibited a significantly better therapeutic effect than drugs currently in use (P b 0.001), while no significant adverse effects were observed. Cawello et al. (1995) reported that when a dose of PGE1 below 120 μg/d was intravenously infused in healthy volunteers, the blood concentration increased with increasing injection dose without increasing significant adverse reactions. Zhang (2012) also reported that for early diabetic nephropathy, injection with 20 μg/d of PGE1 achieved better clinical results than a dose of 10 μg/d, while no significant adverse reactions were increased by the high-dose PGE1 therapy. Consistent with these reports, the clinical observations in the present study show that use of lipo-PGE1 injection at a high dose is more effective than a low dose for the treatment of painful DPN. Since no significant adverse reactions have been reported, high-dose lipo-PGE1 therapy should be considered for treatment of painful DPN. There are many other methods are available for clinical treatment of painful DPN. Juhn, Parsons, Varvara, and Sadosky (2015) reported that pregabalin monotherapy in the treatment of DPN is valid. Devi et al. (2012) reported that gabapentin, duloxetine and pregabalin monotherapy had some effect on painful diabetic peripheral neuropathy. Since 2010, more than 5 international guidelines for treatment of painful DPN have been issued; the choice of agent in any given patient should depend on patient characteristics. Our results should be interpreted within the following study’s limitations: One is the power of VAS test was not adequate (b 80%) to detect difference between low dose group/control and high dose group/low dose group. The reasons maybe as follow: the insufficient sample size in the control group, and the older subjects (N 60 years). The sample size and age distribution should be improved in our future studies. The other limitation is that we did not test the endothelin (ET)-1. ET-1 concentrations are thought to correlate with the onset
and progress of diabetic microangiopathy (Itoh et al., 2001). The role of ET-1 in the treatment of DPN, especially its relationship with mecobalamin and Lipo-PGE1 treatment, needs to be further studied. Acknowledgments We would like to thank the patients who participated in the study for their efforts. References Bai, L. N., Zhou, H., & Li, Y. H. (2008). Research advances in the pharmacological mechanism of lipo-prostaglandin E1 preparation. Journal of China-Japan Friendship Hospital, 22(1), 47–50. Boulton, A. J., Vinik, A. I., Arezzo, J. C., Bril, V., Feldman, E. L., Freeman, R., et al. (2005). Diabetic neuropathies: A statement by the American Diabetes Association. Diabetes Care, 28(4), 956–962. Cawello, W., Leonhardt, A., Schweer, H., Seyberth, H. W., Bonn, R., & Lomeli, A. L. (1995). Dose proportional pharmacokinetics of alprostadil (prostaglandin E1) in healthy volunteers following intravenous infusion. British Journal of Clinical Pharmacology, 40(3), 273–276. Chen, Y., Wan, J. X., Jiang, D. W., Fu, B. B., Cui, T., & Li, G. F. (2013). Clinical efficacy and safety of sequential treatment with alprostadil and beraprost sodium for chronic renal failure induced by chronic glomerulonephritis. Journal of Southern Medical University, 33(10), 1521–1524. Clifford, P. C., Martin, M. F., Dieppe, P. A., Sheddon, E. J., & Baird, R. N. (1983). Prostaglandin E1 infusion for small vessel arterial ischaemia. The Journal of Cardiovascular Surgery, 24(5), 503–508. Devi, P., Madhu, K., Ganapathy, B., Sarma, G., John, L., & Kulkarni, C. (2012). Evaluation of efficacy and safety of gabapentin, duloxetine, and pregabalin in patients with painful diabetic peripheral neuropathy. Indian Journal of Pharmacology, 44(1), 51–56. Fu, H. J., Du, F. C., Hu, Y., Chen, S., Ye, X. Z., Ma, J., et al. (2013). Effect of alprostadil on oxidative damage in type 2 diabetic nephropathy. Journal of Medical Postgraduates, 26(8), 801–803. Itoh, Y., Yasui, T., Kakizawa, H., Makino, M., Fujiwara, K., Kato, T., et al. (2001). The therapeutic effect of lipo PGE1 on diabetic neuropathy-changes in endothelin and various angiopathic factors. Prostaglandins & Other Lipid Mediators, 66(3), 221–234. Juhn, M. S., Parsons, B., Varvara, R., & Sadosky, A. (2015). Pregabalin for painful diabetic peripheral neuropathy: Strategies for dosing, monotherapy vs. combination therapy, treatment-refractory patients, and adverse events. Current Medical Research and Opinion, 31(5), 1017–1026. Liu, X. Y., Wu, D. F., & Li, J. (2012). Clinical research on mecobalamine with various administrations in diabetic neuropathy patients. China Pharmacist, 15(4), 526–528. Nie, L. H., Jiang, Y. B., & Li, G. C. (2007). Systematic evaluation of alprostadil in the treatment of diabetic peripheral neuropathy. Guangdong Medical Journal, 28(6), 988–989. Tong, A. H. (2011). The effect observation of alprostadil combined with mecobalamine in diabetic peripheral neuropathy. Chinese Journal of Clinical Rational Drug Use, 4(17), 15–16. Zhang, X. N. (2012). Observation on curative effect of treatment with varied dosage of prostaglandin E1 injection for early diabetic nephropathy. Journal of China-Japan Friendship Hospital, 26(5), 284–286. Zhao, L., Ma, Y. H., & Peng, Y. D. (2014). The therapeutic effect of α-lipoic acid on the treatment of diabetic neuropathy. Chinese Journal of Diabetes, 22(3), 207–209. Ziegler, D. (2007). Management of painful diabetic neuropathy: What is new or in the pipeline for 2007. Current Diabetes Reports, 7(6), 409–415.
Please cite this article as: Hong, L., et al., Clinical efficacy of different doses of lipo-prostaglandin E1 in the treatment of painful diabetic peripheral neuropathy, Journal of Diabetes and Its Complications (2015), http://dx.doi.org/10.1016/j.jdiacomp.2015.08.001
Contents lists available at ScienceDirect
Journal of Diabetes and Its Complications journal homepage: WWW.JDCJOURNAL.COM
Clinical efficacy of different doses of lipo-prostaglandin E1 in the treatment of painful diabetic peripheral neuropathy Lihua Hong a, b, Jian Zhang b, Jianguo Shen a,⁎ a b
Department of Endocrinology, The First Affiliated Hospital of Zhejiang University School of Medicine, 79# Qingchun Road, Hangzhou, Zhejiang Province, PR China 310003 Lin'an People's Hospital, 548# Yijin Road, Jincheng Town, Lin'an, Hangzhou, Zhejiang Province, PR China 311300
a r t i c l e
i n f o
Article history: Received 26 February 2015 Received in revised form 1 August 2015 Accepted 4 August 2015 Available online xxxx Keywords: Diabetes mellitus Diabetic peripheral neuropathy Lipo-prostaglandin E1 Mecobalamin Dose
a b s t r a c t Objective: To observe the clinical efficacy of different doses of alprostadil (lipo-prostaglandin E1, lipo-PGE1) in the treatment of painful diabetic peripheral neuropathy (DPN). Methods: Sixty patients with painful DPN were equally and randomly assigned into three groups. Two groups received different doses of lipo-PGE1 by intravenous drip injection (A group: low-dose lipo-PGE1; B group: high-dose lipo-PGE1) following intravenous bolus injection of mecobalamin (MeCbl, 0.5 mg once daily (QD)); the third group received MeCbl alone (C group). All patients received optimized treatment to lower blood glucose, blood pressure, and blood lipids to target levels. The efficacy of lipo-PGE1 in the three groups of patients was observed after 3 weeks of treatment. Results: The overall response rate was 90% in the B group, significantly higher than that in the A and C groups (80% and 55%, respectively; P b 0.05). During the observation period, there was no incidence of serious adverse reactions (e.g., acute heart failure, sudden drop in blood pressure, or malignant arrhythmias) in any of the three groups. Conclusions: High-dose lipo-PGE1 has better efficacy than low-dose lipo-PGE1 or MeCbl alone in the treatment of painful DPN. © 2015 Elsevier Inc. All rights reserved.
1. Introduction Diabetic peripheral neuropathy (DPN) is a common complication of type 2 diabetes mellitus. DPN can involve systemic nerve injury or necrosis, seriously affecting patients’ health and quality of life. More than 50% of diabetic patients exhibit concomitant peripheral neuropathy (Boulton et al., 2005). Early DPN manifests as sensory disturbances, with limb numbness and symptoms of hyperalgesia such as prickling, burning, and/or stabbing pain. Late DPN can affect motor nerves, leading to a reduction of muscle tension and the occurrence of limb weakness and walking difficulty (Zhao, Ma, & Peng, 2014). Although a great many methods are available for clinical treatment of DPN, few have demonstrated significant efficacy. The lack of effective therapy can lead to serious sensory loss, pain, intractable ulcers, infections, and impaired wound healing, which may eventually lead to amputation. In our hospital, alprostadil (lipo-prostaglandin E1, lipo-PGE1) was used in the treatment of DPN in addition to standardized control of blood glucose, blood pressure, and blood lipid levels, in accordance with current understanding of the multiple pathogenic mechanisms of DPN and associated physiopathological changes. Different doses of lipo-PGE1 preparation were provided with Conflicts of interest: The authors have no conflict of interest to declare. ⁎ Corresponding author. Tel.: +86 186 0651 7106. E-mail address: [email protected] (J. Shen).
the nutritive supplement, mecobalamin (MeCbl) for combination therapy of painful DPN, which achieved satisfactory clinical results. We report here the efficacy of lipo-PGE1 in the treatment of painful DPN. 2. Subjects and methods 2.1. Subjects The study recruited 60 patients who were diagnosed with painful DPN in our department from September 2012 to June 2014. The patients were stratified by age, gender, glycemic control, and severity of neuropathy. A stratified random control approach was used to assign the patients into control (C) and treatment (A and B) groups. The C group included 11 males and 9 females, aged 60–75 years old, with an average age of 63.4 ± 7.1 years; the duration of diagnosed diabetes was 8.1 ± 4.3 years and the glycosylated hemoglobin (HbA1c) level was 9.2% ± 0.8%. The A group included 8 males and 12 females, aged 60– 76 years old, with an average age of 63.9 ± 7.0 years; the duration of diagnosed diabetes was 7.9 ± 4.6 years and the HbA1c level was (9.3% ± 0.7%. The B group included 9 males and 11 females, aged 60– 77 years old, with an average age of 63.5 ± 6.9 years; the duration of diagnosed diabetes was 8.0 ± 4.5 years and the HbA1c level was 9.1% ± 0.9%. Comparison of the three groups of patients showed no significant differences (P N 0.05) in gender composition, age, duration
http://dx.doi.org/10.1016/j.jdiacomp.2015.08.001 1056-8727/$© 2015 Elsevier Inc. All rights reserved.
Please cite this article as: Hong, L., et al., Clinical efficacy of different doses of lipo-prostaglandin E1 in the treatment of painful diabetic peripheral neuropathy, Journal of Diabetes and Its Complications (2015), http://dx.doi.org/10.1016/j.jdiacomp.2015.08.001
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L. Hong et al. / Journal of Diabetes and Its Complications xxx (2015) xxx–xxx
of diagnosed diabetes, HbA1c levels, body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), low-density lipoprotein cholesterol (LDL-c), and triglyceride (TG) levels during the treatment, confirming the comparability of the three groups (Table 1). 2.2. Inclusion criteria All three groups of patients met the following criteria: (1) the 1999 WHO diagnostic criteria for diabetes; (2) typical clinical manifestations of painful DPN; (3) neurophysiological examination of lower limb motor nerve conduction velocity (MCV) reduction: MCV b 45 m/s, and (or) sensory nerve conduction velocity (SCV) b40 m/s; (4) exclusion of nerve injures due to other causes; and (5) no heart, liver or kidney function abnormalities, and no contraindication for use of PGE1. 2.3. Treatment methods The study was approved by the Ethics Committee of ZheJiang University, and all patients gave their informed consent to participate in this study. The recruited patients were orally administered hypoglycemic agents and/or insulin to control blood glucose (target fasting glucose b 8 mmol/L, and target 2 h postprandial blood glucose b10.0 mmol/L) and lower blood pressure (target SBP/DBP b140/90 mmHg). The patients of the C group were administered mecobalamin (MeCbl) (Eisai, China; License No.: SFDA J20070063) by intravenous bolus injection (0.5 mg QD). Following MeCbl injection, the patients of the A group were administered lipo-PGE1 injection (Tide Pharmaceuticals, Beijing, China; License No.: SFDA H10980023) by intravenous drip (10 μg QD, in 100 mL of 0.9% sodium chloride; drip time, 2 h). The patients of the B group were administered 20 μg of lipo-PGE1 following MeCbl injection as performed for the A group. All three groups of patients were treated for 3 consecutive weeks. The use of painkillers and peripheral vasodilators was avoided during the observation period.
to normal levels, and increase in the EMG-nerve conduction velocity (NCV) (N5 m/s); partial response (PR): alleviation of subjective symptoms, incomplete return of the tendon reflex to normal levels, and increase in the EMG-NCV (≤ 5 m/s); and no response (NR): either no improvement or aggravation of subjective symptoms, and no improvements in the tendon reflex or EMG-NCV. Total response number ¼ CR number þ PR number; Total response rate ¼ total response number=total patient number 100%:
2.6. Statistical analysis Data were statistically analyzed using SPSS 17.5 (SPSS Inc., Chicago, IL, USA). Continuous data were expressed as mean ± standard deviation (SD). Two-sided Student t-test was performed for two-group comparison. Multi-group comparisons of continuous data were performed using analysis of variance, and ordinal data were compared using the rank-sum test. P b 0.05 and power N 0.8 were considered statistically significant. 3. Results 3.1. Comparison of clinical efficacy among three groups of patients In the C group, there were 4 cases of CR, 7 cases of PR, and 9 cases of NR, with a total response rate of 55%. In the A group, there were 7 cases of CR, 9 cases of PR, and 4 cases of NR, with a total response rate of 80%. In the B group, there were 10 cases of CR, 8 cases of PR, and 2 cases of NR, with a total response rate of 90% (Table 2). 3.2. Comparison of pre- and post-treatment MCV, SCV, and VAS changes among three groups of patients
2.4. Outcome measures Blood glucose, blood pressure, and blood lipid levels were measured in the patients before and after treatment. Additionally, clinical indicators of safe medication were monitored, including routine blood, urine, and stool tests, liver and kidney function tests, and electrocardiogram. Algesthesia and knee tendon reflex were measured and recorded by a specialist. The following clinical parameters of the patients were observed before and after treatment: fasting plasma glucose (FPG), 2 h postprandial glucose (2hPG), SBP, DBP, serum total cholesterol (T-CHOL), triglyceride (TG), high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c), and visual analogue scale (VAS). Electromyograph (EMG) was used to record the pre- and post-treatment MCV and SCV of the median and common peroneal nerves in the right medial and lateral limbs. 2.5. Efficacy evaluation Patients were assigned to the following groups: complete response, partial response or no response. Complete response (CR): disappearance of all subjective symptoms, return of the tendon reflex
The three groups of patients had no significant differences in the pre-treatment median and common peroneal nerve MCV or SCV (P N 0.05). In the C group, the post-treatment values of the median nerve MCV and SCV as well as the common peroneal nerve SCV were significantly improved compared with pre-treatment values (P b 0.05). However, no significant difference occurred in the post-treatment common peroneal nerve MCV (P N 0.05). In both the A and B groups, the post-treatment values of the median and common peroneal nerve MCV and SCV were significantly improved compared with pre-treatment values (P b 0.05). Comparison among the three groups of patients showed that: the post-treatment values of the median and common peroneal nerve MCV and SCV were significantly improved in the A and B groups relative to the C group (P b 0.05); the post-treatment median and common peroneal MCV and SCV values were also significantly improved in the B group relative to the C and A groups (P b 0.05). The pre-treatment VAS was not significantly different among the three groups of patients (P N 0.05). Compared with the pre-treatment values, the post-treatment VAS scores relatively decreased in all the three groups, showing statistically significant differences (P b 0.05). The post-treatment VAS scores also
Table 1 Comparison of general clinical data (mean ± standard deviation) before treatment. Group
Case number (n, male/female)
Age (year)
Duration of diagnosed DM (year)
HbA1c (%)
BMI
SBP (mmHg)
DBP (mmHg)
LDL-c (mmol/L)
TG (mmol/L)
Control Treatment A Treatment B
20 (11/9) 20 (8/12) 20 (9/11)
63.4 ± 7.1 63.9 ± 7.0 63.5 ± 6.9
8.1 ± 4.3 7.9 ± 4.6 8.0 ± 4.5
9.2 ± 0.8 9.3 ± 0.7 9.1 ± 0.9
23.5 ± 0.8 23.6 ± 0.7 23.4 ± 0.9
152.8 ± 10.5 154.6 ± 10.2 153.8 ± 10.6
95.5 ± 6.4 94.7 ± 6.6 95.3 ± 6.9
3.51 ± 0.60 3.42 ± 0.71 3.63 ± 0.52
2.80 ± 0.41 2.91 ± 0.52 2.82 ± 0.63
Control, mecobalamin alone; Treatment A, low-dose lipo-PGE1 plus mecobalamin; Treatment B, high-dose lipo-PGE1 plus mecobalamin; DM, diabetes mellitus; HbA1c, glycosylated hemoglobin; BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; LDL-c, low-density lipoprotein cholesterol; TG, triglyceride.
Please cite this article as: Hong, L., et al., Clinical efficacy of different doses of lipo-prostaglandin E1 in the treatment of painful diabetic peripheral neuropathy, Journal of Diabetes and Its Complications (2015), http://dx.doi.org/10.1016/j.jdiacomp.2015.08.001
L. Hong et al. / Journal of Diabetes and Its Complications xxx (2015) xxx–xxx Table 2 The therapeutic effect of lipo-prostaglandin E1 (lipo-PGE1) among three groups of patients with painful diabetic peripheral neuropathy. Group
CR (n)
PR (n)
NR (n)
Total RR (%)
Control Treatment A Treatment B
4 7 10
7 9 8
9 4 2
55 80 90
CR, complete response number; PR, partial response number; NR, no response number; and RR, response rate.
significantly differed among the three groups (P b 0.05), with the greatest decrease in the B group (Table 3). 3.3. Adverse reactions During the observation period, the C group had 1 case each of chest tightness, nausea, vomiting, bloating, diarrhea, pruritus, and mild hypoglycemia; the A group had 2 cases each of dizziness, diarrhea, and mild hypoglycemia and 1 case each of nausea, vomiting, bloating, skin rash, and pruritus; the B group had 2 cases each of nausea and diarrhea and 1 case each of dizziness, rash, and mild hypoglycemia. The above discomfort disappeared upon symptomatic treatment. Routine blood, urine, and stool test or liver and kidney function monitoring before and after treatment showed no significant abnormal changes in the three groups. Serious adverse reactions such as acute heart failure, sudden drop in blood pressure, and malignant arrhythmia were not observed. No patients withdrew from treatment. 4. Discussion The etiology and mechanism of DPN are generally believed to be associated with microvascular lesions, metabolic disorders, neurological factor decrease, and oxidative stress reactions in diabetic patients. The combined action of these factors leads to nervous system damage, injuring the sensory, motor, and autonomic nervous systems. This can exhibit in the patient as the sensation of numbness and pain, as well as motor disorders. In severe cases, lower limb gangrene may occur. At present, DPN is often treated by allowing damaged nerves to repair, thus alleviating disease symptoms and slowing disease progression. This is achieved through the strict control of blood glucose and improvement of the microcirculation to correct nerve fiber ischemia and hypoxia (Ziegler, 2007). MeCbl is methylated vitamin B12, which primarily promotes cellular synthesis of nucleic acids, proteins and lipids through methylation reactions. MeCbl especially promotes the formation of axons and myelin sheath. It can directly enter nerve cells to stimulate the synthesis of lecithin, repair the myelin sheath and enable the regeneration of damaged axonal areas, as well as promote the repair of injured nerve tissues, ultimately improving nerve conduction. Therefore, MeCbl has been widely used to repair various nerve
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systems following injury (Liu, Wu, & Li, 2012), improve NCV, and ease the symptoms of limb pain and numbness in DPN patients. However, clinical observations have shown that the efficacy of MeCbl treatment alone is limited among DPN patients who have a longer course of disease with severe illness and severe damage to the neural structure. The major component of lipo-PGE1 is PGE1, a highly active bio-substance that not only has a significant role in vasodilation, but also inhibits platelet aggregation, reduces blood viscosity and erythrocyte aggregation, improves microcirculation, prevents atherosclerotic lipid plaque formation, and alleviates nerve damage (Bai, Zhou, & Li, 2008). Owing to its encapsulation by lipid microspheres in lipo-PGE1, PGE1 in this formulation is unlikely to be deactivated and has less stimulatory effect on local blood vessels, with fewer adverse reactions (Tong, 2011). Moreover, lipo-PGE1 possesses targeting properties for easy distribution to damaged vessel sites (Nie, Jiang, & Li, 2007) and thus can better aggregate in inflamed lesions and vessels and effectively improve the ischemic and hypoxic conditions of the nervous system. Early in the 1980s, the use of PGE1 for the treatment of peripheral arterial occlusive disease was reported overseas, achieving good efficacy (Clifford, Martin, Dieppe, Sheddon, & Baird, 1983). PGE1 has a significant and extensive role in vasodilation. Additionally, it can inhibit platelet adhesion and aggregation, prevent smooth muscle cell migration and proliferation, reduce endothelin-1 levels, and improve the blood supply. Therefore, the indication for PGE1 has been gradually extended from the treatment of chronic arterial occlusive disease to improvement in cardiovascular and microcirculatory disorders (Chen et al., 2013). Substantial clinical data also show that the use of PGE1 for DPN can improve associated symptoms and increase the NCV of the lesion. A recent study has found that PGE1 has anti-oxidative stress activity and its beneficial effect on anti-oxidative stress injury is independent from blood glucose decline (Fu et al., 2013). The present study focuses on 60 patients with painful DPN. These patients were stratified by age, gender, glycemic control, and severity of neuropathy and then assigned into the control (C) and treatment (A and B) groups by a stratified random control approach. The three groups of patients displayed no statistically significant differences in gender composition, age, duration of diagnosed diabetes, or HbA1c, BMI, blood pressure, or lipid levels (P N 0.05). All patients received optimized treatment to lower blood glucose, blood pressure, and blood lipids to specific target levels. MeCbl injection of 0.5 mg QD was administered by intravenous bolus injection as a nutritive supplement for neurons. Following MeCbl administration, the treatment groups (A and B) received a combination therapy with different doses of lipo-PGE1 for 3 weeks. The clinical efficacy was evaluated in different groups after treatment and the total response rates were 55% in the C group, 80% in the A group, and 90% in the B group. Clearly, the total response rate in the B group administered high-dose lipo-PGE1 was significantly higher than those in the other two groups. In all three groups, post-treatment VAS statistically significantly decreased
Table 3 Comparison of pre- and post-treatment MCV, SCV, and VAS among three groups of patients with painful diabetic peripheral neuropathy (mean ± standard deviation). Group
Control Treatment A Treatment B
Case number (n) Pre-T Post-T Pre-T Post-T Pre-T Post-T
20 20 20 20 20 20
MCV (m/s)
SCV (m/s)
VAS (points)
Median nerve
Common peroneal nerve
Median nerve
Common peroneal nerve
41.02 46.14 41.33 52.35 40.67 57.89
38.11 40.32 37.85 45.57 38.09 52.12
39.21 45.32 38.96 50.66 38.84 56.91
29.21 32.12 29.71 37.42 30.55 44.62
± ± ± ± ± ±
3.18 4.22⁎ 4.24 5.16⁎,⁎⁎ 4.38 4.50⁎,⁎⁎,⁎⁎⁎
± ± ± ± ± ±
4.02 4.34 3.68 4.18⁎,⁎⁎ 3.90 4.31⁎,⁎⁎,⁎⁎⁎
± ± ± ± ± ±
4.20 4.41⁎ 3.98 4.35⁎,⁎⁎ 3.72 4.20⁎,⁎⁎,⁎⁎⁎
± ± ± ± ± ±
3.31 3.89⁎ 3.20 4.16⁎,⁎⁎ 3.36 4.29⁎,⁎⁎,⁎⁎⁎
5.32 4.14 5.25 3.28 5.19 2.48
± ± ± ± ± ±
1.57 1.21⁎ 1.51 1.20⁎,⁎⁎ 1.48 1.11⁎,⁎⁎,⁎⁎⁎
Control, mecobalamin alone; Treatment A, low-dose lipo-PGE1 plus mecobalamin; Treatment B, high-dose lipo-PGE1 plus mecobalamin; Pre-T, pre-treatment; Post-T, post-treatment; MCV, motor nerve conduction velocity; SCV, sensory nerve conduction velocity; VAS, visual analogue scale; ⁎ Compared with pre-treatment data, P b0.05. ⁎⁎ Compared with control group, P b0.05. ⁎⁎⁎ Compared with treatment A, P b0.05.
Please cite this article as: Hong, L., et al., Clinical efficacy of different doses of lipo-prostaglandin E1 in the treatment of painful diabetic peripheral neuropathy, Journal of Diabetes and Its Complications (2015), http://dx.doi.org/10.1016/j.jdiacomp.2015.08.001
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L. Hong et al. / Journal of Diabetes and Its Complications xxx (2015) xxx–xxx
relative to the pre-treatment values (P b 0.05). Post-treatment VAS in the B group was significantly lower than those in the C and A groups. The analysis of EMG parameters revealed significant improvements in the post-treatment values of the median nerve MCV and SCV in both the A and B groups (P b 0.05), with the B group exhibiting significantly better improvement than the A group. Group comparisons and analysis showed that the high-dose group (20 μg of lipo-PGE1; intravenous infusion, QD) had a significantly better effect than the low-dose group (10 μg of lipo-PGE1; intravenous infusion, QD) and the C group, without increasing the incidence of clinical adverse reactions. Nie et al. (2007) performed a meta-analysis on the efficacy and adverse reactions of PGE1 therapy for diabetic DPN with data retrieved from the China Academic Journals Full-text Database (January 1994–December 2006). The results showed that PGE1 can significantly reduce the clinical symptoms of DPN patients and improve NCV. PGE1 exhibited a significantly better therapeutic effect than drugs currently in use (P b 0.001), while no significant adverse effects were observed. Cawello et al. (1995) reported that when a dose of PGE1 below 120 μg/d was intravenously infused in healthy volunteers, the blood concentration increased with increasing injection dose without increasing significant adverse reactions. Zhang (2012) also reported that for early diabetic nephropathy, injection with 20 μg/d of PGE1 achieved better clinical results than a dose of 10 μg/d, while no significant adverse reactions were increased by the high-dose PGE1 therapy. Consistent with these reports, the clinical observations in the present study show that use of lipo-PGE1 injection at a high dose is more effective than a low dose for the treatment of painful DPN. Since no significant adverse reactions have been reported, high-dose lipo-PGE1 therapy should be considered for treatment of painful DPN. There are many other methods are available for clinical treatment of painful DPN. Juhn, Parsons, Varvara, and Sadosky (2015) reported that pregabalin monotherapy in the treatment of DPN is valid. Devi et al. (2012) reported that gabapentin, duloxetine and pregabalin monotherapy had some effect on painful diabetic peripheral neuropathy. Since 2010, more than 5 international guidelines for treatment of painful DPN have been issued; the choice of agent in any given patient should depend on patient characteristics. Our results should be interpreted within the following study’s limitations: One is the power of VAS test was not adequate (b 80%) to detect difference between low dose group/control and high dose group/low dose group. The reasons maybe as follow: the insufficient sample size in the control group, and the older subjects (N 60 years). The sample size and age distribution should be improved in our future studies. The other limitation is that we did not test the endothelin (ET)-1. ET-1 concentrations are thought to correlate with the onset
and progress of diabetic microangiopathy (Itoh et al., 2001). The role of ET-1 in the treatment of DPN, especially its relationship with mecobalamin and Lipo-PGE1 treatment, needs to be further studied. Acknowledgments We would like to thank the patients who participated in the study for their efforts. References Bai, L. N., Zhou, H., & Li, Y. H. (2008). Research advances in the pharmacological mechanism of lipo-prostaglandin E1 preparation. Journal of China-Japan Friendship Hospital, 22(1), 47–50. Boulton, A. J., Vinik, A. I., Arezzo, J. C., Bril, V., Feldman, E. L., Freeman, R., et al. (2005). Diabetic neuropathies: A statement by the American Diabetes Association. Diabetes Care, 28(4), 956–962. Cawello, W., Leonhardt, A., Schweer, H., Seyberth, H. W., Bonn, R., & Lomeli, A. L. (1995). Dose proportional pharmacokinetics of alprostadil (prostaglandin E1) in healthy volunteers following intravenous infusion. British Journal of Clinical Pharmacology, 40(3), 273–276. Chen, Y., Wan, J. X., Jiang, D. W., Fu, B. B., Cui, T., & Li, G. F. (2013). Clinical efficacy and safety of sequential treatment with alprostadil and beraprost sodium for chronic renal failure induced by chronic glomerulonephritis. Journal of Southern Medical University, 33(10), 1521–1524. Clifford, P. C., Martin, M. F., Dieppe, P. A., Sheddon, E. J., & Baird, R. N. (1983). Prostaglandin E1 infusion for small vessel arterial ischaemia. The Journal of Cardiovascular Surgery, 24(5), 503–508. Devi, P., Madhu, K., Ganapathy, B., Sarma, G., John, L., & Kulkarni, C. (2012). Evaluation of efficacy and safety of gabapentin, duloxetine, and pregabalin in patients with painful diabetic peripheral neuropathy. Indian Journal of Pharmacology, 44(1), 51–56. Fu, H. J., Du, F. C., Hu, Y., Chen, S., Ye, X. Z., Ma, J., et al. (2013). Effect of alprostadil on oxidative damage in type 2 diabetic nephropathy. Journal of Medical Postgraduates, 26(8), 801–803. Itoh, Y., Yasui, T., Kakizawa, H., Makino, M., Fujiwara, K., Kato, T., et al. (2001). The therapeutic effect of lipo PGE1 on diabetic neuropathy-changes in endothelin and various angiopathic factors. Prostaglandins & Other Lipid Mediators, 66(3), 221–234. Juhn, M. S., Parsons, B., Varvara, R., & Sadosky, A. (2015). Pregabalin for painful diabetic peripheral neuropathy: Strategies for dosing, monotherapy vs. combination therapy, treatment-refractory patients, and adverse events. Current Medical Research and Opinion, 31(5), 1017–1026. Liu, X. Y., Wu, D. F., & Li, J. (2012). Clinical research on mecobalamine with various administrations in diabetic neuropathy patients. China Pharmacist, 15(4), 526–528. Nie, L. H., Jiang, Y. B., & Li, G. C. (2007). Systematic evaluation of alprostadil in the treatment of diabetic peripheral neuropathy. Guangdong Medical Journal, 28(6), 988–989. Tong, A. H. (2011). The effect observation of alprostadil combined with mecobalamine in diabetic peripheral neuropathy. Chinese Journal of Clinical Rational Drug Use, 4(17), 15–16. Zhang, X. N. (2012). Observation on curative effect of treatment with varied dosage of prostaglandin E1 injection for early diabetic nephropathy. Journal of China-Japan Friendship Hospital, 26(5), 284–286. Zhao, L., Ma, Y. H., & Peng, Y. D. (2014). The therapeutic effect of α-lipoic acid on the treatment of diabetic neuropathy. Chinese Journal of Diabetes, 22(3), 207–209. Ziegler, D. (2007). Management of painful diabetic neuropathy: What is new or in the pipeline for 2007. Current Diabetes Reports, 7(6), 409–415.
Please cite this article as: Hong, L., et al., Clinical efficacy of different doses of lipo-prostaglandin E1 in the treatment of painful diabetic peripheral neuropathy, Journal of Diabetes and Its Complications (2015), http://dx.doi.org/10.1016/j.jdiacomp.2015.08.001