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Therapeutic Potential of Ursolic Acid in Cancer and Diabetic Neuropathy Diseases.
Alam, M, Ali, S, Ahmed, S, Elasbali, AM, Adnan, M, Islam, A, Hassan, MI, Yadav, DK
International journal of molecular sciences. 2021;(22)
Abstract
Ursolic acid (UA) is a pentacyclic triterpenoid frequently found in medicinal herbs and plants, having numerous pharmacological effects. UA and its analogs treat multiple diseases, including cancer, diabetic neuropathy, and inflammatory diseases. UA inhibits cancer proliferation, metastasis, angiogenesis, and induced cell death, scavenging free radicals and triggering numerous anti- and pro-apoptotic proteins. The biochemistry of UA has been examined broadly based on the literature, with alterations frequently having been prepared on positions C-3 (hydroxyl), C12-C13 (double bonds), and C-28 (carboxylic acid), leading to several UA derivatives with increased potency, bioavailability and water solubility. UA could be used as a protective agent to counter neural dysfunction via anti-oxidant and anti-inflammatory effects. It is a potential therapeutic drug implicated in the treatment of cancer and diabetic complications diseases provide novel machinery to the anti-inflammatory properties of UA. The pharmacological efficiency of UA is exhibited by the therapeutic theory of one-drug → several targets → one/multiple diseases. Hence, UA shows promising therapeutic potential for cancer and diabetic neuropathy diseases. This review aims to discuss mechanistic insights into promising beneficial effects of UA. We further explained the pharmacological aspects, clinical trials, and potential limitations of UA for the management of cancer and diabetic neuropathy diseases.
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Vitamin B12 Supplementation in Diabetic Neuropathy: A 1-Year, Randomized, Double-Blind, Placebo-Controlled Trial.
Didangelos, T, Karlafti, E, Kotzakioulafi, E, Margariti, E, Giannoulaki, P, Batanis, G, Tesfaye, S, Kantartzis, K
Nutrients. 2021;(2)
Abstract
AIM: To investigate the effect of normalizing vitamin B12 (B12) levels with oral B12 (methylcobalamin) 1000 μg/day for one year in patients with diabetic neuropathy (DN). PATIENTS AND METHODS In this prospective, double-blind, placebo-controlled trial, 90 patients with type 2 diabetes on metformin for at least four years and both peripheral and autonomic DN were randomized to an active treatment group (n = 44) receiving B12 and a control group (n = 46) receiving a placebo. All patients had B12 levels less than 400 pmol/L. Subjects underwent measurements of sural nerve conduction velocity (SNCV), sural nerve action potential (amplitude) (SNAP), and vibration perception threshold (VPT), and they performed cardiovascular autonomic reflex tests (CARTs: mean circular resultant (MCR), Valsalva test, postural index, and orthostatic hypotension). Sudomotor function was assessed with the SUDOSCAN that measures electrochemical skin conductance in hands and feet (ESCH and ESCF, respectively). We also used the Michigan Neuropathy Screening Instrument Questionnaire and Examination (MNSIQ and MNSIE, respectively) and questionnaires to evaluate quality of life (QoL) and level of pain (pain score). RESULTS B12 levels increased from 232.0 ± 71.8 at baseline to 776.7 ± 242.3 pmol/L at follow-up, p < 0.0001, in the active group but not in the control group. VPT, MNSIQ, QoL, pain score, SNCV, SNAP, and ESCF significantly improved in the active group (p < 0.001, p = 0.002, p < 0.0001, p < 0.000, p < 0.0001, p < 0.0001, and p = 0.014, respectively), whereas CARTS and MNSIE improved but not significantly. MCR, MNSIQ, SNCV, SNAP, and pain score significantly deteriorated in the control group (p = 0.025, p = 0.017, p = 0.045, p < 0.0001, and p < 0.0001, respectively). CONCLUSIONS The treatment of patients with DN with 1 mg of oral methylcobalamin for twelve months increased plasma B12 levels and improved all neurophysiological parameters, sudomotor function, pain score, and QoL, but it did not improve CARTS and MNSIE.
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Salviae miltiorrhizae and ligustrazine hydrochloride injection combined with mecobalamin for treating diabetic peripheral neuropathy: A protocol for systematic review and meta-analysis.
Deng, Z, Wang, M, Fan, Y, Liu, M
Medicine. 2021;(3):e24103
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Abstract
OBJECTIVE Currently, it is unclear whether the salviae miltiorrhizae (Danshen Salvia) and ligustrazine hydrochloride (Chuanxiong Chuanxiong) (SMLH) injection combined with mecobalamin can improve diabetic peripheral neuropathy (DPN). We conducted a systematic analysis to evaluate the clinical effects of SMLH injection combined with mecobalamin for treating DPN. METHODS Seven databases, including PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), Wan Fang Database (Wang Fang), Chinese Biomedical Literature Database (CBM), and VIP Database for Chinese Technical Periodicals (VIP) were searched for systematic literature retrieval. Each database was searched up to 2020 to identify randomized controlled trials on DPN treated with SMLH injection combined with mecobalamin. We used the RevMan 5.3 and Stata 14.0 software to assess the risk of bias in the included trials. RESULTS A total of 15 publications, including 1349 samples, were reviewed. The total effective rate of SMLH injection combined with mecobalamin was 31% higher than that of mecobalamin alone (95% confidence interval [CI] = 1.23-1.38; P < .00001). The experimental group showed a significant increase in the motor conduction velocity (MCV) of the peroneal nerve (weighted mean difference [WMD] = 4.81, 95% CI 3.53-6.09; P < .00001). In addition, SMLH injection combined with mecobalamin showed a statistical significant effect on the sensory conduction velocity (SCV) of the peroneal nerve (WMD = 5.03, 95% CI = 4.16-5.90; P < .00001), and MCV of the median nerve (WMD = 5.38, 95% CI = 4.05-6.72; P < .00001). The WMD for the change in SCV in the median nerve was 4.89 m/s (95% CI = 3.88-5.89; P < .00001). The P-values of the Egger and Begg tests were 0.967 and 0.961, respectively, indicating no publication bias. Subgroup and sensitivity analyses indicated that the results for MCV and SCV of the peroneal nerve and the median nerve were stable. CONCLUSION SMLH injection combined with mecobalamin can improve DPN, compared with mecobalamin alone.
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A randomized comparative study of methylcobalamin, methylcobalamin plus pregabalin and methylcobalamin plus duloxetine in patients of painful diabetic neuropathy.
Sharma, C, Kaur, I, Singh, H, Grover, IS, Singh, J
Indian journal of pharmacology. 2021;(5):358-363
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CONTEXT Diabetic neuropathy affects 10.5%-32.2% of diabetic population posing clinical burden onto society. AIMS We aimed to study the efficacy, safety, and tolerability of methylcobalamin, methylcobalamin plus pregabalin, and methylcobalamin plus duloxetine in patients of painful diabetic neuropathy. SETTINGS AND DESIGN It is a prospective, randomized, open-label, interventional, and parallel-group study done in patients of painful diabetic neuropathy. MATERIALS AND METHODS A total of 100 patients were recruited and randomized to three study groups A, B, and C on methylcobalamin, methylcobalamin and pregabalin, and methylcobalamin and duloxetine, respectively. Patients were assessed at day 0 and 4, 8, and 12 weeks. The tuning fork test, monofilament test, Thermal Sensitivity testing, and Visual Analog Scale (VAS) were used to analyze vibration, pressure, thermal sensitivity, and pain. STATISTICAL ANALYSIS USED The results are expressed as mean ± standard deviation. Appropriate statistical methods were used to calculate P value (<0.05 - significant). RESULTS The increase in number of patients with vibration perception is 11.6%, 37.9%, and 41.4%; pressure sensation is 7.6%, 37.9%, and 37.9%; and thermal sensitivity is 15.4%, 31.1%, and 37.9% in Groups A, B, and C, respectively. The decrease in VAS scores is 0.58 ± 0.14, 3.82 ± 0.05, and 4.17 ± 0.48 in Groups A, B, and C correspondingly. The adverse effects reported in Groups A, B, and C are 0%, 6.9%, and 10.3%, respectively. CONCLUSIONS Group C is more efficacious when compared to Groups A and B while Group B is safer.
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Relative Efficacy and Safety of Pharmacotherapeutic Interventions for Diabetic Peripheral Neuropathy: A Systematic Review and Bayesian Network Meta-Analysis.
Asrar, MM, Kumari, S, Sekhar, BC, Bhansali, A, Bansal, D
Pain physician. 2021;(1):E1-E14
Abstract
BACKGROUND Diabetic peripheral neuropathy (DPN) is a most common devitalizing complication of diabetes mellitus, which is primarily characterized by sensory loss, paresthesia, prickling, pain, or allodynia. OBJECTIVES To evaluate the relative efficacy and safety of the interventions used in the DPN pain management and rank their order. STUDY DESIGN A systematic review and Bayesian network meta-analysis (NMA). METHODS Randomized, controlled trials were identified through a comprehensive, systematic literature exploration, primarily utilizing the PubMed, EMBASE, Ovid, and Cochrane Library databases. The efficacy and safety outcomes consist of the proportion of patients reporting either 30% or 50% pain reduction and overall withdrawal or withdrawal due to adverse drug events, respectively. Effect estimates from Bayesian NMA were presented as odds ratio (OR) with 95% credible intervals (CrI). Heterogeneity and convergence were assessed by using I2 and deviation information criteria. The risk of bias was evaluated by using Pedro Scale. RESULTS A total of 3,246 potentially relevant trials were identified and screened, finally 43 trials consisting of 7,877 randomized patients met the inclusion criteria. Statistically significant treatment difference for 50% pain reduction was reported for duloxetine vs. placebo (OR: 2.50; CrI: 1.62-3.91), mirogabalin vs. placebo (OR: 3.25; CrI: 1.16-9.35), pregabalin vs. placebo (OR: 2.33; CrI: 1.69-3.27), duloxetine vs. carbamazepine (OR: 3.37; CrI: 1.07-10.90), mirogabalin vs. carbamazepine (OR: 4.39; CrI: 1.01-19.63), mirogabalin vs. lamotrigine (OR: 4.05: CrI: 1.07-15.77), pregabalin vs. lamotrigine (OR: 2.90, CrI: 1.19-7.22) and pregabalin vs. nortriptyline (OR: 4.10, CrI: 1.13-5.28). Nortriptyline reported the highest possibility of achieving 30% and 50% pain reduction. Sodium valproate and benztropine reported the highest probability of total withdrawals and withdrawals due to adverse drug events, respectively. LIMITATION The different follow-up time of the included studies can result in the variation of intended results. CONCLUSION Nortriptyline reported the advantage relative to other drugs in achieving 30% and 50% pain reduction from the baseline. Gabapentin reported a significance of 50% pain reduction relative to placebo.
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Current Pharmacological Treatment of Painful Diabetic Neuropathy: A Narrative Review.
Ardeleanu, V, Toma, A, Pafili, K, Papanas, N, Motofei, I, Diaconu, CC, Rizzo, M, Stoian, AP
Medicina (Kaunas, Lithuania). 2020;(1)
Abstract
Background and Objectives: Distal symmetrical polyneuropathy (DSPN) is one of the most common chronic complications of diabetes mellitus. Although it is usually characterized by progressive sensory loss, some patients may develop chronic pain. Assessment of DSPN is not difficult, but the biggest challenge is making the correct diagnosis and choosing the right treatment. The treatment of DSPN has three primary objectives: glycemic control, pathogenic mechanisms, and pain management. The aim of this brief narrative review is to summarize the current pharmacological treatment of painful DSPN. It also summarizes knowledge on pathogenesis-oriented therapy, which is generally overlooked in many publications and guidelines. Materials and Methods: The present review reports the relevant information available on DSPN treatment. The search was performed on PubMed, Cochrane, Semantic Scholar, Medline, Scopus, and Cochrane Library databases, including among others the terms "distal symmetrical polyneuropathy", "neuropathic pain treatment", "diabetic neuropathy", "diabetes complications", "glycaemic control", "antidepressants", "opioids", and "anticonvulsants". Results: First-line drugs include antidepressants (selective serotonin reuptake inhibitors and tricyclic antidepressants) and pregabalin. Second- and third-line drugs include opioids and topical analgesics. While potentially effective in the treatment of neuropathic pain, opioids are not considered to be the first choice because of adverse reactions and addiction concerns. Conclusions: DSPN is a common complication in patients with diabetes, and severely affects the quality of life of these patients. Although multiple therapies are available, the guidelines and recommendations regarding the treatment of diabetic neuropathy have failed to offer a unitary consensus, which often hinders the therapeutic options in clinical practice.
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Is there cardiac autonomic neuropathy in prediabetes?
Zilliox, LA, Russell, JW
Autonomic neuroscience : basic & clinical. 2020;:102722
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Abstract
Although there is considerably more data showing an association between type 2 diabetes mellitus (T2DM) and autonomic neuropathy, accumulating evidence indicates that cardiovascular autonomic neuropathy (CAN) is common in persons with impaired glucose tolerance (IGT). Furthermore, CAN may occur early after a metabolic insult and obesity, especially among mean, and seems to play an important role in the early pathogenesis of CAN. Autonomic symptoms are common in subjects with IGT. In addition to defects in CAN, in subjects with IGT, there is impaired sudomotor function and abnormalities of endothelial peripheral vasoreactivity. At the present time, the only interventions that may be effective in preventing or reversing IGT associated autonomic neuropathy are lifestyle improvement. These include a tailored diet and exercise program. Other approaches that may be beneficial include modulation of oxidative stress and improvement of metabolic regulation in subjects with IGT. Interventions are most likely to be effective early in the course of disease and therefore it is extremely important to have early diagnosis of IGT and autonomic neuropathy.
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Manual Acupuncture or Combination with Vitamin B to Treat Diabetic Peripheral Neuropathy: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.
Jiang, HL, Jia, P, Fan, YH, Li, MD, Cao, CC, Li, Y, Du, YZ
BioMed research international. 2020;:4809125
Abstract
METHODS Randomized controlled trials on manual acupuncture treatment of DPN were retrieved from the Medline, Web of Science, PubMed, Cochrane Library, EMBASE, CNKI, WanFang, and VIP databases. Extracted research data were summarized in the tables, and methodological assessment was performed using the risk-of-bias assessment tool of Cochrane. Meta-analysis was performed by Revman 5.3, Stata 14.0, and TSA 0.9.5.10 Beta software. RESULTS A total of 18 randomized clinical trials (RCTs) were recruited: (1) 11 RCTs were acupuncture alone compared with vitamin B; (2) 7 RCTs were acupuncture combined with vitamin B compared with vitamin B, involving 1200 participants. Acupuncture alone improved clinical efficacy (P < 0.05) and nerve conduction velocity of the four peripheral nerves: peroneal nerve, tibial nerve, median nerve, and ulnar nerve (P < 0.05), but there was no significant difference between the group of acupuncture alone and the group of vitamin B (P = 0.36 > 0.05) in improving median nerve SCV (sensory nerve conduction velocity). Acupuncture combined with vitamin B improved clinical efficacy and nerve conduction velocity of the three peripheral nerves, peroneal nerve, tibial nerve, and median nerve (P < 0.05), and decreased the scores of the Toronto clinical scoring system (TCSS) (P < 0.05). CONCLUSION Acupuncture alone and vitamin B combined with acupuncture are more effective in treating DPN compared to vitamin B. However, more high-quality RCTs on vitamin B combined with acupuncture are required to confirm our results.
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Association between Iron Intake and Diabetic Peripheral Neuropathy in Type 2 Diabetes: Significance of Iron Intake and the Ratio between Iron Intake and Polyunsaturated Fatty Acids Intake.
Kim, K, Song, Y, Oh, TJ, Choi, SH, Jang, HC
Nutrients. 2020;(11)
Abstract
We aimed to investigate the association of iron and polyunsaturated fatty acid (PUFA) intake with diabetic peripheral neuropathy (DPN) in individuals with type 2 diabetes. This cross-sectional study included 147 individuals with type 2 diabetes. Dietary intake was assessed using three-day food records. DPN was diagnosed on the basis of a Michigan Neuropathy Screening Instrument-Physical Examination score ≥2.5. Adjusted for total energy intake, iron intake was significantly higher in individuals with DPN than in those without DPN (10.9 ± 4.0 mg vs. 9.9 ± 3.6 mg, p = 0.041). In addition, the iron/PUFA ratio was significantly higher in individuals with DPN (1.4 ± 0.8 vs. 1.1 ± 0.4, p = 0.005). Logistic regression analyses showed that iron intake (odds ratio (OR): 1.152; 95% confidence interval (CI): 1.012, 1.311) and iron/PUFA ratio (OR: 2.283; 95% CI: 1.066, 4.887) were associated with DPN after adjustment for total energy intake, sex, age, body mass index, systolic blood pressure, diabetes duration, estimated glomerular filtration rate, glycated hemoglobin, low-density lipoprotein cholesterol, and smoking. In conclusion, high dietary iron intake and an elevated iron/PUFA ratio were associated with the presence of DPN. The present study suggests the importance of the dietary pattern of iron and PUFA intake in individuals with type 2 diabetes.
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Long-term safety and efficacy of mirogabalin in Asian patients with diabetic peripheral neuropathic pain.
Baba, M, Matsui, N, Kuroha, M, Wasaki, Y, Ohwada, S
Journal of diabetes investigation. 2020;(3):693-698
Abstract
AIMS/INTRODUCTION Diabetic peripheral neuropathic pain (DPNP) affects the functionality, mood and sleep patterns of patients with diabetes. Mirogabalin, an α2 δ ligand with a slower dissociation for α2 δ-1 versus α2 δ-2 subunits, showed efficacy and safety in a randomized, double-blind, placebo-controlled, 14-week study in Asian patients with DPNP. This open-label extension study evaluated the long-term safety and efficacy of mirogabalin in Asian patients with DPNP. MATERIAL AND METHODS This 52-week open-label extension study was carried out in Japan, Korea and Taiwan in patients with DPNP. Patients received mirogabalin, initiated at 5 mg twice daily and increased to a flexible maintenance dosage of 10 or 15 mg twice daily. Adverse events were monitored throughout the study. Patients provided a self-assessment of pain using the Short-Form McGill Pain Questionnaire. RESULTS Of the 214 patients who entered the study, 172 (80.4%) completed the extension study. Of 172 patients who completed the study, 149 received the highest dosage of mirogabalin (15 mg twice daily). The most common treatment-emergent adverse events were nasopharyngitis, diabetic retinopathy, peripheral edema, somnolence, diarrhea, increased weight and dizziness. Most treatment-emergent adverse events were mild or moderate in severity. The incidence of treatment-emergent adverse events leading to treatment discontinuation was 13.1%. The visual analog scale and all other Short-Form McGill Pain Questionnaire subscales (sensory score, affective score, total score and present pain intensity) generally decreased over time from baseline until week 52. CONCLUSIONS This extension study showed the safety and efficacy of a long-term flexible dosing regimen of mirogabalin 10 or 15 mg twice daily in patients with DPNP.