Manejo racional de las neuropatías diabéticas: consenso multidisciplinario de expertos / Rational management of the diabetic neuropathies: a multidisciplinary expert group consensus

Resumen: La diabetes mellitus, un padecimiento crónico y progresivo, ocupó el tercer lugar en defunciones durante el período comprendido de enero a junio de 2021 en México. Su complicación crónica más frecuente es la neuropatía diabética que tiene un impacto importante en el sistema nervioso. En la Ciudad de México se reunió un grupo multidisciplinario de expertos para establecer un algoritmo de tratamiento que considere los aspectos sintomáticos y etiopatogénicos de la neuropatía diabética. Se utilizó un método Delphi en tiempo real con dos rondas de preguntas interactivas. La implementación del algoritmo propuesto permitirá abordar de manera integral al paciente diabético con neuropatía dolorosa y no dolorosa, tanto en el terreno de los síntomas como en la etiopatogenia. Este abordaje brinda la oportunidad de mejorar la calidad de vida y lograr la reinserción a la vida familiar y laboral. El panel de expertos recomienda al ácido tióctico como tratamiento etiopatogénico de primera línea en la neuropatía diabética.

Abstract: Diabetes mellitus, a chronic and progressive condition, was the third most common cause of death in Mexico between January and June 2021. Its most frequent chronic complication is diabetic neuropathy, which has a major impact on the nervous system. A multidisciplinary group of experts met in Mexico City to establish a treatment algorithm considering the symptomatic and etiopathogenic aspects of diabetic neuropathy. A real-time Delphi method with two rounds of interative questions was used. The implementation of the proposed algorithm will allow a comprehensive approach to the diabetic patient with painful and non-painful neuropathy, both in terms of symptoms and etiopathogenesis. This approach provides the opportunity to improve quality of life and achieve reintegration into family and work life. The expert panel recommends thioctic acid as the first line etiopathogenic treatment for diabetic neuropathy.

Effect of alpha-lipoic acid on hepatic ischemia/reperfusion injury and role of ALDH2 / 中华麻醉学杂志

Objective:To evaluate the effects of the alpha-lipoic acid on hepatic ischemia/reperfusion (I/R) injury and the role of (ALDH2).Methods:This experiment was performed in two parts in vivo and in vitro experiments. In vivo experiment Twenty-four male Sprague-Dawley rats, aged 8-10 weeks, weighing 250-300 g, were divided into 4 groups ( n=6 each) by the random number table method: sham operation group (Sham group), hepatic I/R group (IR group), and hepatic I/R plus α-lipoic acid group (IR+ ALA group) and hepatic I/R+ α-lipoic acid+ daidzin group (IR+ ALA+ D group). Hepatic I/R was induced by occlusion of the left and middle hepatic lobes for 60 min, followed by 6 h of reperfusion in anesthetized rats.In IR+ ALA+ D group, ALDH2 inhibitor daidzin 50 mg/kg was intraperitoneally injected at 45 min before ischemia.Alpha-lipoic acid 100 mg/kg was intraperitoneally injected at 30 min before ischemia in IR+ ALA group and IR+ ALA+ D group.Blood samples from the inferior vena cava were collected at the end of reperfusion to determine serum AST and ALT activities.Then the rats were sacrificed, and livers were removed for microscopic examination of pathological changes of the lung tissues which were scored and for determination of ALDH2 activity, level of reactive oxygen species (ROS) and expression of 4-hydroxy-trans-2-nonenal (4-HNE) and malondialdehyde (MDA) (by immuno-histochemistry). In vitro experiment Rat BRL-3A hepatocytes cultured in vitro were divided into 4 groups ( n=15 each) by the random number table method: control group (C group), hypoxia-reoxygenation group (HR group), hypoxia-reoxygenation+ α-lipoic acid group (HR+ ALA group) and hypoxia-reoxygenation+ α-lipoic acid+ daidzin group (HR+ ALA+ D group). BRL-3A hepatocytes were exposed to 95% N 2-5% CO 2 in an incubator at 37 ℃ for 6 h followed by reoxygenation with 95% O 2-5% CO 2 for 24 h. At 60 min before hypoxia, alpha-lipoic acid 100 μmol/L was addded in HR+ ALA group, and alpha-lipoic acid 100 μmol/L and daidzin 60 μmol/L were added in HR+ ALA+ D group.At 24 h of reoxygenation, cell viability was measured by CCK-8 method, ALDH2 activity was determined by spectrophotometry, ROS level was detected by DCFH-DA fluorescent probe method, and mitochondrial membrane potential (MMP) was measured by JC-1 method. Results:In vivo experiment Compared with Sham group, the serum AST and ALT activities, liver injury score, level of ROS in liver tissues and expression of 4-HNE and MDA were significantly increased ( P<0.05), and no significant change was found in ALDH2 activity in IR group ( P>0.05). Compared with IR group, the serum AST and ALT activities, liver injury score, level of ROS in liver tissues and expression of 4-HNE and MDA were significantly decreased, and the ALDH2 activity was increased in IR+ ALA group ( P<0.05). Compared with IR+ ALA group, the serum AST and ALT activities, liver injury score, level of ROS in liver tissues and expression of 4-HNE and MDA were significantly increased, and the ALDH2 activity was decreased in HR+ ALA+ D group ( P<0.05). In vitro experiment Compared with C group, the cell viability and MMP were significantly decreased, and the level of ROS was increased ( P<0.05), and no significant change was found in the activity of ALDH2 in HR group ( P>0.05). Compared with HR group, the cell viability, ALDH2 activity and MMP were significantly increased, and the level of ROS was decreased in HR+ ALA group ( P<0.05). Compared with HR+ ALA group, the cell viability, ALDH2 activity and MMP were significantly decreased, and the level of ROS was increased in HR+ ALA+ D group ( P<0.05). Conclusions:Alpha-lipoic acid can reduce hepatic I/R injury in rats, and the mechanism is related to activation of ALDH2, reduction of accumulation of toxic aldehyde and restoration of MMP.

Influence of alpha lipoic acid supplementation on urinary bladder morphology of diabetic rats / Influencia de la suplementación con ácido alfa lipoico en la morfología de la vejiga urinaria de ratas diabéticas

Diabetes Mellitus (DM) is a condition marked by hyperglycaemia that causes systemic complications, including urinary vesicle dysfunction due to oxidative stress. Further, antioxidants, as well as alpha lipoic acid (ALA), may be a response to this pathological condition. The present study verified the action of ALA as a supplement in ration on glycemia and urinary vesicle structures of rats induced by streptozotocin. The rats were divided into 4 groups: Control (CG), Alpha Lipoic (ALAG), Diabetic control (DCG), and the Diabetic alpha lipoic (DALAG) group. For induction, the diabetic groups were initially induced with streptozotocin (dose 60 mg/kg). Subsequently, group glycemia was evaluated weekly. After 8 weeks, the rats were euthanized and the bladder was collected. The bladders were histologically processed and the slides were stained with Masson's Trichrome for the histomorphometry of epithelial height, connective and muscular tissue and coloration of PicroSirius Red for further analysis of collagen fibers of the bladder. The data of the glycemia demonstrated an inferior median in DALAG compared to DGC (p<0.01). The epithelial height and percentage of the muscle tissue were greater in DALAG compared to the DGC, but not significant. However, GDAL showed improvement in the organization of collagen fibers. In conclusion, bladder the morphology alterations caused by DM were not alleviated by the administration of ALA in 8 weeks of the experiments.

La diabetes mellitus (DM) es una afección marcada por hiperglucemia que causa complicaciones sistémicas, incluida la disfunción de la vejiga urinaria debido al estrés oxidativo. Además, los antioxidantes, así como el ácido alfa lipoico (ALA), pueden ser una respuesta a esta condición patológica. El presente estudio verificó la acción de ALA como suplemento en la ración sobre la glucemia y las estructuras de la vejiga urinaria de ratas inducidas por estreptozotocina. Las ratas se dividieron en 4 grupos: control (CG), alfa lipoico (ALAG), control diabético (DCG) y el grupo diabético alfa lipoico (DALAG). Para la inducción, los grupos diabéticos se aplicó estreptozotocina (dosis 60 mg/kg). Posteriormente, la glucemia grupal se evaluó semanalmente. Después de 8 semanas, las ratas se sacrificaron y se retiró la vejiga urinaria. Las vejigas se procesaron histológicamente y las muestras se tiñeron con tricromo de Masson para la histomorfometría y así evaluar la altura epitelial, el tejido conectivo y muscular. Además se tiñeron cond PicroSirius Red para un análisis posterior de las fibras colágenas de la vejiga urinaria. Los datos de la glucemia demostraron una mediana inferior en DALAG en comparación con DGC (p <0,01). La altura epitelial y el porcentaje de tejido muscular fueron mayores en DALAG en comparación con el DGC, pero no estadísticamente significativos. Sin embargo, GDAL mostró una mejora en la organización de las fibras de colágeno. En conclusión, la morfología de las alteraciones de la vejiga causada por DM no se alivió con la administración de ALA en 8 semanas de estudio.

Comparison of the Quality of Generic and Original Preparations of Thioctic Acid Injection and Study on Its Acute Toxicity Test in Mice / 中国药房

OBJECTIVE： To compare the quality of original preparations of Thioctic acid injection and generic preparations from 2 domestic manufacturers， discuss the acute toxicity test of mice and to investigate the project of consistency evaluation methods. METHODS： According to the quality standard that stated in Chinese Pharmacopeia， physicochemical properties （characters， pH， osmotic pressure， etc.， contents and related substances of samples of Thioctic acid injection as well as LD50 in acute toxicity test （n＝10）， and mortality of mice after administration of injection solution （n＝30） were compared among 3 manufacturers. RESULTS： The physicochemical properties as and related substances of the original drug and 2 generic drugs were all in line with the quality standard； the contents of 3 samples ranged 95％-105％. The acute toxicity test results showed that the LD50 values of 2 generic drugs （LD50： 247.911 mg/kg， 95％ confidence interval： 222.209-277.999 mg/kg；LD50： 215.291 mg/kg， 95％ confidence interval： 196.637-235.053 mg/kg） were smaller than that of original drug （LD50： 266.534 mg/kg， 95％ confidence interval： 250.597-283.418 mg/kg）， but there was no statistical difference （P＞0.05）. The results of 3 repeated experiments showed that there was statistical significance in the number of animal death caused by the 2 generic drugs （26， 28） was more than that of the original drug （19） （all P＜0.05）， when injection solution was injected into mice in a single dose. After administration of the original drug， mice showed excitatory reactions such as movement and squeal， while 2 generic drugs showed inhibitory reactions. CONCLUSIONS： 2 generic drugs of Thioctic acid injection and the original drug all conform to the relevant regulations of Chinese Pharmacopoeia in terms of preparation quality standards， but the results of acute toxicity test are quite different， so it is difficult to prove the consistency between the 2 generic drugs and the original drug. Therefore， acute toxicity test is necessary for the consistency evaluation of injections.

Effects of α-lipoic acid on oxidative stress markers in type 2 diabetes patients with nonalcoholic fatty liver disease / 中国基层医药

Objective To study the serum levels of oxidative stress markers in the new type 2 diabetes mellitus (T2DM) patients with nonalcoholic fatty liver disease (NAFLD),and the effect of o-lipoic acid (A-LA) on oxidative stress markers.Methods From August 2016 to August 2017,80 new T2DM patients complicated with NAFLD (T2DM + NAFLD group) and 80 new T2DM patients without NAFLD (T2DM group) admitted to Xuzhou Municipal Hospital Affiliated to Xuzhou Medical University were selected.The serum levels of Fasting blood glucose (FPG),body mass index (BMI),triglyceride (TG),total cholesterol (TC),high density lipoprotein cholesterol (HDL-C),low density lipoprotein cholesterol (LDL-C),insulin resistance index (HOMA-IR),serum superoxide dismutase (SOD),serum malondialdehyde (MDA),glutathione peroxidase (GSH-PX) were detected and compared between the two groups.And then,the T2DM patients with NAFLD were treated by A-LA for two weeks.The SOD,MDA,GSH-PX levels were compared before and after treatment.Results The FPG,BMI,TG,HOMA-IR of the T2DM + NAFLD group were (10.71 ± 3.63) mmol/L,(27.08 ± 3.87) kg/m2,(3.40 ± 1.85) mmol/L,(5.40 ± 2.98),respectively,which were significantly higher than those of the T2DM group[(9.50 ± 3.78)mmol/L,(23.58 ± 2.75) kg/m2,(1.79 ± 1.44) mmol/L,(2.41 ± 1.18)] (t =2.022,6.603,2.829,4.157,all P ＜ 0.05).The age and levels of HbA1c,TC,HDL-C,LDL-C between the two groups had no statistically significant differences (all P ＞ 0.05).The level of MDA in the T2DM + NAFLD group was (5.11 ± 0.25) μmol/L,which was significantly higher than (4.56 ±0.28) μmol/L in the T2DM group(t =2.106,P ＜0.05).The levels of SOD,GSH-PX,SOD/MDA in the T2DM + NAFLD group were (77.42 ± 10.31) U/mL,(69.62 ± 9.24) U,(15.39 ± 2.23),respectively,which were significantly lower than those in the T2DM group [(93.26 ± 11.21) U/mL,(87.54 ± 9.58) U,(20.33 ± 2.93)] (t =2.455,2.653,3.148,all P ＜ 0.05).After treatment with A-LA,the MDA level of the T2DM + NAFLD group was (4.81 ±0.26) μmol/L,which was significantly lower than that before treatment[(5.11 ±0.25) μmol/L,t=2.117,P ＜0.05],the levels of SOD,GSH-PX,SOD/MDA of the T2DM + NAFLD group were (87.15 ± 10.88) U/mL,(78.73 ± 9.57) U,(18.05 ± 2.51),respectively,which were significantly higher than those before treatment (t =2.117,2.207,2.228,3.148,all P ＜ 0.05).Conclusion A-LA might prove usefully in the treatment of patients with T2DM and NAFLD by change the oxidative stress.

Effects of High-Dose α-Lipoic Acid on Heart Rate Variability of Type 2 Diabetes Mellitus Patients with Cardiac Autonomic Neuropathy in Korea

BACKGROUND: Diabetic cardiac autonomic neuropathy (CAN) is one of the important complications of diabetes. It is characterized by reduced heart rate variability (HRV). METHODS: In this randomized, double-blind, placebo-controlled, multicenter trial, 75 patients were randomly assigned to one of two groups. One group (n=41) received α-lipoic acid (ALA) at an oral dose of 600 mg/day for the first 12 weeks and then 1,200 mg/day for the next 12 weeks. The other group (n=34) received placebo treatment for 24 weeks. CAN was assessed by measuring HRVs in people with diabetes. RESULTS: Most of the baseline measures for HRVs were similar between the ALA and placebo groups. Although there were no statistically significant HRV changes in the ALA group compared to the placebo group after 24 weeks of trial, we found a positive tendency in some of the HRV parameters of the ALA group. The standard deviations of normal-to-normal RR intervals in the standing position increased by 1.87 ms in the ALA group but decreased by −3.97 ms in the placebo group (P=0.06). The power spectrum of the low frequency (LF) band in the standing position increased by 15.77 ms² in the ALA group, whereas it declined by −15.04 ms² in the placebo group (P=0.08). The high frequency/LF ratio in the upright position increased by 0.35 in the ALA group, whereas it declined by −0.42 in the placebo group (P=0.06). There were no differences between the two groups regarding rates of adverse events. CONCLUSION: Although a slight improvement tendency was seen in HRV in the ALA group, there were no statistically significant HRV changes in the ALA group compared to the placebo group after 24 weeks of trial. However, the high oral dose of ALA was well-tolerated.

Clinical effects of α-lipoic acid combined with epalrestat in elderly patients with diabetic peripheral neuropathy / 中华老年医学杂志

Objectives To examine the clinical effects of α-lipoic acid(ALA)combined with epalrestat in elderly patients with diabetic peripheral neuropathy(DPN)and its influence on plasma levels of high-sensitivity C-reactive protein(hs-CRP)and homocysteine(Hcy).Methods A total of 120 DPN patients aged over sixty years were randomly divided into the control group and the treatment group with 60 cases in each group.The control group received 0.6 g ALA in 250 ml saline given by an intravenous drip once a day and the treatment group was additionally given 50 mg epalrestat orally three times a day.Both groups were treated for two weeks.Improvement in clinical symptoms,nerve conduction velocity,and peripheral blood levels of hs-CRP and Hcy were compared between the two groups before and after treatment.Results TSS scores of all items and the total scores of the two groups decreased after treatment,with greater margins seen in the treatment group than in the control group(each P＜0.05).NCV increased in both groups after treatment (each P＜ 0.05),with greater increase in the treatment group(each P＜0.05).Levels of hs-CRP and Hcy were significantly reduced (each P＜0.05).A statistically significant difference was observed in hs-CRP(t =2.620,P=0.010) but not in Hcy(t =0.380,P =0.700)between the two groups.Conclusions ALA combined with epalrestat can significantly improve the symptoms of patients with DPN,with better outcomes than ALA alone,and effectively decrease the peripheral blood level of hs-CRP.

Curative effect and mechanism ofαlipoic acid combined with epalrestat and methylcobalamin in the treatment of type 2 diabetic peripheral neuropathy / 中国医师杂志

Objective To investigate the curative effect and mechanism of α lipoic acid combined with epalrestat and methylcobalamin in patients with type 2 diabetes mellitus (T2DM) complicated with pe-ripheral neuropathy ( DPN) . Methods A total of 160 cases of patients with DPN were randomly divided into the control group ( treated with methylcobalamin and epalrestat) and the observation group ( treated with methylcobalamin, epalrestat and α lipoic acid) , and all patients were treated for 4 weeks. The therapeutic effect, nerve conduction velocity, oxidative stress index and related proteins expression in serum were ob-served in two groups. Results The effective rate of treatment in the observation group was higher than that in the control group (87. 50％ vs 75. 0％) (χ2 = 4. 103,P<0. 05). After treatment, the sensory nerve conduction velocity ( SNCV) and motor nerve conduction velocity ( MNCV) of median nerve and common peroneal nerve were significantly better in the observation group than the control group ( P<0. 05 ) . After treatment, the level of superoxide dismutase ( SOD) was significantly higher in the observation group than the control group, while the level of malondialdehyde ( MDA ) was significantly lower the control group (P<0. 05). After treatment, the level of Bcl-2 protein was significantly higher in observation group than the control group, while the levels of Bax and Caspase-3 proteins were significantly lower than the control group (P<0. 05). Conclusions The application ofαlipoic acid combined to epalrestat and methylcobal-amin in the treatment of DPN can significantly improve the sensory and motor nerve conduction.

Injections for nutrition and cosmetic purposes: promoted effect vs. objective evidence

The introduction of intravenous nutritional therapy for cosmetic and health purposes in Korea has been controversial. Because it brings ethical problems of off-label prescribing on the basis of low level of medical evidences for claims of fatigue reduction, detoxification, anti-inflammation effect, skin whitening, antioxidant and anti-aging effects. Despite the lack of clinical studies, the verification of the efficacy and safety of intravenous nutritional therapy and the need to provide objective information to patients are prerequisite for the correct intravenous use. In addition, efforts should be made to prevent the abuse for commercial purposes.

Protective effects of lipoic acid on cardiomyocytes undergoing hypoxia/reoxygenation injury / 中国医师进修杂志

Objective To study the protective effect of lipoic acid (LA) on H9c2 cardiomyocytes hypoxia/reoxygenation injury model, and explore its relevant mechanism. Methods Eight strains of H9c2 cardiomyocytes, passaged after cultured to a full view, were divided into 3 groups:normoxia group, hypoxia/reoxygenation group and LA group. The cell survival rate, lactate dehydrogenase (LDH) activity, malondialdehyde (MDA) and heme oxygenase-1 (HO-1) levels were detected and compared. Results The cell survival rates of H9c2 cardiomyocytes in hypoxia/reoxygenation group and LA group were significantly lower than those in normoxia group:(52.86 ± 6.39)％, (69.25 ± 7.63)％vs. (92.31 ± 7.82)％, while the cell survival rate of H9c2 cardiomyocytes in LA group was significantly higher than that in hypoxia/reoxygenation group, and there were statistical differences (P<0.01). The LDH activity and MDA in hypoxia/reoxygenation group and LA group were significantly higher than those in normoxia group:(286.37 ± 27.49), (209.72 ± 25.63) U/L vs. (126.32 ± 18.94) U/L, and (1.72 ± 0.06), (1.13 ± 0.07)μmol/L vs. (0.68 ± 0.06) μmol/L, while those data in LA group were significantly lower than those in hypoxia/reoxygenation group, and there were statistical differences (P<0.01). The HO-1 in hypoxia/reoxygenation group and LA group were significantly higher than that in normoxia group:(213.71 ± 18.94)％, (367.26 ± 23.07)％vs. (87.92 ± 19.23)％, and HO-1 in LA group was significantly higher than that in hypoxia/reoxygenation group, and there were statistical differences (P<0.01). Conclusions The LA plays a protective role on myocardial cell with hypoxia/reoxygenation injurythough increasing the level of HO-1 against oxidative stress.

Clinical effect of low-frequency electrical pulse therapy combined with α-lipoic acid on diabetic gastroparesis in elderly patients with type 2 diabetes / 中华老年医学杂志

Objective To investigate the clinical effect of low frequency electrical pulse therapy combined with α-lipoic acid on diabetic gastroparesis in elderly patients with type 2 diabetes.Methods A total of 65 patients diagnosed as diabetic gastroparesis were selected from our hospital and divided into three groups according to random number table:the control group(n =23,the α-lipoic acid treatment),the conventional treatment group (n =16),and the experimental group (n =26,treating with α-lipoic acid combined with low-frequency electrical pulse therapy).All patients received the conventional diabetic therapy.Clinical effects,gastric emptying rate and serum gastrin(GAS) and fasting blood glucose levels were compared before versus after treatment among the three groups.Results The cure and total effective rates were higher in the experimental group than in the control group [46.15％ (12 cases) vs.30.43％ (7 cases),80.76％ (20 cases) vs.65.21％ (15 cases),x2 =0.867,P＜0.05].There were significant differences in gastric emptying rate,serum gastrin and fasting plasma glucose levels among the 3 treatment groups before versus after treatment.And the gastric emptying rate and serum gastrin level were better improved in the experimental groups compared with the conventional treatment and control groups.Conclusions The low-frequency electrical pulse therapy combined with α-lipoic acid has a significant clinical efficacy,which can improve clinical effects,promote gastric emptying,decrease fasting plasma glucose levels in elderly patients with type 2 diabetes.

Determination of Related Substances in Thioctic Acid Injection by HPLC / 中国药房

OBJECTIVE:To establish a method for the determination of related substances in Thioctic acid injection. METH-ODS:HPLC was performed on the column of Agilent Eclipse Plus C18 with mobile phase A of 0.005 mol/L potassium dehydroge-nate phosphate solution(adjusted with phosphoric acid to pH 3.0 to 3.1)and B of methanol:aoetonitrile(1∶1,V/V)(gradient elu-tion) at a flow rate of 1.2 ml/min;detection wavelength was 215 nm,column temperature was 35 ℃,and the injection volume was 20 μl. RESULTS:Under the established chromatographic conditions,thioctic acid with impurities and its degradation products were well separated;the linear range of thioctic acid was 0.828-52.992 μg/ml(r=0.999 9);RSDs of precision and stability tests were lower than 3%;recovery of impurity A was 98.45%-105.73%(RSD=2.41%,n=9);the largest single impurity content in mass fraction was 0.152%-0.189%,the total impurity content in mass fraction was 0.487%-0.516%. CONCLUSIONS:The meth-od is simple,accurate,specific and sensitivity,and can be used to determine the related substances of the Thioctic acid injection.

Comparison of R(+)-α-lipoic acid exposure after R(+)-α-lipoic acid 200 mg and 300 mg and thioctic acid 600 mg in healthy Korean male subjects

Alpha-lipoic acid, a physiological form of thioctic acid, is a strong antioxidant that relieves diabetic neuropathic symptoms. R(+)-α-lipoic acid shows superior antioxidative effects to its racemate. We compared the pharmacokinetics (PKs) and tolerability of R(+)- and S(-)-α-lipoic acid after a single oral dose of R(+)-α-lipoic acid, Dexid®, and its racemate, thioctic acid in healthy male subjects. We used an open-label, randomized, single-dose, three-treatment, parallel study design to compare the PK exposure of the active form, R(+)-α-lipoic acid. Thirty subjects completed the study with no clinically relevant safety issues. The peak concentrations (C(max), mean±SD) of R(+)-α-lipoic acid after doses of R(+)-α-lipoic acid 200 mg, 300 mg and thioctic acid 600 mg were 4186.8±1956.7, 6985.6±3775.8 and 6498.4±3575.6 µg/L, respectively, and the areas under the plasma concentration-time curve from 0 to the last measurable concentration (AUC(last)) were 1893.6±759.4, 3575.2±1149.2 and 3790.0±1623.0 µg·h⁻¹·L⁻¹, respectively. The geometric mean ratio and 90% confidence intervals of R(+)-α-lipoic acid 200 mg to thioctic acid 600 mg for the C(max) and AUC(last) were 0.71 (0.43–1.15) and 0.51 (0.37–0.70), respectively. The corresponding R(+)-α-lipoic acid 300 mg to thioctic acid 600 mg values were 1.11 (0.68-1.80) and 0.97 (0.71-1.34), respectively. In conclusion, R(+)-α-lipoic acid 300 mg showed PK characteristics similar to those of thioctic acid 600 mg and both formulations were well tolerated.

Does alfa lipoic acid prevent liver from methotrexate induced oxidative injury in rats?

PURPOSE: To determine the antioxidant and anti-inflammatory effects of alfa lipoic acid (ALA) on the liver injury induced by methotrexate (MTX) in rats. METHODS: Thirty two rats were randomly assigned into four equal groups; control, ALA, MTX and MTX with ALA groups. Liver injury was performed with a single dose of MTX (20 mg/kg) to groups 3 and 4. The ALA was administered intraperitonealy for five days in groups 2 and 4. The other rats received saline injection. At the sixth day the rats decapitated, blood and liver tissue samples were removed for TNF-α, IL-1β, malondialdehyde, glutathione, myeloperoxidase and sodium potassium-adenosine triphosphatase levels measurement and histological examination. RESULTS: MTX administration caused a significant decrease in tissue GSH, and tissue Na+, K+ ATPase activity and which was accompanied with significant increases in tissue MDA and MPO activity. Moreover the pro-inflammatory cytokines (TNF-α, IL- β) were significantly increased in the MTX group. On the other hand, ALA treatment reversed all these biochemical indices as well as histopathological alterations induced by MTX. CONCLUSION: Alfa lipoic acid ameliorates methotrexate induced oxidative damage of liver in rats with its anti-inflammatory and antioxidant effects. .

Efficacy of itopride combined with alpha-lipoic acid for patients with diabetic gastroparesis / 中华全科医师杂志

Objective To evaluate the efficacy of itopride hydrochloride combined with alpha-lipoic acid in treatment of diabetic gastroparesis.Methods One hundred and ten patients with diabetic gastroparesis were randomly assigned to two groups.Sixty patients received α-lipoic acid plus itopride (α-lipoic acid 0.6 g intravenously for 14 d plus itopride 50 mg orally t.i.d), and 50 cases received oral itopride only.The clinical symptoms including postprandial abdominal fullness, belching, acid reflux, anorexia, nausea and vomiting were observed;the gastric emptying rate was tested, and plasma motilin and serum ganstrin levels were measured groups, before and after two weeks of treatment.Results The clinical symptom scores of combination therapy group (4.62 ± 3.46 vs.12.26-± 3.43) and control groups (5.43-± 3.65 vs.12.31-± 3.37) were improved after treatment.The overall effective rate of combination group was 91.6％ and that of itopride therapy group was 78.0％ (x2 =4.098, P ＜ 0.05).Gastric emptying rate of combination group [(76.9 ± 9.7) ％ vs.(37.3 ± 10.2) ％] was increased more markedly than that ofitopridegroup[(57.2-± 10.4)％ vs.(36.8-± 11.2)％] (t =10.221, P ＜0.05).Plasma motilin and serum ganstrin levels in combination group [(640.2 ± 64.4) ng/L vs.(554.0 ± 67.6) ng/L, (152.6 ± 20.3)ng/L vs.(96.8 ± 22.2)ng/L] were reduced more markedly than those in itopride group [(636.3 ±66.4)ng/L vs.(589.4 48.3)ng/L, (153.5-± 19.4) ng/L vs.(120.9 ± 19.7)ng/L] respectively (t =3.100, 5.959, all P ＜ 0.05).Conclusion For patients with diabetic gastroparesis, α-lipoic acid and itopride combination therapy can significantly improve symptoms and gastric emptying rate, decrease motlin and gastrin levels;and the efficacy of combination therapy is better than that of itopride monotherapy.

Efecto del ácido alfa lipoico y la pirfenidona en la modulación antioxidante celular contra el daño oxidativo / Effects of alpha lipoic acid and pirfenidone on liver cells antioxidant modulation against oxidative damage

Background: Liver fibrogenic processes are related to cellular redox state. Glutathione (GSH) is the major cellular antioxidant. GSH induced activation could be related to antifibrogenic effects. Aim: To explore the association between the antifibrogenic effect and pro-antioxidant mechanisms of alpha-lipoic acid (ALA) and pirfenidone (PFD). Material and Methods: HepG2 cells and primary HSC cultures were exposed to menadione 0.1 μM (MEN) as oxidative stress inducer and treated to ALA (5 mM) or PFD (10 μM, 100 μM y 1000 μM). Results: In HSC, PFD decreased cell proliferation and the expression of COL1A1, TGF-β1, TIMP1, IL6, TNFα and MCP1 induced by MEN. Furthermore it was confirmed that ALA and PFD activate diverse antioxidants mediators, however MEN decreases this response. Then, MEN, ALA and PFD induce an antioxidant response, the first one as a response to injury and the latter two as pro-antioxidant inducers. Therefore, when cells are exposed to oxidative stress, endogenous systems activate a battery of mediators that increase the antioxidant potential. When these cells are treated with ALA and PFD, de novo formation of protective genes decreases since previous elicited protection induced in response to injury, enhance ALA and PFD effects. Conclusion: Regardless of the route of action, ALA and PFD induce the biosynthesis of antioxidants mediators which is associated with modulation of fibrogenic processes.

Effects of alpha lipoic acid on diabetic retinopathy and serum levels of serum asymmetric dimethylarginine and oxidative stress / 中国医师杂志

Objective To investigate the effects of alpha lipoic acid on patients with diabetic retinopathy (DR),explore the possible mechanisms,and provide experimental evidence for the treatment of DR with lipoic acid.Methods Totally 75 DR patients were randomly divided into control group and treatment group.Patients in control group received the standard hypoglycemic treatment,antihypertensive therapy,and other comprehensive treatment.Patients from the treatment group were treated with alpha lipoic acid 600 mg + 250 ml 0.9％ sodium chloride injection additionally,avoiding light intravenous therapy,for a total of 4 weeks.Before and after treatment,fundus fluorescein angiography and visual inspection were detected in two groups.In addition,serum level of asymmetric dimethylarginine (ADMA) were detected with high performance liquid chromatography,serum lipid peroxidation product malondialdehyde (MDA) content and superoxide dismutase (SOD) activity were detected to reflect the in vivo oxidative stress before and after treatment in two groups.Results Compared to the control group,visual acuity was improved significantly (P ＜ 0.05),and total efficiency of ocular lesions-improved was increased significantly (84.21％ vs 40.54％,x2 =15.28,P ＜ 0.01).Serum levels of endogenous inhibitor of nitric oxide synthase ADMA [(0.32 ±0.13) μmol/L vs (0.51 ± 0.26) μmol/L,P ＜ 0.05] and MDA [(3.22 ± 0.90) nmol/L vs (5.13 ± 0.42) nmol/ml,P ＜ 0.05] were significantly decreased,while SOD levels [(72.68 ± 1.31) U/ml vs (53.16 ± 1.54) U/ml,P ＜0.05] were significantly increased in DR patients after alpha lipoic acid treatment.Conclusions Alpha lipoic acid had some therapeutic effects for DR patients,which mainly lied in the improvement of visual acuity and eye disease,might be related to the decrease of oxidative stress and serum level of endogenous nitric oxide synthase (NOS) inhibitor ADMA.

Effect of alpha thioctic acid combined with mecobalamin in patients with diabetic peripheral neuropathy / 中国医师进修杂志

Objective To evaluate the effect of alpha thioctic acid combined with mecobalamin in patients with diabetic peripheral neuropathy.Methods Ninety patients with diabetic peripheral neuropathy were divided into observation group and control group by random digits table method with 45 cases each.The patients in observation group received alpha thioctic acid combined with mecobalamin treatment,and patients in control group received alpha thioctic acid treatment only.All patients were treated for 3 weeks.The clinical manifestation and electromyography effects were observed and compared after treatment.Results The total effective rate in observation group was significantly higher than that in control group [93.3％(42/45) vs.55.6％ (25/45)],and there was statistical difference (P ＜ 0.05).The sensory conduction velocity of common peroneal nerve after treatment in observation group was significantly higher than that in control group [(49.5 ± 3.2) m/s vs.(40.2 ± 2.9) m/s],and there was statistical difference (P ＜ 0.05).The sensory conduction velocity of median nerve,the motor conduction velocity of median nerve and common peroneal nerve had no significant differences between two groups (P ＞ 0.05).No adverse reaction happened during and after treatment.Conclusion Alpha thioctic acid combined with mecobalamin may improve the clinical efficacy of patients with diabetic peripheral neuropathy.

Alpha-lipoic acid pretreatments provide protection against hypoxia/reoxygenation injury in human umbilical vein endothelial cell / 实用医学杂志

Objective To observe the protective effect of α-lipoic acid (LA) pretreatment on hypoxia/reoxyg-enation injury in vascular endothelial cells and preliminary explore its mechanism. Methods HUVEC were cultured intro and devided into control group,hypoxia/reoxygenation model group and LA group. Cell morphology was observed under inverted phase contrast microscope,cell viability was detected by MTT,total antioxidant capacity (TAOC),nitric oxide(NO),malondialdehyde (MDA),superoxide dismutase (SOD) activity or level were measured by various commercial kits respectively. Apoptosis of HUVEC in each group were detected by flow cytometry , cleaved caspase-3 level was measured by western blot. Results As compared to control group, the survival rate, TAOC, SOD, NO activity were significantly lower(P<0.05), and MDA level, apoptosis rate and apoptosis protein levels were significantly higher (P < 0.05) in model group. However,LA can increase the survival rate,TAOC, SOD,NO activity (P < 0.05),reduce MDA level and cell apoptosis (P < 0.05)in a dose dependent manner. Conclusion LA pretreatments provide protection against hypoxia/reoxygenation injury in HUVEC. LA exerts protective effects through inhibition of HUVEC apoptosis.

Evaluation of lipoic acid topical application on rats skin wound healing

PURPOSE: To evaluate the effects of lipoic acid (thioctic acid) topical application on wound healing on rats skin, and the consequences of lipoic acid nanoencapsulation on this process. METHODS: The model used was the healing activity on wounds induced by surgical incision on rats skin (n = 44). The parameters analyzed (11 days) were wound healing rate and histology (vascular proliferation, polymorphonuclear or mononuclear cells, and collagen synthesis or reepithelialization), after application of free lipoic acid or lipoic acid- loaded nanocapsules. The antioxidant activity of these formulations was evaluated by lipid peroxidation test. RESULTS: It was demonstrated for the first time that the topical application of lipoic acid improves wound healing. On the seventh day after surgery, the animals treated with lipoic acid showed increased healing rate (60.7 ± 8.4%) compared to the negative control group (43.0 ± 17.4%), as so improvement of histological parameters. The nanoencapsulation reverted the pro-oxidant activity presented in vitro by lipoic acid, whereas diminished wound repair. CONCLUSIONS: The topical application of lipoic acid produced an increase in the skin wound healing, which may be related to its pro-oxidant activity. On the other hand, the nanoencapsulation of the lipoic acid reversed the pro-oxidant activity, although presented minor healing activity.