Lipoic acid scientific update |
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2010 Jun 13;151(24):971-81.
Winkler G, Kempler P.
Szent János Kórház, II. Belgyógyászati Osztály, Budapest. gabor.winkler@mail.janoskorhaz.hu
[Pathomechanism of diabetic neuropathy: background of the pathogenesis-oriented therapy] [Article in Hungarian]
The pathomechanism of diabetic neuropathy remains still poorly understood, however, a broad spectrum of novel findings associated with therapeutic consequences emerged during the last decades. Both disturbed function of primary hemostasis and increased activity of coagulation system contribute to the reduced endoneurial blood flow. Increased superoxide anion production induced by hyperglycemia leads to decreased activity of glycerinaldehid-3-phosphate dehydrogenase and to consequential increased activity of alternative pathways, including the polyol-, hexosamine-, diacilglycerol protein kinase-C- and advanced glycation pathways. Advanced glycation endproducts increase the activity of the nuclear-factor kappa-B, as well as the production of vasoactive factors and cytokines (interleukin-1, -6, tumor necrosis factor alpha). The aim of pathogenetic oriented treatment is to slow down, stop or reverse the progression of neuropathy. Components of pathogenetic oriented treatment are glycaemic control, management of risk factors, benfotiamine and alpha-lipoic acid. On one hand, transketolase-activator benfotiamine inhibits alternative pathways induced by hyperglycemia (the polyol-, hexosamine-, diacilglycerol protein kinase-C-, and advanced glycation pathways), while, on the other hand, it increases the activity of the pentose-phosphate-shunt. The clinical effectiveness of benfotiamine has been shown in many international and Hungarian trials. Alpha-lipoic acid as a powerful antioxidant decreases oxidative stress and this way increases the activity of glycerinaldehid-3-phosphate dehydrogenase. Alpha-lipoic acid administered in infusion or oral treatment decreases both symptoms of neuropathy and neuropathic deficit. In conclusion, the case of diabetic neuropathy illustrates well, how widening of our knowledge on pathogenesis might contribute to successful therapy.
2010 May 23. [Epub ahead of print]
Hah YS, Sung MJ, Lim HS, Jun JS, Jeong YG, Kim HO, Kim J, Hur HJ, Davaatseren M, Kwon DY, Lee SI.
Clinical Research Institute, Gyeongsang National University Hospital and Department of Internal Medicine and Institute of Health Science, Gyeongsang National University College of Medicine, #92, Chilam-dong, Jinju, Gyeongnam, 660-702, Republic of Kor
Dietary alpha lipoic acid supplementation prevents synovial inflammation and bone destruction in collagen-induced arthritic mice.
Rheumatoid arthritis (RA) is a chronic inflammatory disorder characterized by chronic inflammation and joint destruction. In this study, we investigated whether dietary supplementation with alpha lipoic acid (ALA) suppresses collagen-induced arthritis (CIA) in mice. Mice were randomly divided into three groups: (1) a control CIA group was fed a normal diet, (2) a CIA group was fed a 0.1% ALA diet (average ALA intake of 160 mg/kg/day), and (3) a CIA group was fed a 0.5% ALA diet (average ALA intake of 800 mg/kg/day). The ALA-fed mice showed a decreased incidence and severity of arthritis compared to the normal diet group. Radiographic findings revealed a dramatic decrease in bone destruction, and histological findings showed extensively suppressed pathological changes in the ALA-fed mice. The ALA-fed mice exhibited inhibited generation of tartrate resistant acid phosphatase (TRAP)-positive osteoclasts in vivo. Additionally, ALA-fed mice reduced production of various proinflammatory cytokines and the soluble receptor activator of NF-kappaB ligand (sRANKL) in the joint tissues and the sera. In conclusion, dietary supplementation with ALA attenuated inflammatory responses and bone destruction in CIA mice.
2010;16(7):840-6.
Carbonelli MG, Di Renzo L, Bigioni M, Di Daniele N, De Lorenzo A, Fusco MA.
Azienda Ospedaliera San Camillo-Forlanini, Rome, Italy.
Alpha-lipoic acid supplementation: a tool for obesity therapy?
Lipid peroxidation has supposed as the major biochemical alteration underling oxidant-induced cell injury in stress including numerous diseases. One of the natural molecules know to prevent or retard oxidation is alpha-lipoic acid (LA) and, therefore, the lipoic acid/dihydrolipoic acid (LA/DHLA) redox couple has received considerable attention. Recent studies have highlighted the potential of free LA and DHLA as powerful metabolic antioxidants that are able to scavenge the reactive oxygen species, to recycle other antioxidants. Our aim was to investigate the beneficial effects of LA in the treatment of Italian pre-obese and obese subjects. We screened 1612 subjects for enrollment; of these, 1127 subjects (445 men and 682 women, 18-60 age) met enrolment criteria and were enrolled in the study. According to body mass index (BMI) the 53% was obese and the 43% was pre-obese. The subjects were treated for 4 month with 800 mg/day of LA. In pre-obese subject significant reduction (p<0.001) of weight (8%, both gender), BMI (2 points), blood pressure, and abdominal circumference (female 6 cm, male 7 cm) were observed. In obese subjects significant reductions (p<0.001) of weight (9%, both gender), BMI (female 3 point, male 4 point), blood pressure and abdominal circumference (female 9 cm, male 11 cm) were observed. Our study indicated that LA is an ideal antioxidant candidate for the therapy of obesity related diseases. Further clinical studies should be considered to highlight the role and efficacy of LA treatment.
2010 May;23(5):1407-16.
Schwartz L, Abolhassani M, Guais A, Sanders E, Steyaert JM, Campion F, Israël M.
Service de Radiothérapie Hôpital Pitié-Salpétrière, bd. de l'Hôpital, 75013 Paris, France.
A combination of alpha lipoic acid and calcium hydroxycitrate is efficient against mouse cancer models: preliminary results.
The impact of metabolic dysregulation on tumor development has long been established. We have targeted two enzymes that are altered during carcinogenesis: pyruvate dehydrogenase (PDH), which is down-regulated, and ATP citrate lyase, which is overexpressed in cancer cells. Alpha lipoic acid is a cofactor of PDH, while hydroxycitrate is a known inhibitor of ATP citrate lyase. Our hypothesis is that a combination of these drugs may have antitumoral potential. The efficacy of these molecules was screened in vitro by treatment of different human cancer and murine cell lines. Lipoic acid reduced the cell number by 10-50% depending on concentrations (0.1-10 microM) and cell types. Calcium hydroxycitrate reduced the cell number by 5-60% at different concentrations (10-500 microM). When hydroxycitrate and lipoic acid were used together, there was a major cytotoxic effect: complete cell death was seen following 8 microM lipoic acid and 300 microM hydroxycitrate treatment for 72 h. The combination of alpha lipoic acid and hydroxycitrate was administered to healthy mice, at doses currently utilized for other indications than cancer; no demonstrable toxicity was observed. The combination was used to treat mouse syngenic cancer models: MBT-2 bladder transitional cell carcinoma, B16-F10 melanoma and LL/2 Lewis lung carcinoma. The efficacy of this combination appears similar to conventional chemotherapy (cisplatin or 5-fluorouracil) as it resulted in significant tumor growth retardation and enhanced survival. This preliminary study suggests that this combination of drugs is efficient against cancer cell proliferation both in vitro and in vivo. A clinical trial is warranted.
2010 Mar 29. [Epub ahead of print]
Kizhakekuttu TJ, Widlansky ME.
Department of Medicine, Cardiovascular Medicine Division and Department of Pharmacology, Medical College of Wisconsin, Milwaukee, WI, USA.
Natural Antioxidants and Hypertension: Promise and Challenges.
Hypertension reigns as a leading cause of cardiovascular morbidity and mortality worldwide. Excessive reactive oxygen species (ROS) have emerged as a central common pathway by which disparate influences may induce and exacerbate hypertension. Potential sources of excessive ROS in hypertension include nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, mitochondria, xanthine oxidase, endothelium-derived NO synthase, cyclooxygenase 1 and 2, cytochrome P450 epoxygenase, and transition metals. While a significant body of epidemiological and clinical data suggests that antioxidant-rich diets reduce blood pressure and cardiovascular risk, randomized trials and population studies using natural antioxidants have yielded disappointing results. The reasons behind this lack of efficacy are not completely clear, but likely include a combination of (1) ineffective dosing regimens, (2) the potential pro-oxidant capacity of some of these agents, (3) selection of subjects less likely to benefit from antioxidant therapy (too healthy or too sick), and (4) inefficiency of nonspecific quenching of prevalent ROS versus prevention of excessive ROS production. Commonly used antioxidants include Vitamins A, C and E, L-arginine, flavanoids, and mitochondria-targeted agents (Coenzyme Q10, acetyl-L-carnitine, and alpha-lipoic acid). Various reasons, including incomplete knowledge of the mechanisms of action of these agents, lack of target specificity, and potential interindividual differences in therapeutic efficacy preclude us from recommending any specific natural antioxidant for antihypertensive therapy at this time. This review focuses on recent literature evaluating naturally occurring antioxidants with respect to their impact on hypertension.
2010 May 15;292(1-2):89-95. Epub 2010 Mar 11.
Moraes TB, Zanin F, da Rosa A, de Oliveira A, Coelho J, Petrillo F, Wajner M, Dutra-Filho CS.
Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
Lipoic acid prevents oxidative stress in vitro and in vivo by an acute hyperphenylalaninemia chemically-induced in rat brain.
Phenylketonuria (PKU) is a recessive autosomal disorder caused by a severe deficiency of phenylalanine-4-hydroxilase activity which leads to the accumulation of L-phenylalanine (Phe) in the tissues and plasma of patients. The main clinical features are retarded development and intellectual impairment. Recent studies have shown that oxidative stress may be involved in neuropathology of hyperphenylalaninemia. Lipoic acid (LA) is considered a potent antioxidant which is well absorbed from diet and can easily cross the blood-brain barrier. We investigated the neuroprotective effects of lipoic acid against oxidative stress caused by Phe in vivo and in vitro. Lipoic acid prevented the inhibition provoked by Phe on the activities of catalase, superoxide dismutase, glutathione peroxidase, and glucose-6-phosphate dehydrogenase. It also prevented Phe alterations on total radical-trapping antioxidant potential, thiobarbituric acid-reactive substances, glutathione concentration and on production of reactive species. It is concluded that lipoic acid may be an efficient antioxidant in the CNS against oxidative stress induced by hyperphenylalaninemia. If the present results are confirmed in PKU patients, it is possible that supplementation of lipoic acid may contribute to the treatment of PKU as an adjuvant therapeutic approach to Phe-restricted dietary treatment and amino acid mixture. Copyright 2010. Published by Elsevier B.V.
2009 Dec;44(12):1034-7.
Zhou CH, Sun JJ, Gong SS, Gao G.
Center of Otorhinolaryngology of Chinese People's Liberation Army, Naval General Hospital, Beijing 100048, China.
[Comparison of the antioxidants lipoic acid pharmacokinetics in inner ear between intravenous and intratympanic administration in guinea pigs.] [Article in Chinese]
OBJECTIVE: To study the pharmacokinetics of lipoic acid in guinea pig perilymph and to provide experimental evidence for clinical delivery methods and dose in order to compare of intravenous and intratympanic administration using high-performance liquid chromatography (HPLC). METHODS: Fifty-four guinea pigs were randomly divided into two groups of intratympanic and intravenous administration, with 27 ones in each group, and the concentration of lipoic acid was 100 mg/ml. The concentration of lipoic acid in perilymph was detected respectively by HPLC at 0.5, 1, 2, 3, 4, 5, 6, 8 and 10 h after administration. RESULTS: A well linear relation of concentration of lipoic acid in perilymph was shown when the concentration was detected from 0.1 to 200 microg/ml (r(2) = 0.9996). The maximum of concentration of lipoic acid administrated via intratympanic was 171.7 microg/ml, and via intravenous was 33.7 microg/ml; the MRT of intratympanic injection was 3.7 h while intravenous injection was 2.9 h; the half life (t(1/2)) of the former was 1.8 h but the latter was 2.1 h. CONCLUSIONS: The drug concentration could both be detected via intravenous and intratympanic injection in perilymph of guinea pig, But the effect of local administration via intratympanic was obvious superior to systemic administration.
2009;15(3):21-6.
Fedin AI, Kuznetsov MR, Beresten' NF, Kuznetsova VF, Kholopova EA, Ibragimov TM, Tugdumov BV, Dubrovin EE.
[Correction of disordered cerebral blood flow autoregulation in atherosclerosis] [Article in Russian]
The work deals with studying the parameters of autoregulation of the cerebral blood flow in a total of 127 patients subdivided into four groups. Clinical Group I consisted of thirty 45-to-70-year-old male patients (mean age 55.13 +/- 6.44 years) presenting with no signs of systemic atherosclerosis (CAD, chronic arterial insufficiency of the lower extremities, cerebrovascular insufficiency) or any other chronic diseases (chronic cardiac, pulmonary or renal insufficiency, chronic hepatitis, etc.). Clinical Group II comprised 32 patients diagnosed as having varying-degree chronic arterial insufficiency on the background of atherosclerosis obliterans of the lower-limb arteries (average age 57.46 +/- 5.15 years). Clinical Group III was composed of 30 patients presenting with different degrees of chronic cerebral ischaemia and having haemodynamically significant unilateral atherosclerotic lesions of the internal carotid artery (mean age 55.39 +/- 6.25 years), with the Control Group enrolling thirty-five 20-to-25-year-old volunteers. The findings of the work showed that the patients with atherosclerosis had significant impairments of the cerebral blood flow autoregulation, whose type and degree appeared to depend upon localization of the lesion. In the patients with peripheral atherosclerosis, a 10-day therapeutic course of intravenous administration of alpha-lipoic acid (Berlithion) at a dose of 600 mg daily could be used to correct disordered autoregulation of the cerebral vessels and may be considered from the position of preoperative preparation of such patients for reconstructive vascular interventions on the aorta and lower-limb arteries. Efficacy of alpha-lipoic acid (Berlithion) on the alterations in the cerebral blood flow autoregulation in patients presenting with haemodynamic stenosis of the internal carotid artery is insignificant, in connection with which such patients require surgical restoration of the patency of the major cerebral arteries.
2009 Winter;6(4):230-6. Epub 2009 Dec 30.
Vallianou N, Evangelopoulos A, Koutalas P.
Department of Internal Medicine, Polykliniki General Hospital, 3 Pireos Str., 10552 Athens, Greece.
Alpha-lipoic Acid and diabetic neuropathy.
Diabetic neuropathy presents a major public health problem. It is defined by the symptoms and signs of peripheral nerve dysfunction in diabetic patients, in whom other causes of neuropathy have been excluded. Pathogenetic mechanisms that have been implicated in diabetic neuropathy are: a) increased flux through the polyol pathway, leading to accumulation of sorbitol, a reduction in myo-inositol, and an associated reduced Na+-K+-ATPase activity, and b) endoneurial microvascular damage and hypoxia due to nitric oxide inactivation by increased oxygen free radical activity. Alpha-lipoic acid seems to delay or reverse peripheral diabetic neuropathy through its multiple antioxidant properties. Treatment with alpha-lipoic acid increases reduced glutathione, an important endogenous antioxidant. In clinical trials, 600 mg alpha-lipoic acid has been shown to improve neuropathic deficits. This review focuses on the relationship of alpha-lipoic acid and auto-oxidative glycosylation. It discusses the impact of alpha-lipoic acid on hyperglycemia-induced oxidative stress, and examines the role of alpha-lipoic acid in preventing glycation process and nerve hypoxia.
2009 Dec;8(4):416-22.
Berkson BM, Rubin DM, Berkson AJ.
The Integrative Medical Center of New Mexico, Las Cruces, NM, USA.
Revisiting the ALA/N (alpha-lipoic acid/low-dose naltrexone) protocol for people with metastatic and nonmetastatic pancreatic cancer: a report of 3 new cases.
The authors, in a previous article, described the long-term survival of a man with pancreatic cancer and metastases to the liver, treated with intravenous alpha-lipoic acid and oral low-dose naltrexone (ALA/N) without any adverse effects. He is alive and well 78 months after initial presentation. Three additional pancreatic cancer case studies are presented in this article. At the time of this writing, the first patient, GB, is alive and well 39 months after presenting with adenocarcinoma of the pancreas with metastases to the liver. The second patient, JK, who presented to the clinic with the same diagnosis was treated with the ALA/N protocol and after 5 months of therapy, PET scan demonstrated no evidence of disease. The third patient, RC, in addition to his pancreatic cancer with liver and retroperitoneal metastases, has a history of B-cell lymphoma and prostate adenocarcinoma. After 4 months of the ALA/N protocol his PET scan demonstrated no signs of cancer. In this article, the authors discuss the poly activity of ALA: as an agent that reduces oxidative stress, its ability to stabilize NF(k)B, its ability to stimulate pro-oxidant apoptosic activity, and its discriminative ability to discourage the proliferation of malignant cells. In addition, the ability of lowdose naltrexone to modulate an endogenous immune response is discussed. This is the second article published on the ALA/N protocol and the authors believe the protocol warrants clinical trial.
2009 Dec;8(4):416-22.
Berkson BM, Rubin DM, Berkson AJ.
The Integrative Medical Center of New Mexico, Las Cruces, NM, USA.
Revisiting the ALA/N (alpha-lipoic acid/low-dose naltrexone) protocol for people with metastatic and nonmetastatic pancreatic cancer: a report of 3 new cases.
The authors, in a previous article, described the long-term survival of a man with pancreatic cancer and metastases to the liver, treated with intravenous alpha-lipoic acid and oral low-dose naltrexone (ALA/N) without any adverse effects. He is alive and well 78 months after initial presentation. Three additional pancreatic cancer case studies are presented in this article. At the time of this writing, the first patient, GB, is alive and well 39 months after presenting with adenocarcinoma of the pancreas with metastases to the liver. The second patient, JK, who presented to the clinic with the same diagnosis was treated with the ALA/N protocol and after 5 months of therapy, PET scan demonstrated no evidence of disease. The third patient, RC, in addition to his pancreatic cancer with liver and retroperitoneal metastases, has a history of B-cell lymphoma and prostate adenocarcinoma. After 4 months of the ALA/N protocol his PET scan demonstrated no signs of cancer. In this article, the authors discuss the poly activity of ALA: as an agent that reduces oxidative stress, its ability to stabilize NF(k)B, its ability to stimulate pro-oxidant apoptosic activity, and its discriminative ability to discourage the proliferation of malignant cells. In addition, the ability of lowdose naltrexone to modulate an endogenous immune response is discussed. This is the second article published on the ALA/N protocol and the authors believe the protocol warrants clinical trial.
2008 Oct;44(10):783-96.
Stirban A.
Diabetes Clinic at the Heart and Diabetes Center North Rhine-Westphalia Ruhr-University Bochum, Bad Oeynhausen, Germany.
Drugs for the treatment of diabetes complications. Zycose: a new player in the field?
Zycose is a newly released (2006) combined medication containing folic acid (1 mg) benfotiamine (150 mg) and benzamine (850 mg), a proprietary blend of para-aminobenzoic acid (PABA), vitamin E and alpha-lipoic acid (ALA). Zycose protects vascular, retinal and kidney function by improving cellular health and promoting peripheral nerve health in people with diabetes. Zycose's therapeutic benefit is believed to be due to the additive effects of its compounds on lowering homocysteine levels (folic acid), reducing the production of advanced glycation end products (benfotiamine), improving endothelial function (folic acid, benfotiamine, ALA), reducing oxidative stress (ALA, vitamin E) and reducing carbonyl stress (benzamine). The complex composition of Zycose allows the therapeutic intervention of several hyperglycemiamediated disorders. The compound consists mainly of vitamins, therefore explaining, in part, the good safety profile and reduced adverse effects. Copyright 2008 Prous Science, S.A.U. or its licensors. All rights reserved.
2008;80(10):27-30.
Statsenko ME, Poletaeva LV, Turkina SV, Apukhtin AF, Dudchenko GP.
[Mildronate effects on oxidant stress in type 2 diabetic patients with diabetic peripheral (sensomotor) neuropathy] [Article in Russian]
AIM: To clarify mildronate effects on oxidant stress and tissue oxygen in combined treatment of peripheral (sensomotor) neuropathy in patients with type 2 diabetes mellitus (DM). MATERIAL AND METHODS: An open randomized trial investigated 70 matched patients with type 2 DM and sensomotor neuropathy. They were randomized into two groups. The study group received basic anti-diabetic treatment, alpha-lipoic acid and mildronate for 3 months. Patients of the control group received the same treatment but mildronate. RESULTS: Mildronate administration improved clinical condition of the study group patients vs controls by neuropathy and symptoms count scales, electrophysiological properties of the nerve fibers, optimization of oxygen tissue balance, reduced production of lipid peroxidation products and activated enzymes of antioxidant defense. CONCLUSION: It is recommended to add 1 g/day mildronate to standard schemes of treatment for diabetes and sensomotor neuropathy.
2008;86(10):52-9.
Volchegorskiĭ IA, Alekseev MN, Volchegorskaia MI, Rassokhina LM.
[Effect of alpha-lipoic acid and mexidol on neuro- and the affective status in patients at early stages of diabetic foot syndrome] [Article in Russian]
The study was designed to investigate effect of alpha-lipoic acid (alphaLA) and mexidol on clinical manifestations of diabetic neuropathy (DN) and the associated changes of the affective status in patients with diabetes mellitus at early stages of diabetic foot syndrome (DFS). Integral indicator of clinical symptoms of distal symmetric sensorimotor polyneuropathy (according to the neuropathic signs and symptoms scale) significantly decreased within 14 days after the onset of the treatment with alphaLA (600 mg/day) and mexidol (300 mg/day). Antineuropathic effect of alphaLA was associated with a rise in the left ventricular ejection fraction. Mexidol reduced the severity of DN-related depression and was more efficacious than alphaLA in terms of beneficial effect on spasms and paresthesia (pricking and burning sensation, numbness) in distal segments of the lower extremities. The above clinical effects of alphaLA and mexidol were unrelated to changes of glycemia, lipidemia amd lipid peroxidation.
2008 Oct 18;152(42):2298-301.
Bangma HR, Smit GP, Kuks JB, Grevink RG, Wolffenbuttel BH.
Universitair Medisch Centrum Groningen, Postbus 30.001, 9700 RB Groningen.
[Two patients with mitochondrial respiratory chain disease] [Article in Dutch]
A 23-year-old woman and a 13-year-old boy were diagnosed with mitochondrial respiratory chain disease. The woman had muscle pain, fatigue and bilateral ophthalmoplegia--symptoms consistent with Kearns-Sayre syndrome. The boy had aspecific symptoms; eventually, reduced activity of complex 1 was found to be the cause of the mitochondrial respiratory chain disease in the boy and his mother, who had suffered from unexplained fatigue and muscle pain for 15 years. Mitochondrial diseases often involve several organ systems. Diagnosis can be difficult, because laboratory tests such as serum and urinary lactate and creatine kinase have low sensitivity and specificity. Biochemical assessment of muscle biopsy can reveal reduced oxidation ATP synthesis and sometimes specific abnormalities in individual protein complexes. DNA analysis may be helpful in demonstrating mitochondrial or nuclear mutations or deletions. The goal of treatment is to increase mitochondrial ATP production, improve clinical symptoms and enhance stamina. Replacement of the following substances (also referred to as cofactors) may be attempted: co-enzyme Q10, antioxidants (lipoic acid, vitamins C and E), riboflavin, thiamine, creatine and carnitine. Evidence regarding the optimal treatment approach is lacking; one usually has to rely on observing effects in the individual patient.
2008;108(9):36-40.
Kolesnichenko LS, Kulinskiĭ VI, Shprakh VV, Bardymov VV, Verlan NV, Gubina LP, Pensionerova GA, Sergeeva MP, Stanevich LM, Filippova GT.
[The blood glutathione system in cerebral vascular diseases and its treatment with alpha-lipoic acid] [Article in Russian]
The changes of glutathione metabolism are rare in dyscirculatory encephalopathy and ischemic stroke (IS) of mild severity. The frequent and considerable changes have been revealed in IS of moderate and high severity as well as in hemorrhagic stroke. An increase of activities of glutathione peroxidase and glutathione transferase is the most typical. The increase of enzyme activity was not observed at the beginning of treatment after 3 days and in patients with severe degree of disease who died later. A standard therapy decreased the quantity and/or expression of changes of the glutathione metabolism in patients with IS of moderate and high severity while the addition of alpha-lipoic acid (alpha-LA) led to the complete normalization in IS of moderate severity and normalization of most parameters in IS of high severity. The increase of functional activity of the glutathione system at the early stage of treatment of IS and the favorable changes during the treatment, in particular after the addition of alpha-LA, were correlated with the improvement of neurological status assessed with the NIHSS. It has been confirmed that the glutathione system plays an important role in the tolerance to brain ischemia.
2008 Dec;214(2):276-84. Epub 2008 Sep 9.
Melli G, Taiana M, Camozzi F, Triolo D, Podini P, Quattrini A, Taroni F, Lauria G.
Neuromuscular Diseases Unit, IRCCS Foundation Neurological Institute Carlo Besta, Via Celoria, 11 20133, Milan, Italy.
Alpha-lipoic acid prevents mitochondrial damage and neurotoxicity in experimental chemotherapy neuropathy.
The study investigates if alpha-lipoic acid is neuroprotective against chemotherapy induced neurotoxicity, if mitochondrial damage plays a critical role in toxic neurodegenerative cascade, and if neuroprotective effects of alpha-lipoic acid depend on mitochondria protection. We used an in vitro model of chemotherapy induced peripheral neuropathy that closely mimic the in vivo condition by exposing primary cultures of dorsal root ganglion (DRG) sensory neurons to paclitaxel and cisplatin, two widely used and highly effective chemotherapeutic drugs. This approach allowed investigating the efficacy of alpha-lipoic acid in preventing axonal damage and apoptosis and the function and ultrastructural morphology of mitochondria after exposure to toxic agents and alpha-lipoic acid. Our results demonstrate that both cisplatin and paclitaxel cause early mitochondrial impairment with loss of membrane potential and induction of autophagic vacuoles in neurons. Alpha-lipoic acid exerts neuroprotective effects against chemotherapy induced neurotoxicity in sensory neurons: it rescues the mitochondrial toxicity and induces the expression of frataxin, an essential mitochondrial protein with anti-oxidant and chaperone properties. In conclusion mitochondrial toxicity is an early common event both in paclitaxel and cisplatin induced neurotoxicity. Alpha-lipoic acid protects sensory neurons through its anti-oxidant and mitochondrial regulatory functions, possibly inducing the expression of frataxin. These findings suggest that alpha-lipoic acid might reduce the risk of developing peripheral nerve toxicity in patients undergoing chemotherapy and encourage further confirmatory clinical trials.
2007 Oct 16;87(38):2706-9.
Liu F, Zhang Y, Yang M, Liu B, Shen YD, Jia WP, Xiang KS.
Department of Endocrinology & Metabolism, Sixth People's Hospital Affiliated to Shanghai Jiaotong University, Shanghai Clinical Center of Diabetes, Shanghai Institute for Diabetes, Shanghai 200233, China.
[Curative effect of alpha-lipoic acid on peripheral neuropathy in type 2 diabetes: a clinical study] [Article in Chinese]
OBJECTIVE: To evaluate the effect of alpha-lipoic acid (ALA) on diabetic peripheral neuropathy (DPN). METHODS: 95 type 2 diabetic patients complicated with DPN were randomly divided into 2 groups: treatment group (n = 52), receiving ALA 600 mg/d in normal saline 250 ml given by intravenous drip infusion once a day for 14 days; and control group (n = 43), administered with radix salviae 20 ml by intravenous drip infusion once a day for 14 days. Before and 7 and 14 days after the management fasting glucose (FPG), fasting insulin (FINS), supersensitive C reactive protein (sCRP), and HbA1c were measured, and total symptom score (TSS) and Michigan neuropathy screening instrument (MNSI) were used to evaluate the nervous symptoms. RESULTS: 50 cases of the treatment group and 43 control cases completed the study. Compared with the control group, the TSS of the treatment group reduced significantly after 1 week, but the MNSI score did not change significantly. The TSS 7d after ALA administration of the treatment group was significantly lower than that before the ALA treatment in the same group and that of the control group 7 days after the radix salviae infusion as well (both P < 0.05). The TSS and MNSI score 14 days after the management of the treatment group were significantly lower than those of the control group (both P < 0.01). The symptom scores of numbness, sting sensation, and burning sensation reduced significantly 2-weeks after ALA treatment, but there were no significant differences in these symptoms after the management in the control group. The total gratification rate of the treatment group was 90% (45/50), significantly higher than hat of the control group (13.95%, 6/43, P < 0.01). One patient of the 50 patients receiving ALA treatment felt chest distress 2 days after ALA administration, but the symptom was improved in the same day after the velocity of intravenous drip was slowed down, and no other adverse effects were found in these two groups. CONCLUSION: ALA effectively improves the sensitive symptoms of DPN patients and is safe for most of the patients.
2007;(72):189-93.
Hager K, Kenklies M, McAfoose J, Engel J, Münch G.
Department of Medical Rehabilitation and Geriatrics, Henriettenstiftung, Hannover, Germany.
Alpha-lipoic acid as a new treatment option for Alzheimer's disease--a 48 months follow-up analysis.
Oxidative stress and neuronal energy depletion are characteristic biochemical hallmarks of Alzheimer's disease (AD). It is therefore conceivable that pro-energetic and antioxidant drugs such as alpha-lipoic acid might delay the onset or slow down the progression of the disease. In a previous study, 600mg alpha-lipoic acid was given daily to nine patients with AD (receiving a standard treatment with choline-esterase inhibitors) in an open-label study over an observation period of 12 months. The treatment led to a stabilization of cognitive functions in the study group, demonstrated by constant scores in two neuropsychological tests (the mini mental state exam, MMSE and the Alzheimer's disease assessment score cognitive subscale, ADAScog). In this report, we have extended the analysis to 43 patients over an observation period of up to 48 months. In patients with mild dementia (ADAScog < 15), the disease progressed extremely slowly (ADAScog: +1.2 points/year, MMSE: -0.6 points/year), in patients with moderate dementia at approximately twice the rate. However, the progression appears dramatically lower than data reported for untreated patients or patients on choline-esterase inhibitors in the second year of long-term studies. Despite the fact that this study was not double-blinded, placebo-controlled and randomized, our data suggest that treatment with alpha-lipoic acid might be a successful 'neuroprotective' therapy option for AD. However, a state-of-the-art phase II trial is needed urgently.
2007 Nov;32(6):631-6.
Dell'Anna ML, Mastrofrancesco A, Sala R, Venturini M, Ottaviani M, Vidolin AP, Leone G, Calzavara PG, Westerhof W, Picardo M.
San Gallicano Dermatological Institute, IRCCS, Rome, Italy.
Antioxidants and narrow band-UVB in the treatment of vitiligo: a double-blind placebo controlled trial.
BACKGROUND: Vitiligo is an acquired depigmenting disease with uncertain aetiopathogenesis, possibly associated with oxidative stress. Narrowband ultraviolet B phototherapy (NB-UVB) is the most widely used and effective treatment. AIM: To evaluate the clinical effectiveness of NB-UVB and the repairing of oxidative stress-induced damage, using oral supplementation with an antioxidant pool (AP). METHODS: Patients (n = 35) with nonsegmental vitiligo were enrolled in a randomized, double-blind, placebo-controlled multicentre trial. The treatment group received, for 2 months before and for 6 months during the NB-UVB treatment, a balanced AP containing alpha-lipoic acid, vitamins C and E, and polyunsaturated fatty acids. The area and number of lesions, as well as some parameters of the oxidation-reduction (redox) status of the peripheral blood mononuclear cells (PBMCs) were estimated at the beginning, after 2 months, and at the end of the trial. RESULTS: In total, 28 patients completed the study. After 2 months of AP supplementation, the catalase activity and the production of reactive oxygen species (ROS) were 121% and 57% of the basal values (P < 0.05 and P < 0.02 vs. placebo, respectively). The AP increased the therapeutic success of NB-UVB, with 47% of the patients obtaining > 75% repigmentation vs. 18% in the placebo group (P < 0.05). An increase in catalase activity to 114% (P < 0.05 vs. placebo) and decrease in ROS level of up to 60% (P < 0.02 vs. placebo) of the basal value was observed in PBMCs. Finally, the AP intake maintained the membrane lipid ratio (saturated : unsaturated fatty acids 1.8 : 3.1; P < 0.05), counteracting phototherapy-induced saturation. CONCLUSIONS: Oral supplementation with AP containing alpha-lipoic acid before and during NB-UVB significantly improves the clinical effectiveness of NB-UVB, reducing vitiligo-associated oxidative stress.
2007 Sep;58(3):541-9.
Goraca A, Józefowicz-Okonkwo G.
Chair of Experimental and Clinical Physiology, Department of Cardiovacular Physiology, Medical University of Łódź, Poland.
Protective effects of early treatment with lipoic acid in LPS-induced lung injury in rats.
A lipopolysaccharide (LPS) stimulates the synthesis and releases several metabolites from phagocytes which can lead to an endotoxic shock characterized by multiple organ injury with the earliest to occur in the lungs. Among LPS-induced metabolites, reactive oxygen species are considered to play a crucial pathogenetic role in the lung damage. In this study, the effect of early administration of an antioxidant, alpha-lipoic acid (LA), on pulmonary lipid peroxidation, lung hydrogen peroxide (H(2)O(2)) concentration, and lung sulfhydryl group content was evaluated in rats with endotoxic shock induced by administration of LPS (Escherichia coli 026:B6, 30 mg/kg, i.v.). In addition, lung edema was assessed with wet-to-dry lung weight (W/D) ratio. Animals were treated intravenously with normal saline or LA 60 mg/kg or 100 mg/kg 30 min after LPS injection. After a 5 h observation, animals were killed and the lungs were isolated for measurements. Injection of LPS alone resulted in the development of shock and oxidative stress, the latter indicated by a significant increase in the lung thiobarbituric acid reacting substances (TBARS) and H(2)O(2) concentrations, and a decrease in the lung sulfhydryl group content. The increase in the W/D ratio after the LPS challenge indicated the development of lung edema in response to LPS. Administration of LA after the LPS challenge resulted in an increase in the sulfhydryl group content and a decrease in TBARS and H202 concentration in the lungs as compared with the LPS group. An insignificant decrease in the W/D ratio was observed in rats treated with either dose of LA. These results indicate that the LPS-induced oxidative lung injury in endotoxic rats can be attenuated by early treatment with LA. Administration of LA could be a useful adjunct to conventional approach in the management of septic shock.
2007 Jul;45(7):385-93.
Vossler S, Füllert S, Schneider F, Haak E, Haak T, Samigullin R, Tritschler H, Tooke JE, Konrad T.
Institute for Metabolic Research, Academic Institute of the Medical Faculty of Johann Wolfgang Goethe University Frankfurt/Main, Germany.
Pharmacodynamic effects of orally administered dexlipotam on endothelial function in type 2-diabetic patients.
OBJECTIVE: Diabetic endotheliopathy is the result of hyperglycemia and the production of oxygen-free radicals. In vitro and in vivo data have shown beneficial effects of dexlipotam (DEX), a tromethamine salt of R(+)-alpha-lipoic acid, on oxidative stress in hyperglycemic states, but no data are available on the effects of this agent on endothelial function. The purpose of this pilot study was to evaluate the impact of DEX on endothelial function in patients with type 2 diabetes (DM2) and to estimate the safety and tolerability of DEX. MATERIAL AND METHODS: DEX 960 mg and DEX 1,920 mg were investigated in DM2 patients over a period of 4 weeks using a randomized, placebo- (PLA) controlled, double-blinded study with 3 parallel groups. The marker of arterial function after 4-week therapy with DEX was the maximum percentage change versus baseline in the flow-mediated dilation of the brachial artery (FMD) after reperfusion. RESULTS: A total of 114 diabetic patients were randomized to the three study groups. DEX was safe and well tolerated. Dyspepsia appeared to be the most relevant side effect of DEX treatment. Systolic (p = 0.078) and diastolic blood pressure (p = 0.059) tended to be lower in patients treated with DEX at a dose of 1,920 mg. There were no significant differences in FMD between the placebo- and the DEX-treated groups. In patients with poorer glucose control (HbA1c > 6.5% Hb), FMD increased significantly after 4-week treatment with DEX: PLA -1.51 +/- 2.98%, DEX 960 mg +1.22 +/- 3.22, p = 0.027, DEX 1,920 mg +1.47 +/- 3.78, p= 0.012. The magnitude of the mean change compared to placebo was 2.73% (DEX 920) and 2.98% (DEX 1,920) in patients with HbAlc > 7.5% Hb (DEX 960, p = 0.007, DEX 1,920, p = 0.032). The effects of treatment were usually statistically significant in subgroups with more severe vascular stress (longer duration of disease, pretreatment history, higher LDL-C, higher blood pressure). CONCLUSION: DEX therapy appears to reduce endothelial dysfunction in DM2, especially in men with long history of DM2 and having poor glucose control. These findings will be useful in patient selection in future prospective clinical trials with drugs to treat vascular stress.
Biofactors. 2006;27(1-4):157-65
Xiao L, Zhao L, Li T, Hartle DK, Aruoma OI, Taylor EW.
Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, GA 30602 USA.
Activity of the dietary antioxidant ergothioneine in a virus gene-based assay for inhibitors of HIV transcription.
The Long Terminal Repeat (LTR) of HIV-1 is the target of cellular transcription factors such as NF-kappaB, and serves as the promoter-enhancer for the viral genome when integrated in host DNA. The present study concluded that the antioxidant strategy involving ergothioneine derived from food plants might be of benefit in chronic immunodeficiency diseases.
The "Long Terminal Repeat" (LTR) of HIV-1 is the target of cellular transcription factors such as NF-kappaB, and serves as the promoter-enhancer for the viral genome when integrated in host DNA. Various LTR-reporter gene constructs have been used for in vitro studies of activators or inhibitors of HIV-1 transcription, e.g., to show that antioxidants such as lipoic acid and selenium inhibit NF-kappaB-dependent HIV-1 LTR activation. One such construct is the pHIVlacZ plasmid, with the HIV-1 LTR driving expression of the lacZ gene (encoding beta-galactosidase, beta-gal). Typically, for inhibitor screening, cells transfected with pHIVlacZ are activated using tumor necrosis factor-alpha (TNF-alpha), and the colorimetric o-nitrophenol assay is used to assess changes in beta-gal activity. A variant of this assay was developed as described here, in which LTR activation was induced by pro-fs, a novel HIV-1 gene product encoded via a -1 frameshift from the protease gene. Cotransfection of cells with pHIVlacZ along with a pro-fs construct produced a signifcant increase in beta-gal activity over controls. L-ergothioneine dose dependently inhibited both TNF-alpha-mediated and pro-fs-mediated increases in beta-gal activity, with an IC_{50} of about 6 mM. Thus antioxidant strategy involving ergothioneine derived from food plants might be of benefit in chronic immunodeficiency diseases.
Chem Biol Interact. 2004 Apr 15;147(3):259-71.
Sivaprasad TR, Malarkodi SP, Varalakshmi P.
Department of Medical Biochemistry, Dr. A.L.M. PGIBMS, University of Madras, Taramani Campus, Chennai 600113, India.
Therapeutic efficacy of lipoic acid in combination with dimercaptosuccinic acid against lead-induced renal tubular defects and on isolated brush-border enzyme activities.
In the present study the combined therapeutic potentials of lipoic acid and dimercaptosuccinic acid were compared against their sole administrations in restoring the altered lead sensitive indices in urine and isolated renal brush-border preparations. The study mainly resulted that increase in renal lead content was paralleled by a drastic fall in the renal delta-aminolevulinic acid dehydratase and a rise in urinary lead levels. The study indicates its efficacy over the monotherapies.
The combined therapeutic potentials of lipoic acid and dimercaptosuccinic acid were compared against their sole administrations in restoring the altered lead sensitive indices in urine and isolated renal brush-border preparations. Toxicity was induced in male albino rats (Wistar strain) by administering lead acetate (0.2%) in drinking water for 5 weeks, followed by therapy comprising lipoic acid (25 mg/kg body weight) and dimercaptosuccinic acid (20 mg/kg body weight) solely as well as combined during the 6th week. Changes in kidney weights encountered upon lead administration improved after therapy with lipoic acid and dimercaptosuccinic acid. Renal integrity was assessed by measuring the activities of alkaline phosphatase, acid phosphatase, lactate dehydrogenase, leucine aminopeptidase, N-acetyl-beta-D-glucosaminidase, gamma-glutamyl transferase and beta-glucuronidase in urine along with some urinary constituents (urea, uric acid, creatinine, protein and phosphorous). The effects of lead were also studied on isolated brush-border enzymes (alkaline phosphatase, acid phosphatase, gamma-glutamyl transferase and beta-glucuronidase) that showed a decline upon its administration. Increased activities of urinary enzymes were accompanied by increase in the urinary constituents. Increase in renal lead content was paralleled by a drastic fall in the renal delta-aminolevulinic acid dehydratase and a rise in urinary lead levels. Relative to the administration of lead, the combined therapy showed betterment on the renal integrity with respect to the functional parameters assessed, thereby indicating its efficacy over the monotherapies.
Arch Dermatol Res. 2004 Jun 24 [Epub ahead of print]
Venkatraman MS, Chittiboyina A, Meingassner J, Ho CI, Varani J, Ellis CN, Avery MA, Pershadsingh HA, Kurtz TW, Benson SC.
Department Medicinal Chemistry, University of Mississippi, University, MS, USA.
Alpha-Lipoic acid-based PPARgamma agonists for treating inflammatory skin diseases.
The findings from the present study using novel thiazolidinedione derivatives of the potent antioxidant alpha-lipoic suggest that water-soluble lipoic acid-based thiazolidinediones may be efficacious as oral and topical agents for treating inflammatory skin conditions such as contact dermatitis, atopic dermatitis, and psoriasis.
Novel thiazolidinedione derivatives of the potent antioxidant, alpha-lipoic (thioctic, 1,2-dithiolane) acid, were prepared. The prototype N-(2-{4-[2,4-dioxo(1,3-thiazolidin-5-yl)methyl]phenoxy}ethyl)-5-(1,2-dithiolan-3-yl)- N-methylpentanamide (designated BP-1003), and dithioester derivatives thereof were shown to be potent activators of peroxisome proliferator-activated receptor gamma (PPARgamma) (EC(50) range 15-101 n M) and modest activators of PPARalpha (EC(50) 5 micro M). Both the relatively hydrophobic dithiolane prototype, BP-1003, and its water-soluble dithioglycinate derivative, BP-1017, were shown to inhibit the proliferation of human keratinocytes and suppress the production of interleukin-2 by human peripheral lymphocytes to a greater extent than the antidiabetic thiazolidinedione, rosiglitazone. Both oral and topical administration of BP-1017 showed significant antiinflammatory effects in the oxazolone-sensitized mouse model of allergic contact dermatitis (ACD). These findings suggest that water-soluble lipoic acid-based thiazolidinediones may be efficacious as oral and topical agents for treating inflammatory skin conditions such as contact dermatitis, atopic dermatitis, and psoriasis.
Ageing Res Rev. 2004 Jul;3(3):303-18.
Atamna H.
Childrens Hospital Oakland Research Institute (CHORI), 5700 Martin Luther King Jr. Way, Oakland, CA 94609-1673, USA.
Heme, iron, and the mitochondrial decay of ageing.
The present review discusses heme metabolism as related to metabolic changes seen in ageing and age-related disorders and highlights the possible role in iron deficiency. Also it explains heme is responsible for many functions; it converts less reactive oxidants to highly reactive free radicals. Free heme has high affinity for different cell structures triggering site-directed oxidative damage.
Heme, the major functional form of iron, is synthesized in the mitochondria. Although disturbed heme metabolism causes mitochondrial decay, oxidative stress, and iron accumulation, all of which are hallmarks of ageing, heme has been little studied in nutritional deficiency, in ageing, or age-related disorders such as Alzheimer's disease (AD). Biosynthesis of heme requires Vitamin B(6), riboflavin, biotin, pantothenic acid, and lipoic acid and the minerals zinc, iron, and copper, micronutrients are essential for the production of succinyl-CoA, the precursor for porphyrins, by the TCA (Krebs) cycle. Only a small fraction of the porphyrins synthesized from succinyl-CoA are converted to heme, the rest are excreted out of the body together with the degradation products of heme (e.g. bilirubin). Therefore, the heme biosynthetic pathway causes a net loss of succinyl-CoA from the TCA cycle. The mitochondrial pool of succinyl-CoA may limit heme biosynthesis in deficiencies for micronutrients (e.g. iron or biotin deficiency). Ageing and AD are also associated with hypometabolism, increase in heme oxygenase-1, loss of complex IV, and iron accumulation. Heme is a common denominator for all these changes, suggesting that heme metabolism maybe altered in age-related disorders. Heme can also be a prooxidant: it converts less reactive oxidants to highly reactive free radicals. Free heme has high affinity for different cell structures (protein, membranes, and DNA), triggering site-directed oxidative damage. This review discusses heme metabolism as related to metabolic changes seen in ageing and age-related disorders and highlights the possible role in iron deficiency.
J Clin Pharmacol. 2005 Mar;45(3):313-28.
Teichert J, Tuemmers T, Achenbach H, Preiss C, Hermann R, Ruus P, Preiss R.
University of Leipzig, Institute of Clinical Pharmacology, Hartelstr. 16-18, 04107 Leipzig, Germany.
Pharmacokinetics of alpha-lipoic Acid in subjects with severe kidney damage and end-stage renal disease.
The present study concluded that the pharmacokinetics of alpha-lipoic acid are not influenced by creatinine clearance and are unaffected in subjects with severely reduced kidney function or end-stage renal disease. Hemodialysis did not significantly contribute to the clearance of alpha-lipoic acid and dose adjustment of alpha-lipoic acid is not necessary in patients with renal dysfunction.
In an open-label, parallel-group study involving 16 patients (8 with severely reduced renal function, 8 with end-stage renal disease needing hemodialysis), the effect of renal function on the pharmacokinetics, metabolism, and safety and of alpha-lipoic acid (thioctic acid) was evaluated by comparing the pharmacokinetic parameters with those of a reference group of 8 healthy subjects. Alpha-lipoic acid 600 mg was administered orally once daily for 4 days, and the pharmacokinetic parameters were measured on days 1 and 4. The mean percentage of the administered dose excreted in urine as parent compound was 0.2 and 0.05 in healthy subjects and subjects with severely reduced renal function, respectively. Assuming a bioavailability of 30%, this represents 0.67% and 0.17% of the bioavailable amount of alpha-lipoic acid, respectively. The percentage of total urinary recovered amounts of alpha-lipoic acid and 5 of its metabolites was 12.0 on both days. The respective values for patients with severe kidney damage were 5.2% (day 1) and 6.4% (day 4). The total percentage of the administered dose removed by hemodialysis was 4.0 in patients with end-stage renal disease. Renal clearance of alpha-lipoic acid and its major metabolites, 6,8-bismethylthio-octanoic acid, 4,6-bismethylthio-hexanoic acid and 2,4-bismethylthio-butanoic acid, were significantly decreased in subjects with kidney damage compared to the reference group. Apparent total clearance of alpha-lipoic acid was poorly correlated with creatinine clearance. There is strong evidence that alpha-lipoic acid is mainly excreted by nonrenal mechanism or further degraded to smaller units in the catabolic process. The significantly increased area under the curve values of 4,6-bismethylthio-hexanoic acid and half-lives of 2,4-bismethylthio-butanoic acid on both days in patients with severely reduced function and end-stage renal disease were not considered to be clinically relevant. Although trough levels of both metabolites tend to increase slightly in these subjects, no accumulation effects were detected. We conclude that the pharmacokinetics of alpha-lipoic acid are not influenced by creatinine clearance and are unaffected in subjects with severely reduced kidney function or end-stage renal disease. Hemodialysis did not significantly contribute to the clearance of alpha-lipoic acid. Hence, dose adjustment of alpha-lipoic acid is not necessary in patients with renal dysfunction.
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Drug category:Antioxidants and Vitamines
 Lipoic acid scientific update
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