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Biomolecules Aug 2019α-lipoic acid (ALA, thioctic acid) is an organosulfur component produced from plants, animals, and humans. It has various properties, among them great antioxidant... (Review)
Review
α-lipoic acid (ALA, thioctic acid) is an organosulfur component produced from plants, animals, and humans. It has various properties, among them great antioxidant potential and is widely used as a racemic drug for diabetic polyneuropathy-associated pain and paresthesia. Naturally, ALA is located in mitochondria, where it is used as a cofactor for pyruvate dehydrogenase (PDH) and α-ketoglutarate dehydrogenase complexes. Despite its various potentials, ALA therapeutic efficacy is relatively low due to its pharmacokinetic profile. Data suggests that ALA has a short half-life and bioavailability (about 30%) triggered by its hepatic degradation, reduced solubility as well as instability in the stomach. However, the use of various innovative formulations has greatly improved ALA bioavailability. The R enantiomer of ALA shows better pharmacokinetic parameters, including increased bioavailability as compared to its S enantiomer. Indeed, the use of amphiphilic matrices has capability to improve ALA bioavailability and intestinal absorption. Also, ALA's liquid formulations are associated with greater plasma concentration and bioavailability as compared to its solidified dosage form. Thus, improved formulations can increase both ALA absorption and bioavailability, leading to a raise in therapeutic efficacy. Interestingly, ALA bioavailability will be dependent on age, while no difference has been found for gender. The present review aims to provide an updated on studies from preclinical to clinical trials assessing ALA's usages in diabetic patients with neuropathy, obesity, central nervous system-related diseases and abnormalities in pregnancy.
Topics: Animals; Antioxidants; Biological Availability; Central Nervous System Diseases; Diabetic Neuropathies; Humans; Obesity; Thioctic Acid
PubMed: 31405030
DOI: 10.3390/biom9080356 -
Expert Opinion on Pharmacotherapy Dec 2014Neuropathy is a serious complication of diabetes. Its management focuses on glycaemic control, multifactorial cardiovascular risk intervention, pathogenesis-oriented... (Review)
Review
INTRODUCTION
Neuropathy is a serious complication of diabetes. Its management focuses on glycaemic control, multifactorial cardiovascular risk intervention, pathogenesis-oriented therapy, and analgesics where needed.
AREAS COVERED
The objective of this review is assessment of efficacy and safety of α lipoic acid (ALA, also thioctic acid) in pathogenesis-oriented treatment of diabetic neuropathy. The mechanisms of action of ALA in experimental diabetic neuropathy include reduction of oxidative stress along with improvement in nerve blood flow, nerve conduction velocity, and several other measures of nerve function. There is ample evidence from randomised, double-blind, placebo-controlled clinical trials and meta-analyses, suggesting that ALA is efficacious and safe for the diabetic neuropathy, accomplishing clinically meaningful improvements.
EXPERT OPINION
ALA is a valuable therapeutic option for diabetic neuropathy. When compared with currently licensed analgesic drugs, it is better tolerated, has a more rapid onset of action, and improves paraesthesiae, numbness, sensory deficits, and muscle strength in addition to neuropathic pain. In clinical practice, ALA may be chosen in patients with early neuropathic deficits and symptoms, in whom clinical improvement is more likely. ALA should also be considered when comorbidities render other analgesics less appropriate or in the presence of cardiovascular autonomic neuropathy.
Topics: Antioxidants; Clinical Trials as Topic; Diabetes Complications; Diabetes Mellitus; Diabetic Neuropathies; Half-Life; Humans; Reactive Oxygen Species; Thioctic Acid
PubMed: 25381809
DOI: 10.1517/14656566.2014.972935 -
Treatments in Endocrinology 2004Diabetic neuropathy represents a major health problem, as it is responsible for substantial morbidity, increased mortality, and impaired quality of life.... (Review)
Review
Diabetic neuropathy represents a major health problem, as it is responsible for substantial morbidity, increased mortality, and impaired quality of life. Near-normoglycemia is now generally accepted as the primary approach to prevention of diabetic neuropathy, but is not achievable in a considerable number of patients. A growing body of evidence suggests that oxidative stress resulting from enhanced free-radical formation and/or defects in antioxidant defense is implicated in the pathogenesis of diabetic neuropathy. Markers of oxidative stress such as superoxide anion and peroxynitrite production are increased in diabetic patients in relation to the severity of polyneuropathy. In experimental diabetic neuropathy, oxygen free-radical activity in the sciatic nerve is increased, and treatment with thioctic acid, a potent lipophilic antioxidant, results in prevention or improvement of the diabetes-induced neurovascular and metabolic abnormalities in various organ systems. Pharmacodynamic studies have shown that thioctic acid favorably influences the vascular abnormalities of diabetic polyneuropathy such as impaired microcirculation, increased indices of oxidative stress, and increased levels of markers for vascular dysfunction, such as thrombomodulin, albuminuria, and nuclear factor-kappaB. Thus far, seven controlled randomized clinical trials of thioctic acid in patients with diabetic neuropathy have been completed (Alpha-Lipoic Acid in Diabetic Neuropathy [ALADIN I-III], Deutsche Kardiale Autonome Neuropathie [DEKAN], Oral Pilot [ORPIL], Symptomatic Diabetic Neuropathy [SYDNEY], Neurological Assessment of Thioctic Acid in Neuropathy [NATHAN] II) using different study designs, durations of treatment, doses, sample sizes, and patient populations. Recently, a comprehensive analysis was undertaken of trials with comparable designs that met specific eligibility criteria for a meta-analysis to obtain a more precise estimate of the efficacy and safety of thioctic acid (600mg intravenously for 3 weeks) in diabetic patients with symptomatic polyneuropathy. This meta-analysis included the largest sample of diabetic patients (n = 1258) ever to have been treated with a single drug or class of drugs to reduce neuropathic symptoms, and confirmed the favorable effects of thioctic acid based on the highest level of evidence (Class Ia: evidence from meta-analyses of randomized, controlled trials). The following conclusions can be drawn from these trials: (i) short-term treatment for 3 weeks using intravenous thioctic acid 600 mg/day reduces the chief symptoms of diabetic polyneuropathy to a clinically meaningful degree; (ii) this effect on neuropathic symptoms is accompanied by an improvement of neuropathic deficits, suggesting potential for the drug to favorably influence underlying neuropathy; (iii) oral treatment for 4-7 months tends to reduce neuropathic deficits and improve cardiac autonomic neuropathy; and (iv) clinical and postmarketing surveillance studies have revealed a highly favorable safety profile of the drug. Based on these findings, a pivotal long-term multicenter trial of oral treatment with thioctic acid (NATHAN I) is being conducted in North America and Europe to investigate effects on progression of diabetic polyneuropathy, using a clinically meaningful and reliable primary outcome measure that combines clinical and neurophysiological assessment.
Topics: Animals; Antioxidants; Diabetic Neuropathies; Humans; Thioctic Acid
PubMed: 16026113
DOI: 10.2165/00024677-200403030-00005 -
Ceska a Slovenska Farmacie : Casopis... 2020To identify possible interactions of components in dosage forms, studies are usually carried out at the stage of pharmaceutical development. Such studies can predict...
To identify possible interactions of components in dosage forms, studies are usually carried out at the stage of pharmaceutical development. Such studies can predict compatibility of active pharmaceutical ingredients and excipients in order to optimize drug formulation and certain parameters of technological process. Compatibility of some components of a newly developed neuroprotective medicinal product Neuronucleos, namely, thioctic acid, pyridoxine hydrochloride, magnesium stearate and magnesium lactate, was studied by means of differential scanning calorimetry (DSC) and Fourier-transform infrared spectroscopy (FTIR). No interactions were observed between thioctic acid and pyridoxine hydrochloride. Formation of an intermolecular complex between thioctic acid and magnesium stearate was established, in which this acid substitutes the crystalline water of magnesium stearate. No significant interactions were found for magnesium lactate with thioctic acid or magnesium stearate. Thus, pharmaceutical compatibility of the most of the tested Neuronucleos components was studied and established, with the only exception (thioctic acid with magnesium stearate). Moreover, the present study provides valuable information about thermal effects in a certain temperature range, which is important for setting the technological process parameters.
Topics: Excipients; Magnesium Compounds; Pyridoxine; Stearic Acids; Thioctic Acid
PubMed: 32460509
DOI: No ID Found -
Biochimica Et Biophysica Acta Oct 2009Alpha-lipoic acid (LA) has become a common ingredient in multivitamin formulas, anti-aging supplements, and even pet food. It is well-defined as a therapy for preventing... (Review)
Review
Alpha-lipoic acid (LA) has become a common ingredient in multivitamin formulas, anti-aging supplements, and even pet food. It is well-defined as a therapy for preventing diabetic polyneuropathies, and scavenges free radicals, chelates metals, and restores intracellular glutathione levels which otherwise decline with age. How do the biochemical properties of LA relate to its biological effects? Herein, we review the molecular mechanisms of LA discovered using cell and animal models, and the effects of LA on human subjects. Though LA has long been touted as an antioxidant, it has also been shown to improve glucose and ascorbate handling, increase eNOS activity, activate Phase II detoxification via the transcription factor Nrf2, and lower expression of MMP-9 and VCAM-1 through repression of NF-kappa B. LA and its reduced form, dihydrolipoic acid, may use their chemical properties as a redox couple to alter protein conformations by forming mixed disulfides. Beneficial effects are achieved with low micromolar levels of LA, suggesting that some of its therapeutic potential extends beyond the strict definition of an antioxidant. Current trials are investigating whether these beneficial properties of LA make it an appropriate treatment not just for diabetes, but also for the prevention of vascular disease, hypertension, and inflammation.
Topics: Animals; Diabetic Neuropathies; Dietary Supplements; Humans; Hypertension; Inflammation; Models, Biological; Molecular Structure; Thioctic Acid; Vascular Diseases
PubMed: 19664690
DOI: 10.1016/j.bbagen.2009.07.026 -
The Journal of International Medical... May 2018Objective To examine the effect of α-lipoic acid on neuropathic symptoms in patients with diabetic neuropathy (DN). Methods Patients with painful DN were treated with... (Clinical Trial)
Clinical Trial
Objective To examine the effect of α-lipoic acid on neuropathic symptoms in patients with diabetic neuropathy (DN). Methods Patients with painful DN were treated with 600 mg/day α-lipoic acid, orally, for 40 days. Neuropathy Symptom Score (NSS), Subjective Peripheral Neuropathy Screen Questionnaire (SPNSQ) and douleur neuropathique (DN)4 questionnaire scores were assessed at baseline and day 40. Quality-of-life treatment effects were assessed by Brief Pain Inventory (BPI), Neuropathic Pain Symptom Inventory (NPSI) and Sheehan Disability Scale (SDS). Changes in body weight, arterial blood pressure, fasting serum glucose and lipids were also assessed. Results Out of 72 patients included, significant reductions in neuropathic symptoms were shown by reduced NSS, SPNSQ and DN4 scores at day 40 versus baseline. BPI, NPSI, and SDS in terms of work disability, social life disability, and family life disability scores were also significantly reduced. Moreover, 50% of patients rated their health condition as 'very much better' or 'much better' following α-lipoic acid administration. Fasting triglyceride levels were reduced, but no difference was found in body weight, blood pressure, fasting glucose, or other lipids at day 40 versus baseline. Conclusions A-lipoic acid administration was associated with reduced neuropathic symptoms and triglycerides, and improved quality of life.
Topics: Adult; Aged; Demography; Diabetic Neuropathies; Disability Evaluation; Female; Humans; Male; Neuralgia; Quality of Life; Surveys and Questionnaires; Thioctic Acid
PubMed: 29517942
DOI: 10.1177/0300060518756540 -
Neurochemical Research Jul 2022Lipoic acid (α-LA) (1,2-dithiolane3-pentanoic acid (CHOS) is also called thioctic acid with an oxidized (disulfide, LA) and a reduced (di-thiol: dihydro-lipoic acid,... (Review)
Review
Lipoic acid (α-LA) (1,2-dithiolane3-pentanoic acid (CHOS) is also called thioctic acid with an oxidized (disulfide, LA) and a reduced (di-thiol: dihydro-lipoic acid, DHLA) form of LA. α-LA is a potent anti-oxidative agent that has a significant potential to treat neurodegenerative disorders. α-LA is both hydrophilic and hydrophobic in nature. It is widely distributed in plants and animals in cellular membranes and in the cytosol, which is responsible for LA's action in both the cytosol and plasma membrane. A systematic literature review of Bentham, Scopus, PubMed, Medline, and EMBASE (Elsevier) databases was carried out to understand the Nature and mechanistic interventions of the α-Lipoic acid for central nervous system diseases. Moreover, α-LA readily crosses the blood-brain barrier, which is a significant factor for CNS activities. The mechanisms of α-LA reduction are highly tissue-specific. α-LA produces its neuroprotective effect by inhibiting reactive oxygen species formation and neuronal damage, modulating protein levels, and promoting neurotransmitters and anti-oxidant levels. Hence, the execution of α-LA as a therapeutic ingredient in the therapy of neurodegenerative disorders is promising. Finally, based on evidence, it can be concluded that α-LA can prevent diseases related to the nervous system.
Topics: Animals; Antioxidants; Neurodegenerative Diseases; Neuroprotective Agents; Oxidation-Reduction; Thioctic Acid
PubMed: 35445914
DOI: 10.1007/s11064-022-03598-w -
Molecules (Basel, Switzerland) Jul 2014Oligonucleotide gold nanoparticle conjugates are being used as diagnostic tools and gene silencing experiments. Thiol-chemistry is mostly used to functionalize gold...
Oligonucleotide gold nanoparticle conjugates are being used as diagnostic tools and gene silencing experiments. Thiol-chemistry is mostly used to functionalize gold nanoparticles with oligonucleotides and to incorporate DNA or RNA molecules onto gold surfaces. However, the stability of such nucleic acid-gold nanoparticle conjugates in certain conditions may be a limitation due to premature break of the thiol-gold bonds followed by aggregation processes. Here, we describe a straightforward synthesis of oligonucleotides carrying thioctic acid moiety based on the use of several thioctic acid-L-threoninol derivatives containing different spacers, including triglycine, short polyethyleneglycol, or aliphatic spacers. The novel thioctic-oligonucleotides were used for the functionalization of gold nanoparticles and the surface coverage and stability of the resulting thioctic-oligonucleotide gold nanoparticles were assessed. In all cases gold nanoparticles functionalized with thioctic-oligonucleotides had higher loadings and higher stability in the presence of thiols than gold nanoparticles prepared with commercially available thiol-oligonucleotides. Furthermore, the thioctic derivative carrying the triglycine linker is sensitive to cathepsin B present in endosomes. In this way this derivative may be interesting for the cellular delivery of therapeutic oligonucleotides as these results provides the basis for a potential endosomal escape.
Topics: Gold; Metal Nanoparticles; Oligodeoxyribonucleotides; Thioctic Acid
PubMed: 25045890
DOI: 10.3390/molecules190710495 -
Zhurnal Nevrologii I Psikhiatrii Imeni... 2011
Review
Topics: Antioxidants; Humans; Hyperglycemia; Oxidative Stress; Thioctic Acid
PubMed: 22500323
DOI: No ID Found -
Neuroscience Letters Apr 1994Thioctic acid (alpha-lipoic acid) and dihydrolipoic acid are endogenous, interconvertible cofactors of the mitochondrial pyruvate dehydrogenase and alpha-ketoglutarate...
Thioctic acid (alpha-lipoic acid) and dihydrolipoic acid are endogenous, interconvertible cofactors of the mitochondrial pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase complexes. These compounds help to maintain glutathione and alpha-tocopherol in their reduced states, and they possess intrinsic free radical scavenging properties. We examined whether systemic treatment with thioctic acid or dihydrolipoic acid is protective against direct- and indirect-acting excitotoxins. Adult rats were treated for 10 days with intraperitoneal injections of vehicle, thioctic acid or dihydrolipoic acid, and on day 7 of treatment animals received unilateral stereotaxic injections of NMDA or malonic acid into the striatum. Histological assessment 3 days after the stereotaxic injections revealed a marked reduction in lesion volume in animals treated with thioctic acid or dihydrolipoic acid. We conclude that thioctic acid and dihydrolipoic acid are neuroprotective against direct and indirect excitotoxic insults.
Topics: Animals; Injections, Intraperitoneal; Male; Malonates; Mitochondria; N-Methylaspartate; Neostriatum; Rats; Rats, Sprague-Dawley; Thioctic Acid
PubMed: 8084483
DOI: 10.1016/0304-3940(94)90593-2