J Clin Pharmacol. 2005 Mar;45(3):313-28. Pharmacokinetics of alpha-lipoic Acid in
subjects with severe kidney damage and end-stage renal disease.
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.
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.
Ageing Res Rev. 2004 Jul;3(3):303-18. Heme, iron, and the mitochondrial decay
of ageing.
Atamna H.
Childrens Hospital Oakland Research Institute (CHORI), 5700 Martin
Luther King Jr. Way, Oakland, CA 94609-1673, USA.
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.
Arch Dermatol Res. 2004 Jun 24 [Epub ahead of
print] alpha-Lipoic acid-based PPARgamma agonists
for treating inflammatory skin diseases.
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.
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.
Chem Biol Interact. 2004 Apr 15;147(3):259-71.
Therapeutic efficacy of lipoic acid in combination
with dimercaptosuccinic acid against lead-induced renal tubular
defects and on isolated brush-border enzyme activities.
Sivaprasad TR, Malarkodi SP, Varalakshmi P.
Department of Medical Biochemistry, Dr. A.L.M. PGIBMS, University
of Madras, Taramani Campus, Chennai 600113, India.
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.
Curr Med Chem. 2004 May;11(9):1135-46. Lipoic acid as a potential therapy for chronic
diseases associated with oxidative stress.
Smith AR, Shenvi SV, Widlansky M, Suh JH, Hagen TM.
Dept. of Biochemistry and Biophysics and the Linus Pauling Institute,
571 Weniger Hall, Oregon State University, Corvallis, Oregon 97331,
USA.
alpha-Lipoic acid (LA), a naturally occurring dithiol compound,
has long been known as an essential cofactor for mitochondrial
bioenergetic enzymes. Aside from its enzymatic role, in vitro
and in vivo studies suggest that LA also acts as a powerful micronutrient
with diverse pharmacologic and antioxidant properties. Pharmacologically,
LA improves glycemic control, polyneuropathies associated with
diabetes mellitus, and effectively mitigates toxicities associated
with heavy metal poisoning. As an antioxidant, LA directly terminates
free radicals, chelates transition metal ions (e.g. iron and copper),
increases cytosolic glutathione and vitamin C levels and prevents
toxicities associated with their loss. These diverse actions suggest
that LA acts by multiple mechanisms both physiologically and pharmacologically,
many of which are only now being explored. Herein, we review the
known biochemical properties of LA with particular reference to
how LA may be an effective agent to ameliorate certain pathophysiologies
of many chronic diseases.
Plant Physiol Biochem. 2004 Apr;42(4):329-34.
The role of lipoic acid in the regulation
of the redox status of wheat irrigated with 20% sea water.
DAmico ML, Navari-Izzo F, Sgherri C, Izzo R.
Dipartimento di Chimica e Biotecnologie Agrarie, Via del Borghetto,
80-56124 Pisa, Italy.
The effect of irrigation with 20% sea water was studied in 14
and 21-day-old seedlings of durum wheat (Triticum durum, cv. Ofanto).
Comparisons between control (Hoagland's 2 solution) and treated
(20% sea water in Hoagland's solution) plants included, besides
HPLC determination of reduced (DHLA) and oxidised (LA) forms of
lipoic acid, ascorbate and glutathione contents, their redox status,
the activity of ascorbate peroxidase (APX, EC 1.11.1.11.) and
glutathione reductase (GR, EC 1.6.4.2.). The results indicated
a more relevant presence of lipoic acid in the roots in comparison
to the shoots. An involvement of its reduced form in the regeneration
of the reduced glutathione, at least at 14 days of treatment,
suggested, besides its role as dehydrogenase enzyme cofactor,
a role in the recycling of the other antioxidants. The amount
of LA always increased with growth in shoots and decreased in
roots, while DHLA remained constant in control and increased in
treated plants. Besides, the oxidised form always decreased with
sea water while the reduced form decreased in shoots and increased
in roots. The ascorbate pool exerted its positive influence especially
in the shoots, while APX and GR activities resulted differently
modulated by the salinity level.
Diabet Med. 2004 Feb;21(2):114-21. Treatment of symptomatic diabetic polyneuropathy
with the antioxidant alpha-lipoic acid: a meta-analysis.
Ziegler D, Nowak H, Kempler P, Vargha P, Low PA.
German Diabetes Research Institute, Leibriz Institute at the Heinrich
Heine University, Dusseldorf, Germany.
AIMS: To determine the efficacy and safety of 600 mg of alpha-lipoic
acid given intravenously over 3 weeks in diabetic patients with
symptomatic polyneuropathy. METHODS: We searched the database
of VIATRIS GmbH, Frankfurt, Germany, for clinical trials of alpha-lipoic
acid according to the following prerequisites: randomized, double-masked,
placebo-controlled, parallel-group trial using alpha-lipoic acid
infusions of 600 mg i.v. per day for 3 weeks, except for weekends,
in diabetic patients with positive sensory symptoms of polyneuropathy
which were scored by the Total Symptom Score (TSS) in the feet
on a daily basis. Four trials (ALADIN I, ALADIN III, SYDNEY, NATHAN
II) comprised n=1258 patients (alpha-lipoic acid n=716; placebo
n=542) met these eligibility criteria and were included in a meta-analysis
based on the intention-to-treat principle. Primary analysis involved
a comparison of the differences in TSS from baseline to the end
of i.v. Treatment between the groups treated with alpha-lipoic
acid or placebo. Secondary analyses included daily changes in
TSS, responder rates (> or =50% improvement in TSS), individual
TSS components, Neuropathy Impairment Score (NIS), NIS of the
lower limbs (NIS-LL), individual NIS-LL components, and the rates
of adverse events. RESULTS: After 3 weeks the relative difference
in favour of alpha-lipoic acid vs. placebo was 24.1% (13.5, 33.4)
(geometric mean with 95% confidence interval) for TSS and 16.0%
(5.7, 25.2) for NIS-LL. The responder rates were 52.7% in patients
treated with alpha-lipoic acid and 36.9% in those on placebo (P<0.05).
On a daily basis there was a continuous increase in the magnitude
of TSS improvement in favour of alpha-lipoic acid vs. placebo
which was noted first after 8 days of treatment. Among the individual
components of the TSS, pain, burning, and numbness decreased in
favour of alpha-lipoic acid compared with placebo, while among
the NIS-LL components pin-prick and touch-pressure sensation as
well as ankle reflexes were improved in favour of alpha-lipoic
acid after 3 weeks. The rates of adverse events did not differ
between the groups. CONCLUSIONS: The results of this meta-analysis
provide evidence that treatment with alpha-lipoic acid (600 mg/day
i.v.) over 3 weeks is safe and significantly improves both positive
neuropathic symptoms and neuropathic deficits to a clinically
meaningful degree in diabetic patients with symptomatic polyneuropathy.
J Neuroimmunol. 2004 Mar;148(1-2):146-53. Alpha-lipoic acid is effective in prevention
and treatment of experimental autoimmune encephalomyelitis.
Morini M, Roccatagliata L, Dell'Eva R, Pedemonte E, Furlan R,
Minghelli S, Giunti D, Pfeffer U, Marchese M, Noonan D, Mancardi
G, Albini A, Uccelli A.
Molecular Oncology Laboratory, National Cancer Research Institute,
Genoa, Italy.
Alpha-lipoic acid (alpha-LA) is a neuroprotective metabolic antioxidant
that has been shown to cross the blood brain barrier. We tested
whether alpha-LA is capable to prevent MOG35-55-induced experimental
autoimmune encephalomyelitis (EAE), an established model of multiple
sclerosis (MS). Daily oral administration of alpha-LA, starting
at the time of immunization, significantly prevented EAE progression
as compared to control mice. This was associated with a reduction
of CNS infiltrating T cells and macrophages as well as decreased
demyelination. We then tested alpha-LA in a therapeutic protocol
aimed at suppressing EAE after its onset. Intraperitoneal (i.p.),
but not oral, administration of alpha-LA significantly prevented
disease progression when compared to vehicle-treated controls.
Similarly, we observed significant reduction of demyelination
and inflammatory infiltration. This clinical effect was not due
to an impairment of MOG35-55 recognition by encephalitogenic T
cells. In contrast, MOG-specific T cells showed a decreased production
of IFNgamma and IL-4, suggesting an immunosuppressive activity
on both Th1 and Th2 cytokines. In addition, alpha-LA inhibited
the proteolytic activity of MMP2 and MMP9 only at very high doses.
Our data indicate that alpha-LA can effectively interfere with
the autoimmune reaction associated with EAE through mechanisms
other than its antioxidant activity and supports further studies
on the use of alpha-LA as a potential therapy for MS.
Cochrane Database Syst Rev. 2004;(1):CD004244.
Alpha lipoic acid for dementia.
Sauer J, Tabet N, Howard R.
Section of Old Age Psychiatry, Institute of Psychiatry, De Crespigny
Park, London, UK, SE5 8AF.
BACKGROUND: Oxidative processes have been implicated in the pathogenesis
of neurodegenerative dementias including Alzheimer's disease.
Protecting the central nervous system against these damaging mechanisms
may be a useful therapeutic approach. Alpha lipoic acid (ALA)
is an endogenous antioxidant that interrupts cellular oxidative
processes in both its oxidized and reduced forms. These properties
might qualify ALA for a modulatory role in the treatment of people
with dementia. OBJECTIVES: To assess the role and clinical efficacy
of alpha lipoic acid in the treatment of dementia. SEARCH STRATEGY:
A search of the Specialized Register of the Cochrane Dementia
and Cognitive Improvement Group (CDCIG) on 3 February 2003 using
the terms 'alpha lipoic acid' and 'thioctic'. The CDCIG Specialized
register is updated regularly and contains records from all major
health care databases (MEDLINE, EMBASE, PsycInfo, CINAHL) as well
as from many trials databases. SELECTION CRITERIA: All double-blind
randomized placebo-controlled trials examining the efficacy of
alpha lipoic acid in dementia DATA COLLECTION AND ANALYSIS: No
trials were found that met the selection criteria MAIN RESULTS:
No meta-analysis could be performed. A systematic search of the
Specialized Register of the Cochrane Dementia and Cognitive Improvement
Group, as well as registers of ongoing and unpublished trials
could not identify any studies investigating the use of ALA for
dementia. REVIEWER'S CONCLUSIONS: In the absence of randomized
double-blind placebo-controlled trials investigating ALA for dementia,
no evidence exists to explore any potential effects. Until data
from trials become available for analysis, ALA cannot be recommended
for people with dementia.
J Biol Chem. 2004 Mar 12;279(11):9693-7. Epub
2003 Dec 29. Lipoic acid protects efficiently only against
a specific form of peroxynitrite-induced damage.
Rezk BM, Haenen GR, van der Vijgh WJ, Bast A.
Department of Pharmacology and Toxicology, Faculty of Medicine,
Universiteit Maastricht, The Netherlands.
The ability of the sulfur-containing compounds glutathione (GSH),
glutathione disulphide (GSSG), S-methylglutathione (GSMe), lipoic
acid (LA), and dihydrolipoic acid (DHLA) to protect against hypochlorous
acid (HOCl)-mediated damage and peroxynitrite (ONOOH)-induced
damage has been compared. Protective activity was assessed in
competition assays by monitoring several detectors, i.e. dihydrorhodamine-123
(DHR-123) oxidation, alpha(1)-antiproteinase (alpha(1)-AP) inactivation,
and glutathione S-transferase P1-1 (GST-P1-1) inactivation. In
addition, nitration of tyrosine was measured to assess protection
of the sulfur-containing compounds against ONOOH. For protection
against HOCl, the efficacy of the antioxidant was controlled by
the ratio of the reaction rates of the antioxidant and the detector
molecule with the oxidant. The rank order of the activity of the
antioxidants (GSH > DHLA approximately LA approximately GSMe
> GSSG) appeared to be independent of the detector used. However,
the rank order of the antioxidants against ONOOH-induced damage
is strongly dependent on the detector. LA was 40 times less active
than GSH in the inhibition of ONOOH-induced DHR-123 oxidation,
whereas LA was 20 times more active than GSH in preventing the
inhibition of GST-P1-1 by ONOOH. This points to different molecular
mechanisms of ONOOH damage to DHR-123 compared with ONOOH damage
to GST-P1-1. LA is a poor antioxidant in protecting against the
form of ONOOH damage involved in DHR-123 oxidation. In the form
of ONOOH toxicity involved in GST-P1-1 inhibition, LA is the most
potent sulfur-containing antioxidant in our series. It is proposed
that an intermediate product in which both sulfur atoms of LA
have reacted is involved in the reaction of ONOOH with LA. The
high potency of LA to protect GST-P1-1 against ONOOH might be
of therapeutic interest.
Avian Pathol. 2003 Dec;32(6):645-53. Prophylactic action of lipoic acid on oxidative
stress and growth performance in broilers at risk of developing
ascites syndrome.
Diaz-Cruz A, Serret M, Ramirez G, Avila E, Guinzberg R, Pina E.
Department of Animal Nutrition and Biochemistry, Faculty of Veterinary
Medicine and Zootechnics, National Autonomous University of Mexico,
Mexico.
The objective of this study was to assess the effects of dietary
supplementation with lipoic acid (LA) on broilers maintained at
2235 m above sea level with high risk to develop ascites syndrome
(AS). A total of 2040 chicks were fed under commercial conditions
with water and specific diets ad libitum during 7 weeks in two
consecutive experiments. Mortality and indicators of performance
and oxidative stress were compared weekly in broilers fed a basal
diet plus 0, 10, 20, or 40 parts/10(6) LA. The effects of LA at
40 parts/10(6) were also studied during the initial 3 weeks or
the last 4 weeks of the production cycle. Diets supplemented with
40 parts/10(6) of LA during 7 weeks significantly improved feed
conversion, decreased general mortality and mortality attributable
to AS, and lowered thiobarbituric acid reactive substances and
hydroxyl radicals in liver, and increased total glutathione pool.
Smaller doses or shorter periods of exposure to LA were partially
effective. In conclusion, LA under our experimental conditions
has a prophylactic action in broilers with high risk to develop
AS due to oxygen availability limitation.
Toxicol In Vitro. 2003 Oct-Dec;17(5-6):753-9.
Protective effect of lipoic acid against
hydrogen peroxide in yeast cells.
Della Croce C, Bronzetti G, Cini M, Caltavuturo L, Poi G.
Institute of Biology and Agricultural Biotechnology (IBBA), CNR
Research Area, Via Moruzzi, 56124 Pisa, Italy.
Lipoic acid (LA) is found in all kinds of cells, it is widely
used in medicine and as a dietary supplement, and it is involved
in different physiological functions. Even if there are many papers
regarding therapeutic effects of LA, medical research does not
always support its effectiveness and little is known about LA
metabolism in eukaryotic cells. In this work the probable protective
effect of LA was investigated employing five strains of yeast
Saccharomyces cerevisiae through short term assays. In particular
LA behaviour in oxidative stress conditions was studied. For this
purpose hydrogen peroxide was used as oxidant. In D7 strain, LA
showed antimutagenic effects against hydrogen peroxide and decreased
significantly cytochrome P450. To better elucidate the effect
of LA the following yeast strains carrying deletions in superoxide
dismutase genes (SOD) were employed: EG-103 (wild type), EG-110
strain (without mytochondrial SOD), EG-118 (without cytoplasmatic
SOD) and EG-133 (without both enzymes). LA increased the number
of mitotic divisions in EG-103, EG-110 and EG-133 and in growing
cells (EG-103, EG-110, EG-118) it increased survival percentage
with respect to hydrogen peroxide. The positive action was evident
in D7 and in EG strains and it showed that LA can be protective
and antimutagenic against oxidants in yeast cells, via its antioxidant
activity.
Arch Environ Health. 2003 Aug;58(8):528-32. Lipoic acid as a potential first agent for
protection from mycotoxins and treatment of mycotoxicosis.
Rogers SA.
Northeast Center for Environmental Medicine, Sarasota, Florida,
USA.
Mycotoxins--toxic substances produced by fungi or molds--are ubiquitous
in the environment and are capable of damaging multiple biochemical
mechanisms, resulting in a variety of human symptoms referred
to collectively as "mycotoxicosis." In fact, mycotoxins
mimic multiple xenobiotics, not only with respect to their ultimate
damage, but also in their routes of detoxification. This suggests
potential therapeutic options for the challenging treatment of
mycotoxicosis. In this brief review, the author examines the use
of lipoic acid as an example of an inexpensive and available nutrient
that has been shown to protect against, or reverse, the adverse
health effects of mycotoxins.
