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Title
Trial of d-alpha-tocopherol in Huntington`s disease.
Author
Peyser CE; Folstein M; Chase GA; Starkstein S; Brandt J; Cockrell
JR;
Bylsma F; Coyle JT; McHugh PR; Folstein SE
Address
Department of Psychiatry' Johns Hopkins University School of
Medicine'
USA.
Source
Am J Psychiatry, 152(12):1771-5 1995 Dec
Abstract
OBJECTIVE: Evidence suggests that the neuropathology of Huntington`s
disease' a neuropsychiatric disorder due to a mutation on chromosome
4'
results from excessive activation of glutamate-gated ion channels'
which kills neurons by oxidative stress. Therefore' the authors
hypothesized that alpha-tocopherol' which reduces oxyradical
damage to
cell membranes' might slow the course of Huntington`s disease.
METHOD:
A prospective' double-blind; placebo-controlled study of high-dose
d-alpha-tocopherol treatment was carried out with a cohort of
73
patients with Huntington`s disease who were randomly assigned
to either
d-alpha-tocopherol or placebo. Patients were monitored for changes
in
neurologic and neuropsychologic symptoms. RESULTS: Treatment
with
d-alpha-tocopherol had no effect on neurologic and neuropsychiatric
symptoms in the treatment group overall. However' post hoc analysis
revealed a significant selective therapeutic effect on neurologic
symptoms for patients early in the course of the disorder. CONCLUSIONS:
Antioxidant therapy may slow the rate of motor decline early
in the
course of Huntington`s disease.
Title
Pharmacokinetics and tissue uptake of d-alpha-tocopherol in sheep
following a single intraperitoneal inJection.
Author
Toutain PL; Hidiroglou M; Charmley E
Address
Ecole Nationale V]et]erinaire de Toulouse Unit]e Associ]ee INRA
de
Physiopathologie et Toxicologie exp]erimentales' Toulouse' France.
Source
J Dairy Sci, 78(7):1561-6 1995 Jul
Abstract
d-alpha-tocopherol in an emulsible base was administered i.p.
to four
groups of five sheep each at doses of 0' 1250' 2500' and 5000
IU. Blood
was sampled regularly until slaughter at 7 d after administration.
Plasma and tissue concentrations of d-alpha-tocopherol were measured
by
HPLC. Pharmacokinetic analysis of plasma concentrations' for
the three
tested doses' showed an absence of significant difference for
lag time
to absorption (.9 to 2.5 h)' half-time of absorption (15 to 30
h)'
plasma half-life (31 to 42 h)' and time of maximal concentration
(18 to
31 h). In contrast' dose had a significant effect on area under
the
tocopherol plasma curve and on the maximal concentration. For
both
parameters' statistical evidence indicated nonlinearity for disposition
of D-alpha-tocopherol' but without biological significance; by
7 d
after dosing' amounts of residue of tocopherol were highest in
the
pancreas and adrenal glands (approximately 65 and 47 micrograms/g'
respectively' for the 5000 IU dose) and lowest in neck muscle
(approximately 4 micrograms/g for the 5000 IU dose). Kidney had
an
intermediate level of tocopherol. The intraperitoneal route is
an
efficient route for tocopherol administration in sheep.
Title
d-alpha-tocopherol treatment prevents glomerular dysfunctions
in
diabetic rats through inhibition of protein kinase C-diacylglycerol
pathway.
Author
Koya D; Haneda M; Kikkawa R; King GL
Address
Third Department of Medicine, Shiga University of Medical Science,
Otsu, Japan.
Source
Biofactors, 7(1-2):69-76 1998
Abstract
Since diabetes now accounts for 35% of all new cases of end-stage
renal
disease in the United States, it is really important to prevent
the
onset of diabetic nephropathy. Activation of protein kinase C
(PKC) is
implicated to be one of the causal factors in the development
of renal
dysfunctions in diabetes. In this study, we have demonstrated
that
total diacylglycerol (DAG) contents and PKC activity in glomeruli
were
significantly increased in diabetic rats as compared to control
rats,
but intraperitoneal injection of d-alpha-tocopherol prevented
these
biochemical abnormalities in parallel with normalization of glomerular
dysfunction such as increased glomerular filtration rate (GFR)
in
diabetic rats. Albuminuria in diabetic rats was also significantly
increased as compared to control rats, whereas d-alpha-tocopherol
treatment again ameriolated increased albuminuria in parallel
with the
inhibition of glomerular PKC activation by diabetes. Moreover,
we have
observed that the activity of DAG kinase, which metabolizes DAG
to
phosphatidic acid and acts as an attenuator for the DAG-PKC pathway,
was enhanced by d-alpha-tocopherol treatment. These results suggest
that the increase in the DAG-PKC pathway might play an important
role
for the development of glomerular dysfunctions in diabetes and
d-alpha-tocopherol treatment could be helpful in diabetic nephropathy.
Title
Antioxidant and cytotoxic tocopheryl quinones in normal and cancer
cells.
Author
Thornton DE; Jones KH; Jiang Z; Zhang H; Liu G; Cornwell DG
Address
Department of Medical Biochemistry' Ohio State University' Columbus
43210' USA.
Source
Free Radic Biol Med, 18(6):963-76 1995 Jun
Abstract
We found previously that [d -alpha-tocopherol (alpha-T) and [d
-gamma-tocopherol (gamma-T) are lipid antioxidants (thiobarbituric
acid
test) in model systems containing arachidonic acid (AA)' cumene
hydroperoxide' and Fe3+ and in smooth muscle cell (SMC) cultures
challenged with AA. We now show that [d -alpha-tocopherylquinone
(alpha-TQ)' [d -delta-tocopherylquinone (delta-TQ)' and [d
-gamma-tocopherylquinone (gamma-TQ) are antioxidants at low
concentrations and prooxidants at high concentrations in the
model
system. Prooxidant activity is greater with gamma-TQ than either
alpha-TQ or delta-TQ. Low concentrations of alpha-TQ' delta-TQ'
and
gamma-TQ are also antioxidants in SMC cultures challenged with
AA.
Unlike alpha-TQ' partially substituted gamma-TQ and glutathione
(GSH)
form a Michael adduct which has been purified and characterized.
We
found previously that alpha-T' gamma-T' and alpha-TQ are mitogenic
in
SMC. We now report that both delta-TQ and gamma-TQ but not alpha-TQ
show concentration-dependent cytotoxicity (changes in morphology'
propidium iodide stain) in SMC cultures. Cytotoxicity is greater
with
gamma-TQ than delta-TQ. An acute lymphoblastic leukemia (ALL)
cell line
shows greater chemosensitivity (MTT and Neutral Red assays) to
gamma-TQ
than to either doxorubicin (DOX) or vinblastine (VLB). An ALL
cell line
resistant to both DOX and VLB retains the same chemosensitivity
to
gamma-TQ as the drug-sensitive ALL cell line. ALL cell lines
are
unaffected by either alpha-TQ or the GSH Michael adduct of gamma-TQ.
These data show that partially substituted tocopheryl quinones
capable
of forming Michael adducts are potential chemotherapeutic agents
for
multidrug-resistant cancer cells.
Title
Fat-soluble vitamin levels in familial hypercholesterolemia.
Author
Tonstad S; Aksnes L
Address
Medical Department A' National Hospital' Oslo' Norway.
Source
J Pediatr, 130(2):274-80 1997 Feb
Abstract
OBJECTIVE: To examine serum levels of retinol' 25-hydroxyvitamin
D' and
alpha-tocopherol and their potential determinants in familial
hypercholesterolemia (FH). SUBJECTS: Study 1: 151 boys and girls
with
FH aged 7 to 16 years who were following a lipid-reduced diet
but not
taking lipid-lowering drugs. Study 2: 87 boys and girls with
FH' of
whom 24 were taking bile acid-binding resins in addition to the
diet'
and 30 age- and sex-matched control subJects. DESIGN: Cross-sectional
survey. SETTING: Lipid referral clinic. RESULTS: None of the
subJects
had suboptimal retinol or 25-hydroxyvitamin D levels. Only one
girl had
a low alpha-tocopherol level and alpha-tocopherol/lipid ratio.
In
multiple regression analysis' pubertal onset and gender were
associated
with retinol and 25-hydroxyvitamin D levels. The triglyceride
level was
positively related to level of retinol' and body mass index was
inversely related to 25-hydroxyvitamin D level. Vitamin supplementation
was positively related to 25-hydroxyvitamin D level and the
alpha-tocopherol/lipid ratio. This ratio was lower in subJects
whose
total cholesterol level was above the median (8.0 mmol/L (310
mg/dl))
than in subJects whose cholesterol level was below the median
(p =
0.01). In study 2' the alpha-tocopherol/lipid ratio in control
subJects
(median' 5.1 mumol/mmol) was higher than in subJects with FH
who were
not taking resins (median' 3.3 mumol/mmol; p < 0.05) but similar
to the
ratio in treated subJects (median' 5.4 mumol/mmol). CONCLUSIONS:
Pubertal onset' gender' lipid levels' vitamin supplementation'
and body
mass index are significant predictors of fat-soluble vitamin
levels in
children with FH. Though children following a lipid-lowering
diet have
normal serum levels of fat-soluble vitamins' the alpha-tocopherol
level
does not appear to increase proportionately to the increase in
cholesterol level. Treatment with resins may restore a normal
alpha-tocopherol/lipid ratio.
Title
A pilot study of the effects of d-alpha-tocopherol on hepatic
stellate
cell activation in chronic hepatitis C.
Author
Houglum K; Venkataramani A; Lyche K; ChoJkier M
Address
Department of Medicine' Veterans Affairs Medical Center' San
Diego'
California' USA.
Source
Gastroenterology, 113(4):1069-73 1997 Oct
Abstract
BACKGROUND & AIMS: Oxidative stress mediates activation and
stimulates
collagen production of cultured hepatic stellate (Ito) cells.
The aim
of this study was to assess whether oxidative stress contributes
to
hepatic fibrogenesis in chronic hepatitis C. METHODS: In liver
biopsy
specimens of patients with chronic hepatitis C' the following
fibrogenesis cascade was analyzed: (1) oxidative stress' determined
by
the presence of malondialdehyde protein adducts; (2) activation
of
stellate cells as indicated by their expression of alpha-smooth
muscle
actin; (3) stimulation of c-myb expression in stellate cells'
a
critical step in the activation of these cells; and (4) induction
of
collagen gene expression as detected by in situ hybridization.
RESULTS:
Treatment with d-alpha-tocopherol (1200 IU/day for 8 weeks) in
6 of
these patients' who were refractory to interferon therapy' prevented
the fibrogenesis cascade observed before antioxidant treatment.
In
addition' d-alpha-tocopherol treatment significantly decreased
the
carbonyl modifications of plasma proteins' a sensitive index
of
oxidative stress. However' 8 weeks of d-alpha-tocopherol treatment
did
not significantly affect serum alanine aminotransferase levels'
hepatitis C virus titers' or histological degree of hepatocellular
inflammation or fibrosis. CONCLUSIONS: These data suggest that
enhanced
oxidative stress initiates a fibrogenesis cascade in the liver
of
patients with chronic hepatitis C.
Title
Water-soluble prodrug of vitamin E for parenteral use and its
effect on
endotoxin-induced liver toxicity.
Author
Takata J; Ito S; Karube Y; Nagata Y; Matsushima Y
Address
Faculty of Pharmaceutical Sciences' Fukuoka University' Japan.
Source
Biol Pharm Bull, 20(2):204-9 1997 Feb
Abstract
The acid salts of aminoalkanecarboxylic acid esters of
d-alpha-tocopherol were in a previous in vitro study identified
as
prodrug candidates for a parenteral form of d-alpha-tocopherol.
The
disposition of d-alpha-tocopheryl N'N-dimethylaminoacetate
hydrochloride (TDMA)' the most potential candidate for the prodrug'
after a single intravenous administration was investigated and
compared
with that of the d-alpha-tocopheryl acetate (TA) and
dl-alpha-tocopherol' solubilized with HCO-60' in order to establish
the
utility as a prodrug for i.v. administration. The preventive
effect of
the prodrug against endotoxin (lipopolysaccharide (LPS))-induced
liver
lipid peroxidation was also investigated in mice. The plasma
and liver
levels of alpha-tocopherol (Toc) were increased rapidly after
i.v.
administration of the prodrug. The distribution of Toc and TDMA
in the
plasma and the liver at 1 h was as follows; 2.1 +/- 0.2 (plasma'
Toc)'
2.0 +/- 0.2 (plasma' TDMA)' 32.8 +/- 2.9 (liver' Toc)' and 35.3
+/-
6.5% of dose (liver' TDMA). The rapid and liver-selective uptake
and
liver-esterase specific regeneration characteristics of the prodrug
enhance the delivery of Toc to liver. The liver availability
of Toc
after i.v. administration of TDMA' TA and Toc were 116' 50 and
100%'
respectively. The elevation of liver lipid peroxide induced with
LPS
was significantly suppressed to a normal range by a single i.v.
postadministration of TDMA (over 10 mg/kg equivalent for Toc).
These
results indicated that the water-soluble and liver-esterase
hydrolyzable derivative of Toc was a potential candidate for
a
parenteral prodrug which can thus achieve the systemic liver-specific
delivery of Toc. Such effective and selective delivery of Toc
into the
liver can therefore lead to enhanced pharmacological efficacy
against
liver oxidative inJury associated with free radicals.
Title
The effects of alpha tocopherol supplementation on monocyte function.
Decreased lipid oxidation' interleukin 1 beta secretion' and
monocyte
adhesion to endothelium.
Author
DevaraJ S; Li D; Jialal I
Address
Department of Internal Medicine' University of Texas Southwestern
Medical Center' Dallas 75235-9052' USA.
Source
J Clin Invest, 98(3):756-63 1996 Aug 1
Abstract
Low levels of alpha tocopherol are related to a higher incidence
of
cardiovascular disease and increased intake appears to afford
protection against cardiovascular disease. In addition to decreasing
LDL oxidation' alpha tocopherol may exert intracellular effects
on
cells crucial in atherogenesis' such as monocytes. Hence' the
aim of
this study was to test the effect of alpha tocopherol supplementation
on monocyte function relevant to atherogenesis. Monocyte function
was
assessed in 21 healthy subJects at baseline' after 8 wk of
supplementation with d-alpha tocopherol (1'200 IU/d) and after
a 6-wk
washout phase. The release of reactive oxygen species (superoxide
anion' hydrogen peroxide)' lipid oxidation' release of the potentially
atherogenic cytokine' interleukin 1 beta' and monocyte-endothelial
adhesion were studied in the resting state and after activation
of the
monocytes with lipopolysaccharide at 0' 8' and 14 wk. There was
a
2.5-fold increase in plasma lipid-standardized and monocyte alpha
tocopherol levels in the supplemented phase. After alpha tocopherol
supplementation' there were significant decreases in release
of
reactive oxygen species' lipid oxidation' IL-1 beta secretion'
and
monocyte-endothelial cell adhesion' both in resting and activated
cells
compared with baseline and washout phases. Studies with the protein
kinase C inhibitor' Calphostin C' suggest that the inhibition
of
reactive oxygen species release and lipid oxidation is due to
an
inhibition of protein kinase C activity by alpha tocopherol.
Thus' this
study provides novel evidence for an intracellular effect of
alpha
tocopherol in monocytes that is antiatherogenic.
Title
Correlation between human vascular smooth muscle cell proliferation
and
protein kinase C alpha-expression: effect of d-alpha-tocopherol.
Author
Marilley D; Mosieniak G; Boscoboinik D; Azzi A
Address
Institut f ur Biochemie und Molekularbiologie' Universit at Bern'
Switzerland.
Source
Biochem Mol Biol Int, 40(4):699-707 1996 Nov
Abstract
Population doublings of four different human aortic vascular
smooth
muscle cell strains correlate with the amount of protein kinase
C alpha
present in these cells. d-alpha-tocopherol inhibits' at different
extents' protein kinase C activity in all cells studied. Furthermore'
the extent of inhibition positively correlates with amount of
protein
kinase C alpha expression and not with that of the other isoforms.
It
is suggested that' in human aortic smooth muscle cells' protein
kinase
C alpha modulates cell proliferation and serves as a target for
d-alpha-tocopherol inhibition.
Title
Effect of vitamin E and beta carotene on the incidence of angina
pectoris. A randomized' double-blind' controlled trial [see comments
Author
Rapola JM; Virtamo J; Haukka JK; Heinonen OP; Albanes D; Taylor
PR;
Huttunen JK
Address
National Public Health Institute' Helsinki' Finland.
Source
JAMA, 275(9):693-8 1996 Mar 6
Abstract
OBJECTIVE: To examine the effect of supplementation with vitamin
E
(alpha tocopherol)' beta carotene' or both on the incidence of
angina
pectoris in men without known previous coronary heart disease.
DESIGN:
Randomized' double-blind' placebo-controlled trial. SETTING AND
PARTICIPANTS: Participants in the Alpha Tocopherol' Beta Carotene
Cancer Prevention Study (N=29133) were male smokers aged 50 through
69
years who were living in southern and western Finland. Of these
men'
22269 were considered free of coronary heart disease at baseline
and
were followed up for the incidence of angina pectoris. INTERVENTION:
Participants were randomized to receive 50 mg/d of alpha tocopherol'
20
mg/d of beta carotene' both' or placebo in a 2x2 design. OUTCOME
MEASURES: An incident case was defined as the first occurrence
of
typical angina pectoris identified in administering the annually
repeated World Health Organization (Rose) Chest Pain Questionnaire.
RESULTS: During a median follow-up time of 4.7 years (96427
person-years)' 1983 new cases of angina pectoris were detected.
Comparing alpha tocopherol-supplemented subJects with non-alpha
tocopherol-supplemented subJects showed a relative risk (RR)
of angina
pectoris incidence of 0.91 (95% confidence interval[CI ' 0.83
to 0.99;
P=.04). The RR for incidence of angina pectoris for the beta
carotene-
supplemented subJects compared with those not receiving beta
carotene
was 1.06 (95% CI' 0.97 to 1.16; P=.19). Compared with those receiving
placebo' the RRs for incidence of angina pectoris were 0.97 (95%
CI'
0.85 to 1.10) and 0.96 (95% CI' 0.85 to 1.09) in the alpha tocopherol
and alpha tocopherol plus beta carotene groups' respectively'
and 1.13
(95% CI' 1.00 to 1.27) in the beta carotene group (P=.06). Baseline
dietary intakes and serum levels of alpha tocopherol and beta
carotene
did not predict incidence of angina pectoris. CONCLUSIONS:
Supplementation with alpha tocopherol was associated with only
a minor
decrease in the incidence of angina pectoris. Beta carotene had
no
preventive effect and was associated with a slight increase of
angina.
Title
Prodrugs of vitamin E. 1. Preparation and enzymatic hydrolysis
of
aminoalkanecarboxylic acid esters of d-alpha-tocopherol.
Author
Takata J; Karube Y; Nagata Y; Matsushima Y
Address
Faculty of Pharmaceutical Sciences' Fukuoka University' Japan.
Source
J Pharm Sci, 84(1):96-100 1995 Jan
Abstract
Nine aminoalkanecarboxylic acid esters of d-alpha-tocopherol
were
synthesized and evaluated as potential water-soluble prodrugs
suitable
for parenteral administration. The hydrochloric acid salts of
the
esters were soluble in water. The kinetics of hydrolysis of the
esters
was studied in isotonic phosphate buffer' rat plasma' human plasma'
and
rat liver homogenate at 37 degrees C. The hydrolysis of the esters
was
proved to be catalyzed by liver esterases. The susceptibility
of the
esters to undergo liver esterase hydrolysis was affected by the
structure of the amino functionality and size of the acyl moiety
on the
promoiety. The N-methylaminoacetyl and N'N-dimethylaminoacetyl
esters
of d-alpha-tocopherol were more rapidly hydrolyzed than
d-alpha-tocopheryl acetate' a commercially available d-alpha-tocopheryl
ester. These results suggested that the salts of the
N-methylaminoacetyl and N'N-dimethylaminoacetyl esters are promising
prodrug candidates of d-alpha-tocopheryl for parenteral use. |
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