ALPHATOCOPHERYL ACETATE
Alphatocopheryl acetate or vit E are similar, so see record of vit E below for the
details.
Vitamin E Substances
Vitamin E is a generic term applied to a large
number of natural or synthetic compounds. The
most important substances are the tocopherols of
which alpha tocopherols are the most active and
widely distributed in nature; other naturally occur-
ring tocopherols include beta. gamma, and delta to-
copherols, but these are not used in therapeutics.
The other group of compounds with vitamin E activ-
ity are the tocotrienols.
Alpha tocopherols occur naturally in the d optical
isomer form, which is more active than the synthetic
racemic dl form: for further details concerning the
comparative activities of the different forms and iso-
mers of vitamin E compounds, see under Units, be-
low.
d-Alpha Tocopheryl Acid Succinate
Pharmacopoeias. In Eur. US allows it under the title
Vitamin E. USNF also includes Vitamin E Polyethylene Glycol
Succinate, a mixture formed by the esterification of d-alpha to
copheryl acid succinate with a macrogol.
A practically odourless white or almost white crystalline
powder. Practically insoluble in water: soluble in alcohol and
in dehydrated alcohol: soluble in acetone, in ether, and in veg-
etable oils: very soluble in chloroform and in dichlorometh-
ane: slightly soluble in alkaline solutions. Unstable to alkalis.
Store in airtight containers. Protect from light.
Units
Though the potency of preparations of vitamin E is
still sometimes expressed in units, the International
Standard for vitamin E was discontinued in 1956.
The International Unit was the activity contained in
I mg of a standard preparation of alpha-tocopheryl ace-
tate. Past editions of the USP have stated that in ex-
pressing vitamin E activity of tocopherol products,
the following equivalents of I mg were to be
employed:
β’ dl-alpha tocopheryl acetate, I unit
. dl-alpha tocopheryl acid succinate, 0.89 unit
β’ dl-alpha tocopherol. I.I units
β’ d-alpha tocopheryl acetate, 1.36 units
β’ d-alpha tocopherol, 1.49 units
β’ d-alpha tocopheryl acid succinate. 1.21 units.
For dietary purposes, vitamin-E activity may now be
expressed in terms of alpha tocopherol equivalents
(alpha-TEs). One alpha-TE is the activity contained in I mg
0f d-alpha tocopherol (natural alpha tocopherol,
RRR-alpha-tocopherol). 1.4 mg dl-alpha tocopherol.
1.1 mg d-alpha tocopheryl acetate, 1.5 mg dl-alpha
tocopheryl acetate, 1.2 mg d-alpha tocopheryl acid
succinate, or 1.7 mg dl-alpha tocopheryl acid succi-
nate.
A practically odourless white or almost white, crystalline
powder. Practically insoluble in water: soluble in alcohol and
dehydrated alcohol, soluble in acetone, in ether, and in vege-
table oils: very soluble in chloroform and in dichloromethane:
slightly soluble in alkaline solutions. Unstable to alkalis.
Store in airtight containers. Protect from light.
Stability. A review of the compatibility and stability of com-
ponents of total parenteral nutrition solutions when mixed in
I - or 3-litre flexible containers' Vitamin E may bind strongly
to plastic which can lead to significant losses to the bag and
administration set. Vitamin E losses from paediatric TPN
mixtures have been estimated to be about 30 to 36% over a
24-hour administration period. The quantity of vitamin E de-
livered depends on infusion rate, type of administration set,
composition of mixture, and total volume infused.
Adverse Effects and Precautions
Vitamin E is usually well tolerated. Large doses may
cause diarrhoea, abdominal pain, and other gastro
intestinal disturbances, and have also been reported
to cause fatigue and weakness. Contact dermatitis
has occurred following topical application.
Large doses of vitamin E have been reported to in-
crease bleeding tendency in vitamin-K deficient pa-
tients such as those taking oral anticoagulants.
However, it has also been suggested that it may in-
crease the risk of thrombosis in some patients, such
as those taking oestrogens. The clinical significance
of these effects is not known.
A higher incidence of necrotising enterocolitis has
been noted in premature infants weighing less than
1.5 kg treated with vitamin E.
Interactions
Various drugs may interfere with the absorption of
vitamin E including cholestyramine, colestipol, and
orlistat. High doses of vitamin E may increase the
effects of oral anticoagulants.
Pharmacokinetics
Absorption of vitamin E from the gastro-intestinal
tract is dependent on the presence of bile and on nor
mal pancreatic function. The amount of vitamin E
absorbed varies widely between about 20% and
80% and appears to decrease as the dose is in-
creased. It enters the bloodstream via the chylomy
crons in the lymph bound to beta lipoprotein. It i:
widely distributed to all tissues, and stored in adi-
pose tissue. Some vitamin E is metabolised in the
liver to glucuronides of tocopheronic acid and its y-
lactone. Some is excreted in the urine, but most of a
dose is slowly excreted in the bile. Vitamin E ap-
pears in breast milk but is poorly transferred across
the placenta.
Human Requirements
The daily requirement of vitamin E has not been
clearly defined but is probably about 3 to 12 mg of
d-alpha tocopherol or the equivalent of other vita-
min E substances. Requirements increase with in-
creased dietary amounts of polyunsaturated fatty
acids. There appears to be no evidence that supple-
ments are required in subjects on balanced diets.
Vitamin E is widely distributed in food. The richest
sources are vegetable oils especially wheat-germ
oil, sunflower oil, and cottonseed oil: cereals and
eggs are also good sources. It does not appear to be
destroyed by cooking processes.
In the United Kingdom neither a reference nutrient intake
(RNI) nor an estimated average requirement
(EAR) has been set for vitamin E although daily intakes of
4 mg and 3 mg a-tocopherol equivalents (see under Units,
above) were considered adequate for men and women, re-
spectively.
in the United States, recommended dietary allowences have
been published for vitamin E. Differing amours are recom-
mended for infants and children of varying ages, adult males
and females, and pregnant and lactating women. The allow-
ance is expressed in terms of alpha tocopherol equivalents and
is 10 mg alpha-TE and 8 mg alpha-TE for adult males and females
respectively.
Uses and Administration
The primary role of vitamin E, a fat-soluble vitamin.
is the prevention of oxidation of polyunsaturated fat-
ty acids. Vitamin E reacts with free radicals, which
are the cause of oxidative damage lo cell mem-
branes, without the formation of another free radical
in the process.
Vitamin E deficiency develops when the dietary in-
take is inadequate although deficiency is rare. In
children with congenital disorders such as cystic fi-
brosis or biliary atresia malabsorption of fat may
lead to a vitamin E deficiency, similarly a deficiency
may oceur in children with abnormalities of lipid
transport such as in abetalipoproteinaeima. Low vi-
tamin E concentrations are also found in premature.
very low birth-weight infants. In previously healthy
adults malabsorption and low intake of vitamin E
must continue for a number of years before signs of
deficiency appear. The major signs of vitamin E de-
ficiency are the development of myopathic and neu-
rological disorders.
Vitamin E is used in the treatment and prevention of
vitamin E deficiency. It is usually given by mouth.
generally the preferred route, but may also be given
by intramuscular or intravenous routes. It may be
given as d- or d/-alpha tocopherol or as the respec-
tive acetates or acid succinates.
Recommended doses vary, in part because of differ-
ences in the activity of different preparations; how-
ever. a daily dose of 4 to 5 times the recommended
dietary allowance (RDA). or around 40 to 50 mg of
d-alpha tocopherol, has been suggested for deficien-
cy syndromes; somewhat higher daily doses have
been given in cystic fibrosis ( 100 to 200 mg of dl-
alpha tocopheryl acetate, or about 67 to 135 mg of
d-alpha tocopherol) and much higher daily doses in
abetalipoproteinaeima (50 to 100 mg of dl-alpha
tocopheryl acetate per kg body-weight, or about 33
to 67 mg d-alpha tocopherol per kg).
Vitamin E has also been tried in retinopathy of pre-
maturity and intraventricular haemorrhage in ne-
onates (see Perinatal Disorders, below), and in a
wide variety of other disorders, usually on the basis
of its antoxidant properties, for which the evidence
of value is generally lacking.
Other substances with vitamin-E activity which
Have been used include dl-alpha tocopheryl palmitate & tocofersolan, a substance
Which is d-alpha tocopheryl acid succinate com-
Bined with a macrogol. Wheat-germ oil is also wide-
ly used as a source of vitamin E.
Vitamin E is also often used as an antoxidant in
pharmaceutical manufacturing.
Dementia. A hypothesis that free radicals may initiate and
marntain mechanisms responsible for neurodegeneration in
Aizheimer's disease has prompted the investigation
of various drugs for antoxidant therapy. Preliminary studies'
suggest that alpha tocopherol may possibly slow progression.
Muscle spasm. Vitamin E is one of a number of drugs that
have been tried in the management of nocturnal cramps
but there is little convincing evidence to support its
use. It has also been tried for haemodialysis-induced
cramp.
Muscular dystrophies. Vitamin E substances have been
used in some countries in the management of muscular dys-
trophies, but controlled studies' have failed to demonstrate
any benefit.
Parkinsonism. Vitamin E has been tried (as dl-alpha toco-
pherol) in an attempt to slow neurodegeneration in patients
with Parkinson's disease but has proved ineffective.
Perinatal disorders. The primary biological action of vita-
min E is known to be the protection of polyunsaturated fatty
acids, and thus membranes, from oxidation. Two disorders
which may particularly affect premature and very tow birth-
weight infants are retinopathy of prematurity (below) and in-
traventricular haemorrhage and as both may have
some association with the occurrence of excess oxygen or ox-
idant stress interest has been shown in the possible role vita-
min E may have in their prevention.
Retinopathy of prematurity. Retinopathy of prematurity
(retrolental fibroplasia) is a disease associated with immature
vascularisation of the retina. Formation of retinal lesions may
interfere with normal development resulting in neovasculari-
sation and fibrovascular proliferation. Some cases regress
spontaneously but advanced cases can lead to fractional reti-
nal detachment and loss of vision. The pathogenesis of retin-
opathy of prematurity is not clearly understood, but is likely
lo be multifactorial.
Following the acknowledgement of a link between retinopa-
thy of prematurity and oxygen therapy, the use of oxygen was
reduced arid the incidence of this disorder declined. The ris-
ing incidence since then probably reflects the larger numbers
of extremely premature infants who are surviving due to im-
prove 1 neonatal care. A safe concentration of arterial oxygen
has not been defined and antoxidants such as vitamin E have
been used prophylactically for several decades. However, this
use is controversial. Studies assessing the efficacy of vitamin
E prophylaxis have not produced clear results. Some consid-
ered that vitamin E prophylaxis had a beneficial effect and
recommended routine prophylaxis as soon as possible after
birth for infants less than 1.5 kg body-weight.' However, oth-
ers feel that there is no data to support prophylaxis with vita-
min E and that antoxidants cannot be recommended for
routine use.' The various studies have recently been re-evalu-
ated by meta-analysis, the results of which suggest that vita-
min E may reduce the incidence of stage 3+ retinopathy of
prematurity.' The authors recommend that a well-controlled
trial should now be conducted.
Other agents suggested for prophylaxis include dexametha-
sone, but again no adequate studies have been performed.
Reduction in ambient-light exposure did not alter the inci-
dence of retinopathy of prematurity.
Tardive: dyskinesia : Evidence that vitamin E may improve
the symptoms of antipsychotic-induced tardive dyskinesia
has generally come from small studies with methodological problems.