Igho J. Onakpoya and Jeffrey K.

Aronson

34

Vitamins, amino acids, and

drugs and formulations used
in nutrition

VITAMIN A
(CAROTENOIDS)

[SED-15,
3642; SEDA-32, 607; SEDA-33, 691;
SEDA-34, 531]
Systematic reviews In a systematic review
of randomized clinical trials of vitamin A
supplementation in the prevention of morbidity and mortality in infants aged
6 months or less, there was an increased
risk of bulging fontanelle with maternal
vitamin A supplementation: (RR 1.55;
95% CI 1.05, 2.28). However, the studies
included in the analysis were reported to be
of low quality [1M].
Electrolyte balance Hypercalcemia with
acute renal damage due to abuse of a combination of vitamins A, D, and E has been
reported in a 19-year-old man who used a
parenteral vitamin formulation intended
for veterinary use [2A].

Side Effects of Drugs, Annual 35

J.K. Aronson (Editor)
ISSN: 0378-6080
http://dx.doi.org/10.1016/B978-0-444-62635-6.00034-6
# 2014 Elsevier B.V. All rights reserved.

VITAMINS OF THE B
GROUP [SED-15, 1432, 3668;
SEDA-32, 608; SEDA-33, 693;
SEDA-34, 531]

Cobalamins (vitamin B12)

Observational studies In a single-arm, open
study of vitamin B12 replacement therapy for
3 months in 30 patients with gastric cancers
and vitamin B12 deciency after total gastrectomy there were no adverse reactions related
to oral or intramuscular vitamin B12 [3c].
Combination studies In patients with Angelmans syndrome, vitamin B12 was combined
with betaine, metafolin, and creatine in an
attempt to reduce antisense transcript production, increase UBE3A expression, and
ameliorate symptoms [4c]. There were no
benecial effects and adverse events included
worsening of seizures, new or worse sleep
problems, constipation, and anorexia.
Drug administration route In an open,
parallel-group study, oral vitamin B12 was
compared with an intramuscular formulation
in patients with low cobalamin concentrations
[5c]. The most common adverse events
reported were abdominal pain, constipation,
diarrhea, nausea, fatigue, bronchitis, upper
respiratory tract infections, procedural pain,
arthralgia, back pain, headache, and oropharyngeal pain. The adverse events were
reportedly mild or moderate in intensity.

607

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Chapter 34

Igho J. Onakpoya and Jeffrey K. Aronson

Drugdrug interactions Antidepressants In

a randomized controlled study of the effects
of folic acid and vitamin B12 supplementation and antidepressant medications in 900
adults with depressive symptoms, there
was no signicant interaction between the
vitamin supplements and antidepressants
[6C]. The authors concluded that there
was little evidence for potentiation of antidepressants by folic acid and B12.

A 45-year old woman had an allergic

reaction, with generalized urticaria, angioedema, and difculty in swallowing 30 minutes
after taking oral folic acid 5 mg [12A]. Prick
tests and intradermal tests with folic acid
(pteroylmonoglutamic acid) were strongly
positive and skin tests were negative with
folinic acid and tetrahydrofolic acid. Graded
oral doses of folic acid up to a single dose of
400 micrograms were well tolerated. Blood
concentrations of folate and vitamin B12
and a full blood count were normal.

Folic acid and folinic acid

Genotoxicity The effect of folic acid supplementation on gene expression in lymphoblastoid cells has been investigated in a
whole-genome
expression
microarray
[13E]. High concentrations of folic acid
caused dysregulation in more than 1000
genes, including many imprinted genes, in
concentrations as low as 15 mg/l, and there
was evidence of aberrant promoter methylation. The authors suggested that excessive
folic acid supplementation may require
careful monitoring in women who are planning or are in the early stages of pregnancy.
They also cautioned that aberrant expression of genes during early brain development may affect behavioral characteristics.

Observational studies In a retrospective,

population-based study of the association
between folate supplementation and survival in children with acute lymphoblastic
leukemia, there was no relation between
the use of folate and therapeutic failure [7c].
Systematic reviews The effects of folic acid
supplementation on cardiovascular outcomes
have been evaluated in a meta-analysis of 16
studies in 44 841 participants; there was no
signicant risk of adverse events [8M].
Respiratory In a cohort study of maternal
folate supplementation in pregnancy and
the risk of atopy, asthma, and lung function
in childhood, there was no association [9c].
The evidence of an association between
maternal folate exposure in pregnancy and
childhood asthma or wheeze has been
reviewed [10M]. Of four identied studies,
two showed statistically signicant associations between childhood asthma and maternal folic acid exposure in late pregnancy,
one showed a statistically signicant association between childhood wheeze and maternal
folic acid exposure in early pregnancy, and
the fourth showed little association between
maternal dietary folate in pregnancy and
infantile wheeze. The authors concluded
that the evidence regarding an association
between folate in pregnancy and childhood
asthma or wheeze is conicting.
Immunologic A woman with colon cancer
had an anaphylactic reaction after intravenous folinic acid; it was reversed by
adrenaline [11A].

Pregnancy In a telephone survey of 5952

mothers there was no evidence of an association between folate supplementation in pregnancy and the risk of preterm delivery [14c].

Hopantenic acid
Placebo controlled studies In a doubleblind, randomized study in 20 patients with
partial epilepsy adjunctive hopantenic acid
(homopantothenic acid) 1800 mg/day was
not associated with adverse events [15C].

Pyridoxine
Skin Allergic contact dermatitis has been
attributed to a combination of pyridoxine
hydrochloride and ranitidine hydrochloride
[16A].

Vitamins, amino acids, and drugs and formulations used in nutrition

Riboavin
Sensory systems Herpetic keratitis occurred
in a 31 year old woman without previous
herpetic eye disease after corneal collagen
cross-linking with riboavin and ultravioletA for progressive keratoconus [17A].

Tetrahydrobiopterin and
sapropterin
Observational studies In an open study of
long-term treatment with sapropterin in
patients with phenylketonuria, adverse
events of mild to moderate intensity
reported as possibly related to sapropterin
were difculty in concentrating, a reduced
platelet count, and intermittent diarrhea;
gastroesophageal reux was reported as a
serious adverse event [18c].
Oral tetrahydrobiopterin has been evaluated in 18 patients with pulmonary hypertension; there were no important adverse
events and in particular no cases of systemic
hypotension, even when tetrahydrobiopterin
was combined with sildenal [19c].
Sapropterin has been studied in six children with phenylketonuria; diarrhea in
one patient at the start of therapy was the
only adverse event reported [20c].

Thiamine
Placebo-controlled studies In a double-blind,
randomized, pilot study of the effects of
thiamine on metabolic prole, cytokines, and
inammatory markers in drug-nave patients
with type 2 diabetes mellitus, reported
adverse events were headache and increased
appetite, but they were not considered to have
been related to thiamine [21c].

VITAMIN C (ASCORBIC
ACID) [SED-15, 351; SEDA-32,

Chapter 34

609

vitamin C vaginal tablets for bacterial vaginosis in 277 out-patients, there were no differences in adverse events between vitamin C
and placebo [22C].
Systematic reviews In a meta-analysis of
four randomized, placebo-controlled studies
of low-dose aspirin and vitamins C and E in
prevention of pre-eclampsia in high-risk
women, there was no signicant difference
from placebo in the numbers of neonates
who were small for gestational age or had
intrauterine growth restriction [23C].
Skin Contact dermatitis has been ascribed
to ascorbyltetraisopalmitate [24A].
A 54-year-old woman developed a skin reaction 2 days after rst applying an anti-ageing
skin-care product, Hydracyd C20. The reaction started on the face and spread to the arms
and chest. Patch testing with the ingredients
of the product gave a strong positive reaction
to ascorbyltetraisopalmitate (diluted 20% in
liquid parafn), which gave negative results
on patch testing in 20 control subjects. Tests
with ascorbic acid and with ascorbylpalmitate
and isopropylpalmitate, which are chemically
analogous to ascorbyltetraisopalmitate, were
negative.

Nails Yellow discoloration of the nails has

been reported after local application of
ascorbic acid [25A].
A 74-year-old man applied a topical formulation, intended to prevent onychomycosis, containing ascorbic acid 1%, uprednidene
acetate 0.1%, and miconazole nitrate cream
2%, to the nails on his hands and toes and
developed a yellow discoloration, which
spared the proximal side of each nail plate.
The border of the yellow area had an inward
curvature, which suggested that the nail
matrix was intact and that therefore an exogenous dye was responsible.

VITAMIN D ANALOGUES
611;

[SED-15, 3669; SEDA-32, 612; SEDA33, 695; SEDA-34, 532]

SEDA-33, 694; SEDA-34, 531]

Placebo-controlled studies In a double-blind,
randomized, placebo-controlled study of

Comparative studies In a 3-year, doubleblind, randomized, active comparator, superiority study, eldecalcitol was compared with

610

Chapter 34

Igho J. Onakpoya and Jeffrey K. Aronson

alfacalcidol in the prevention of osteoporotic

fractures; there were 31 adverse events in
those who used eldecalcitol, and 40 with
alfacalcidol [26C]. There was no signicant
difference in the frequency of adverse
events between the groups, but increases in
serum and urinary calcium were larger in
those who used eldecalcitol.

0.1 mmol/l respectively were reported to

be the most clinically important treatmentemergent adverse events.

Placebo-controlled studies High-dose vitamin D 50 000 IU/week for alleviation of

aromatase inhibitor-induced musculoskeletal symptoms has been investigated in a 6month study in 60 women; no adverse
events were observed [27c].

[SED-15, 3677;
SEDA-32, 612; SEDA-33, 696;
SEDA-34, 533]

Systematic reviews In a meta-analysis of six

randomized studies of the effects of vitamin
D supplementation on bone density in 884
healthy children, there was a trend to a
small effect on lumbar spine bone mineral
density (standardized mean difference
0.15; 95% CI 0.01, 0.31); reports of
adverse events were limited [28M].
Cardiovascular The relationships between
calcium, vitamin D, and cardiovascular disease have been reviewed [29R]. There are
negative correlations between vitamin D
concentrations and the risks of hypertension, myocardial infarction, and stroke.
However, the effect of vitamin D supplementation on blood pressure is unclear,
and vitamin D supplementation does not
affect coronary heart disease or stroke.
In a 7-year, randomized, placebocontrolled study of calcium 1 g/day and vitamin D 400 IU/day in 36 282 postmenopausal
women, there was an interaction between
personal use of calcium supplements and
prescribed calcium and vitamin D for cardiovascular events. In meta-analyses of placebocontrolled trials of calcium or calcium +
vitamin D, 1384 individuals had an incident
myocardial infarction or stroke [30M]. Calcium supplements with or without vitamin D
modestly increased the risk of cardiovascular
events, especially myocardial infarction.
Mineral balance The use of eldecalcitol in
the management of osteoporosis has been
reviewed [31R]. Increases in blood and urinary calcium to over 2.6 mmol/l and over

VITAMIN E
(TOCOPHEROL)

Systematic reviews The effect of vitamin E

supplementation on all-cause mortality has
been evaluated in a meta-analysis of 57 randomized studies of at least 1 year duration.
There was an overall risk ratio of 1.00 (95%
CI 0.98, 1.02); additional analyses suggested no association between dosage and
risk of death [32M].
Cardiovascular In a 7-week study of
a-tocopherol 250 mg/kg/day and corn oil
versus corn oil alone in rats, there were
echocardiographic abnormalities suggestive
of cardiotoxicity in animals that were given
a-tocopherol [33E]. Treatment with atocopherol was associated with signicant
reductions in left ventricular end-diastolic
and aortic diameters, left ventricular fractional shortening, ejection fraction, and
transmitral ow early peak velocity. Histology of the myocardium showed nuclear
necrosis, myocyte degeneration, and disorganization of myobrillar morphology.
Suggested mechanisms included lipid peroxidation due to increased concentrations
of a-tocopheroxyl radicals [34R].

VITAMIN K ANALOGUES
[ SED-15, 3681; SEDA-34, 533]
Toxicological studies A synthetic form
of vitamin K2, menaquinone-7 has been
studied in mice and rats [35E]. In an
acute oral toxicity test, in which mice were
given a single oral dose of 2000 mg/kg, there
was no evidence of toxicity during the
14-day observation period. In a subchronic

Vitamins, amino acids, and drugs and formulations used in nutrition

oral toxicity test, rats were given doses

of 2.5, 5, and 10 mg/kg for 90 days by
gavage; no adverse reactions were observed.

AMINO ACIDS
Arginine
Skin Arginine hydrochloride, which has been
used to evaluate the causes of short stature
and in the management of disorders of the
urea cycle and of MELAS (mitochondrial
encephalomyopathy, lactic acidosis, strokelike episodes), is available as a solution for
intravenous infusion. The solution is hyperosmolar and it is important to avoid extravasation, which can cause tissue damage [36A].

Glycine
In an open study in 29 patients with schizophrenia and predominantly negative symptoms, the addition of glycine 60 g/day for
6 weeks to standard antipsychotic drug
therapy produced signicant improvement
in positive and negative symptoms and general psychopathology [37c]. Adverse reactions were mainly gastrointestinal (nausea
and vomiting).

Ornithine
Sensory systems Ornithine supplementation
has been used to achieve ammonium
detoxication in the hyperornithinemia
hyperammonemiahomocitrullinuria
syndrome, but there have been reports of
retinal toxicity associated with high-dose
ornithine, which have been reviewed [38M].
In vivo and in vitro high concentrations of
ornithine and its metabolites are toxic to
retinal pigment epithelial cells. Long-term
exposure to high concentrations of ornithine
in the blood (exceeding 600 mmol/l) cause
retinal toxicity in patients with gyrate
atrophy of the choroid and retina, but intermittent high concentrations of ornithine do
not cause retinal lesions. Constant blood

Chapter 34

611

ornithine concentrations of 250600 mmol/l

either are not associated with retinal lesions
or cause slowly progressive retinal degeneration. Blood ornithine concentrations below
250 mmol/l do not affect the retina at all. The
authors concluded that long-term, high-dose
ornithine may cause retinal damage and that
patients with gyrate atrophy of the choroid
and retina should avoid taking it.

ENTERAL AND
PARENTERAL NUTRITION
[SED-15, 1221, 2700; SEDA-32, 613;
SEDA-33, 697; SEDA-34, 536]
Observational studies In a postmarketing
study of an enteral nutritional suspension
(TPF-FOS, Jevity) in 103 patients with acute
strokes, only 18 adverse events were thought
to have been related to the product; most
were gastrointestinal reactions [39c].
The safety of early enteral feeding after
emergency gastrointestinal surgery has been
investigated in 53 patients; 33 of whom were
treated in intensive care [40c]. There were
wound complications in 18 patients, and
post-feeding abdominal pain in seven. Anastomotic leakage and intra-abdominal abscess
occured in two patients, and one patient
required reoperation to treat anastomotic
disruption. One developed pneumonia and
sepsis. No deaths were reported.
The effectiveness of nasojejunal nutrition
has been evaluated in 58 patients with chronic
pancreatitis [41c]. Complications were relatively minor and infrequent. There was diarrhea in 14 patients and nausea in nine; 11
required re-admission for tube blockage and
10 for tube displacement, requiring catheter
reinsertion or re-positioning. There were no
complications associated with nasojejunal
catheter insertion.
Infection risk Enteral tube feeding has
been compared with oral feeding in 98
elderly subjects [42c]. Pyrosequencing data
showed that 22 bacterial genera, including
Corynebacterium, Peptostreptococcus, and
Fusobacterium, were signicantly more

612

Chapter 34

predominant in those who were tube-fed, and

the dominant genera in the orally-fed subjects, such as Streptococcus and Veillonella,
were present in much lower proportions.
Opportunistic pathogens rarely detected in
the normal oral microora, such as Corynebacterium striatum and Streptococcus agalactiae, were often found in high proportions
in the tube-fed subjects. The authors concluded that the indigenous microora is
disrupted by the use of enteral feeding, allowing health-threatening bacteria to thrive.

Aluminium
See Chapter 22.

Soybean
Soybean in the diet can lower cholesterol,
and the FDA has agreed that soy protein
25 g/day, as part of a diet low in saturated
fat and cholesterol, may reduce the risk of
heart disease. Soy may also reduce symptoms of the menopause and the risk of
osteoporosis. Soy products may prevent certain hormone-dependent cancers, including
breast, endometrial, and prostate cancers.
Among individuals who are not allergic to
soy, no serious short-term or long-term
adverse reactions have been reported from
eating soy foods. However, common mild
adverse reactions, including stomach ache,
constipation, and diarrhea, have been
reported. Soy contains moderate amounts of
natural purines, consumption of large amounts
of which can make gout worse [43S,44S].

Igho J. Onakpoya and Jeffrey K. Aronson

Observational studies A lipid emulsion containing a mixture of soybean oil, mediumchain triglycerides, olive oil, and sh oil
(SMOFlipid 20%), with reduced n-6 fatty
acids, increased monounsaturated and n-3
fatty acids, and enriched in vitamin E, has
been compared with a soybean oil-based
emulsion in 60 premature infants, gestational
ages up to 34 weeks, birth weights
10002500 g [45C]. They received parenteral
nutrition with either SMOFlipid 20% or a
conventional lipid emulsion (Intralipid 20%,
controls) for 714 days. Lipid supply started
at 0.5 g/kg/day on day 1 and increased stepwise in increments of 0.5 g up to 2 g/kg/day
on days 414. There were no differences
between the groups in adverse events, serum
triglycerides, vital signs, or local tolerance. At
the end of the study, gamma-glutamyl transferase activity was lower in the study versus
the control group (108 versus 189 IU/l).
Low intake of soy protein had no major
adverse effects in a 90-day study of its
effects on oxidative stress and the components of the metabolic syndrome [46c].
Comparative studies A soy isolate protein
supplement has been compared with a milk
protein supplement in Chinese adults with
moderate hypercholesterolemia; gastrointestinal complaints were reported as the
only adverse events observed in the soy
group [47c].
Placebo-controlled studies In a randomized,
double-blind,
placebo-controlled
study of the effectiveness of isoavone soy
protein supplementation on subclinical
atherosclerosis, no major adverse events
were reported [48C].

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