Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT02068807 |
| Other study ID # |
NEO-LUT-2011 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
Phase 1/Phase 2
|
| First received |
February 17, 2014 |
| Last updated |
February 24, 2014 |
| Start date |
January 2011 |
| Est. completion date |
October 2013 |
Study information
| Verified date |
February 2014 |
| Source |
University of Siena |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
Italy: Ministry of Health |
| Study type |
Interventional
|
Clinical Trial Summary
The balance of the redox state is important for normal embryonic and fetal development .
During the perinatal period, a variety of conditions are responsible for an excessive
production of free radicals. The following oxidative stress is exacerbated by a lack of
antioxidant substances that have not yet matured. At the moment there are no therapeutic
strategies with single or combined antioxidants that have been shown to be clinically
effective.
Breastfeeding is important for the contribution of the antioxidant defenses of the newborn
and the nutritional status of the mother plays a key role because it influences the
nutritional status of the newborn. Lutein is a carotenoid that is not produced by the body ,
but taken with food or supplements. The molecule carries out different activities :
antioxidant, anti-inflammatory, anticancer , neuroprotective. Its main activity of
inhibition of peroxidation of membrane lipids is peculiarly important for the photoreceptors
and neurons whose membranes are rich with polyunsaturated fatty acids. Current evidence on
its role as an antioxidant indicate that supplementation with lutein may play a significant
role in the prevention of free radical disease in the newborn
Description:
In recent years many scientific studies demonstrated that lutein, a nutrient belonging to
the family of carotenoids, may constitute a valid and important preventive and protective
factor against a large number of chronic diseases affecting millions of people around the
world . Studies from literature highlight and confirm that lutein is able to reduce the risk
of developing some ocular diseases or slow down their progression. Lutein is a fat-soluble
derivative of polar hydroxylated xanthophyll which belongs to the family of carotenoids.
Carotenoids are linear polyenes, ie double bonds conjugated hydrocarbons containing 40 atoms
of carbon. Today there are 35 known carotenoids that are ingested, absorbed, metabolised and
found in human serum. Lutein is the most important corotenoid and it is only in the retina,
in the macula and in the lens. In tissues and serum lutein is found together with its
isomer, the zeaxanthin. Lutein, commonly ingested with other foods, is partially eliminated
directly in the faeces (50-90%) and partially absorbed with fatty foods. It is incorporated
into chylomicrons reaching the blood where it binds some lipoprotein and thanks to its fat
solubility it reaches different organs: liver, breast, colon, cervix, lens, iris and the
retina where it is concentrated in the central region: the macula. Inside cells Lutein is
placed through the lipid bilayer binding its polar groups with those of cell membranes.
Lutein and zeaxanthin are present in the umbilical cord and pass through the placental
barrier. They are also found in high concentrations in breast milk (higher than in plasma),
particularly in colostrum; indicating an active secretion in milk. The rates of lutein in
blood increases of 67% versus 14% for beta-carotene after the intake of foods rich in
carotenoids. Coordinated and interdisciplinary studies, conducted both in vitro and in vivo,
have shown that lutein plays a role in tissues defense through a functional mechanisms using
the phenomenon of deactivation (quenching) of singlet oxygen and of reactive oxygen species
(ROS). This action gives the molecule different activities: antioxidant and
anti-inflammatory properties, promotion of anti-carcinogenic effects, induction of
detoxifying enzymes and promotion of proteins with a positive effect on the junctional
communication (up-regulation). New chemical and experimental data show that oxidative stress
and harmful effects of ROS may play an important role in the pathogenesis of some
neurological diseases like Alzheimer, Parkinson, etc.. This could be explained by the fact
that the central nervous system is characterized by membranes rich of polyunsaturated lipids
that are the first target of ROS attack (lipid peroxidation). A similar mechanism may occur
in some ocular tissues (macula, lens, retina), which are more vulnerable than other tissues
to oxidative damage being particularly rich in polyunsaturated fatty acids. The
photo-protective action seems to be predominant in the iris, while in the retinal pigment
epithelium may operate both light filtering and antioxidant mechanisms. The development of
the human eye includes a complex series of consecutive events beginning with the first
differentiation of the fertilized egg cell and continuing after birth until the first years
of life. The eye of the newborn, although smaller than that of adults, has a well developed
and mature dioptric apparatus, consisting of cornea, aqueous humor, lens and vitreous,
transparent structures that allow the passage of light and focus images on the retina.
Contrariwise the macula and its central part (fovea), useful for vision and color
discrimination, are not yet mature at birth. The full development of the fovea occurs only
after the 4 / 5 month of life. This process along with the development of more sensitive
ways, gives to the child a greater resolving power and a distinct vision. The partial
pressure of blood gases that regulates blood flow to the retina has the same importance.
Indeed oxygen consumption by the retina is constant and a defect or an excess of this gas
can be highly detrimental for the natural development of retinal structures. An example of
the importance of oxygen partial pressure in regulating retinal blood flow is represented by
retinopathy of prematurity (ROP), an usually bilateral condition, affecting the immature
retinal vessels. ROP has been one of the major cause of blindness in infants in the past.
Nowadays the use of oxygen concentrations based on the levels of its partial pressure in the
arterial blood, has reduced the incidence of retinopathy. The vascularization of the retina
begins on the 4th month of gestation. The vessels progress from the center to the periphery,
reaching the nasal area at the 8th month and the temporal at the 9th month of intrauterine
life. In the retinopathy of prematurity, the development of retinal vasculature is impaired
because the increase in PA02 levels leads to an arteriolar vasoconstriction and to the
obliteration of the newly formed capillaries. Consequently the mesenchyme stops to
proliferate, forming a marginal tissue. The arteries and veins of this margin does not drain
their blood in capillaries, but in small arteriovenous anastomosis forming shunt. The
endothelium of these new vessels is also very permeable because it is immature and
incomplete. The capillary bed of the shunt is largely obliterated, and this causes anomalies
of pressure responsible of dilation and tortuosity, microaneurysms, neovascularization and
resulting in exudative and haemorrhagic phenomena with the possibility of developing
vitreous traction and retinal detachment. This represents the active phase of the disease,
which often regresses spontaneously, and the magnitude of which depends on the precocity of
hyperoxia. The evolution could be the regression, the scarring, or more frequently, a
combination between the two. During pregnancy, the percentage of fatty acids in maternal
plasma increases to 51%. The polyunsaturated fatty acids are significantly prone to
oxidation, the changes in their plasma levels affect the status of the antioxidant systems
in pregnant and consequently in the newborn. Several studies reported that the increased
susceptibility to peroxidation of polyunsaturated fatty acids in pregnancy is accompanied by
an equivalent increase in plasma tocopherol levels but its level decreases dramatically
immediately after birth. Plasma antioxidant levels of the newborn were found lower if
compared with those of the mother. Tocopherols and carotenoids levels are significantly
lower in the umbilical cord than those recorded in maternal plasma and the concentration of
polyunsaturated fatty acids in the newborn is higher than that of the mother. Many
scientific studies have also shown an increasing interest in oxidative stress and reactive
oxygen species that accumulate after birth. OS is assessed by the quantification of
thiobarbituric acid reactive species (TBRS) in plasma. TBRS levels were significantly
increased in premature infants after the exposure to blue light for 96 hours. Studies on
premature infants have shown a correlation between low plasma levels of antioxidants and an
increased risk of free-radical relates diseases. Therefore it could be useful to increase
antioxidant defenses in infants in order to restore the redox unbalance and to prevent the
damage caused by a prolonged exposure to high levels of free radicals and reactive oxygen
species. Oxidative stress is considered one of the main determinants of retinal damage as in
age-related diseases. A proper balance between oxidant and antioxidant factors may help to
prevent or reduce eye damage that can occur in newborns, especially in preterm infants, such
as ROP. Indeed preterm babies are often exposed to potentially harmful concentrations of
oxygen due to respiratory problems or undergo phototherapy with high intensity blue light.
These therapies are sources of free radicals. Lutein and zeaxanthin in the macular pigment,
may play an important role in protecting the eyes of the newborn from the damage of light
thanks to their ability to absorb blue light and their antioxidant action. Lutein increases
macular pigment density and can protect through two synergistic mechanisms: the absorption
of blue light before it reaches the sensitive retinal structures, namely the photoreceptors
inducing a photochemical damage, the quencing effect that determines the neutralization of
singlet oxygen and of other free radicals.
There are many evidences that suggest a protective effect of lutein against photo-oxidation
damage in adult (Leeuwen 2006, AREDS 1, AREDS 2).
Lutein and zeaxanthin are present in the umbilical cord and several studies have shown that
there is a direct correlation between mother and newborn plasma levels of lutein. Lutein is
also present in breast milk in concentrations three times higher than other carotenoids with
the same plasma concentrations. There is also a correlation between plasma levels of lutein
in the mother and levels in the breastfed infant. Studies on infants have shown that
carotenoids levels in the first four/six months of life are very low. This is probably due
to the fact that the infants diet is entirely made of milk without solid foods (such as
green leafy vegetables) sources of this nutrient. Children breastfed have higher lutein
plasma levels than children fed with formula milk. The different types of formula milks are
currently not enriched with these carotenoids and their content of both lutein and
zeaxanthin is very low, except for some formulations which are prepared using egg homogenate
but they are not sold in Italy. Breast milk is therefore the only source of lutein for
infants before the weaning, and the breastfeeding is very important as a primary source of
these nutrients for the proper development and protection of the vision. Considering the
correlation between lutein content in plasma and in breast milk and the lowering of lutein
levels in milk already six days after birth, it is really important to take foods rich in
lutein during lactation. A diet enriched with lutein is especially important for mothers of
premature or low birth weight newborns. Indeed the premature and underweight children need
many nutrients essential for a rapid growth because they did not receive highly nutritious
elements and energy transferred from the mother during the last weeks of gestation.
Moreover, their gastrointestinal and renal functions are not fully developed and this could
reduce the absorption and retention of some micronutrients including important antioxidants
that protect the infant from exposure to high levels of free radicals produced in excess at
birth and often as a result of the resuscitation technics used. Breastfeeding is important
for the intake of antioxidant defenses in the newborn and the nutritional status of the
mother plays certainly a key role because it affects the nutritional status of the infant,
and especially the status of some soluble nutrients such as lutein and zeaxanthin. The
preparations of lutein and zeaxanthin have never had gastrointestinal or systemic toxic
effects in humans after supplementation. In recent studies, no adverse effects after
administration of 20 mg/day of lutein or zeaxanthin administered for 6 months or
interactions with other fat-soluble nutrients were reported.
