LITHIUM in Oratate 1X/2X/3X, GABA
3X, Albumin (USP) 1X/2X/3X. In a base of
not more than USP Glycerine and Purified Saline Solution.
Symmetry is the first FDA registered homeopathic lithium orotate
spray. In combining the highest quality lithium orotate with GABA
and Albumin, HBC has created a formula that is designed to reduce
stress while elevating mental and emotional well-being. Symmetry
may also assist other depression treatments associated with symptoms
of depression, stress, mania as it helps supports the body's ability
to reduce stress for better overall health. The Lithium orotate
used in this formula is the most powerful in its class..
Recommended Daily Allowance for Lithium is 14.6 mgs per day.
Four sprays of Symmetry yields 14 mgs of pure lithium orotate per
day; 100 mgs of GABA, and 100 mgs of Albumin
There are 140 sprays per 1/2 ounce bottle.
At four sprays per day each bottle of Symmetry should last 35 days.
Stimulating clue hints how lithium works SCIENCE NEWS, MARCH 14, 1998, VOL. 153 BY: J. TRAVIS
Some 50 years ago, Australian physician John Cade observed the
calming effect that lithium had on small animals. After testing
the safety of lithium on himself, Cade ventured to try it on people
suffering from the wild mood swings of manic depression.
Millions of prescriptions later, lithium remains the most popular
choice for treating manic depression, although scientists do not
understand how it quells mania or relieves depression. "It's
still a mystery," says De-Maw Chuang of the National Institute
of Mental Health in Bethesda, Md.
Now, there's a new clue to this riddle. Chuang and his colleagues
have found that lithium protects brain cells from being stimulated
to death by glutamate, one of the many chemicals that transmit messages
in the brain.
The new data suggest that lithium may calm overexcited areas of
the brain or, more provocatively, preserve the life of brain cells
whose presence guards against manic depression.
This finding "potentially contributes a lot to the field,"
says Husseini K. Manji of Wayne State University in Detroit. "If
we could figure out how lithium works, we could theoretically come
up with better drugs and perhaps understand what's going on in manic
depression."
Chuang and his colleagues tested the response of various types
of rat brain cells to glutamate. Many normal cells and cells soaked
in lithium for only a day died from a form of suicide that often
results when this neurotransmitter over-stimulates a brain cell.
Yet rat brain cells soaked in lithium for about a week committed
suicide much more rarely when exposed to glutamate, Chuang's group
reports in the March 3 Proceedings of the National Academy of Sciences.
The effect was seen in cells from several brain regions.
The delay in protection is particularly striking, notes Manji,
since a hallmark of lithium therapy is that it can take a week or
longer to benefit people. Consequently, scientists have been looking
for the long-term actions of lithium on brain cells.
Chuang's team also examined the role of the NMDA receptor, the
cell surface protein that glutamate binds to when it excites a cell.
While cells soaked in lithium for a week had as many NMDA receptors
as untreated cells, the treated cells responded differently.
Normally, activation of the NMDA receptor by glutamate triggers
an influx of calcium ions, setting off a signaling cascade inside
cells. However, cells soaked in lithium for a week let in far less
calcium when exposed to glutamate.
In people with manic depression, lithium may correct a dysfunction
of the NMDA receptor by limiting calcium influx, speculates Chuang.
Both Chuang and Manji also note that a small body of evidence suggests
that people with mania or depression may lose brain cells. Lithium
may thwart that cell death, they say. Indeed, Manji has some evidence
that lithium-treated cells eventually begin to overproduce a protein
that stymies the cell's internal suicide program.
If lithium protects brain cells from death by glutamate over-stimulation,
it may have uses beyond manic depression. This form of cell death
occurs in strokes and in Alzheimer's, Parkinson's, and Huntington's
diseases. Chuang is investigating whether lithium protects mice
from similar neurodegenerative illnesses.
GABA
The brain's chief inhibitory neurotransmitter
GABA (Gamma-Aminobutryic Acid) is an amino acid that was first discovered
in 1883 in Berlin. Classified as a neurotransmitter, GABA abundantly
present in the brain, and serves as a balancer between excitation
and inhibition. As a neurotransmitter in the central nervous system,
GABA is essential for brain metabolism, aiding in balanced brain
function, especially during episodes of anxiety, stress, depression,
epilepsy, and Parkinson's disease. There are more GABA sites in
the brain than for other neurotransmitters, including dopamine or
serotonin.
How
does GABA work?
As the chief inhibitory neurotransmitter in the brain, GABA exerts
its effects by binding to two distinct receptors, GABA-A and GABA-B.
The GABA-A receptors form a Cl- channel. The binding of GABA to GABA-A
receptors increases the Cl- conductance of presynaptic neurons. The
anxiolytic drugs of the benzodiazepine family exert their soothing
effects by potentiating the responses of GABA-A receptors to GABA
binding. The GABA-B receptors are coupled to an intracellular
G-protein and act by increasing conductance of an associated K+
channel. Several amino acids have distinct excitatory or inhibitory
effects upon the nervous system. The amino acid derivative, g-aminobutyrate,
also called 4-aminobutyrate, (GABA) is a well-known inhibitor of
presynaptic transmission in the CNS, and also in the retina. The
formation of GABA occurs by the decarboxylation of glutamate
catalyzed by glutamate decarboxylase (GAD). GAD is present in many
nerve endings of the brain as well as in the b-cells of the
pancreas. Neurons that secrete GABA are termed GABAergic.
What does that mean?
What this means is that rather than stimulating neurons to fire,
GABA balances neuronal activity, and is
therefore associated with both muscle relaxation, as well as mental
states of calm, serenity, and symmetry.GABA basically acts as an
inhibitory transmitter, keeping the brain and body from going into
"overdrive." Supplementation of GABA seems to be quite effective
for anxiety disorders as well as insomnia (especially the type of
insomnia where racing thoughts keep the individual from falling
asleep). Hence, those suffering from depression exacerbated by anxiety
might want to consider taking this supplement.
An example of how GABA helps alleviate depression.
When people use alcohol, and or drugs (Heroin, cocaine, ecstasy,
marijuana . . . ) they do not feel depressed. They can not feel
their depression. They have temporarily masked by flooding their
brain with artificial opiods. When the drugs wear off, the depression
returns. But, NOT exactly at the same point of use. Why? Because
their GABA level remains temporarily high. The brain has been tricked
into thinking its natural opiod level is high. Symmetry works to
provide the brain and the body with the necessary nutrients that
it needs to produce and keep opiod and GABA neurotransmitter levels
up. Studies with oral administration of sodium valproate (an enhancer
of endogenous GABA activity) and the muscle relaxant Baclofen (an
agonist* of the GABA B receptor) demonstrate their ability
to stimulate increased HGH levels.
Agonist.* 1. Any molecule that improves the activity of a
different molecule; e.g., a hormone, which acts as an agonist when
it binds to its receptor, thus triggering a biochemical response.
2. A drug that both binds to receptors and has an intrinsic effect.
How does GABA enhance sleep?
Studies have shown that GABA increases the body’s sleeping cycle
and patients reported much more vivid dreams. A good night’s sleep
leads to more energy throughout the day. More energy feelings of
vigor are common side effects of supplementing with GABA
Research has shown that GABA plays a key role in anxiety and sleep
by potentially counteracting the excitatory effects of glutamate.
Recent evidence suggests a very important role for GABAeric agents
in the treatment of anxiety disorders like generalized anxiety disorder
(GAD), social anxiety disorder (SAD), posttraumatic stress disorder
(PTSD) both for modulating anxiety and also for treating the sleep
disturbances that are inherent to these disorders.
What about GABA & alcohol?
In the absence of alcohol (left), GABA
opens GABAA receptor chloride (Cl-) channels and inhibits neurotransmission.
Alcohol enhances the effect of GABA (middle),
allowing more Cl- to flow into the cell and producing more inhibition.
In alcohol dependence (right), both GABA
and alcohol have smaller effects on GABA receptors. This results
in less Cl- influx and more activation of neurons that may underlie
anxiety and seizure susceptibility in alcohol dependence and withdrawal.
What's this about GABA and eyesight?
GABAC receptors are expressed in many brain regions, with prominent
distributions on retinal neurons, suggesting these receptors play
important roles in retinal signal processing.
Recent studies indicate GABAc receptors are present on various other
types of retinal neurons. GABAc receptor mediated responses have
been recorded from cone-driven horizontal cells in catfish (Dong
et al., 1994; Kaneda et al., 1997), cone photoreceptors (Picaud
et al, 1998), and some types of ganglion cells (Zhang and Slaughter,
1995). GABAc responses are particularly prominent in bipolar cells
of every species examined thus far (Feigenspan et al., 1993; Qian
and Dowling, 1995; Lukasiewicz et al., 1994; Lukaisiewicz and Wong,
1997; Qian et al., 1997; Nelson et al., 1999), and both immunocytochemistry
and in situ hybridization studies indicate GABAc receptors are present
on bipolar cells (Qian et al., 1997; Enz et al., 1995, 1996; Koulen
et al., 1997). It appears that these receptors play an important
role in shaping signal transmission from bipolar cells to third
order neurons in the retina.
Fig. 7 illustrates some examples of bipolar cells isolated from
white perch retina. These bipolar cells keep their morphology when
isolated in culture. They usually have a pear-shaped cell body from
which several dendrites and one axon extends. The GABA responses
of bipolar cells in white perch retina have both transient and sustained
components, indicating both GABAA and GABAc receptors are present
as shown in Fig. 8. The transient component can be selectively blocked
by the co-application of bicuculline, leaving a more sustained response.
Thus, the electrophysiological and pharmacological properties of
GABAc receptors on bipolar cells are very similar to those of GABAc
receptors on rod-driven horizontal cells (Qian and Dowling 1995;
Lukasiewicz et al., 1994; Feigenspan and Bormann, 1994).
Different kinetic properties of GABAA and GABAc
receptors suggest that they play different roles in mediating inhibition
on bipolar cell terminals (Qian et al., 1997; Lukasiewicz and Shields,
1998). Furthermore, various subtypes of bipolar cells exhibit different
proportions of GABAA and GABAc receptors. For example, in the rat
retina, there is a clear difference in the contribution of GABAA
and GABAc receptors to rod and cone bipolar cells (Euler and
Wassle,
1998). In white perch too, different morphological types of bipolar
cells exhibit different proportions of GABAc receptor mediated components
(Qian and Dowling, 1995). These results strongly suggest that different
subtypes of bipolar cell utilize various mixtures of GABAA and GABAc
receptors to perform different activities and help create the variety
of functional pathways through the retina.
Because of the presence of multiple GABA receptors on retinal neurons,
it is sometimes difficult to isolate the contributions of each receptor.
Recent studies on ganglion cell responses reveal some interesting
features of GABAc receptors in retinal information processing. For
example, activation of GABAc receptors leads to more transient light
responses in ganglion cells (Dong and Werblin, 1998) and the delayed
inhibition mediated by GABAc receptors is thought to play a major
role in shaping edge-enhancement of ganglion cell receptive fields
(Jacobs and Werblin, 1998). The bipolar cell to ganglion cell synapse
is probably heavily influenced by inhibitory amacrine feed forward
or feedback synapses and these appear to be via primarily GABAc
receptors.
References
Albrecht, B.E., Breitenbach. U., Stuhmer, T., Harvey, R.J. and
Darlison, M.G. (1997) In situ hybridization and reverse transcription-polymerase
chain reaction studies on the expression of the GABA(C) receptor
rho1- and rho2-subunit genes in avian and rat brain. Eur. J.
Neurosci.
9, 2414-2422.
Amin, J. and Weiss, D. S. (1996) Insights into the activation mechanism
of r1 GABA receptors obtained by coexpression of wild type and activation-impaired
subunits. Proc. R. Soc. 263, 273-282.
Boue-Grabot, E., Roudbaraki, M., Bascles, L., Tramu, G., Bloch,
B. and Garret, M. (1998) Expression of GABA receptor rho subunits
in rat brain. J. Neurochem. 70, 899-907.
Calvo, D. J., Vazquez, A. E. and Miledi, R. (1994) Cationic modulation
of r1-type g-aminobutyrate receptors expressed in Xenopus oocytes.
Proc. Natl. Acad. Sci. USA 91, 12725-12729.
Chang, Y, Amin, J. and Weiss, D. S. (1995) Zinc is a mixed antagonist
of homomeric r1 g-aminobutyric acid-activated channels. Mol.
Pharmacol.
47, 595-602.
Chang, Y. and Weiss, D. S. (1999) Channel opening locks agonist
onto the GABAC receptor. Nat. Neurosci. 2, 219-225.
Cutting, G.R., Lu, L., Zoghbi, H., O'Hara, B.F., Kasch, L.M.,
Montrose-Rafizader,
C., Donovan, D.M., Shimada, S., Antonarakis, S.E., Guggino, W.,
Uhl, G.R. and Kazazian, H.H.Jr. (1991) Cloning of the g-aminobutyric
acid (GABA) rho 1 cDNA: a GABA receptor subunit highly expressed
in the retina. Proc. Natl. Acad. Sci. USA 88, 2673-2677.
Cutting, G.R., Curristin, S., Zoghbi, H., O'Hara, B., Selden, M.F.
and Uhl, G.R. (1992) Identification of a putative gamma-aminobutyric
acid (GABA) receptor subunit rho2 cDNA and colocalization of the
genes encoding rho2 (GABRR2) and rho1 (GABRR1) to human chromosome
6q14-q21 and mouse chromosome 4. Genomics 12, 801-806.
Dong, C. J. and Werblin, F. S. (1994) Dopamine modulation of GABAC
receptor function in an isolated retinal neuron. J. Neurophysiol.
71, 1258-1260.
Dong, C. J., Picaud, S. A. and Werblin, F. S. (1994) GABA transporters
and GABAC-like receptors on catfish cone- but not rod-driven horizontal
cells. J. Neurosci. 14, 2648-2658
Dong, C. J. and Werblin, F. S. (1995) Zinc down modulates the GABAc
receptor current in cone horizontal cells acutely isolated from
the catfish retina. J. Neurophysiol. 73, 916-919.
Dong, C. J. and Werblin, F. S. (1998) Temporal contrast enhancement
via GABAC feedback at bipolar terminals in the tiger salamander
retina. J. Neurophysiol. 7, 2171-2180.
Enz, R. and Cutting, G.R. (1999) GABAC receptor rho subunits are
heterogeneously expressed in the human CNS and form homo- and heterooligomers
with distinct physical properties. Eur. J. Neurosci. 11, 41-50.
Enz, R., Brandstätter, J.H., Hartveit, E., Wässle, H. and
Bormann,
J. (1995) Expression of GABA receptor rho 1 and rho 2 subunits in
the retina and brain of the rat. Eur. J. Neurosci. 7, 1495-1501.
Enz, R., Brandstätter, J.H., Wässle, H. and Bormann, J. (1996) Immunocytochemical
localization of the GABAC receptor rho subunits in the mammalian
retina. J. Neurosci. 16, 4479-4490.
Euler, T. and Wassle, H. (1998) Different contributions of GABAA
and GABAC receptors to rod and cone bipolar cells in a rat retinal
slice preparation. J. Neurophysiol. 79, 1384-1395.
Feigenspan, A. and Bormann, J. (1994a) Modulation of GABAC receptors
in rat retinal bipolar cells by protein kinase C. J. Physiol. (Lond)
481, 325-330.
Feigenspan, A. and Bormann, J. (1994b) Differential pharmacology
of GABAA and GABAC receptors on rat retinal bipolar cells. Eur J.
Pharmacol. 288, 97-104.
Feigenspan, A., Wässle, H. and Bormann, J. (1993) Pharmacology of
GABA receptor Cl- channels in rat retinal bipolar cells. Nature
361, 159-163.
Filippova, N., Dudley, R. and Weiss, D. S. (1999) Evidence for
phosphorylation-dependent
internalization of recombinant human r1 GABAC receptors. J.
Physiol. (Lond) 518, 385-399.
Hanley, J. G., Koulen, P., Bedford, F., Gordon-Weeks, P. R. and
Moss, S. J. (1999) The protein MAP-1B links GABA(C) receptors to
the cytoskeleton at retinal synapses. Nature 397, 66-69.
Jacobs, A. L. and Werblin, F. S. (1998) Spatiotemporal patterns
at the retinal output. J. Neurophysiol. 80,447-451.
Johnston, G.A.R. 1986 Multiplicity of GABA receptors. in Receptor
Biochemistry and Methodology, (eds. Olsen R.W. & Venter, J.C.)
Alan R. Liss, Inc., Vol. 5, pp 57-71
Kaneda, M., Mochizuki, M. and Kaneko, A. (1997) Modulation of GABAC
response by Ca2+ and other divalent cations in horizontal cells
of the catfish retina. J. Gen. Physiol. 110,741-747.
Koulen, P., Brandstätter, J.H., Kröger, S., Enz, R., Bormann, J.
and Wässle, H. (1997) Immunocytochemical localization of the
GABA(C)
receptor rho subunits in the cat, goldfish, and chicken retina.
J. Comp. Neurol. 380, 520-532.
Kusama, T., Sakurai, M., Kizawa, Y., Uhl, G. R. and Murakami, H.
(1995) GABA rho1 receptor: inhibition by protein kinase C activators.
Eur. J. Pharmacol. 291, 431-434.
Lukasiewicz, P.D. and Shields, C. R. (1998) Different combinations
of GABAA and GABAC receptors confer distinct temporal properties
to retinal synaptic responses. J. Neurophysiol. 79, 3157-3167.
Lukasiewicz, P.D. and Wong, R.O.L. (1997) GABAC receptors on ferret
retinal bipolar cells: a diversity of subtypes in mammals? Vis.
Neurosci. 14, 989-994.
Lukasiewicz, P.D., Maple, B.R. and Werblin, F.S. (1994) A novel
GABA receptor on bipolar cell terminals in the tiger salamander
retina. J. Neurosci. 14, 1202-1212.
Morris, K. D., Moorefield, C. N. and Amin J (1999) Differential
modulation of the gamma-aminobutyric acid type C receptor by neuroactive
steroids. Mol. Pharmacol. 56, 752-759.
Nelson, R., Schaffner, A.E., Li, Y.-X. and Walton, M.C. (1999) Distribution
of GABA(C)-like responses among acutely dissociated rat retinal
neurons. Vis. Neurosci. 16,179-190.
Pan, Z.-H. and Lipton, S. A. (1995) Multiple GABA receptor subtypes
mediate inhibition of calcium influx at rat retinal bipolar cell
terminals. J. Neurosci 15, 2668-2679.
Picaud, S., Pattnaik, B., Hicks, D., Forster, V., Fontaine, V.,
Sahel, J. and Dreyfus, H. (1998) GABAA and GABAC receptors in adult
porcine cones: evidence from a photoreceptor-glia co-culture model.
J. Physiol. (Lond) 513, 33-42.
Polenzani, L., Woodward, R. M. and Miledi R (1991) Expression of
mammalian g-aminobutyric acid receptors with distinct pharmacology
in Xenopus oocytes. Proc. Natl. Acad. Sci. USA 88, 4318-4322.
Qian, H. and Dowling, J.E. (1993) Novel GABA responses from rod-driven
retinal horizontal cells. Nature 361,162-164.
Qian, H. and Dowling, J. E. (1994) Pharmacology of novel GABA receptors
found on rod horizontal cells of the white perch retina. J.
Neurosci.
14, 4299-4307.
Qian, H. and Dowling, J.E. (1995) GABAA and GABAC receptors on hybrid
bass retinal bipolar cells. J. Neurophysiol. 74, 1920-1928.
Qian, H., Hyatt, G., Schanzer, A., Hazra, R., Hackam, A., Cutting,
G. R. and Dowling, J. E. (1997a) A comparison of GABAC and rho subunit
receptors from the white perch retina. Vis. Neurosci. 14, 843-851.
Qian, H., Li, L., Chappell, R.L. and Ripps, H. (1997b) GABA receptors
of bipolar cells from the skate retina: actions of zinc on GABA-mediated
membrane currents. J. Neurophysiol. 78, 2402-2412.
Qian, H., Dowling, J.E. and Ripps, H. (1998) Molecular and pharmacological
properties of GABA-rho subunits from white perch retina. J.
Neurobiol.
37, 305-320.
Qian, H., Dowling, J. E. and Ripps, H. (1999) A Single Amino Acid
in the Second Transmembrane Domain of GABA r Subunits is a Determinant
of the Response Kinetics of GABAC Receptors. J. Neurobiol. 40, 67-76.
Ragozzino, D., Woodward, R. M., Murata, Y., Eusebi, F., Overman,
L. E. and Miledi, R. (1996) Design and in vitro pharmacology of
a selective gamma-aminobutyric acidC receptor antagonist. Mol.
Pharmacol.
50,1024-30
Shimada S, Cutting G, Uhl GR (1992) g-aminobutyric acid A or C receptor?
g-aminobutyric acid r1 receptor RNA induces bicuculline-, barbiturate-,
and benzodiazepine-insensitive g-aminobutyric acid responses in
Xenopus oocytes. Mol. Pharmacol. 41, 683-687.
Sivilotti, L. and Nistri, A. (1991) GABA receptor mechanisms in
the central nervous system. Prog. Neurobiol. 36, 35-92.
Wang, T. L., Hackam, A., Guggino, W. B. and Cutting, G. R. (1995)
A single histidine residue is essential for zinc inhibition of GABA
rho 1 receptors. J. Neurosci. 15, 7684-7691.
Wegelius, K., Pasternack, M,, Hiltunen, J.O., Rivera, C., Kaila,
K., Saarma, M. and Reeben, M. (1998) Distribution of GABA receptor
rho subunit transcripts in the rat brain. Eur. J. Neurosci. 10,
350-357.
Wellis, D. P. and Werblin, F. S. (1995) Dopamine modulates GABAc
receptors mediating inhibition of calcium entry into and transmitter
release from bipolar cell terminals in tiger salamander retina.
J. Neurosci. 15, 4748-4761.
Woodward, R. M., Polenzani, L. and Miledi, R. (1992a) Effects of
steroids on g-aminobutyric acid receptors expressed in Xenopus oocytes
by poly(A)+ RNA from mammalian brain and retina. Mol. Pharmacol.
41, 89-103.
Woodward, R. M., Polenzani, L. and Miledi, R. (1992b) Characterization
of bicuculline/baclofen-insensitive g-aminobutyric acid receptors
expressed in Xenopus oocytes I. effects of Cl- channel inhibitors.
Mol. Pharmacol. 42,165-173.
Woodward, R. M., Polenzani, L. and Miledi, R. (1993) Characterization
of bicuculline/baclofen-insensitive (r-like) g-aminobutyric acid
receptors expressed in Xenopus oocytes. II. pharmacology of g-aminobutyric
acid A and g-aminobutyric acid B receptor agonists and antagonists.
Mol. Pharmacol. 43, 609-625.
Zhang, D, Pan, Z.H., Zhang. X., Brideau, A.D. and Lipton, S.A. (1995)
Cloning of a gamma-aminobutyric acid type C receptor subunit in
rat retina with a methionine residue critical for picrotoxinin channel
block. Proc. Natl. Acad. Sci. USA 92, 11756-11760.
Zhang, J. and Slaughter M. M. (1995) Perferential suppression of
the ON pathway by GABAC receptors in the amphibian retina. J.
Neurophysiol.
74,1583-1592.
Albumin Albumin has several essential physiologic
functions in the human body.
Definition: \Al*bu"min\, n. (Chem.)
A thick, viscous nitrogenous substance, which is the chief
and characteristic constituent of white of eggs and of the
serum of blood, and is found in other animal substances, both
fluid and solid, also in many plants. It is soluble in water
and is coagulated by heat and by certain chemical reagents.
Albumin is the protein of the highest concentration
in plasma responsible for transporting many small molecules. (Calcium,
progesterone, drugs . . . ) It is also of prime importance in maintaining
the oncotic pressure of the blood (Keeping the fluid from leaking
out into the tissues. When administered intravenously albumin increases
total blood volume by drawing fluid from the extravascular tissues.).
Unlike small molecules such as sodium and chloride, the concentration
of albumin in the blood is much greater than it is in the extracellular
fluid. Albumin is synthesized by the liver, therefore decreased
serum albumin may be caused by liver disease. It can also result
from kidney disease, which allows albumin to escape into the urine.
Albumin has been shown to offer therapeutic advantages in shock,
acute liver failure, burns, hypoproteinemia, adult respiratory distress
syndrome, cardiopulmonary bypass, neonatal hemolytic disease, renal
dialysis, acute nephrosis, erythrocyte resuspension, acute peritonitis,
pancreatitis, mediastinitis and cellulitis. Adverse reactions to
albumin are rare. Decreased albumin may also be explained by malnutrition
or a low protein diet.*
Albumin is also called albuminate, plasbumin, buminate, albutein
and albuminar. It is prepared as a sterile solution, contains no
preservatives and is treated to prevent transmitting viruses. The
elimination half life of serum albumin is twenty days. The U.S.
Food and Drug Administration (FDA) regulates its preparation, distribution
and use.
What is albumin?
Albumin is a protein (single polypeptide, 585 amino acids) manufactured
by the liver, (9-12g/day) it is also a powerful antioxidant. It
is a major source of sulphydryl groups, these "thiols"
scavenge free radicals (nitrogen and oxygen species). It may also
be an important free radical scavenger in sepsis. (In sepsis there
is an increased rate of albumin loss into the tissues - this is
probably related to increased capillary membrane permeability).
What does albumin do?
Albumin is also involved in between fifty and one hundred biological
functions. Our body’s main transport system, it moves vitamins,
minerals, hormones, fatty acids, and other essential substances
to their destinations. Other functions include maintaining the "osmotic
pressure" that causes fluid to remain within the blood stream
instead of leaking out into the tissues.
Why is albumin important?
1. Binding and transport. There are actually
four binding sites on albumin and these have varying specificity
for different substances.Competitive binding of drugs may occur
at the same sit or at different sites (conformational changes) [eg.
warfarin and diazepam]. The drugs that are important for albumin
binding are: warfarin, digoxin, NSAIDS, midazolam, thiopentone.
The relevence of a low albumin and drug binding is unknown.
2. Maintenance of colloid osmotic pressure.
Albumin is responsible for 75 - 80 % of osmotic pressure.Starling's
equation: Transcapillary Flow = k [(Pcap + p i) - (Pi + p cap )]
Remember that albumin is the main protein both in the plasma and
in the interstitium and it is the COP gradient rather than the absolute
plasma value that is important: this is what distinguishes hypoalbuminaemia
derived from redistribution (capillary leak) from that of pure full
body deficiency.
3. Free radical scavenging. Albumin is
a major source of sulphydryl groups, these "thiols" scavenge
free radicals (nitrogen and oxygen species). Albumin may be an important
free radical scavenger in sepsis.
4. Platelet function inhibition and antithrombotic
effects. The anticoagulant and antithrombotic effects of
albumin are poorly understood this may be due to binding nitric
oxide radicals inhibiting inactivation and permitting a more prolonged
antiaggregatory effect. In diabetes, glycosylated albumin may increase
the incidence of thrombotic events and atherosclerosis.
5. Effects on vascular permeability.
In sepsis there is an increased rate of albumin loss into the tissues
- this is probably related to increased capillary membrane permeability.
Which diseases cause albumin to be too low?
Liver disease, kidney disease, and malnutrition are the major causes
of low albumin. A diseased liver produces insufficient albumin.
Diseased kidneys sometimes lose large amounts of albumin into the
urine faster than the liver can produce it (this is termed nephrotic
syndrome). In malnutrition there is not enough protein in the patient's
diet for the liver to make new albumin. The British Heart Study,
published in the British medical journal The Lancet in 1989, followed
7,735 middle-aged British men for 9.2 years, finding that men with
the lowest albumin levels had the highest rates of death from a
plethora of causes.
What is a normal level of albumin?
The normal value depends on the laboratory running the test. Most
labs consider roughly 3.5 to 5 grams per deciliter to be normal.
What happens if it gets too low?
In a healthy person with normal nutrition, the liver will simply
manufacture more and the level will normalize. If albumin gets very
low swelling can occur in the ankles (edema) and fluid can begin
to accumulate in the abdomen (ascites) and in the lungs (pulmonary
edema).
Why does albumin fluctuate so much?
Albumin levels are also dependant on the state of hydration of the
body. A person that is deficient of water ("dry") because
of dehydration will have an artificially low albumin level. This
returns to normal when the dehydration is corrected. Albumin fluctuates
so widely because it is very sensitive to changes in hydration of
the body.
What causes serum albumin to decrease?
1. Decreased synthesis 2. Increased catabolism [ very slow ] 3.
Increased loss: Nephrotic syndrome, exudative loss in burns, hemorrhage,
gut loss, redistribution: hemodilution, ncreased capillary permeability
(Increased interstitial albumin) decreased lymph clearance.
What are the consequences of decreased plasma
albumin?
1. Decreased ligand binding. 2. Decreased plasma colloid pressure:
decreased colloid oncotic pressure, and oedema formation. The formation
of oedema is determined by: the rate of fluid flux. The clearance
of fluid by lymphatics.
* HBC Protocols strongly believes that medical
information is best conveyed to patients by their licensed healthcare
providers. The materials presented here should be considered supplemental
to that information. Should you have any questions, please consult
your healthcare provider.
How does Lithium Orotate
work?
We begin with the fact that the orotate salts are electrically
neutral and relatively stable against dissociation, properties that
seem to be crucial for the ability of orotates to participate in
intracellular mineral uptake and transport. Dissociation is the
process that takes place when a salt is dissolved in a solvent such
as water and breaks up into its component ions. Table salt dissolved
in water, for example, dissociates into sodium and chloride ions.
At physiological pH the orotate salts are much more stable than
table salt and will not readily dissociate into free orotic acid
plus a mineral ion.
Free orotic acid (OA) itself is known to get into cells by simply
leaking (diffusing) through cell membranes, rather than by being
actively transported. But diffusion is a relatively inefficient
process, which limits the amount of OA that can enter a cell. By
contrast, uracil a compound almost identical to OA, only minus the
carboxylic acid group is taken up efficiently by a transporter protein
that binds to uracil molecules and drags them into the cell.1
This transporter appears to be specific for uracil or similar molecules
which are uncharged, but not for uracil's close cousin OA (which
is negatively charged at body pH).
Bind the orotic acid with a mineral, however, and you end up with
a stable electrically neutral salt. This property is just what is
needed for OA along with its bound mineral to be taken up directly
by the uracil transporter. At the same time, neutralizing the charge
on OA makes the resulting complex more lipophilic or "fat-loving"
than free OA; as a result, the stable orotate complex would be expected
to diffuse more easily through the lipid membranes of cells. Essentially
just such a mechanism was proposed by Nieper for enhancing the diffusion
of mineral ions across cell membranes.2
Either way via enhanced diffusion or active transport complexing
a mineral with orotate results in increased uptake of both components
of the complex by cells.
That's still not the whole story of orotate, however. Here and
there in his papers, Nieper gives
tantalizing clues about the role of the "pentose phosphate
pathway" or PPP in mediating the effects of his mineral orotates.2-4
The PPP is a well-known biochemical cycle which, among other vital
functions, is responsible for synthesizing D-ribose 5-phosphate.
D-ribose is of course the sugar which gets incorporated into nucleotides
(a process known as ribosylation) and ultimately into RNA/DNA. Was
Nieper attempting to signal a deep connection between the ribosylation
of orotate and its activity as a mineral transporter?
The answer is yes. To see what Dr. Nieper was hinting at, we need
some additional background information on OA, also known as vitamin
B13.
Although orotic acid isn't officially considered a vitamin these
days, over 40 years ago it was found to have growth-promoting, vitamin-like
properties when added to the diets of laboratory animals. Subsequent
nutritional studies in humans and animals revealed that OA has a
"sparing" effect on vitamin B12, meaning that supplemental
OA can partially compensate for B12 deficiency.5,6
OA also appears to have a direct effect on folate metabolism.7
Many of the vitamin-like effects of OA are undoubtedly due to its
role in RNA and DNA synthesis. (B12 and folate are also involved
in DNA synthesis, but at a point downstream from where OA comes
in.) Our bodies produce OA as an intermediate in the manufacture
of the pyrimidine bases uracil, cytosine, and thymine.8,9
Together, these pyrimidines constitute half of the bases needed
for RNA/DNA, the other half coming from the purine bases adenine
and guanine which are synthesized independently of OA.
The enzyme orotate phosphoribosyltransferase (OPRTase), which is
found in organisms ranging from yeast to humans, is responsible
for catalyzing the first step in the conversion of orotic acid into
uridine. It does so by facilitating the attachment of a ribose plus
phosphate group to OA. The net result is the formation of a molecule
named OMP (orotidine 5'-monophosphate), which in turn is the immediate
precursor to UMP (uridine 5'-monophosphate).
Because the enzyme OPRTase requires magnesium ions for its activity,
some researchers wondered whether a magnesium complex of orotic
acid might be involved in binding orotate to the enzyme.10
They found that the true substrate for OPRTase is not orotate itself
but rather a magnesium orotate complex. The fact that the complex
is electrically neutral compared to the negatively charged orotate
ion means that the complex is more easily transportable to the active
site of the enzyme.10
These researchers suggested that the magnesium complex helps position
orotate within the enzyme in the proper orientation for conversion
to OMP. In the process the magnesium ion in the complex gets exchanged
with the magnesium ion bound to the active site of the enzyme, the
net result being that one magnesium ion is released.
So far, so good. Following up on Nieper's hint, we see that orotate-and
specifically magnesium orotate-can interact with the pentose phosphate
pathway (PPP) to generate OMP and ultimately uridine.2,10
But Nieper also pointed out that the mineral-transport activity
of the orotates does not necessarily have anything to do with the
formation of RNA or DNA. To resolve this apparent contradiction,
we must seek out an additional metabolic role for orotate independent
of RNA/DNA synthesis.
In fact, not all the uridine formed from orotic acid does wind
up in RNA or DNA. There are other vital roles for orotic acid and
uridine in the body-for example, OA gets taken up by red blood cells
where it is rapidly converted to UDP-glucose by way of OPRTase and
other enzymes. Here UDP is the nucleotide uridine diphosphate. The
red blood cells can then act as a storage and distribution pool
for delivering glucose and uridine to tissues such as brain, heart,
and skeletal muscle.9 Because UDP-glucose is a
precursor for glycogen (a storage form of glucose), the delivery
of UDP-glucose to heart muscle and its conversion there to glycogen
might account for some of the cardioprotective effects of orotic
acid.11,12
Which brings us right back to Dr. Nieper's work.
Based on the available scientific evidence, it seems clear that
magnesium orotate can get channeled directly into OMP synthesis
and ultimately into UDP-glucose, which can then resupply a heart
under stress with carbohydrates and nucleotides. Thus a mechanism
exists for explaining why magnesium orotate works even better than
orotic acid for heart conditions.11-13
In contrast, some of the mineral orotates such as copper and nickel
either inhibit OPRTase or, in the case of calcium orotate, neither
activate nor inhibit the enzyme.10This suggests that the body preferentially uses magnesium
orotate for promoting uridine synthesis. In a sense, complexing
OA with magnesium magnifies the "vitamin-like" properties
of vitamin B13.
Another effect of magnesium orotate is to inhibit the development
of atherosclerosis when administered orally to humans14
or experimental animals.15
The animal study in particular tells us that magnesium orotate performs
better than orotic acid, which in turn outperforms magnesium chloride,
in inhibiting atherosclerotic changes caused by high levels of cholesterol
in the diet.15 In other words, a synergy exists
between magnesium and orotic acid such that the complex they form
magnesium orotate is more potent than either one alone. Dr. Nieper
explained this effect by suggesting that when OA in the magnesium
orotate complex is coupled with ribose (ribosylated) in the walls
of blood vessels, the magnesium ion is liberated during this process
and becomes locally available for activating cholesterol-metabolizing
enzymes.3
The increase in potency of magnesium in going from a chloride
salt to an orotate salt is notable and certainly consistent with
Nieper's ideas about orotate as a mineral transporter. But notice
that orotic acid also increases in potency in going from free OA
to its magnesium complex, an enhancement consistent with the idea
that magnesium orotate gets preferentially directed toward uridine
synthesis by OPRTase. It is just this combination of properties
enhanced transport of magnesium, itself known16
for its anti-atherosclerotic and anti-cholesterol effects, and enhanced
synthesis of uridine from orotic acid9,10
that makes magnesium orotate so helpful for treating cardiovascular
disorders.
By contrast, the very similar compound calcium orotate has none
of the effectiveness of magnesium orotate in lowering serum cholesterol,
although it does have other characteristics beneficial for treating
arterial disease.2
The difference in activity between magnesium and calcium orotate
can best be explained by the specific effects of magnesium in activating
cholesterol turnover2
as well as by the specificity of magnesium orotate-but not calcium
orotate-for activating OPRTase.10
As the preceding example shows, the various mineral orotates are
likely to be targeted to distinct metabolic pathways in specific
tissues. Another example is provided by an experiment involving
lithium metabolism in the brain.17
Lithium is well known for its ability to moderate manic-depressive
illness. In an experiment to evaluate lithium-induced changes in
brain metabolism, rats were injected with a solution of lithium
chloride daily for two weeks. One hour after the last lithium treatment
all rats received an injection of radiolabeled orotic acid into
the cerebral ventricles. At various intervals thereafter RNA was
extracted from rat brains, separated into fractions, and analyzed
for radioactivity. The results showed that lithium increases RNA
turnover markedly in brain (but not in other tissues such as liver).
The authors suggested that lithium acts at the membrane level and
that the effects on RNA metabolism are due to changes in the transport
of radiolabeled orotic acid-an explanation entirely consistent with
Nieper's idea that lithium combines with OA to yield a transportable
complex.
In summary, the evidence tends to support Nieper's criteria for
orotate as an electrolyte carrier, namely, (1) a low dissociation
constant, (2) an affinity for specific cellular systems or organs,
and (3) a metabolic pathway which liberates the transported mineral
within the targeted organ or system.
18 References:
[1] Wohlhueter RM, McIvor RS,
Plagemann PG. Facilitated transport of uracil and 5-fluorouracil,
and permeation of orotic acid into cultured mammalian cells. J Cell
Physiol. 1980;104(3):309-19. [Abstract
] [2] Nieper HA. The anti-inflammatory and immune-inhibiting
effects of calcium orotate on bradytrophic tissues. Agressologie.
1969;10(4):349-57. Available as article #CM14 from the A. Keith
Brewer International Science Library at (608) 647-6513 or on the
Web . [3] Nieper HA. The clinical applications of lithium
orotate. A two years study. Agressologie. 1973;14(6):407-11. Available
as article #CM12 from the A. Keith Brewer International Science
Library at (608) 647-6513 or on the Web
. [4] Nieper HA. The clinical effect of calcium-diorotate
on cartilage tissue, the specific function dependent upon the pentose
metabolism of bradytrophic tissue [in German]. Z prÿkt Geriatrie.
1973;3(4):82-9. English translation available as article #CM29 from
the A. Keith Brewer International Science Library at (608) 647-6513
or on the Web . [5] Rundles RW, Brewer SS Jr. Hematologic responses
in pernicious anemia to orotic acid. Blood. 1958;13(2):99-115. [6] Moruzzi G, Viviani R, Marchetti M. Orotic acid
as a "growth factor" for chickens and its relation to
vitamin B12 and methionine [in German]. Biochem Z. 1960;333:318-27.
[7] Pasquali P, Landi L, Caldarera CM, Marchetti
M. Effects of orotic acid on dihydrofolate dehydrogenase and on
tetrahydrofolate-dependent enzymes in the chick liver. Biochim Biophys
Acta. 1968;158(3):482-4. [8] OäSullivan WJ. Orotic acid. Aust N Z J Med.
1973;3(4):417-22. [9] Connolly GP, Duley JA. Uridine and its nucleotides:
biological actions, therapeutic potentials. Trends Pharmacol Sci.
1999;20(5):218-25. [Abstract
] [10] Dodin G, Lalart D, Dubois JE. Role of magnesium
cations in the yeast orotate phosphoribosyltransferase catalyzed
reaction. Mechanism of the inhibition by Cu++ and Ni++ ions. J Inorg
Biochem. 1982;16(3):201-13. [Abstract
] [11] Donohoe JA, Rosenfeldt FL, Munsch CM, Williams
JF. The effect of orotic acid treatment on the energy and carbohydrate
metabolism of the hypertrophying rat heart. Int J Biochem. 1993;25(2):163-82.
[Abstract
] [12] Ferdinandy P, Fazekas T, Kadar E. Effects
of orotic acid on ischaemic/reperfused myocardial function and glycogen
content in isolated working rat hearts. Pharmacol Res. 1998;37(2):111-4.
[Abstract
] [13] Rosenfeldt FL. Metabolic supplementation with
orotic acid and magnesium orotate. Cardiovasc Drugs Ther. 1998;12(Suppl
2):147-52. [Abstract
] [14] Villanyi P, Votin J, Rahlfs V. Arteriosclerosis,
myocardial infarct and blood lipids, their therapeutic modification
by magnesium orotate [in German]. Wien Med Wochenschr. 1970;120(5):76-83.
[15] Jellinek H, Takacs E. Morphological aspects
of the effects of orotic acid and magnesium orotate on hypercholesterolaemia
in rabbits. Arzneimittelforschung. 1995;45(8):836-42. [Abstract
] [16] Ouchi Y, Tabata RE, Stergiopoulos K, Sato
F, Hattori A, Orimo H. Effect of dietary magnesium on development
of atherosclerosis in cholesterol-fed rabbits. Arteriosclerosis.
1990;10(5):732-7. [Abstract
] [17] Dewar AJ, Reading HW. Effect of lithium administration
on RNA metabolism in rat brain. Psychol Med. 1971;1(3):254-9. [18] Nieper HA. Recalcification of bone metastases
by calcium diorotate. Agressologie. 1970;11(6):495-502. Available
as article #CA21 from the A. Keith Brewer International Science
Library at (608) 647-6513 or on the Web
.
In the 
