Vitamin B6 at risk?

[Guest guest]

It appears the FDA has struck again....throwing another curve ball at health freedom by removing a valuable nutrient from store shelves. I wonder when this will happen, and how it will affect things like nutritional yeast?Pyridoxamine's Status Has Changed

Up until now Pyridoxamine has been marketed and sold as a dietary supplement, but recently the FDA has changed its status to a drug. This change means that the product will be removed from sale in US nutrition outlets. Read about the change here The rare antiaging B vitamin

Pyridoxamine is one of the

three naturally occurring vitamin B6’s (the others being pyridoxal and

pyridoxine), but pyridoxamine as a supplement is the rarest form,

perhaps partly due to its high per Kg. price.

Recent clinical trials have supported facts about

pyridoxamine that do not appear to be present in the more commonly

available B6 vitamins.

One of the most noticeable features of pyridoxamine is

the fact that it is the most potent natural substance to inhibit

glycosylation. This process (also known as cross-linking) inhibits the

actions of proteins to go about there functions, it is formed when

sugar (normally as glucose) meets oxygen and protein.

More glycated proteins leads to more incidences of

aging disorders such as cataracts, hardened skin, tough collagen

(thereby more inefficient cell and arterial walls) and it is a well

know fact that diabetics have large numbers of glycated proteins, a

prominent feature of the diabetic disease.

In animal models, pyridoxamine has inhibited both

development and progression of diabetic nephropathy for type 1 and 2

diabetes. Human trials are ongoing but show promise at doses of 50 mg.

twice daily, and whilst some patients have taken as much as 300 mg

daily, they have not shown any signs of serious side effects or

contraindications.

Glycation, particularly as Advanced Glycated End

products (AGE) has been associated with aging for many years and forms

a fundamental theory of aging. There are a number of stages, both early

and late, in the formation of AGE’s and whilst excellent anti-glycators

such as Aminoguanidine show excellent ability to prevent early-stage

glycation, it is not so effective in post or late stage glycation. This

is where pyridoxamine has been shown to be most effective. One study,

(Booth AA, Khalifah RG, Todd P, Hudson BG, In-vitro kinetic studies of

formation of antigenic advanced glycation end products. Novel

inhibition of post-Amadori glycation pathways, Journal of Biological

Chemistry, Feb 28;272(9):5430-7), stated that; “…[pyridoxamine] may

compliment others, such as Aminoguanidine, known to either prevent

initial sugar attachment or scavenge highly reactive dicarbonyl

intermediates.â€

Apart from inhibiting AGE formation, pyridoxamine also

“traps†advanced lipoxidation end-products (ALE’s). This fact has not

escaped researchers interested in atherosclerosis, because this is

viewed as an age-related disease and the presence of an excess of ALE’s

seem to set the stage to affect the structure and function of the

vascular wall. In animal experiments, pyridoxamine is noted to help

reduce the formation of ALE and has therefore been suggested that it

could help prevent (or slow) the formation of atherosclerosis, which

would naturally assist in the avoidance of heart disease.

Further interesting animal experiments with

pyridoxamine have shown improvement for kidney disorders, in particular

helping to prevent the formation of kidney stones.

Dosages:

Normal dosages are considered to be 50 mg once daily. http://www.antiaging-systems.com/extract/pyridoxamine.htmPYRIDOXAMINE: A Universal Weapon against aging

By Kaufmann, MS

We are constantly being bombarded with messages from the media, the

department of public health, and the World Health Organization (WHO)

about how overweight and sedentary we have become. The incidence of

obesity has reached epidemic proportions. Our growing waistlines

coupled with our sedentary lifestyles have put us at risk for

developing Type 2 diabetes as well as a host of other chronic

degenerative diseases. I raise this issue, because in the face of all

this public discussion, it is easy to ignore the public health

warnings, particularly if you are an individual of normal weight and

consider yourself at low risk of developing diabetes.

Actually, when one looks at the disease Diabetes Mellitus (DM), it

is apparent that what is truly occurring is an accelerated form of

aging. Aging is occurring in all of us. It is important to make note of

the many microvascular and macrovascular complications of diabetes

because these complications provide us with clues from which we can

form a logical and rational anti-aging protocol.

There are a number of different theories of aging. One of the oldest

and best known theories is Denham Harman’s ‘free radical’ theory of

aging which dates back to 1956. This theory posits that unpaired oxygen

electrons, which are produced during aerobic respiration, cause

cumulative oxidative damage, resulting in the effects of aging and

death. Harman posited that endogenous oxygen radical generation occurs

within the body, as a by product of enzymatic redox chemistry.

Therefore the necessary ingredient for life – oxygen – is a double

edged sword. While we can’t live without breathing in oxygen, we cannot

utilize oxygen without it damaging our cells.

Another theory of aging is the cross-linking theory of aging. The

cross-linking theory of aging and the free radical theory of aging are

not mutually exclusive, but synergistic. Ironically the cross-linking

theory of aging is actually based upon processes described by the food

chemist Louis Camille Maillard in 1912 who outlined the non-enzymatic

chemical reactions between proteins and carbohydrates that cause foods

to turn brown and further enhance their flavors. This process also

occurs in the body when a reduced sugar (usually glucose) attaches to a

protein. An intermediate reversible product is formed. That product is

a Schiff base. As the protein/glucose complex continues to be exposed

to additional sugar a more stable, less reversible complex forms. That

complex is known as an Amadori product. Amadori products further

degrade into a number of highly reactive carbonyl compounds. These

compounds are known as Advanced Glycation End products (AGEs) or when

lipids or fats are involved Advanced Lipoxidation End products (ALEs).

AGE/ALEs go on to react with other fats, proteins, amino acids, nucleic

acids and a variety of other cells. AGEs in tissues increase the rate

of free radical production, cause tissue injury, inflammation, and can

deposit anywhere. For example, when AGEs attach to LDL cholesterol, the

LDL cholesterol is rapidly oxidized and is more likely to deposit

within a blood vessel thereby contributing to plaque formation and

atherosclerosis. AGEs form at an accelerated rate in hyperglycemia,

diabetes, and metabolic syndrome. However, AGEs are a universal

symptoms of aging. They can deposit in any organ or tissue, including

the skin, the lungs, the blood vessels, the lens of the eye, the

neurons in the brain, and in the filtering mechanism in the kidney.

Whenever and wherever AGEs deposit, the normal functioning of that

organ, tissue or cell is compromised. There is evidence that AGEs can

bind with DNA and have a mutagenic effect (contributing to the risk of

cancer and autoimmune disease).

When we think of the formation of AGEs and ALEs we generally think

of them forming endogenously as a result of the glucose that is already

within the body. We often forget that there are also dietary AGEs and

ALEs. Our exposure to AGEs and ALEs occurs as an end result of normal

metabolism. However we can also be contributing to the problem through

the intake of dietary, exogenous AGEs. So, no matter who we are, how

fit we are, how thin we are, we cannot escape the effects of these

cross linked proteins.

Pyridoxamine

Vitamin B6 exists in 3 naturally occurring forms: pyridoxine,

pyridoxal, and pyridoxamine (PM). Pyridoxine is the form most commonly

seen in supplements. However, each can be phosphorylated at the 5

position. Pyridoxal 5’ phosphate (PLP) and pyridoxamine 5’ phosphate

(PMP) are the active coenzyme forms. Pyridoxine is found in plant

sources. Pyridoxamine and pyridoxal are found in animal sources where

they exist mainly in their phosphorylated forms. All 3 forms have some

ability to function as anti-glycation agents inhibiting the formation

of AGE/ALEs, but it is pyridoxamine that is the most potent agent of

the three forms. Pyridoxamine prevents the formation of AGEs. It works

by trapping reactive carbonyl groups and it also demonstrates free

radical quenching properties. Accumulation of AGEs is a physiologic

consequence of tissue aging. Tissue deposits of AGEs and circulating

AGEs are a hallmark of diabetes mellitus. Damage from AGEs is also seen

in a variety of other vascular and degenerative diseases. AGE

generation potentiates oxidative damage and lipid peroxidation in

target tissues. The tissue damage caused by AGEs and ALEs further

drives inflammation. The more we understand about the role of AGEs in

‘normal’ global aging, the more important a pharmacologic agent like

pyridoxamine becomes. Pyridoxamine has multiple mechanisms of action

which can are best summarized in a study published in 2005. “…PM

inhibits post Amadori steps of the Maillard reaction by sequestering

catalytic metal ions and blocking oxidative degradation on Amadori

intermediate. PM also has the capacity to scavenge toxic carbonyl

products of sugar and lipid degradation, and to inhibit reactive oxygen

species.†Pyridoxamine has been shown to limit the formation of AGEs

without affecting glycemic control. There is additional evidence that

high blood lipids contribute to the formation of AGE/ALEs even in the

absence of hyperglycemia. Pyridoxamine inhibited the formation of both

toxic end products demonstrating a protective effect on vascular and

renal function in an animal model. It is quite unique that PM

demonstrates the ability to prevent lipid peroxidation and therefore

ALE formation. Pyridoxamine inhibited the formation of ALEs by trapping

malondialdehyde (MDA) an important intermediate in ALE formation. The

beauty of pyridoxamine lies not only in its multiple mechanisms of

action, but also in its tolerability. There are little or no

contraindications for its use.

The Role of AGEs in Health and Disease

There are a variety of chronic and degenerative diseases associated

with the accumulation of AGEs in tissues and organs. Many of these

conditions we consider a normal part of growing older. The toxic AGEs

can deposit anywhere compromising physiologic function. AGEs deposit in

the lens of the eye leading to the formation of cataracts. When AGEs

deposit in the vascular system, long lived proteins such as collagen

and elastin become stiff and hypertension is just one of many possible

consequences. It is hard to envision a chronic degenerative condition

or disease of aging that would not benefit from the inhibition of

AGE/ALEs formation. “Although AGEs in proteins are probably

correlative, rather than causative, with respect to aging, they

accumulate to high levels in tissues in age-related chronic diseases

such as atherosclerosis, diabetes, arthritis and neurodegenerative

disease.†Inhibition of AGE formation could inhibit oxidative and

inflammatory damage in target tissues, slowing the progression and

pathophysiology of aging. This could lead to a significant improvement

of the quality of life of the aging population. It is evident that

AGE/`ALEs likely contribute to both diabetic and non diabetic vascular

damage. AGEs accumulate in tissues and organs in rheumatoid arthritis

and Alzheimer disease. As mentioned above, diabetes mellitus provides

us with a model of accelerated aging. AGE/ALEs contribute to the

various microvascular and macrovascular complications which occur in

the disease. Just as AGEs compromise the flexibility and efficiency in

the vascular system, AGE deposition in the kidney compromise the

kidney’s filtering capacity and can lead to nephropathy and kidney

failure. Culling the most recent literature was enlightening. There is

now evidence that AGEs may contribute to colon cancer and melanoma.

Pyridoxamine may prove to be a therapy for primary hyperoxaluria (which

causes the formation of kidney stones. AGEs may well interfere with

osteoclast activity by altering the structural integrity of bone matrix

proteins and osteoclast induced bone resorption, thereby contributing

to an increased risk of bone fracture. There may even prove to be a

link between AGEs and osteoarthritis (OA) the most common cause of

chronic pain and disability in older adults. In conclusion,

pyridoxamine may prove one of our most powerful weapons in the war

against chronic degenerative disease and aging itself.

1 Harman D. Aging: a theory based on free radical and radiation chemistry. J Gerontol. 1956; 2: 298-300

2 Hipkiss AR. Accumulation of altered proteins and ageing: causes and effects. Exp Gerontol. 2006; 41(5):464-73

3 Kikuchi S, Shinpo K, Takeuchi M, et al. Glycation-a sweet tempter for neuronal death. Brain Res Rev. 2003;41(2-3):306-23

4 Ulrich P, Cerami A. Protein glycation, diabetes and aging. Recent Prog Horm Res. 2001;56:1-21

5 Brownlee M. The pathological implications of protein glycation. Clin Invest Med. 1995; 18:275-82

6 Brownlee M. Advanced protein glycosylation in diabetes and aging. Annu Rev Med. 1995;46:223-34

7 Vlassara H. Advanced glycation in health and disease: role of modern environment. Ann N Y Acad Sci. 2005;1043:452-60

8 Leklem, JE: Vitamin B6 In Handbook of Vitamins. 2nd Ed. Edited by L.J. Machlin. New York, Marcel Decker, 1991, 341-392

9 Voziyan PE et al. A post Amadori inhibitor pyridoxamine. J Biol Chem. 2002;277(5):3397-3403

10 Jain SK, Lim G. Pyridoxin and Pyridoxamine inhibit superoxide

radicals and prevent lipid peroxidation and protein glycosylation. Free

Rad Biol Med. 2001;30(3):232-37

11 Negre-Salvayre A, Coattieux C, Inqueneau C, et al. Advanced lipid

peroxidation end products in oxidative damage to proteins. Potential

role in diseases and therapeutic prospects for inhibitors. Br J

Pharmacol. 2007 [Epub ahead of print]

12 Voziyan PA, Hudson BG. Pyridoxamine: the many virtues of maillard reaction inhibitor. Ann N Y Acad Sci. 2005;1043:807-16

13 Alderson NL, Chachich ME, Youssef NN, et al. The AGE inhibitor of

pyridoxamine inhibits lipemia and development of renal and vascular

disease in Zucker obese rats. Kidney Int. 2003; 63(6):2123-33

14 Kang Z, Li H, Li G, Yin D. Reaction of pyridoxamine with

malondialdehyde: mechanism of formation of advanced lipoxidation end-

products. Amino Acids. 2006;30(1)55-61

15 Padival S, Nagaraj RH. Pyridoxamine inhibits maillard reactions in diabetic rat lenses. Opthalmic Res. 2006; 38(5):294-302

16 Bakris GL, Bank AJ, Kass DA, et al. Advanced glycation

end-product cross-link breakers. A novel approach to cardiovascular

pathologies related to the aging process. Am J Hypertens. 2004; 17(12

Pt 2):23S-30S

17 Baynes JW. The role of AGEs in aging: causation or correlation. Exp Gerontol. 2001;36(9):1527-37

18 Mene P, Festuccia F, Pugliese F. Clinical potential of advanced

glycation end product inhibitors in diabetes mellitus. Am J Cardiovasc

Drugs. 2003;3(5):315-20

19 Boulanger E, Puisieux F, Gaxatte C, Wautier JL. Aging: role and

control of glycation. Rev Med Interne. 2007; [Epub ahead of print]

20 ME, Tuttle KR. The next generation of diabetic

nephropathy therapies: an update. Adv Chronic Kidney Dis.

2005;12(2):212-22

21 Yamagishi S, Nakamura K, Inoue H, Kikuchi S, et al. Possible

participation of advanced glycation end products in the pathogenesis of

colorectal cancer in diabetic patients. Med Hypotheses.

2005;64(6):1208-10

22 Chetyrkin SV, Kim D, Belmont JM, et al. Pyridoxamine lowers

kidney crystals in experimental hyperoxaluria: a potential therapy for

primary hyperoxaluria. Kidney Int. 2005;67(1):53-60

23 Valcourt U, Merle B, Gineyts E, et al. Non-enzymatic glycation of

bone collagen modifies osteoclastic activity and diffentiation. J Biol

Chem. 2007; 28(8):5691-703

24 Loeser RF Jr. Aging cartilage and osteoarthritis—what’s the link? Sci Aging Knowledge Environ. 2004;2004(29):p31