One amino acid leads the way in helping to
restore the functionality of damaged tissues …
Homer’s Iliad stands out by providing the first thorough description
of the damage and treatment of war-inflicted wounds
For a physician has the worth of many other
warriors, both for the excision of arrows and
for the administration of soothing drugs.
— Homer, Iliad XI.514-515
The hero of the Trojan War (and the Iliad), Achilles, tending the wounded Patroclus (Attic red-figure kylix, ca. 500 BC)
It has been said that conventional medicine was born on the battlefield and therefore that it excels in emergencies. But what about non-emergencies? The truth is that medicine has no upper hand when it comes to prevention and health maintenance. Worse yet, the medicine that is required away from the crisis of war—on the “battlefield” of every-day life—is virtually ignored by most medical schools.
In the history of warfare, Homer’s Iliad stands out in the Western epic literature by providing the first thorough description of the damage and treatment of war-inflicted wounds, such as it was understood by Homer, 2800 years ago. However, given Homer’s and his contemporaries’ limited understanding of anatomy, what is reported in the Iliadisn’t always reliable. “… [S]ome wounds which have appeared problematic become realistic, but some which have been accepted as straightforward become problematic.”1And reliability is even less so when it comes to “soothing drugs.” Nevertheless, it is through this window in time that we peer, and see as much as we can. As a result, we are better able to appreciate the advantages not only of today’s surgery, but also of its healing medicines. And this leads us to modern nutrition’s ability to heal what could not be healed in the past. As with the relative invulnerability of Achilles, who only could be deeply wounded through his heel and who rapidly healed other wounds to his body, there are now significant recuperative nutritional modalities available. These can provide benefits on par with some of those possessed by the mythical Greek warrior of the Trojan War.
From Dehiscence to Wound Repair
Leaping forward 3200 years (from the time of the Iliad) to the present, we learn from a new study that wound dehiscence (a splitting open or separation of the layers of a surgical wound) caused by surgical site infection, can be treated successfully with L-arginine (hereafter arginine),2 an amino acid that has also recently been shown to be effective for the treatment of pressure ulcers, also known as bedsores.3–13*
With Arginine, The Kids Are All Right
In this study, six pediatric patients with wound dehiscence due to surgical site infection received negative pressure wound therapy† along with 1 to 1.5 g of arginine combined with a number of vitamins and minerals.‡ The average age of the patients was 12.2 months of age (they were either late infants or early toddlers), and the operations endured included laryngotracheal separation (the result of intractable respiration, aka breathlessness), radical operation for spinal bifida (a developmental congenital disorder caused by the incomplete closing of the embryonic neural tube), gastrostomy (creation of an artificial external opening into the stomach for nutritional support or gastrointestinal compression), colostomy (surgical construction of an artificial excretory opening from the colon), anorectoplasty (plastic surgery to create a functional anus and rectum), and tumor extirpation (a minimally invasive small incision surgical technique enabling removal of pancreatic tumors that are benign or scant). The poor kids!
* Pressure ulcers (aka, bedsores) are lesions caused by varied factors including unrelieved pressure, friction, humidity, shearing forces, temperature, age, continence, and medication. They may occur to any part of the body, especially portions over bony or cartilaginous areas such as sacrum, elbows, knees, and ankles. Bedsores are often fatal—even under the auspices of medical care—and are one of the leading iatrogenic causes of death reported in developed countries, second only to adverse drug reactions. An iatrogenic disease is one that is induced inadvertently by a physician or surgeon or by medical treatments or diagnostic procedures.
† Negative pressure wound therapy is a technique that uses a vacuum dressing to promote healing in acute or chronic wounds and enhance healing of first and second degree burns, as well as other wounds. The therapy involves the controlled application of sub-atmospheric pressure to the local wound environment.
‡ For an adult weighing from 50 to 75 kg, the dose for a pressure ulcer would be 7.5 g arginine, plus correlative amounts of choline, citrulline, vitamins, and minerals in a well-designed formulation.
A new study has found that
wound dehiscence (a splitting open
or separation of the layers of a
surgical wound) caused by
surgical site infection, can be
treated successfully with L-arginine.
The two therapies used in the study—negative pressure wound therapy and the enteral (nasogastric intubation) administration of the arginine formulation—resulted in the complete healing of the wounds within one month after the introduction of arginine therapy, and without any other complications. Six months after, a follow-up study found no complications associated with the wounds. Thus, negative pressure wound therapy combined with arginine administration was effective in inducing early healing of infected wound complications following surgery.
Enhanced Wound Collagen Disposition
This is but one of the more recent papers published in a lengthy succession over the last 50 years about arginine and wound healing. Long a champion of arginine for wound healing, the formidable surgical scientist Adrian Barbul of the Department of Surgery, Sinai Hospital of Baltimore and Johns Hopkins Medical Institutions has written that “[arginine] administration in quantities above those required for growth and reproduction results in a marked enhancement in wound collagen deposition.”14
The Mechanisms of Arginine Healing
A number of mechanisms have been postulated to explain the positive effect of arginine on wound healing. One Barbul study has demonstrated that while supplemental dietary arginine enhances wound healing in normal mice, the loss of a functional inducible nitric oxide synthase (iNOS) gene abolishes the beneficial effect of arginine in wound healing. This suggests that the metabolism of arginine via the NO pathway is one mechanism by which arginine enhances wound healing.15 However, arginine supplementation has recently been found to increase net protein balance in skin wound and muscle by a mechanism that is independent of nitric oxide production.16
Negative pressure wound therapy
combined with arginine
administration was effective in
inducing early healing of
infected wound complications
Regarding how growth hormone (GH) may be involved, there are reports showing that the principal factor in wound healing by arginine may lie in the effects of GH-stimulated production of insulin-like growth factor-1 (IGF-1) in topical wounds.17 IGF-1 activates fibroblast proliferation and keratinocyte migration. Both are necessary for wound healing. A very recent study finds that growth hormone-releasing hormone (GHRH), induced by arginine, has a direct involvement in wound healing.18 While we know that GHRH stimulates GH production and release in the pituitary, the researchers focused on the recent identification of wound-associated fibroblasts as a direct target of GHRH.
Healing Skin Cuts
The effect of arginine supplementation on growth and healing of skin incisional wounds (cuts) was studied in rats.19 One group was fed a chemically defined diet lacking arginine; the other a laboratory chow containing 1.8% arginine. Those rats that received arginine-free diet grew more poorly than did arginine-supplemented rats (1.8 vs. 7.0 g/day) before the incisions were made. After the incisionary operation, arginine-deficient animals grew very poorly (1 g/day), while arginine-supplemented rats gained 4.3 g/day.
Those animals deprived of arginine were found to have impaired wound healing, with the diminished breaking strengths of their incisions 10 days after wounding (228 vs. 293 g for the arginine-supplemented rats). The same arginine-deprived rats also showed decreased collagen deposition in a specific wound site. In rats fed the commercial chow with arginine, there were decreases in the postoperative weight loss associated with injury in one experiment and improved wound strength in two experiments (312 vs. 188 g in one experiment and 309 vs. 246 g in another).
“[Arginine] administration in
quantities above those required for
growth and reproduction results in
a marked enhancement in
wound collagen deposition.”
The researchers concluded that arginine has two roles in wounded animals. It is essential for the synthesis of the increased amounts of reparative collagen required for wound healing. Secondly, it decreases some of the negative aspects of the metabolic responses to injury. Arginine’s growth advantages are thought to be associated with an arginine-induced GH release.
In another study, supplemental dietary arginine minimized immediate post-wounding weight loss, accelerates wound healing, and was found to be thymotropic (increasing thymus weight) for uninjured and wounded rats.20 The thymus helps produce T-cells, which are critical for proper immune function.
Improving Wound Healing in the Elderly
In a randomized double-blind study, researchers investigated the effect of arginine supplementation on wound healing and T-cell function in elderly human beings (> 65 years).21 Thirty elderly, healthy, human volunteers (15 men and 15 women) were given 30 g/day of arginine aspartate (17 g free arginine). Fifteen volunteers (nine men and six women) received a placebo. After fibroplastic wound responses were assessed and epithelialization was examined, a 2 x 2 cm split thickness wound was created on the upper thigh. Arginine supplementation for two weeks significantly enhanced wound catheter hydroxyproline accumulation (26.49 nmol/cm vs 17.41 nmol/cm) and total protein content (43.47 µg/cm vs 21.95 µg/cm). Peripheral blood lymphocyte responses to mitogenic (cell division) and allogenic (being genetically different although belonging to or obtained from the same species) stimulation were greater in the arginine supplemented group. Plus, serum IGF-1 levels were significantly elevated in the arginine group. The researchers conclude that arginine supplementation may improve wound healing and immune responses in the elderly.
In another study with elderly adults, the effect of oral supplementation with arginine on the metabolism of 45 healthy, nonsmoking, elderly volunteers was investigated.22Divided into two groups, one received either arginine aspartate (17 g free arginine; n = 30) while the other got a placebo (n = 15). After two weeks, dietary control ended and blood chemistry, lipid profiles, and as an index of nutritional status, serum IGF-1 levels and nitrogen balance were taken. These measurements were compared to those taken before supplementation began. A significant elevation of serum IGF concentrations and an improved and positive nitrogen balance (2.0 g N) when compared with controls (0.11 g N). Also, the arginine-supplemented group demonstrated a decreased total serum cholesterol with a reduction in the low-density lipoprotein, but not the high-density lipoprotein fraction, resulting in an increase in the ratio of low- to high-density lipoprotein fraction. That’s good. No adverse effects were observed at this dosage of arginine. The data suggest that oral arginine supplementation may be used safely in elderly humans.
Increased Lymphocyte Mitogenesis
Arginine enhances wound healing and T-cell-mediated immune function in rodents. In a study, 36 healthy, nonsmoking human volunteers were given either (1) daily supplements of 30 g arginine hydrochloride (24.8 g free arginine); (2) 30 g arginine aspartate (17 g free arginine) daily; or (3) placebo. At the end of two weeks, dietary intake control ended.23
Arginine’s growth advantages
are thought to be associated with
growth hormone release.
Wound Healing Following Trauma/Hemorrhagic Shock
Cell division (mitogenesis) responses were assayed at the start of study and at one and two weeks after supplementation began. At two weeks, arginine supplementation significantly enhanced the amount of collagen deposited into a standardized wound as measured by the amount of hydroxyproline present (10.1 nmol/cm graft in controls vs 17.57 nmol/cm in the arginine aspartate group, and vs 23.85 nmol/cm in the arginine hydrochloride group). In parallel, arginine supplementation at both doses increased lymphocyte mitogenesis. These results suggest that arginine may be of clinical benefit in improving wound healing and immune responses.
Another study set out to determine whether arginine supplementation enhances the impaired wound healing of rats subjected to trauma/hemorrhagic shock.24 Impaired wound healing after trauma and shock has been documented experimentally and clinically. And arginine has been shown to enhance wound strength and collagen synthesis in rodents and humans. However, its efficacy under conditions of impaired wound healing is not as clear. So in the study, 48 male rats were split into two groups with 24 rats undergoing trauma/hemorrhagic shock before wounding. The other 24 served as controls. Following a dorsal skin incision with implantation of polyvinyl-alcohol sponges, half of the animals in each group were assigned to receive 1 g/kg/day of arginine by body cavity injection in three divided doses,* while the other half received saline injections only.
* This is the equivalent of about 14 g/day for a 187 lb human.
Ten days following wounding, wound-breaking strength and other relevant factors were determined. While trauma/hemorrhage greatly decreased wound-breaking strength, with a concomitant diminution in collagen deposition, arginine significantly enhanced wound-breaking strength (19%) and increased collagen deposition (21%) levels in control animals. In rats subjected to trauma/hemorrhage, the increases were +29% and +40%, respectively, compared with their saline-treated counterparts. As well, Procollagen I and III mRNA levels were elevated by arginine treatment in both trauma/hemorrhage and control rats. Altogether the data demonstrate that the impaired healing subsequent to trauma/hemorrhage can be greatly alleviated by arginine supplementation.
The Impact of Sepsis on Wound Healing
A recent paper reviewed the multiple pathways of arginine metabolism, along with its various enzyme systems.25 Also examined were the effects of arginine on nutrition, healing, and immune function; and how it could be used clinically. Although sepsis (whole body inflammation) has been postulated to be an arginine-deficient state, a variety of different immune-enhancement nutritional formulations containing various nutritional components have been employed clinically.
Yet while the effects often are attributed to arginine alone, guidelines have been developed recommending against the use of arginine-supplemented diets in critically ill patients. This may be unwarranted, given the broad efficacy of arginine, not to mention its safety. But there is a lack of evidence for benefit in sepsis, so well-defined studies examining arginine used alone or in the context of full nutritional support should be carried out so as to define the possible clinical uses of arginine in critically ill and septic patients.
The Evidence is In and More is Forthcoming
Wounds are inevitable throughout life, whether they be merely superficial or severe (the results of accidents), disease caused, or caused by an operation or an inadvertent induction, such as a bedsore. They can be a type of injury in which skin is torn, cut, or punctured (an open wound), or where blunt force trauma causes a contusion (a closed wound). Pathologically, a wound specifically refers to a sharp injury which damages the dermis of the skin, but it can be internal, wherever tissue is damaged. Open wounds include incisions or incised wounds, lacerations, abrasions (grazes), puncture wounds, penetration wounds, and gunshot wounds. Closed wounds include contusions (bruises), hematomas (blood tumors), crush injury, and chronic, acute, or traumatic wounds. All of these, it would appear, can be healed more successfully with the use of arginine, especially as we age. Then it might be possible to multiply the speed and thoroughness of healing, perhaps even equalling what we experienced in youth. So don’t miss out on how you can protect yourself against what is unavoidable throughout life. To quote the great Bard,To be, or not to be: that is the question:
The Power of a Well-Designed
For Improved Arginine GH Release: Choline and Vitamin B5
Their investigation didn’t end with arginine, but was extended step by step to include many other nutrients. A study had shown that anticholinergic agents, which inhibit the production or action of the neurotransmitter acetylcholine, could also block the effects of arginine in releasing growth hormone. So Durk & Sandy included choline(an acetylcholine precursor) and vitamin B5 in their formulation, the B5 because it enhances the conversion of choline to acetylcholine.
Then, around 1990, another paper demonstrated that acetylcholine activates an enzyme that catalyzes the production of nitric oxide (NO) from arginine. The version of NO that’s activated by acetylcholine is endothelial nitric oxide synthase (eNOS), found in our blood vessels. It’s critically important for the maintenance of cardiovascular health, and significant deficiencies in eNOS activity are characteristic of cardiovascular disease. The winners of the Nobel Prize for the discovery of how NO works had also discovered that NO from eNOS induces mitochondrial biogenesis, the creation of new mitochondria in our cells. Other scientists have found a link between that and the mechanism of caloric restriction, which extends the lifespans of many different kinds of organisms, from yeasts to mammals.
Mitochondria decline both in quantity and in functional quality with age—older people have proportionally more defective ones in their cells than younger people do. And as damage mounts, mitochondria are less capable of producing ATP, the universal energy molecule. Consequently, you’re more likely to release large quantities of harmful superoxide free radicals. Thus it’s very important to maintain the vitality of your mitochondria.
For Greater NO Bioavailability and More: Folic Acid
Three recently published papers on NO have led Durk & Sandy to include high levels of folic acid in their latest arginine formulations, one of which indicates that an enzyme, dihydrofolate reductase, can enhance the bioavailability of NO, thereby reducing hypertension. Also, under oxidative stress, the normal metabolic pathway that produces NO from arginine can become disrupted so as to lead in an altered direction. This is called uncoupling, a process that can lead to the production of superoxide radicals instead of NO, leading to the formation of an extremely powerful oxidizer called peroxynitrite.
Also, a deficiency of tetrahydrobiopterin, which is a cofactor in the production of NO, can be destroyed easily by oxidative stress. But added folic acid can either enhance the availability of tetrahydrobiopterin or perform the same function.
The other two folic acid papers deal with endothelial dysfunction, a key feature of most cardiovascular diseases. In these it was found that folic acid actually reverses that dysfunction and normalizes the action of eNOS. Thus it appears that folic acid is a powerful protector of the cardiovascular system.
Thus it appears that folic acid is a
Folic acid also lowers homocysteine, which interferes with eNOS, and helps to produce NO, rather than superoxide radicals, which in turn helps increase the number of mitochondria. That’s why hypertension seems to have a generalized accelerated aging effect on people. It’s more work for your heart. Exercise is more work for your heart too, but it doesn’t cause aging, and incidentally increases the number of mitochondria.
To Reduce Homocysteine Levels: Vitamins B12 and B6
Next was the addition of 200 mcg of vitamin B12 per serving, not only to lower homocysteine levels, but also to ensure that the high folic acid levels don’t mask the hematological symptoms of pernicious anemia (B12 deficiency). Even with deficient production of hydrochloric acid or intrinsic factor in the stomach, this amount of vitamin B12 can almost always prevent pernicious anemia. In addition, Durk & Sandy have added 12 mg of vitamin B6 per serving to further help lower homocysteine levels.
For Higher Levels of Arginine: Citrulline
Several papers on the amino acid L-citrulline (hereafter citrulline) are important in regard to other improvements in their formulations. Citrulline is not found in the diet, but is synthesized in the body via a mechanism called the urea cycle. In this metabolic cycle, arginine is converted to urea and ornithine; the ornithine is converted to citrulline, which is converted to argininosuccinate, which is converted to arginine, thus completing the cycle.
Once citrulline is produced by
For Enhanced NO Production: Magnesium Aspartate
One of the enzymes involved in the conversion of citrulline to arginine is argininosuccinate synthase. This enzyme catalyzes the reaction of citrulline with aspartate (which is the ionized form of aspartic acid) to form argininosuccinate—and that compound, as described above, is converted to arginine. Because aspartate is essential to this process, Durk & Sandy have added magnesium aspartate to their formulations. They explain, “The lone nitrogen atom in aspartate becomes the N atom in arginine that winds up in the NO molecule (arginine has four N atoms). Even if that N atom were to come from citrulline, however, aspartate would still be just as indispensable to the process as citrulline is.”
In summary, magnesium aspartate supplies aspartate, which is necessary for arginine regeneration and also supplies magnesium, which is relevant because the enzymatic action of argininosuccinate synthase is magnesium-dependent. So both parts are beneficial.
It is important to understand that magnesium deficiency is quite common in our society. At one time, the recommended daily allowance (RDA) used to be 800 mg, but hardly anyone was getting that much from food. Because a large number of entitlement programs, such as Food Stamps, require that RDA amounts be obtained from food rather than from supplements, the FDA concluded that the amount of food needed to provide 800 mg/day of magnesium was prohibitively expensive. So they reduced the RDA by half to 400 mg, allowing politics to win out over science.
The FDA reduced the RDA of
Unfortunately, too much magnesium you can give you the runs, so a soluble fiber has been added to create a time-release formulation. This slows down the absorption of nutrients, therefore allowing the amount of magnesium aspartate to be doubled.
Also, research has been done on the bioavailability of magnesium in different forms, and it was found that the most bioavailable was magnesium aspartate chelate, a form in which the magnesium ion is chelated by aspartate rather than being chemically bound in the usual way. This is exactly what you need for the reaction catalyzed by argininosuccinate synthase.
For Inflammatory Protection: Glycine and Betaine
Two other nutrients that Durk & Sandy have added to both of their arginine formulations are the amino acid glycine and its trimethyl derivative, betaine. Both of these nutrients have anti-inflammatory effects, which are useful in reducing the damaging effects of age-related inflammation.
Many people take a GH-releasing supplement before exercising. But if you overdo exercise and cause some damage—which is fairly common—certain inflammatory immune-system proteins called cytokines are released, along with increased levels of superoxide radical. Glycine works as an anti-inflammatory agent reducing superoxide levels and protecting against cytokines, including one called TNF-alpha. This cytokine is activated by an antigen from an invading infection.
Inflammation can’t be blocked entirely—nor should it be. As a natural body process, it is there for a reason, and inflammation is one way that your immune system responds to the presence of a bacterial or viral infection. If you have an infection, it may not be advisable to take powerful, nonselective anti-inflammatories.
What is needed are selective anti-inflammatories—which corticosteroids are not. In fact, the ads for inhalable corticosteroids for controlling asthma warn you that you may become more susceptible to infections when you switch to these products. That is because they disarm the inflammatory part of your immune system that deals with infections. What Durk & Sandy are using in their formulations is more selective. A recent paper on the anti-inflammatory properties of betaine has found that aging mechanisms bring about a proinflammatory state. If you take no action to forestall this, you produce more collateral damage.
Among the damaging effects of inflammation is the stimulation of the proliferation and migration of endothelial and smooth muscle cells in atherosclerosis. Glycine can reduce such damage, suggesting that it may also be beneficial for inhibiting graft rejection, cardiovascular disease, and angiogenesis (the proliferative creation of new blood vessels.
For Reducing Prolonged Oxidative Stress: Gamma-Tocopherol
The more powerful of their two arginine formulations has some additional, fairly expensive ingredients for those who are under unusually high levels of prolonged oxidative stress. In this formulation, 40 mg of gamma-tocopherol from 100 mg of mixed tocopherols has been added per serving.
Gamma-tocopherol is especially effective in promoting the decomposition of peroxynitrite. Recall that this powerful pro-oxidant is made by the reaction of superoxide with NO, so if you do have excessive superoxide production because of oxidative stress, gamma-tocopherol will help neutralize the resulting peroxynitrite. You can’t get the amount found in just one serving—40 mg of gamma-tocopherol—from even a very good diet.
For Added Mitochondrial Energy Production: Coenzyme Q10
Durk & Sandy have also added 30 mg of coenzyme Q10 per serving, because CoQ10plays an essential role in energy production in the mitochondria. It’s also a potent antioxidant that helps neutralize the reactive oxygen species, such as superoxide radicals, that are generated in the mitochondrial energy-production process. A bonus, indeed.
If you’re taking a statin to lower your LDL-cholesterol levels, you should know that these drugs have an unintended and undesirable consequence. Via the mechanism though which they operate to inhibit the biosynthesis of cholesterol, they also inhibit the biosynthesis of CoQ10. The enzyme whose action they interfere with, HMG-CoA reductase, is crucial for the biosynthesis not only of cholesterol but also of CoQ10. If you block one you block the other. Anyone using a statin should also take a CoQ10supplement.
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