Background
Wound healing is one of the most important processes in maintaining the health of a person. Multiple factors affect wound healing in humans regardless of age. A partial list includes diabetes, hereditary healing disorders, obesity, drugs, alcoholism, smoking and compromised immune condition. Infection, stress, nutrition, and radiation therapy can also contribute to delayed or incomplete wound healing (Guo & DiPietro, 2010).
In the start of a wound, an inflammatory response is initiated. Blood vessels expand, helping white blood cells and nutrients to reach the wound. Wound healing is achieved through the processes of hemostasis, inflammation, proliferation, and remodeling. Proper sequence and time frame are required for healthy healing. In the elderly population, this response is much slower (Guo & DiPietro, 2010).
Some specific problems of the elderly people directly related to wound healing are reduction in skin elasticity and high occurrence of diabetes. Loss of skin elasticity prevents timely recovery from open wounds. As people grow older their skin loses elasticity. This can prevent or slow the healing process (Held et al., 2015).
Arginine is thought to be of help in improving wound healing. It is an important amino acid that is a part of the urea cycle, and can be converted to ornithine, citrulline, and agmatine. Arginine is developed in the healthy body but more arginine is required for young and developing animals. Moreover, additional amount is required for burns and certain infections. Every gram of dietary protein gives nearly 54 mg of arginine. However, this amount of arginine can change significantly from one food to another. It is also important to note that arginine can be destroyed by the process of cooking. Therefore, 4 to 5 grams of arginine is taken by adult population having an average diet in the United States. It has been found that nearly 2 gm of arginine is produced daily by kidney from the chemical citrulline in the kidneys (Alexander & Supp, 2014).
Highly reactive nitric oxide (NO) is developed from arginine by the enzyme nitric oxide synthase (NOS), which is also involved in the release of citrulline and can be recycled into arginine. NO is found to have numerous biological effects as, for example, the effects associated with the maintenance of blood flow and vascular tone, thereby regulating the problems such as atherosclerotic disease and hypertension. Arginine administration can help in improving the blood flow to different limbs of healthy as well as diseased individuals. It has also been reported that some of the effects of arginine may remain even after many weeks of intravenous (IV) infusion of arginine. Research has also shown that arginine can stimulate the release of growth hormone and insulin-like growth factor I (IGF-1), and both of these are also involved in the process of wound healing. Agmatine can also enhance vasodilatation and can reduce blood pressure (Alexander & Supp, 2014).
Researchers have proposed two mechanisms behind the wound healing process as a result of arginine. These mechanisms are related to NOS isoforms and arginase isoforms. The synthesis of inducible nitric oxide synthase (iNOS) reaches at its peak level within 24 hours to 72 hours of the production of wounding, generating NO as well as citrulline. NO has an antimicrobial activity and can also improve blood flow to the wounds that are in the process of healing. The iNOS pathway is stopped by transforming growth factor-β (TGF- β), which controls the macrophage NO synthesis. TGF- β in addition activates the arginase pathway and synthesis of collagen. Conditions such as diabetes and the presence of corticosteroids in the body can impair the wound healing process as they inhibit iNOS. On the other hand, arginase helps in breaking down arginine to ornithine as well as urea, and is found to be the final step in the urea cycle. Arginase 1 and arginase 2 are two isoforms of arginase, and both of them are involved in the wound healing process as they help in the production of ornithine, which is metabolized to polyamines through the activity of ornithine decarboxylase. Polyamines are involved in cellular growth. They also regulate various genes (Alexander & Supp, 2014).
After oral administration, arginine is found to be absorbed quickly that ranges from 21% to 68% having a half life of 1.5 to 2 hours after taking 6g of arginine in oral dose. After absorption and utilization by the body, arginine is excreted by the kidney. However, it can almost completely be reabsorbed. Arginine is normally found ingredient of the diet that can be administered in oral doses of 2 to 3 times the normal intake of diet without producing any substantial toxicity (Alexander & Supp, 2014).
Specific nutritional therapy characterized by high concentration of protein, arginine, and micronutrients were studied to determine if there were wound healing benefits of supplementation. In a study on patients of ulcers, researchers found that these nutritional supplements not only accelerate the healing of pressure ulcers but also decrease the intensity of the wound care necessary (von Anhalt et al., 2010). In a multicenter follow-up study, researchers tested the use of arginine in patients with pressure ulcers, diabetic foot ulcers, and leg ulcers. They tested not only the progress of healing but also the opinions of the patients regarding the oral nutritional supplement of arginine. The researchers determined that arginine was beneficial for all three types of chronic ulcers (Schols, Neyens, Rondas, & van Leen, 2013).
Arginine is naturally found in many substances, and it has no problem of bad taste or odor, therefore, the use of arginine can be related to increased patient compatibility. The use of arginine would also help in decreasing the costs. It has been estimated that wounds that fail to heal affect about 3 to 6 million people in the United States. Those over the age of 65 account for 85% of such occurrences. The result of a high frequency of non-healing wounds is a tremendous expenditure in health care. The total cost estimated at more than $3 billion per year (Guo & DiPietro, 2010). Therefore, it is necessary to work on cost-effective strategies of wound healing.
In a recent study, a model of wound-healing therapy was created. In the study, rats were used as the animal models to help in the determination of the healing effect of L-arginine, pentadecapeptide BPC 157, and L-nitro-arginine methyl ester on duodenocutaneous fistula. The study found that L-arginine produced significant results in wound healing improvement. The research indicates that healing of the duodenocutaneous fistula, in combination with the return of sphincter function, results from a newly considered nitric oxide-system in conjunction with arginine (Skorjanec et al., 2015).
Wound healing in elderly people is more delayed as compared to younger people. Here, we hypothesized that arginine possesses antiaging qualities that can improve wound healing in elderly people without causing any serious adverse effects. A working hypothesis for the study is that arginine possesses anti-aging properties that can help in improving skin qualities, thereby reducing wrinkles, in older people. So,
H0: Arginine does not possess anti-aging qualities that can improve wound healing in elderly adults.
H1: Arginine possesses anti-aging qualities that can improve wound healing in elderly adults.
This research would contribute worth considering results to the literature as the researches on the use of arginine on wound healing in older people are scarce. This article also helps to answer the research question “How does arginine affect wound healing in elderly adults?”
Specific Aims
This study will help in knowing the efficacy of arginine as a therapeutic intervention in the wound healing process in older population. Moreover, this study would also help in knowing the antimicrobial effectiveness of daily oral intake of arginine in patients, who are already having wound healing process. Finally, the study will help in knowing the decreased level of side effects as a result of the use of arginine for wound healing.
The efficacy of arginine as a therapeutic intervention in the wound healing process in the older population
Activity of arginine in the wound healing process has been studied by researchers for many decades. Researchers performed studies on animal models, and found that the animals, which were previously given arginine-deficient diet, when given arginine, showed improved survival rate. Arginine also helped the animals in increasing the wound-breaking strength and wound collagen accumulation. Further studies by researchers showed that the supplementation of 1% arginine with the diet improved wound healing in the animals (Alexander & Supp, 2014).
In human beings, very few studies have been conducted on the efficacy of arginine in wound healing. Moreover, studies are rare on the use of arginine in the wound healing process in elderly population. In a study, researchers worked on the patients of pressure ulcers. They provided 4.5 gm or 9 gm of arginine orally two-times daily to participants of the study. The study was done for 3 weeks. Those patients showed improved healing rate as compared to historical control patients. In another study, researchers worked on elderly population. They divided the participants of the study into two groups. One group was asked to get 17 g free arginine for a period of 14 days, while the other group was asked to take placebo for 14 days. Researchers found that arginine helped in improving IGF-1 and nitrogen balance as compared to controls. In another research, healthy elderly participants were selected and divided into two groups. One group was provided 17 gm free arginine and the other group was provided placebo for 2 weeks. Volunteers also got small split thickness wounds on upper thigh. Researchers found that arginine improved the production of collagen. However, it was unable to increase the rate of wound epitheliazation (Alexander & Supp, 2014).
Our primary aim in this study is to work on the efficacy of arginine in wound healing in older people. This work is helpful as the number of elder population is continuously increasing in the world, and many of them lack effective treatment strategies for the chronic wounds.
The effectiveness of daily intake of oral nutrition supplements of arginine and its antimicrobial activity in patients, who already have wound healing
In this study, we are going to study the effectiveness of daily intake of arginine supplements for patients, who are already showing the process of wound healing. This aim has also been combined with the antimicrobial activity of daily intake of arginine. It has been found that arginine produces NO having antimicrobial activity. Therefore, this study would also help in studying the antimicrobial efficacy of daily intake of oral nutrition supplements of arginine in patients with wound healing process.
Decreased side effects due to the activity of arginine in the body
L-arginine is a naturally occurring amino acid that is a part of multiple metabolic pathways within the human body. It is involved in the synthesis of proteins, urea, polyamines, proline, glutamate, creatine and agmatine. In mammals, it is essential for the elimination of toxic ammonia. L-arginine is also associated with the biosynthesis of signal molecule NO, which is critical to immunity, cytotoxicity, neurotransmission and vasorelaxation (Gad, 2010).
During the process of wound healing, NO created by keratinocytes is a significant factor in controlling cellular proliferation. Epidermal growth factor stimulates cell growth, while controlling the production of free radicals and facilitating the reduction of wound inflammation. This healing process begins with arginine and would fail without it (Heck, Laskin, Gardener, & Laskin, 1992). Studying the mechanisms behind the process of wound healing would also help in knowing the side effects caused by arginine.
Study Method and Design (Protocol)
In order to know the efficacy of arginine on elderly population, a randomized, controlled trials was conducted. The study was conducted in the Burn unit of the University hospital and the emergency center, where elderly people with wounds came. In the study, 75 eligible people having the age of 65 or older were selected. They were provided an informed consent for the performance of study on them. Sixty people were ready to take part in the study. Therefore, they were divided into two groups of thirty participants each. One group was provided with a control of supplements without arginine, while the other was arginine taking group. Participants of the study were unaware of the presence of arginine in the nutrition.
The participants of the study were collected during a four months period. Only those participants were considered who were older in age, i.e. age of 65 years or more, and who were admitted to the hospital due to acute injuries or wounds. People were excluded, if they had burns covering over 20% of the total body surface; had some sort of allergies to medications; were polytraumatized, and/or were already enrolled in any other clinical trials.
The primary outcome of the study was wound closure. Secondary outcome was the number of participants with healed wounds. Wound status was assessed by visual inspection. Participants of the study were asked to have 1 to 3 visits at 8-week intervals. During each visit of the patients, they were assessed for wound status; asked about the ease of use of the therapeutic intervention; assessed for costs associated with the intervention, and the adverse events related to the use of intervention. Infection, associated with the wounds was also checked to know about the antimicrobial activity of arginine. Moreover, the skin features (wrinkles) of the participants were checked with the help of digital image processing.
Participants of the study were also checked for the presence of NO in the body with the help of fluorescent dye indicators (Kojima et al., 1998). In the group, who received arginine therapeutic intervention, the amount of NO was estimated and then compared to the other group. Moreover, epidermal growth factor was examined in various tissues with the help of biochemical assays. Study of the NO and epidermal growth factor helped in knowing the mechanism of the wound healing as a result of arginine intake and activity in the body.
Results and Discussion
Wound healing is an essential process for a healthy life. However, with the passage of time, efficiency of this process declines as, for example, elderly population may show decreased wound healing activity. Therefore, it is important to develop novel and patient-compatible ways of increasing wound healing in older ages. In this regard, arginine could be of sufficient help.
In this randomized, controlled trial on arginine activity in wound healing, most important parts were the specific aims:
First aim of the research was to study the efficacy of arginine as a therapeutic intervention in the wound healing process in the older population. The study showed that arginine could be of sufficient help in reducing the problem of defective or decreased wound healing in older people.
Second aim of the research was to study the effectiveness of daily intake of oral nutrition supplements of arginine in patients, who already have wound healing. The study showed that the use of arginine is compatible to the patients and its daily intake is effective even for patients, who already have wound healing.
Third aim of the research was to study the decreased side effects due to the activity of arginine in the body, and the study confirmed that arginine has decreased adverse events.
This study can help other researchers to perform more studies and it is one of the strengths of the study. Moreover, the factors including extraneous variables such as age, place of living, and the physical activity were controlled that is another important strength of the study. One of the most important limitations of the study is that it is not generalizable as it has been performed in a particular set of people living in a specific area, who would not represent all the people from different parts of the world. However, the ease of the research method can help in performing the research in different parts of the world, thereby helping in working on larger population. Another limitation of the study is that arginine was not given alone but it was administered along with some other ingredients, which are commonly used in the preparation of the tablets such as Stearic Acid, Cellulose, and Silica, to the participants of the study that can also affect the healing process. Therefore, further studies can be conducted with arginine alone. Overall, this study is a meaningful addition to the research literature as the researches on the efficacy of arginine in elder population is scarce.
References
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Skorjanec, S., Kokot, A., Drmic, D., Radic, B., Sever, M., Klicek, R., et al. (2015). Duodenocutaneous fistula in rats as a model for "wound healing-therapy" in ulcer healing: the effect of pentadecapeptide BPC 157, L-nitro-arginine methyl ester and L-arginine. J Physiol Parmacol, 581-590.
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