Dental research Studies, PerioTherapy Supplements

PerioTherapy™
Periodontal Formulas
Physician Information
by Clark Hansen, N.M.D.

Periodontal Disease

Overview
Approximately 60% of young adults, 80% of the middle-aged and 90% of Americans over age 65 have periodontal disease. The customary treatment of this problem with antibiotics, prophylaxis, and root planing have shown only modest success in slowing the progression of this disease. More effective, functional medicines and preventive measures are needed for this extremely common disorder.

Although periodontal disease is generally considered a normal part of the aging process, it doesn’t have to happen to your patients. Current research has shown that it is preventable and can even be reversed by the prescription of the ingredients found in the new functional medicines known as PerioTherapy and PerioCare.

Etiology
Periodontal disease is an inflammatory condition that encompasses both inflammation of the gingiva (gingivitis) as well as the extension to the underlying tissues of the periodontium (periodontitis). Recent studies of gingival crevicular fluid, periodontal pocket exudate and tissue biopsies of patients with advanced periodontitis have revealed a clearer understanding of the biochemical and cellular mediators of this disease, as well as new functional medicines for its treatment.

Bacterial aggregation on teeth at the gingival crevice is the primary initiating factor associated with the development of gingivitis, the deposition of plaque and the progression to periodontal disease. Microorganisms form aggregations that attach to the tooth surface as dental plaque. As plaque accumulates at the gingival crevice together with food debris, it becomes calcified, resulting in the formation of calculus.

Calculus is composed of an organic framework of bacterial and mycotic organisms, desquamated epithelial cells, leukocytes, and food debris that contains calcium phosphate deposits. It acts as both a mechanical and biological irritant. The expanding crystalline structure of the calculus creates pressure and generates mechanical irritation within the gingival crevice. Biological irritants come from bacterial production of hyaluronidase, collagenase, endotoxins, and antigens that stimulate immunologic activation. Additional biological irritants come from inflammatory agents released by neutrophilic lysosomes including oxygen free radicals, collagenase, serine proteases, and histamine from mast cells.

The constant irritation and inflammation caused by this process places high demands on the production of the energy substrate Adenosine Triphosphate (ATP) and pushes the pathways of cellular detoxification to the limits. The strain on these systems depletes the body reserves of specific co-enzymes and essential nutrient factors that weaken the host resistance and allow periodontitis to advance.

In summary, there are three main categories of causative factors involved in the initiation and advancement of periodontal disease. In order to improve treatment success rate and decrease the recurrence rate of periodontitis, all of these etiological elements have been effectively addressed by these new functional medicines.

Table 1. Etiology of Periodontitis

Mechanical Irritants

• Bacterial Aggregation
• Calculus Formation
• Exudative Suppuration

Biological Irritants

• Collagenase
• Hyaluronidase
• Oxygen Radicals
• Serine Protease
• Histamine
• Bacterial Endotoxins
• Bacterial Antigens

Cellular Dysfunction

• Abnormal ATP Metabolism
• Squamous Dysplasia

Clinical Manifestations
Gingivitis. Gingivitis is a chronic inflammation of the gingival margins. Clinical manifestations include pain and bleeding upon probing, erythema, and inflammatory hyperplasia. A predisposition to gingivitis occurs during pregnancy, in a number of nutritional deficiency states, including scurvy (vitamin C deficiency) and pellagra (niacin deficiency), leukemia and in thrombocytopenia.

Periodontitis. Progression from gingivitis to periodontitis is to a large extent dependent upon the host’s resistance to the mechanical and biological irritants. If the host resistance is insufficient, the inflammatory process extends from the gingiva to the underlying periodontal tissues – the periodontal membrane, alveolar bone, and cementum of the teeth. In addition to gingivitis, clinical manifestations include pathologically deepened gingival crevice or periodontal pocket, bacterial suppuration within the periodontal pocket, tooth mobility resulting from resorption of alveolar bone, deposition of calculus within the periodontal pocket, ulceration of the epithelium, migration of the epithelial attachment towards the root of the tooth, and gradual loss of teeth.

Conventional Therapeutic Rationale
Conventionally, gingivitis and periodontitis have been treated by removal of the periodontal plaque via mechanical scaling of the tooth, the surgical removal of the epithelial attachment and the institution of a disciplined regimen of improved oral hygiene. When the irritants are removed, the gingiva reattaches to the tooth surface and the periodontal pocket is reduced, however, the destroyed periodontal tissue is rarely restored to its original height. Furthermore, although bacterial aggregation on teeth at the gingival crevice has been shown to be the primary initiating factor in periodontal disease, antibiotic therapy has not provided significant prophylactic or therapeutic benefits.

Functional Therapeutic Rationale
In order to improve the success rate in periodontitis, a novel new treatment aimed at early intervention, the enhancement of host resistance and the inhibition of the biological and mechanical irritants involved in the onset of gingivitis and the progression to periodontal disease has been developed. This new treatment focuses on the enhancement of the function of the oral environment to resist the initiating etiological factors. This functional approach employs the use of biological plant extracts, selected co-enzymes and specific vitamins to strengthen and support the tissues of the oral cavity and the resistance of the host.

New Functional Medicines

PerioTherapy^TM

Overview
Pharmaden™, the leader of functional medicine in dentistry, has developed a unique proprietary formulation that significantly enhances the biological resistance of the gingiva and periodontium to periodontal disease. This proprietary product is backed by hundreds of scientific studies and years of clinical research. It includes, Vitis vinifera seed extract, which has been found to bind to proline-rich proteins in bacterial membranes, preventing them from forming the aggregations that initiate the onset of periodontal disease. 2 It also inhibits collagenase and serine proteases secreted by bacteria and white blood cells and deactivates oxygen free radicals that lead to the destruction of the periodontium. Echinacea stimulates cellular immunity and inhibits the release of bacterial hyaluronidase that allows bacteria to spread deeper into the gingival crevice. CoEnzyme Q10 enhances the production of ATP energy in the gingiva, which improves the healing response. Folic acid ensures the normal development of healthy squamous epithelium and binds to the plaque derived bacterial endotoxins preventing additional irritation. Finally, PerioTherapy and PerioCare contain Piper nigrum extract, which enhances the absorption and bioavailability of all of the other ingredients.

Functional Properties

Collagenase Inhibition
Studies have demonstrated that proanthocyanidin bioflavonoids have a highly selective affinity for proline-rich proteins and polymers, especially collagen and elastin of the connective tissue.19, 20 Investigation at the Centred Experimentation Pharmaceutique, in Bordeaux, France, found that proanthocyanidin and oligomeric proanthocyanidin complexes (OPC) labeled with Carbon-14 are absorbed and rapidly distributed throughout the body within sixty minutes of oral consumption.21 By selectively binding to collagen, and elastin, proanthocyanidin bioflavonoids protect mammalian connective tissue from oxygen free radicals as well as collagenase released by bacteria and neutrophillic lysosomal degranulation associated with bacterial cytotoxicity.

Dr. Jacques Masquelier has reported that proanthocyanidins even attach to the polymeric filaments in bacterial membranes, thereby inhibiting their aggregation and thus preventing the key initiating factor that leads to periodontal disease. 21

In response to bacterial aggregation along the gingival crevice, neutrophils release large quantities of collagenase to break their filamentous bonds and disrupt their attachment to the teeth surfaces. In the process, neutrophillic collagenase can destroy the structural integrity of the connective tissue of the gingiva and periodontium if the over spray is not controlled. Endogenous antioxidants like Superoxide Dismutase (SOD) and Catalase function to minimize the oxidative damage to host tissues, but they do not possess the ability to inhibit collagenase or serine protease.

However, researchers from the Department of Periodontology, University of Helsinki, Finland, have found that proanthocyanidins inhibit extracellular and interstitial collagenase.10-17 They isolated interstitial collagenases from extracts of inflamed human gingiva, gingival crevicular fluid and saliva, and found it to be the same as that released by human neutrophils.

Other researchers have isolated 28 strains of collagenase and 26 strains of serine protease producing bacteria from periodontal pockets in patients with advancing periodontitis. They concluded that these strains of bacteria, particularly Bacteroides species (mainly B. gingivalis and B. intermedius) may exert an important influence on the exacerbation of periodontal disease.22

Hyaluronidase Inhibition
Hyaluronic acid is a polysaccharide portion of the proteoglycan ground substance of the connective tissue. It is the matrix, or latticework, of the connective tissue that holds everything together. In addition to holding tissues together, hyaluronic acid functions as a tissue capsule, which prevents bacterial spread and aggregation.25, 26 A number of hyaluronidase secreting bacteria have been found in saliva.26, 27 These bacteria break down hyaluronic acid allowing bacterial aggregations to spread further and deeper into the gingival crevice, leading to the advancement of periodontal disease.

Echinacea has been found to possess strong hyaluronidase inhibiting activity. Four main antihyaluronidase constituents have been found in Echinacea, including chicoric and caftaric acids which have the greatest antihyaluronidase activity: (IC50 = 0.42 and 0.61 mm/l), followed by cynarine and chlorogenic acid (antihyaluronidase activity: IC50 = 1.85 and 2.25 mm/l).28 Vitis vinifera Proanthocyanidin has also been found to possess hyaluronidase inhibiting activity (antihyaluronidase activity: IC50 = 300 mm/l).29 In addition to its antihyaluronidase activity, Echinacea also stimulates fibroblasts that manufacture new connective tissue ground substance.47

Antioxidant Protection
One of the key factors involved in the onset of periodontal disease is the exposure of the gingiva and periodontal tissue to damaging effects of oxygen free radicals released by neutrophils in fighting bacterial aggregation of the oral cavity. (See Figure 3) Accompanying an immunological response to aggregating bacteria in the gingival crevices, neutrophillic lysosomal degranulation releases a large quantity of cytotoxic oxygen free radicals, as well as collagenase, and serine proteases. These cytotoxic agents are aimed at bacteria but can also damage the host tissues if not controlled.

As a group, Vitis vinifera proanthocyanidins have been reported to exhibit a wide range of biological, pharmacological and chemoprotective properties against oxygen free radicals that are present in the oral cavity and released by neutrophils in the fight against bacteria. In 1987, oligomeric proanthocyanidin complexes were found to possess an oxygen free radical scavenging ability 20 times greater than vitamin C and 50 times greater than vitamin E.2

In 1997, a group of researchers from the School of Pharmacy, Creighton University, Omaha, assessed the concentration-dependent oxygen free radical scavenging abilities of a Vitis vinifera seed proanthocyanidin extract, compared to vitamin E succinate and vitamin C as well as superoxide dismutase, and catalase. Their results confirm the fact that Vitis vinifera seed proanthocyanidin extract is a more potent scavenger of oxygen free radicals than vitamin E or vitamin C and demonstrates that it is approximately equal to the endogenous antioxidants superoxide dismutase and catalase. 3 Proanthocyanidins have been shown to scavenge the water-soluble free radicals, superoxide (02-), hydroxyl (OH-), and hydrogen peroxide (H202), as well as lipid peroxide radicals, in a dose dependent fashion.9

Gallic acid, found in Vitis vinifera seeds, has been shown to possess strong antioxidant activity.1 Gallic esters of proanthocyanidin are the most potent antioxidant components of Vitis vinifera. Gallic acid and its esters have been shown to protect mammalian cells against H2O2-induced cell damage produced as a consequence of neutrophillic bacterial cytotoxicity. 4 Gallic acid and its esters have also been shown to have a synergistic sparing effect on vitamin C (ascorbic acid), and visa versa, resulting in an enhancement of the antioxidant and beneficial cytotoxic effects of both. 5-6

A study conducted at the Research Center for Natural Products and Phytopharmaceuticals, Faculty of Pharmacy, University of Utrecht, The Netherlands, found that gallic acid buffers the release of superoxide free radicals and myeloperoxidase released by neutrophils in the fight against bacteria.7 Gallic acid in this way seems to prevent the cellular damage caused by the otherwise inevitable over spray of cytotoxic agents secreted by neutrophils involved in the cellular immune response to bacteria and the consequent cascade of inflammation.

Catechin and epicatechin, monomers of Vitis vinifera seed extract, also possess antioxidant properties, which have been found to be slightly less than that of gallic acid against the aqueous phase oxidants, but superior to gallic acid against propagating lipid peroxyl radical species. 23 Ferulic acid, from Vitis vinifera, also possesses antioxidant properties, but is weaker than catechin.24

Ascorbic acid (vitamin C) is an intracellular and intercellular aqueous antioxidant. It is the first line of antioxidant protection in the body, possessing direct oxygen free radical scavenging ability. It also works synergistically with bioflavonoids and vitamin E, by regenerating their oxidized states.

Serine Protease Inhibition
Serine protease is released along with collagenase from neutrophilic lysosomes as well as from certain bacteria. Serine proteases activate the salivary and gingival interstitial collagenases.10,18 Proanthocyanidins inhibit serine proteases. 10,18 Gallic acid has been shown to inhibit the protease activity of periodontopathic bacteria, including three strains of Bacteroides gingivalis, three strains of Bacteroides intermedius and two strains of Treponema denticola. These findings suggest that gallic acid may interfere with the virulence and growth of periodontopathic bacteria. 8

Histamine Reduction
Mast cells are normal components of connective tissues throughout the body, including the periodontium. Mast cells present in the gingival connective tissues may participate in the inflammatory response by liberating histamine. 30 A group of Turkish researchers have found that mast cell numbers are increased in inflamed gingiva compared to healthy tissues. The increase is closely related with the degree of inflammation. 31 Histamine is an autopharmacological agent released by human mast cells to prevent the excessive release of neutrophilic lysosomal enzymes, including collagenase and serine protease. 32 However, histamine also causes capillary dilation and increased permeability, which leads to edema, erythema and pain.

Two components of Vitis vinifera seed extract combine to buffer this inflammatory cascade. (+)-Catechin monomers block the excessive production of histamine by inhibiting the converting enzyme histidine decarboxylase, 33,54 while proanthocyanidin assists in mitigating the excessive release of the neutrophillic lysosomal enzymes, collagenase and serine protease as discussed above. Thus the positive aspects of histamine’s functions are supported while the negative aspects are reduced, including the edema, erythema and pain.

Ascorbic acid may also play an important role in regulating histamine’s effects in gingivitis. Ascorbic acid deficiency has been shown to be a conditioning factor in the development of gingivitis. When humans are placed on ascorbic acid deficient diets there is increased edema, redness and swelling of the gingiva. These changes have been attributed to deficient collagen production by gingival blood vessels. However, this may also be due to an antihistamine role of ascorbic acid. This vitamin may act to directly detoxify histamine or effect a change in the level of enzymes responsible for histamine metabolism. This could occur through the influence of ascorbic acid in altering cyclic AMP (c-AMP) levels. Such changes in the level of this regulatory molecule could result in increased histamine-N-methyl transferase and other enzymes responsible for the breakdown of histamine. 34

Anti-Inflammatory
In addition to the anti-inflammatory effects produced by the above mentioned antioxidant and antihistaminic, Vitis vinifera seed extract has also been shown to possess direct anti-inflammatory effects, including the reduction of postoperative swelling.55 Echinacea polysaccharides and alkylamides also possess direct anti-inflammatory effects.51 Echinacea also exerts a mild, direct, enhancing effect on the secretion of adrenal cortisone. 48-49,52

Immune Enhancement
Echinacea activates the alternate complement pathway of the immune system, which enhances leukocyte chemotaxis into the area of infection. Echinacea enhances T cell replication, macrophage activity, antibody binding, and increases the number of circulating neutrophils that engulf and destroy bacteria. 48-50

Cellular Dysfunction & CoEnzyme Q10
CoEnzyme Q10 (CoQ10) is a fat-soluble quinone found in the mitochondria of mammalian cells. It is an essential transport carrier in the synthesis of adenosine triphosphate (ATP) involved in the production of cellular energy in the Citric Acid Cycle. Repair and maintenance of periodontal tissue requires a high level of cellular energy production. A deficiency of CoQ10 in the periodontal tissue could limit host resistance and allow periodontal damage to exceed repair.

Several studies have reported that gingival and leukocytic deficiencies of CoQ10 found in patients with periodontal disease predispose to or accentuates the disease process.35-37,56,57 In one study, gingival biopsies of 29 patients showed that all 29 had a reduction of CoQ10 activity of at least 20-63%. Blood studies showed that 24/28 (86%) of the patients had a reduction of Leukocyte CoQ10 activity of 20-66% compared to controls, indicating that the deficiency was likely systemic.36 treatment with CoQ10 supplementation restores gingival CoQ10 activity. 38

CoQ10 has shown impressive results in reducing periodontal scores (p less than 0.01) as well as decreasing periodontal pocket depth (p less than 0.05).38 The healing has been viewed as “extraordinarily effective,” by Dr. Edward Wilkinson, a former U.S. Air Force periodontist, and his team of researchers. They commented that “healing was so excellent 5-7 days post-biopsy that the biopsy sites were difficult to locate.” 38

In a 3 week, double-blind clinical trial, eighteen patients with periodontal disease were given either 50 mg CoQ10 or a placebo and evaluated according to a “Periodontal Score” for swelling, bleeding, redness, pain, exudate, periodontal pocket depth, and mobility of teeth. All 8 patients in the CoQ10 group (100%) improved, while only 3 of 10 (30%) of the placebo group improved. 39 One prosthodontist among the eight dentists in the trial commented that “the degree of healing seen in three weeks usually took about six months.”

The widespread deficiency of CoQ10 in periodontal tissues and human leukocytes creates a bioenergetic cellular dysfunction of the Citric Acid Cycle, leading to hypercitricemia.40 Restoration of adequate levels of CoQ10 in the periodontium reverses this dysfunction, enhances host resistance, raises the rate of repair above the degree of damage and reverses periodontal disease.

Cellular Dysfunction & Folate
Folate, also known as Folic acid, works with vitamin B12 in many functional processes throughout the body, including the periodontium. It is critical to cellular division and new cell production because it is an essential co-factor in normal DNA synthesis. Repair and maintenance of periodontal tissue generates a high turnover rate of squamous epithelium. Without Folate, epithelial cells do not divide properly. A deficiency of Folate may predispose the tissues to periodontitis and/or lead to an accentuation of the disease process.

Several double-blind studies have shown that Folate, either internally or topically, produces significant reduction of gingival inflammation as determined by decreased redness, bleeding, tenderness, exudate, and plaque scores. 41-45

Folate supplementation may be especially important in Pregnant women and women on oral contraceptives who are known to have an increased incidence of gingivitis. It appears that the high estrogen levels in these two conditions stimulates a folate binding molecule in leukocytes that creates a functional folate deficiency in these women.46 Folate supplementation in these cases produces significant reduction in gingivitis. Folate mouthwash (one-half ounce of a 0.1 % folate) has been shown to be more effective than oral supplementation, suggesting a local effect, perhaps related to folate’s ability to bind toxins produced by bacterial aggregations in periodontal plaque. 43-45

Functional Ingredients

Vitis vinifera

Description
Vitis vinifera, grapes, have been cultivated for centuries as a food and as a beverage. In 1970 a French biochemist by the name of Jacques Masquelier discovered that grapes, especially the seeds contain a rich supply of certain bioflavonoids that possess significant therapeutic benefits. Vitis vinifera seeds contain a complex mixture of polyphenols containing a variable number of bioflavonoid units, including catechin, epicatechin, proanthocyanidin, and oligomeric proanthocyanidin complexes. In 1972, Dr. Masquelier’s discovery led to the development of a French prescription drug, known as Endotelon™, for the treatment of venous insufficiency and other disorders of the vascular integument. Ongoing research with standardized extracts of Vitis vinifera seeds has led to the discovery of a significant functional application in the field of dentistry.

Chemistry
The chemical composition of Vitis vinifera seeds includes catechin and epicatechin monomers, dimers of catechin and epicatechin, known as leucoanthocyanidin, or proanthocyanidin B1, B2, B3, and B4 in free and esterified form with gallic acid, trimers and tetramers of catechin and epicatechin, oligomers of various combinations of flavan units of 5 or more catechin and epicatechin monomers, trace amounts of tannins and hydroxycinnamic acids, including caffeic acid, p-coumaric acid, and ferulic acid. (See figure 1)
The chemical composition of Vitis vinifera seeds includes catechin and epicatechin monomers, dimers of catechin and epicatechin, known as leucoanthocyanidin, or proanthocyanidin B1, B2, B3, and B4 in free and esterified form with gallic acid, trimers and tetramers of catechin and epicatechin, oligomers of various combinations of flavan units of 5 or more catechin and epicatechin monomers, trace amounts of tannins and hydroxycinnamic acids, including caffeic acid, p-coumaric acid, and ferulic acid. (See figure 1)

Various extraction methods and variations in annual Vitis vinifera harvests can produce significant variations in the percentage of each of the individual components in the seeds. Pharmaden uses a highly concentrated and standardized Vitis vinifera seed extract, which provides a consistent HPLC profile containing trace amounts of hydroxycinnamic acids, 0.6% gallic acid, 18%, monomers, 20% dimers, 15.5% trimers and tetramers, and the balance made up of the oligomeric fraction of five or more flavan units. It is regarded as the industry standard for purity, potency, and effectiveness.

Summary of Functional Properties

1. Attaches to the fibers surrounding bacterial membranes, preventing them from binding together to cause the accumulation of bacterial plaque that can lead to periodontal disease.21
2. Potent Antioxidant: has been shown to be 20 times more potent than Vitamin C and 50 times more potent than Vitamin E as an antioxidant.2
3. Has a selective affinity for the connective tissue of the body.19,20
4. Strengthens and protects collagen and elastin fibers of the connective tissue found in the periodontium, as well as the skin, heart, blood vessels, joints, mucous membranes, cell membranes, and etc.19,20
5. Anti-Histamine: inhibits excessive production of histamine, reducing inflammatory swelling of the gums and other tissues.54
6. Anti-Inflammatory: inhibits inflammatory swelling including postoperative swelling.55 Reduces the inflammation associated with bacterial toxins, free radicals, mechanical trauma, allergies, and other environmental influences.
7. Blocks the connective tissue destroying enzyme collagenase, as well as hyaluronidase, released by bacteria.21

CoEnzyme Q10

Description
CoEnzyme Q10, also know as Ubiquinone, is a naturally occurring molecule that is similar in structure to Vitamin K. It is a cofactor in the biochemical production of energy in the body. Although CoQ10 can be made by the body under usual circumstances, a deficiency has been found to exist in many clinical conditions including periodontal disease.

Chemistry

CoQ10 is a lipid soluble quinone. The “10” refers to the number of isoprenoid units in the side chain. (See Figure 4)

Summary of Functional Properties

1. Required for the efficient energy production of cellular metabolism necessary for healing and repair of periodontal tissue.
2. Reported in several studies to be frequently deficient in patients with periodontal disease.35-37,56,57
3. Improves periodontal scores, including reduced gingival pocket depth, swelling, bleeding, redness, pain, exudate, and looseness of teeth.39
4. Has shown “very impressive” acceleration of healing of periodontal disease.38,39
5. In an open clinical trial produced “extraordinary” post surgical healing (2-3 times as fast as usual) in patients with advanced periodontal disease.38
6. Echinacea angustifolia

Description
Echinacea (purple coneflower) species are perennial herbs native to Midwestern North America. Native American Indians used Echinacea more than any other plant for the treatment of illness or injuries. The entire plant is used for medicinal purposes, including the aerial portion, leaves, stems and roots.

Chemistry
Echinacea contains a broad spectrum of chemical components that provides synergistic effects. Water-soluble polysaccharides stimulate cellular immune activation while the fat-soluble components stimulate macrophage phagocytosis. The most important chemical constituents include polysaccharides, flavonoids, caffeic acid derivatives, essential oils, polyacetylenes, and alkylamides. (See Figure 5, 6 and Table 1).

Summary of Functional Properties

1. Antihyaluronidase. A number of hyaluronidase secreting bacteria have been found in saliva. 26, 27 These bacteria break down hyaluronic acid to form bacterial aggregations along the gingival crevice that can lead to periodontal disease.
2. Immune enhancement. Echinacea enhances T cell replication, macrophage activity, antibody binding, and increases the number of circulating neutrophils that engulf and destroy bacteria. 48-50
3. Anti-inflammatory. Echinacea polysaccharides and alkylamides possess direct anti-inflammatory effects. 51 Echinacea also exerts a mild, direct, enhancing effect on the secretion of adrenal cortisone. 48-49,52

Folate (Folic acid)

Description
Folic acid is a B Vitamin that the body uses to manufacture DNA, the building block for cell growth and normal tissue development.

1. The most common nutrient deficiency in the world.58
2. Has been shown in double-blind studies to significantly reduce gingivitis as shown by reduced bleeding, swelling and plaque scores. 41-45
3. Has been shown to bind plaque-derived endotoxin, a major contributor to the inflammation associated with periodontal disease.43-45
4. Necessary for normal DNA synthesis and cellular development.
5. Especially important for pregnant women or women on estrogen birth control pills since it becomes molecularly bound in these two conditions and rendered functionally deficient.46

Cyanocobalamin (Vitamin B12)

Description
Vitamin B12 is added to the formula to insure that sufficient quantities are available for use by the body to prevent a state of anemia that could be temporarily masked by Folate in the case of a vitamin B12 deficiency.

1. Deficiencies can cause anemia.49
2. Vitamin B12, in conjunction with Folate and Vitamin B6, has been shown to prevent elevated levels of Homocysteine, known to be a factor in the onset of arteriosclerosis.45
3. Deficiency can cause neuropsychiatric disorders even in the absence of anemia.49

d-alpha Tocopheryl Succinate (Vitamin E)

Description
The natural form of Vitamin E is added to PerioCare in order to provide comprehensive long-term antioxidant protection. Vitamin E is the body’s major fat-soluble antioxidant defense against free radical damage. In addition to Periodontal Disease, free radical induced cell damage has been linked in research studies to a variety of cancers, hardening of the arteries and heart disease, premature aging, cataract formation, and arthritis. Research suggests that Vitamin E enhances the action of the immune system, reduces the stickiness of blood platelets that can otherwise cause blood clots and provides protection against radiation from the sun, air pollutants and other environmental toxins. Vitamin E has recently been found to prevent oxidation of LDL cholesterol, the key factor leading to hardening of the arteries and heart disease.

For reasons of purity and potency, Pharmaden uses only natural-source Vitamin E. Natural-source Vitamin E comes from plants. Synthetic Vitamin E is produced from petrochemicals. Recent studies of animals and human subjects indicate that natural-source Vitamin E is almost twice as effective and stays in the body tissues much longer than synthetic Vitamin E.

Selenium (Selenomethionine)

Description
Selenium is added to PerioCare in order to provide comprehensive long-term antioxidant protection. Selenium is closely related in nutritional function to Vitamin E. Selenium plays a key role in the activity of glutathione peroxidase which protects cellular membranes from oxidative damage. It may also have specific antioxidant effects of its own. In animals moderate selenium supplementation decreases the frequency of various chemically induced cancers and spontaneous mammary tumors as well as the mutagenic activity of several known cancer causing agents.

Moderate supplementation of Selenium enhances immune function. Selenium also possesses anti-inflammatory properties, which are potentiated by Vitamin E. Veterinarians have long used a combination of Vitamin E and Selenium in the treatment of arthritis, hip dysplasia, lameness, peripheral blood vessel disease, and coronary insufficiency in dogs. Selenium deficiency in humans has been shown to pose an increased risk of coronary and cardiovascular death and myocardial infarction. Since Selenium is markedly depleted from our soils it is important to take a daily supplement of this important antioxidant cofactor.

Bioperine R (Piper nigrum)

Description
Bioperine is a pure piperine extract obtained from an Indian spice, black pepper fruit, cultivated in the damp, nutrient rich soil regions of southern India. The patented piperine extract (US Patent # 5,536,506) has been shown in human clinical trials to significantly enhance the bioavailability of various supplemented nutrients through increased absorption.53 The Bioperine R absorption studies, conducted on healthy volunteers in the U.S., showed dramatic increases in the blood levels of all nutrients tested compared to the control group receiving the nutrients alone. Nutrients tested included fat-soluble vitamins (beta-carotene), water-soluble vitamins (vitamin B6), minerals (selenomethionine), and coenzymes (Coenzyme Q10). Absorption rates were shown to increase 30 to 60 percent. 53 (See Figure 7-8)

Product Safety
Vitis vinifera seed extract has been shown to be devoid of any toxic, carcinogenic, or teratogenic effects. It does not impair fertility and has been shown to be safe for use during pregnancy and breast feeding with no peri-natal or post-natal toxicity. Due to its bitter nature, occasional nausea or stomach upset has been reported. Temporary skin irritation has occurred in patients with a specific hyper-sensitivity to grapes. Chronic toxicity studies have shown it to be safe even at extremely high doses (132mg/lb body weight/day for twelve months in dogs). LD50>4000 mg/kg in rats and mice.

CoEnzymeQ10 is well tolerated. No serious adverse effects have been reported with long-term use. Rarely minor side effects have been reported at the following rates: epigastric discomfort (0.39%), loss of appetite (0.23%), nausea (0.16%), and diarrhea (0.12%).52 Because safety during pregnancy and lactation has not been proven, CoQ10 is not recommended during these times unless the potential clinical benefit outweighs the possible, although improbable, risk.

No acute or chronic toxicity reactions have ever been reported in the long history of use of Echinacea. The polysaccharides in Echinacea (aerial portion) have an LD50 of 1,000-2,500 mg/kg in mice (I.P. injection). Chronic administration of Echinacea to rats at doses many times the human therapeutic dose produced not toxic effects. 59 Mutagenicity studies demonstrated not activity. 48,49

Vitamin C is extremely safe. Doses in excess of 1,000 mg at a given time can cause gas, distension, or diarrhea that is self limiting. Although there is some concern in medical editorials that high doses of vitamin C could cause calcium oxalate kidney stone formation, numerous studies indicate otherwise. Vitamin C administration of up to 10 grams per day has not been shown to raise urinary oxalate levels. 60,61

Folate is a water soluble B Vitamin. It has been found to be safe even at high doses (e.g. 5-10 mg/day), although it can cause flatulence, nausea, and loss of appetite in that range. Doses in excess of 5 mg per day have occasionally been associated with increased seizure activity in epileptics. Folate supplementation should always include vitamin B12 because folate can mask an underlying vitamin B12 deficiency. Although folate supplementation can prevent the macrocytic anemia usually associated vitamin B12 deficiency, it cannot prevent the neurological damage that can be caused by a significant vitamin B12 deficiency.

Vitamin B12 has no known toxicity.

Vitamin E supplementation is extremely safe. Recent clinical trials using Vitamin E at doses as high as 3,200 I.U. per day in a wide variety of conditions for periods of up to two years have not shown any unfavorable side effects.

Selenium is required only in small amounts on a daily basis, usually less than 400mcg. High intakes of two and a half times that amount (1,000 mcg) or more per day over prolonged periods of time can produce signs of selenium toxicity in some people. Signs and symptoms related to chronic toxicity include depression, nervousness, emotional instability, nausea and vomiting.

Bioperine® has been shown to be devoid of any toxic effects. The recommended amount of 5 mg of piperine per dose, is seven times less than the daily amount of piperine typically consumed by the average U.S. citizen from black pepper.

Dosage
Take one tablet twice daily, or as directed by your dentist.

Bibliography

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