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Saliva

Of all the organs in the craniofacial-oral-dental complex, it is perhaps the salivary glands and their remarkable secretory product, saliva, that forge the strongest link between oral and systemic health. Salivary function is extremely sensitive to changes in our general well-being, ranging from subtle effects of over-the-counter cold medications to the devastation of life-threatening disease.

Even the ancients recognized an association between the human condition and saliva, which served as judge and jury in cases of wrong-doing. A suspect was given a mouthful of dry rice. If his anxiety reduced his saliva flow so that he could not swallow it, the verdict was guilty as charged. To this day, "cotton mouth" betrays all of us at some point in our lives, signaling to the world that our nerves have taken control.



Gatekeeper

With its vast antimicrobial arsenal, saliva represents a remarkable evolutionary selective advantage for the host against invading pathogens such as HIV, the fungus Candida albicans, and a host of bacteria associated with oral and systemic diseases. Secretory antibodies, for example, directed against viral pathogens such as poliovirus and cold viruses, as well as the anti-HIV agent SLPI, are found in saliva. Large salivary glycoproteins called mucins appear to have antiviral properties as do cystatins, a family of cysteine-rich proteins that are active against herpes viruses.

Saliva also contains histatins, antifungal proteins that are potent inhibitors of candida, which is normally kept in check at extremely low levels in the mouth. When the oral balance is upset, however, by HIV infection or other immunosuppressive and debilitating disorders, antifungal defenses are overwhelmed and candida flourishes uncontrolled.Reinforcing saliva's antiviral and antifungal activity are salivary constituents that thwart bacterial attack. These enzymes destroy the opposition by various mechanisms, including degrading bacterial membranes, inhibiting the growth and metabolism of certain bacteria, and disrupting vital bacterial enzyme systems.

Functioning in concert, these and other protective factors in saliva help to maintain the oral environment in optimal working order and restore it to more normal conditions when disturbed. But protection of the oral tissues reflects only one dimension of this versatile fluid and its constituents. Research has found a new role for saliva as an effective laboratory tool.

Familiarity with the composition, function and normal flow of saliva will give the practitioner a better understanding of the sequelae of hyposalivation.Saliva initiates the digestive process and contributes to the maintenance of healthy oral tissues. Whole saliva consists of secretions from the major and minor salivary glands. The parotid gland produces a pure serous secretion, while the submandibular and sublingual glands produce a mixed seromucous or mucous secretion, respectively.About 99 percent of saliva is water. The remaining one percent consists of large and small organic molecules, proteins, lipids and carbohydrates, and electrolytes. Some of these molecules are transported from the blood into salivary secretion; others are locally synthesized.

New Diagnostics

Long known primarily for its protective and lubricating properties, saliva is now meeting the demand for inexpensive, noninvasive, and easy-to-use diagnostic aids for oral and systemic diseases, and for assessing risk behaviors such as tobacco and alcohol use. Detection of HIV by the presence of virus-specific antibodies in saliva, for example, has led to the development of commercially available test kits. These offer the sensitivity of a blood test, but without the discomfort of a needle stick.The strong correlation between HIV antibodies in saliva and serum has spurred the use of saliva as a monitor for other viral antibodies and antigens. Experimental salivary assays have already been developed for detecting antibodies for measles, mumps and rubella.Saliva is also reliable in diagnosing viral hepatitis A, B and C in laboratory tests.

As an investigational diagnostic aid and potential monitor of disease progression, saliva has been used increasingly in systemic disorders that affect salivary composition and gland function, including Alzheimer's disease, Sjِgren's syndrome, cystic fibrosis, diabetes, and diseases of the adrenal cortex. Saliva is also proving to be an effective tool to monitor levels of hormones and therapeutic medications–as well as the presence of illicit drugs.

Saliva


Table 1. Saliva Composition


WaterLarge Organic Molecules

Proteins

Carbohydrates

Lipids


Small Organic Molecules

Creatine Sialic acid

Glucose Urea

Nitrogen Uric Acid



Electrolytes

Ammonia Magnesium

Bicarbonate Phosphates

Calcium Potassium

Chloride Sodium

Fluoride Sulphates

Iodine Thiocyanate

Major Proteins Produced by Acinar or Ductal Cells

Proline-rich proteins

Histatins

Cystatins

Statherin

Mucins (high and low molecular weight)

Amylases

Saliva peroxidases

Lysozyme

Lactoferrin

Secretory component of IgA

Epithelial growth factor



Compounds Transported from Blood into Saliva

Albumin


Immono-globulins IgA, IgG, IgM

Vitamins

Drugs

Hormones



Water

Research opportunities abound to develop more sensitive and specific assays to measure and understand changes in saliva beyond oral and systemic diseases to areas such as genetic defects, nutritional status, and age-specific changes.



Salivary Gland Dysfunction

Although viewed as champions of the oral cavity, the salivary glands are not spared insult or disease. The parotid, submandibular, and sublingual glands that comprise the major salivary glands are directly affected by a variety of conditions, including infection (such as mumps), obstructions, developmental disorders, and tumors. Two major diseases, cystic fibrosis (CF) and Sjِgren's syndrome, can devastate these vital glands.In cystic fibrosis, a defect in chloride ion transport causes exocrine gland secretions, including saliva, to be thick and viscid and leads to chronic lung disease and pancreatic insufficiency. Studies of salivary acinar (salt and water secreting) cells, a convenient model for exploring mechanisms of chloride ion transport, have greatly expanded the understanding of exocrine gland transport systems in human salivary glands. The identification of the defective gene in cystic fibrosis has also led to clinical trials using gene therapy to treat this disorder.



Sjِgren's Syndrome

Eagerly awaiting clinical advances in salivary gene transfer are many thousands of people with Sjِgren's syndrome (SS), an autoimmune disorder that primarily affects women. Classic symptoms include dry mouth, eyes and other mucosal surfaces, accompanied in about half the cases by a connective tissue disease such as rheumatoid arthritis or systemic lupus erythematosus. The oral dryness interferes with normal functions of talking, chewing and swallowing and, deprived of the protective properties of saliva, puts SS patients at high risk for dental and oral infections.Investigators are looking closely at alterations in salivary gland function associated with Sjِgren's syndrome. Because salivary involvement in this disorder is highly variable, ranging from mild impairment to total loss of function, early diagnosis is difficult. Studies are aimed at defining criteria for early and unequivocal diagnosis and establishing clinically useful markers for salivary gland disease activity.The inflammatory cytokine interleukin-6 (IL-6), for example, has been found at elevated levels in the saliva of SS patients and may serve as a marker for this disorder. IL-6 and other elevated cytokines are thought to play a significant role in the pathogenesis of Sjِgren's syndrome; the mechanism, however, is unknown.

Research is also under way to develop a new noninvasive or minimally invasive means of diagnosing salivary gland involvement in SS using laser spectroscopy techniques. Currently, definitive diagnosis requires surgical removal of minor salivary glands. Laser spectroscopy to detect labeled cells specific to Sjِgren's syndrome would not only obviate the need for surgery, but would also permit repeated testing of the salivary glands to follow the course of the disease and effectiveness of therapy.

Xerostomia

Another major source of dry mouth–medication–affects most of us at some time in our lives. More than 400 prescription and over-the-counter drugs are known to have xerostomic effects. Many of these medications are taken daily, particularly by older Americans, to treat chronic conditions such as hypertension and depression. Although salivary gland function does not normally decline with age, the oral dryness experienced by many older persons from certain diseases and long-term medications heightens their risk for oral and dental infections. As the population ages– by 2010, 40 million Americans will be 65 or older–vulnerability to an array of chronic and disabling disorders and the oral effects of medications prescribed for their management will present significant challenges to health care providers.Elderly patients, in or out of the hospital, are more than twice as susceptible to adverse drug reactions than are younger patients. When one considers that the elderly fill 18 prescriptions annually and take three times as many drugs as does the general population, one can understand how xerostomia is a major concern. According to one survey, the three most frequently occurring oral side effects of prescription drugs are xerostomia (80.5%), taste disorders or dysgeusia (47.5%), and stomatitis (33.9%).By further examining only the xerostomia-producing drugs studied in the survey (Table 2), one can see the potential for a compounded xerogenic effect in the patient who takes more than one medication each day. The table shows drugs whose potential ranges from a slight xerogenic effect to those that have a potential of up to 54 percent. The survey covers a limited sampling of all drugs used by the elderly.The dentist is in a treatment dilemma: the cause of the xerostomia is known, but the solution could prove life-threatening to the patient if the medications causing the problem are discontinued. It is critical that the dentist consults with the patient's physician(s)

about replacing the problem drugs with substitutes to palliate the symptoms of xerostomia without creating further health risks.

The drugs with the highest potential for causing dry mouth side effects are tricyclic antidepressants, antihistamines, benzodiazepine sedatives, phenothiazine antipsychotics, and anti-Parkinson medications. Drugs having lower potential for causing dry mouth are antidepressants, such as Prozac and Zoloft, diuretics, antihypertensive and NSAID's.The drugs most commonly prescribed for the elderly are diuretics, antiarthritics, antihypertensives, narcotic analgesics, coronary vasodilators, corticosteroids, digitalis preparations, bronchodihibitors, psychotropics, antispasmodics, alpha/beta blockers and analgesics.Three groups of over-the-counter medications have great potential for causing xerostomia. These include laxatives and cold/allergy products, both of which have a dehydrating effect with long-term use, and weight control products, which may contain the xerogenic agents phenylpropanolamine hydrochloride and caffeine.



Diagnosis of Xerostomia

At the initial patient interview a thorough inquiry is made into the patient's medical, dental, psychosocial, dietary and pharmacological histories, both post and present. The dentist may ask questions pertaining to subjective symptoms, such as, "Do you have increased thirst?" The objective symptoms listed in Table 3 can be a helpful reference in clinical evaluation.After clinical evaluation, a simple chairside salivary flow can be performed to determine stimulated and unstimulated flow rates. The tests involve collecting whole saliva through the following techniques: spitting, draining (drooling), suctioning and swabbing.



The spitting method is a preferred means, since it is an easy chairside procedure that can be performed by the dentist or a trained dental auxiliary. In this approach, the patient is told to swallow any saliva that may be present and then to allow the unstimulated saliva to gradually seep into the mouth. After two minutes, this is expectorated into a graduated collecting vessel. Two more two-minute samples are collected, for a six-minute total. The physical characteristics and volume of the saliva are then recorded. Flow rate is expressed in ml/ minute


Table 3. Subjective and Objective Symptoms of Xerostomia




Increased thirst n Mucositis



Increased fluid intake while eating n Tongue sticks to the palate/or n Difficulties in speaking, eating cheeks or swallowing n Dry eyes, dry skin or dry nose



Oral burning sensation in mouth n Angular chelitis and chapped lips



Sensitivity to acidic (citrus) and spicy n Recurrent decay or new gingival foods n Taste disorders



Parotic gland enlargement n Depapillated, cracked, glossy, n Clicking of tongue fissured or erythematous tongue



Bad breath n Increased food debris in the oral n Cancerophobia, depression cavity (extreme cases) n Accentuated gingival recession



Thin, atrophic, friable marginal gingiva n Increased plaque accumulation

Table 4. Saliva Composition and Flow RatesHealthy individuals



Whole saliva n 0.3-0.5 ml/min n 1.0-3.0 ml/min



Parotid n 0.04 ml/min/gland n 0.7 ml/min/gland



Submandibular/ n 0.15 ml/min n 0.6 ml/min/gland sublingual

Xerostomic Individuals



Whole saliva n 0.01-01. ml/min n 0.5 ml/min



Parotid n 0.02 ml/min/gland n 0.18 ml/min/gland

A standard piece of paraffin wax or sterile elastic bands are used to obtain a stimulated saliva flow sample. The patient is asked first to swallow any accumulated saliva. Next, he or she is instructed to continually chew the wax or bands at a normal rate. Three two-minute samples are obtained. Flow rate (ml/min) and physical appearance are recorded. When paraffin wax cannot be used, two percent citric acid may be administered as a stimulant. The citric acid solution is swabbed on the dorsum of the tongue every 15 seconds. The patient's flow rates can be compared to those listed in Table 4. A less-than-normal salivary flow can readily suggest xerostomia. 


2.


Oral Pilocarpine Hydrochloride

for Radiation-Induced Dry Mouth

  


The FDA has granted marketing approval for an oral preparation of pilocarpine hydrochloride (Salagen/MGI Pharma) for treatment of radiation-induced xerostomia (dry mouth) in patients with cancer of the head and neck. The product is the first pharmacologic treatment for dry mouth. Pilocarpine, which has been used for over a century to treat glaucoma, was first isolated from the leaves of the South American plants Pilocarpus jaborandi and Pilocarpus microphyllous in 1875.

Salagen was developed as an Orphan Drug. An estimated 40,000 cancers of the head and neck are diagnosed each year in the United States, and most of the patients undergo radiation therapy. The radiation can cause permanent damage to the salivary glands, with a major effect on the patient's quality of life. Direct effects can include difficulty in talking, eating, and sleeping; rapid tooth decay; and increased risk of periodontal disease and oral infections. Indirect effects can include nutritional deficiencies, weight loss, and altered social habits.Pilocarpine is a cholinergic parasympathomimetic agent with a broad range of pharmacologic effects. It increases secretion by the exocrine glands and can affect the sweat, salivary, lacrimal, gastric, pancreatic, and intestinal glands and the mucosal cells of the respiratory tract.A 5-mg tablet produces a peak plasma drug concentration of about 15 mg/mL in 1.25 hours, with an elimination half-life of 0.76 hours. Although the mechanisms of metabolism and elimination are uncertain, pilocarpine is believed to be inactivated at the neuronal synapses and probably in the plasma. Pilocarpine and its metabolites are eliminated in the urine.   



Clinical Studies

Two pivotal studies have demonstrated the efficacy of Salagen in improving salivary function in patients with radiation-induced xerostomia. The first [Johnson JT et al. N Engl J Med. 1993;329:390-395] was a prospective, randomized, double-blind trial involving 207 patients who had received radiation therapy for head and neck cancers. The patients received 5 or 10 mg pilocarpine or placebo by mouth three times a day for 12 weeks. Oral dryness improved in 44% of the 5- mg pilocarpine group, compared with 25% of the placebo group. Overall improvement occurred in 54% of the 5-mg group, compared with 25% in the placebo group. These differences were statistically significant (p<0.05). The 10-mg pilocarpine group also showed significantly greater improvement than the placebo group.The second study [LeVeque FG et al. J Clin Oncol. 1993;11:1124-1131] was a randomized, double-blind, placebo-controlled, multicenter trial. A total of 162 patients received placebo or 2.5-mg pilocarpine tablets for 4 weeks, followed by 5-mg tablets for 4 weeks and then 10-mg tablets for 4 weeks. Patients were permitted to adjust their individual doses for best effect (up to increase therapeutic effect, down to reduce side effects). Overall global assessments showed significantly greater improvement with pilocarpine than with placebo. Active treatment also produced less need for artificial saliva, hard candy, water, and other "oral comfort agents." All the drug dosages were found to be safe, and there were no serious treatment-related adverse events.



Severity of Xerostomia Reduced When Taking Salagen Tablets

A study presented at the annual meeting of the American Society for Therapeutic Radiology and Oncology (ASTRO) in Minnesota, Minn. in Oct. 1996 reported that taking Salagen tablets (pilocarpine hydrochloride) during radiation therapy is better at reducing the symptoms of xerostomia (severe dry mouth) than when taking the drug after radiation therapy is completed.According to lead investigator Robert P. Zimmerman, M.D., UCLA Department of Radiation Oncology, Los Angeles, the study compared the severity of xerostomia endured by head and neck cancer patients when Salagen was administered during therapy, after therapy, and not at all. The study involved a total of 29 cancer patients: 17 who received Salagen during radiation therapy and 12 who did not take the drug during therapy. After the radiation therapy was completed, the 12 non-treated patients were placed on Salagen for one month and then compared to the concurrently treated group again. The 17 patients who began taking Salagen tablets concurrently with radiation therapy suffered significantly less from dryness and discomfort and encountered mark


edly less difficulty sleeping, speaking and eating. The most severe xerostomia was seen in post-radiation patients that had not yet received Salagen tablets.The results of this study concur with those from another study presented in May 1996 at the annual meeting of the American Society of Clinical Oncology by Francis G. LeVeque, D.D.S., Chief of Oral Medicine and Oncology at DMC Harper Hospital, Detroit. Dr. Leveque's study in 16 patients showed that using Salagen tablets concurrently with radiation therapy significantly reduced oral dryness and pain, as well as the incidence of oral mucositis (mouth ulcers) by 60 percent.Radiation therapy used to treat tumors of the head and neck damages the salivary glands, reducing their ability to produce saliva. Research shows that a decrease in salivary flow typically begins as early as the first week of radiation therapy. The resultant dry mouth predisposes patients to a multitude of oral complications, including mucositis, oral infections, and tooth decay. Additionally, patients who suffer from this condition can have difficulty speaking, eating and swallowing.Salagen is the only prescription pharmaceutical indicated in the United States for the treatment of symptoms of radiation-induced xerostomia. It works by stimulating the moisture producing glands throughout the body, including the salivary and tear glands.The most common side effect with Salagen treatment has been moderate sweating. Other side effects have included nausea, runny nose, chills, flushing, urinary frequency, dizziness, and fatigue. Salagen use is contraindicated in uncontrolled asthma, known hypersensitivity to pilocarpine, and when miosis (contraction of the pupil) is undesirable, in acute iritis and narrow-angle glaucoma. Patients with cardiovascular disease should receive pilocarpine only under close supervision. Concomitant administration of beta-adrenergic antagonists could result in conduction disturbances.Salagen is available as 5-mg film-coated tablets. The recommended dosage is 5 mg three times a day, titrated up to 10 mg three times a day if the lower dosage is not effective. However, the lowest effective dosage should be used to avoid or minimize side effects.



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