DEVICE SPECIFICATIONS

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DEVICE SPECIFICATIONS

1.         SPECIFICATION OF THE DEVICE

  • presents the intended use of the device;
  • describes the device covered by this petition;
  • explains the principle of action of the device;
  • describes the precautions, warnings and potential adverse effects;
  • presents the alternative practices and procedures to treat xerostomia;

1.1.                 Intended use

Saliwell GenNarino Therapeutic Device for Xerostomia Relief (hereinafter GenNarino) provides relief for xerostomia (dry mouth) that may be induced by damaged salivary function, as may occur in a variety of circumstances including, but not limited to, medication, chemo or radiotherapy, or Sjögren’s Syndrome.

Background

The commonly accepted clinical definition of xerostomia is the subjective sensation of dry mouth. The presence of xerostomia may indicate that salivary output is decreased or altered, placing patients at a higher risk for oral complications. Diverse symptoms and consequences have been associated with xerostomia. Symptoms such as halitosis (bad breath), soreness, oral burning, difficulty with swallowing and altered taste sensation have been linked with xerostomia. In more serious cases, a scalded sensation in the tongue, pharynx and esophagus has been reported. A significant increase in dental caries, periodontal diseases, and denture discomfort/loss of retention and oral infections like candidiasis might also be expected. It is clear that xerostomia represents a serious problem with medical and dental implications. It has a damaging effect on the sufferer in particular and society in general. It affects people at an emotional and social level and deteriorates their overall quality of life. The devastating effects of xerostomia have been widely perceived by health professionals and researchers, as manifested by the extensive publications on risk factors, consequences and treatment of xerostomia[1].

Although xerostomia may be caused by a variety of conditions (head and neck radiotherapy, Sjögren’s Syndrome, medications, etc.), the symptom is basically common to all the sufferers, and varies only in its intensity. Therefore, treatment is non-specific, with the same therapeutic agents and techniques being applied in all cases[2]. As xerostomia is the subjective feeling of dry mouth, the efficacy of treatment of xerostomia is best evaluated by questionnaires[3]. In addition, there is no general agreement about a flow rate value that distinguishes between “normal” and “abnormal”[4]. Patients can be given palliative oral care in the form of application of saliva substitutes. Alternatively, salivary flow can be stimulated by the use of certain pharmaceutical or gustatory preparations or by mechanical or electrical stimuli[5]. Increasing secretion of natural saliva is the most efficient means to relief xerostomia, as natural saliva not only relieves dryness; it also contains essential dental decay-fighting factors and other components critical for oral health[6].

1.2.                 Description

GenNarino is a Therapeutic Device for Xerostomia Relief consisting of two major elements: (a) a mouthpiece unit and (b) an Infra Red control module (remote control unit). See Figure 1.

Figure 1 – GenNarino system

 

(a) The mouthpiece unit

Each unit is casted individually to fit the exact contour of the patient’s lower dental arch, even totally or partially edentulous. It is manufactured by a dental laboratory using a model of the patient’s lower dental arch, which has been casted into an impression taken by a health professional. The device is delivered to the patient by a health professional and adapted to the mouth if adjustments (such as electrodes shortening) are necessary. The mouthpiece is packed in a case (Figure 2).

Figure 2 – GenNarino’s case, closed (left) and open, displaying the mouthpiece (right)

[1] Orellana MF et al (2006). Prevalence of xerostomia in population-based samples: a systematic review. J Public Health Dent. 66(2): 152-8

[2] Brennan MT et al (2002). Treatment of xerostomia: a systematic review of therapeutic trials. Dent Clin North Am. 46(4):847-56

[3] Murray Thomson W (2005). Issues in the epidemiological investigation of dry mouth. Gerodontology 22: 65–76

[4] Ghezzi EM et al (2000) Determination of Variation of Stimulated Salivary Flow Rates. J Dent Res 79(11):1874-1878

[5] Nieuw Amerongen AV, Veerman ECI (2003). Current therapies for xerostomia and salivary gland hypofunction associated with cancer therapies. Support Care Cancer 11:226–231

[6] Nieuw Amerongen AV, Veerman ECI (2002). Saliva – the defender of the oral cavity. Oral Diseases  8:12-22

 

1.1.                 Principle of action

Salivary gland secretion is regulated by the autonomic nervous system. In particular, parasympathetic[1] stimulation produces saliva. Physiologically salivary secretion is regulated by an autonomic reflex arch which consists of three major components:

(i)          afferent nerve fibers (going from the periphery to the brain) carrying impulses induced by:

  1. chemical (gustatory) stimulation (like tasting food),
  2. mechanical stimulation (like chewing food, tactile perception of foreign bodies in the mouth, or mouth muscles -e.g. tongue- movements)[2],[3],
  3. electrical stimulation of the oral mucosa[4],
  4. stimuli coming from other areas of the body, such as smelling food,

(ii)         a central connecting and processing center (salivation center in the brain), as shown by Ivan Pavlov, i.e. the conditioned reflex associated with food[5], and

(iii)        an efferent nerve fibers (in the opposite direction than afferent ones) that innervate their target salivary glands. Afferent nerves carry impulses from the periphery to the salivation center, which in turn directs signals to the efferent part of the reflex arch leading to salivation[6].

GenNarino’s principle of action takes advantage of the physiological mechanism of salivary secretion, deploying electrical stimulation of nerves. It enhances the impulses carried through the afferent nerve fibers through both mechanical and electrical stimulation. On the efferent direction, GenNarino stimulates the fibers signaling the salivary glands to secrete more saliva. To this end, GenNarino is placed in the oral cavity, an advantageous location due to the proximity to the nerves regulating salivary gland activity allowing use of lower voltage and current for stimulation.

GenNarino is recommended to be worn for up to 10 minutes, and not more than once every hour. This statement on the recommended use is supported by the clinical protocol of the long-term study described in the last section of this Petition, allowing patients to use the device up to 10 minutes each time, as frequently as they like but not more than once an hour.

Mechanical stimulation

Mechanical (tactile) stimulation of the oral mucosa (e.g. presence of a foreign body in the mouth) results in increased salivary flow[7]. A well-known phenomenon accompanying the insertion of removable dentures is an increase in salivary flow rate[8]. This increase has also been recorded in patients wearing complete dentures for 10 years when compared with dentate individuals[9]. This phenomenon is attributed to stimulation of mechanoreceptors located under the denture base, which initiates an enhanced salivary reflex through pressure mediated by the dentures[10]. As saliva is essential for maintaining oral health and function, the increase in salivary secretion following wearing of dentures is most opportune. A denture is perceived as a foreign body that could be potentially harmful. Thus, more saliva is subsequently secreted in order to provide enhanced lubrication and defense.

Similarly to dentures, the presence of GenNarino in the oral cavity possibly triggers a mechanical stimulating effect, leading to increased natural saliva production.

Electrical stimulation

GenNarino’s effect is achieved by stimulating the associated nerves. Our knowledge that the nervous system controls the secretion of saliva became evident with Ludwig’s discovery in 1850 that electrical stimulation of the chorda tympani-lingual nerve in the dog caused a copious secretion of submandibular saliva. Since then, electrical stimulation of nerves involved in the salivary secretory process has been extensively used in animal experiments[11],[12],[13],[14],[15],[16].

Electrical stimulation of neural and muscular structures has already been well recognized for its therapeutic potential in many other areas of modern medicine. It is widely used in a variety of applications, such as in the treatment of a range of acute and chronic conditions, pain or muscle weakness, cardiac arrhythmia (pace maker), cosmetic care, etc. Electrical stimulator devices may provide direct alternating, pulsating or pulsed waveform forms of energy. The devices are used to exercise the tissue or the nerve by stimulation through electrodes. Electrical stimulation comes in several system architectures, characteristics, application and acronyms.

Given the autonomic control of salivary secretion, a similar approach is useful also in the management of hypofunction of salivary glands and xerostomia. Application of electric impulses to one or more of the three components of the salivary reflex improves salivary secretion. The application of an electrical current, through the oral mucosa, on afferent pathways was reported to increase salivary production and relieve symptoms of dry mouth in patients with salivary gland hypofunction[17]. It was suggested that such an intra-oral electrical stimulation augments salivation via salivary reflexes, i.e. via production of an effective afferent-efferent barrage of stimuli.

More recently, the use of TENS on the skin covering the salivary glands was reported in few scientific studies to increase saliva production in healthy individuals and patients affected by radiation-induced xerostomia. Those studies were performed using devices named AdvanTeq 2000[18],[19] and Codetron[20].

GenNarino’s electro-stimulation principle is based on applying stimulating signals at the lingual nerve vicinity, which is the main nerve controlling salivary function, as it carries both afferent and efferent fibers[21] (Figure 5).

Figure 5 – View of the lower jaw from behind. The arrow indicates the wisdom tooth area and the lingual nerve

1.2.                 Precautions

It is recommended to consult a specialist in the specific area of the conditions listed below regarding use of GenNarino. The following medical conditions should be considered as a basis for special precautions prior to the use of GenNarino:

§  Use of a pacemaker

§  Pregnancy

§  Psychiatric or psychological disorders

§  Epileptic disorder

§  Involuntary muscle movement disorder (for example Parkinson’s disease)

1.3.                 Warnings

  • The long term effects of chronic electrical stimulation are unknown.
  • GenNarino should be stored at room temperature in its carrying case while not in use.
  • GenNarino should not be exposed to heat or direct sunlight.
  • GenNarino should not be exposed to liquids other than water or saliva.
  • GenNarino should not be cleaned using ultrasound/ultrasonic devices.
  • If the electronic module and/or the coin battery are exposed, stop using the device immediately.
  • Don’t use the equipment in the presence of flammable mixtures with air or with oxygen or nitrous oxide.
  • If GenNarino and especially the electrodes hurt the oral tissue, stop using the device and seek assistance from your clinician, who may shorten slightly the electrodes.
  • If any discomfort (for example, tingling, pain or significant discomfort) is felt, stop immediately using GenNarino and consult your clinician.

1.4.                 Potential adverse events

Potential adverse events of GenNarino use include: infection, inflammation, and allergic reaction of the oral tissues.

1.5.                 Alternative practices and procedures

Xerostomia can be treated using various alternative products, medical devices and medications. When residual secretory capacity is present, it is advisable to stimulate the salivary glands by mechanical or gustatory stimuli as supportive oral care. The most commonly used products are mouthwashes and gels. Alternatively, salivary flow can be stimulated by the use of cholinergic pharmaceutical preparations, such as pilocarpine or cevimeline. When stimulation of salivary secretion fails, patients can be given palliative oral care in the form of application of saliva substitutes[22].

 

 

 

 

2.         SAFETY/EFFECTIVENESS OF GENNARINO

This section provides a full statement of the reasons, together with supporting data of reasonable assurance of the safety and effectiveness of the device.

The petitioner claims that the existing abundant evidence demonstrates the safety and effectiveness of GenNarino. This evidence is provided by preclinical and clinical testing of GenNarino demonstrating biocompatibility, electrical, mechanical and software safety and satisfactory performance.

In determining the safety and effectiveness of GenNarino, the authorities may consider the following, among other relevant factors:

1. Persons for whose use the device is intended;

2. Conditions of use for the device;

3. Probable benefit to health from the use of the device weighed against any probable injury or illness from such use; and

4. Reliability of the device

 

2.1.     Persons for whose use the device is intended

GenNarino is aimed at relieving xerostomia (dry mouth) in persons in which dry mouth has been induced by medications, chemo or radiotherapy, or Sjögren’s Syndrome.

 

[1] opposes physiological effects of the sympathetic nervous system: stimulates digestive secretions; slows the heart; constricts the pupils; dilates blood vessels

[2] Pedersen AM et al (2002). Saliva and gastrointestinal functions of taste, mastication,

swallowing and digestion. Oral Diseases 8:117–129

[3] Blum AL, Makhlouf GM (1971). Determinants of salivary response to mechanical stimulation. Gut 12:650-653

[4] Steller M et al (1988). Electrical Stimulation of Salivary Flow in Patients with Sj6gren’s Syndrome. J Dent Res Res. 67:1334-1337

[5] Pavlov IP (1927). Conditioned Reflexes: An Investigation of the Physiological Activity of the Cerebral Cortex. Translated and Edited by G. V. Anrep. London: Oxford University Press

[6] Edgar M et al. Saliva and Oral Health. 3rd ed. 2004. Br Dent Assoc.

[7] Guinard J-X et al (1998). Relation between parotid saliva flow and composition and the perception of gustatory and trigeminal stimuli in foods. Physiol Behav. 63:109–118

[8] Wolff A et al (2004). The flow rate of whole and submandibular/sublingual gland saliva in patients receiving replacement complete dentures. J Oral Rehab. 31:340–343

[9] Streckfus CF et al (1993). Stimulated parotid gland flow rates in healthy elderly dentulous and edentulous individuals. J Prosthet Dent. 70:496-499

[10] Jensen J et al (1991). Parotid salivary flow rates in two patients during immediate denture treatment. J Oral Rehabil. 18:155

[11] Calvert et al (1998). Autonomic control of submandibular protein secretion in the anaesthetized calf. Exp Physiol. 83:545-556

 

[13] Izumi H et al (1995). Low-frequency subthreshold sympathetic stimulation augments maximal reflex parasympathetic salivary secretion in cats. Am J Physiol. 268:R1188-1195

[14] Edwards AV et al (1996). Nitric oxide and release of the peptide VIP from parasympathetic terminals in the submandibular gland of the anaesthetized cat. Exp Physiol. 81:349-59

[15] Edwards AV et al (1997). Secretory interactions between the sympathetic and parasympathetic innervations of the submandibular gland in the anaesthetized cat. Exp Physiol. 82:697-708

[16] Schneyer CA et al (1991). Effects of varying frequency of sympathetic stimulation on chloride and amylase levels of saliva elicited from rat parotid gland with electrical stimulation of both autonomic nerves. Proc Soc Exp Biol Med. 196:333-337

[17] Talal N et al (1992). The clinical effects of electrostimulation on salivary function of Sjögren´s syndrome patients. A placebo controlled study. Rheumatol Int. 12:43–45

[18] Hargitai IA et al (2005). The effects of electrostimulation on parotid saliva flow: A pilot study. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 99:316-20

[19] Domingo DL (2004). The effects of electrostimulation on saliva production in ostradiation head and neck cancer patients. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 97:464

[20] Wong RK et al (2003). A Phase I-II study in the use of acupuncture-like transcutaneous nerve stimulation in the treatment of radiation-induced xerostomia in head-and-n.eck cancer patients treated with radical radiotherapy. Int J Radiat Oncol Biol Phys. 57:472-80

[21] Hellekant G, Kasahara Y (1973). Secretory fibres in the trigeminal part of the lingual nerve to the mandibular salivary glands of the rat. Acta Physiol Scand 89: 198-207

[22] Nieuw Amerongen AV, Veerman ECI (2003). Current therapies for xerostomia and salivary gland hypofunction associated with cancer therapies. Support Care Cancer 11:226–231

 

1.1.1.   Clinical performance testing

Throughout the development effort of GenNarino, two multi-national clinical trials have been performed. The first was a controlled, short-term usage, double-blinded study performed in three leading medical centers in Europe. The study compared mechanical-electrical stimulation (i.e., stimulating with electrical pulses) vs. mechanical stimulation alone (i.e., no electrical stimulation), both delivered to the oral mucosa of dry mouth patients during 10 minutes. The study’s primary outcome, measured oral dryness and xerostomia symptoms changes as a result of device wearing were assessed, and compared between mechanical vs. mechanical-electrical modes.

Mechanical-electrical stimulation resulted in a significant decrease in oral dryness (as measured by the wetness sensors) with statistical significance of p<0.0001, leading to a beneficial effect on patients’ subjective condition. No significant side-effects were observed.

Three scientific articles reporting the short-term study results have been published in the literature in English language:

  • Fedele S et al. Neuro-electrostimulation in the treatment of hyposalivation and xerostomia in Sjögren’s syndrome: a salivary pacemaker. J Rheumatol 2008; 35(8): 1489-1494
  • Lafaurie G et al. Biotechnological advances in neuro-electro-stimulation for the treatment of hyposalivation and xerostomia. Med Oral Patol Oral Cir Bucal 2009;14(2):E76-80
  • Strietzel et al. Electrostimulating device in the management of xerostomia. Oral Diseases, 2007; 13: 206–213

 

A second, long-term randomized multi-national clinical trial was performed in 14 institutions in 13 countries, including the US and countries in Europe and the Americas. The use of GenNarino was compared among patients with xerostomia secondary to a variety of causes between mechanical stimulation vs. mechanical-electrical stimulation mode for one month each in a double-blind design (Stage I). Thereafter, at Stage II the xerostomia relieving effect of the mechanical-electrically stimulating (‘active’ device) was assessed in an open label design for additional 3 periods of 3 months each. Ninety six patients have finished Stage I, and 56 patients have completed Stage II. No severe or irreversible systemic or local adverse effects that could be unequivocally attributed to GenNarino usage were observed.

In Stage I, patient-reported degree of oral moisture improved 18% on mechanical mode and 26% (with statistical significance level of p<0.002) on mechanical-electrical mode. At the end of Stage II, the level of self-perceived oral moisture improved 34% (p<0.001), and the amount of collected saliva increased 70% (p<0.001). Among 6 out of 8 patients with no salivary flow at the start of the study, salivary flow could be detected on follow-up examinations.

A scientific article reporting the short-term study results has been published: Strietzel FP et al. Efficacy and Safety of an Intraoral Electrostimulation Device for Xerostomia Relief: A Multicenter Randomized Trial. Arthritis & Rheumatism, 2011; 63: 180–190. A second manuscript is been reviewed by another international scientific journal.

Conclusions drawn from the clinical tests provide reliable assurance of the safety and effectiveness of GenNarino.

1.1.2.   Comparison with previous studies on pilocarpine treatment

Over decades, a wide variety of agents and techniques have been used to manage patients with dry mouth complaints. In general, treatment is non-specific, with the same therapeutic agents being applied in all cases. Although there are many published clinical trials and proposed therapies, their experimental quality varies considerably. The most relevant studies to which the present trial can be compared are presented hereinafter.

Fox et al (1991)[1]: Comparison between Fox’s and the present study

  • Subjects: both include a mixed sample of xerostomia patients, 39 subjects in Fox’s study vs. 114 in the present one.
  • Duration: 5 months in Fox’s study vs. 11 months in the present one.
  • Data (including saliva) collection: at each visit, before and after drug intake in Fox’s study vs. one time collection independently from- but not less than 90 minutes after device wearing in the present trial. In both studies home questionnaires were given to the participants.
  • Drop-out: 21% in Fox’s study vs. 30% during the first 5 months of the present one.
  • Side effects: systemic side effects among 84% of the sample in Fox’s study vs. local (oral mucosal) side effects among upon 10% of the cases in the present study.
  • Subjective improvement: among 87% of the participants in Fox’s study vs. 70% in the present one (during the first 5 months).
  • Salivary output increase: among 67% patients, as measured immediately after drug intake in Fox’s study (but no improvement in the response rate during the trial) vs. among 63% subjects, as measured independently from device wearing in the present trial (during the first 5 months).

 

Vivino et al (1999)[2]: Comparison between Vivino’s and the present study

  • Subjects: 373 subjects suffering from SS and demonstrating residual saliva production in Vivino’s study vs. 114 mixed xerostomia patients with no requirements of a minimal saliva secretion in the present study.
  • Duration: 3 months in Vivino’s study vs. 11 months in the present one.
  • Data (including saliva) collection: at each visit, before and after drug intake in Vivino’s study vs. one time collection independently from- but not less than 90 minutes after device wearing in the present trial. In both studies home questionnaires were given to the participants.
  • Drop-out: 13% in Vivino’s study vs. 16% during first 2 months of the present study.
  • Side effects: systemic side effects among 43% of the sample in Vivino’s study vs. local (oral mucosal) side effects among upon 10% of the cases in the present study.
  • Subjective improvement: among 61% of the participants in Vivino’s study vs. 66% in the present one (during the first 2 months).
  • Salivary output increase: no improvement in pre-dose salivary flow (i.e. not related to drug intake) was observed in Vivino’s study vs. 11% increase from baseline in stimulated by chewing saliva collection in the present trial (during the first 2 months).

 

1.1.3.   Discussion

Xerostomia is a chronic and debilitating condition, which generally lasts the patient’s lifetime. It has considerable effect on the quality of life. Normal daily functions like mastication and oral manipulation of food becomes uncomfortable or even painful, which forces patients to adjust their way of life, type of food, drinking etc. Most patients need frequent sips of water while they eat and food ‘stuck’ in their mouth. They wake up more frequently at night due to the extreme dryness of their mouth, which leads to fatigue and impaired performance in daily activities. Difficulty with speech is another common complaint, seriously inhibiting social contacts. Simple activities such as telephone conversations or participation in meetings can become major ordeals for these patients. Furthermore, those patients suffer from increased risk of dental caries or oral infection.

Treatment of xerostomia and its complications is mainly symptomatic. In addition, evaluating effective remedies for dry mouth is a complex and challenging task. No gold standard measure of effectiveness in a xerostomic population currently exists. With large variations in salivary flow rates among those that complain of dry mouth, standard quantitative measures such as salivary flow rate may have less importance and relevance in judging the effectiveness of relief from xerostomia than the subjective self-perceived oral dryness/moisture. Sometimes the amount of saliva may be extremely small and not possible to be collected by standard collection methods. However, “little saliva is needed to overcome the feeling of oral dryness”, as stated by Dr. Leo Sreebny, one of the most prominent experts in xerostomia[3].

Therefore, as a measure of management of symptoms, salivary output may not be the most relevant factor because of the large variation in normal flow rates and the reduction in flow rate required for symptoms of xerostomia to occur. As xerostomia is the subjective feeling of dry mouth, the efficacy of treatment of xerostomia is best evaluated by questionnaires[4].

The results of this investigation demonstrate that GenNarino is both safe and effective. GenNarino appears to be safer than the approved medication (pilocarpine) to treat xerostomia, as the latter causes systemic side effects in a significant number of patients. As opposed to it, long-term use of GenNarino has resulted only in local, mild and transient side effects affecting the oral mucosa of a small number of subjects.

Daily use increased the amount of saliva secreted and improved the perception of oral dryness (i.e., severity and frequency of xerostomia) and discomfort and complications of xerostomia, such as speech, swallowing and sleeping difficulties.

The study shows a positive outcome of GenNarino use in the relief of xerostomia. A slight (though statistically significant) improvement in xerostomia was observed after one month of use of the mechanically stimulating GenNarino. However, the addition of electrical stimulation appeared to empower the stimulation effect, as appreciated in a more significant improvement of this and the other parameters.

The results show an accumulative positive effect of GenNarino over the period of the trial. There was a trend of upgrading of all the parameters from baseline throughout the study.

The improvement observed among patients who started the study with no collectable saliva is noticeable. From 6 out of 8 patients, saliva could be collected on follow-up examinations. It would be expected that a stimulatory device such as GenNarino would be only effective for those patients demonstrating some residual salivary gland function as expressed by the presence of collectable (i.e. expectorated) fluid. However, the absence of expectorated saliva does not necessarily mean that salivary glands’ function has ceased completely or that salivary glands are entirely destroyed. In fact, collectable saliva is restricted to the fluid that during expectoration does not remain attached as a coating layer to the oral mucosa. Thus, a plausible explanation is that GenNarino induces among some apparently 0 saliva secretors small increases in salivary secretion. This situation creates an “excess” of saliva beyond the amount needed to remain as a coating layer of the oral mucosal surfaces, and hence can be expectorated. Therefore, the mere absence of collectable saliva may not be sufficient to exclude a patient from the use of GenNarino (and probably also other salivary stimulants) as a therapeutic agent for xerostomia.

Normally, worsening in patients’ symptoms and clinical signs are expected without intervention, due to the progressive nature of xerostomia[5],[6],[7]. Patient’s symptoms on a given day may reflect not only the quantity of saliva but also the cumulative effect of chronic tissue dehydration. Therefore, it is reasonable to expect that improvement or reversal of symptoms after treatment would have a pattern of slow evolution. For this reason, it seems that a prolonged treatment course with GenNarino (e.g., at least 2 months) should be recommended to patients to allow sufficient time for symptomatic benefits to occur.

In summary, patients with xerostomia show a good response to treatment by the GenNarino device. GenNarino is beneficial and a safe solution for the alleviation of xerostomia symptom.

 

[1] Fox PC et al (1991). Pilocarpine treatment of salivary gland hypofunction and dry mouth (xerostomia). Arch Intern Med. 151(6):1149-1152

[2] Vivino FB (1999). Pilocarpine Tablets for the Treatment of Dry Mouth and Dry Eye Symptoms in Patients with Sjögren’s Syndrome. Arch Intern Med. 159:174-181

[3] Sreebny LM (1987), Xerostomia- A neglected symptom. Arch Intern Med. 147:1333-1337

[4] Murray Thomson W (2005). Issues in the epidemiological investigation of dry mouth. Gerodontology 22: 65–76

[5] Eveson JW (2008) Xerostomia. Periodontology 2000. 48:85–91

[6] Jellema AP et al (2207). Impact of radiation-induced xerostomia on quality of life after primary radiotherapy among patients with head and neck cancer. Int. J. Radiation Oncology Biol. Phys.  69( 3): 751–760 2007

[7] Moutsopoulos HM. Sjögren’s syndrome. In: Schumacher HR et al, eds. Primer of the Rheumatic Diseases. 10th ed. Atlanta, GA: Arthritis Foundation; 1993:131-135.

 

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