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RESEARCH REPORT |
1 School of Dental Medicine, University of Erlangen-Nuremberg, Glückstr. 11, 91054 Erlangen, Germany;
2 Dept. of Dental Public Health Sciences, School of Dentistry, University of Washington, Seattle, USA;
3 Dept. of Pharmacy, Pharmaceutical Technology and Biopharmaceutics, Ludwig-Maximilians-University, Munich, Germany;
4 Dept. of Neurology, University of Erlangen-Nuremberg, Germany; and
5 Smell & Taste Clinic, Dept. of Otorhinolaryngology, University of Dresden, Germany;
* corresponding author, siegfried.heckmann{at}rzmail.uni-erlangen.de
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS & METHODSRESULTSDISCUSSIONREFERENCES |
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KEY WORDS: dysgeusia • gustatory function • mood • zinc therapy
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS & METHODSRESULTSDISCUSSIONREFERENCES |
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MATERIALS & METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS & METHODSRESULTSDISCUSSIONREFERENCES |
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Blinding and Randomization
Before patient recruitment, blinding and randomization were performed by an independent individual using a special computer software program (RANDOM by Joern Loetsch, Institute of Clinical Pharmacology, University of Frankfurt, Germany). To this end, enrollment numbers were established, and the subjects to be investigated were randomized by being grouped. Each group was made up of four patients, i.e., two were assigned zinc, and two were assigned placebo.
Screw-top bottles were prepared containing either 100 zinc gluconate tablets (140 mg, "Zink Verla"®) or 100 placebo tablets (lactose, "Placebo Lichtenstein 10 mm"). The bottles were sealed and labeled with the study code and the enrollment number. After the initial investigation for the baseline data, each patient was given an enrollment number and the corresponding screw-top bottle. The zinc and placebo showed no significant difference in taste. Neither patient nor investigator had any knowledge during the study as to whether the patient was being treated with zinc or placebo. When the study was complete, this information was then revealed by the independent individual.
Treatment
Zinc gluconate (140 mg/day, equivalent to 20 mg/day of elemental zinc; cf. Henkin et al., 1999) and placebo were given to the patients, with 26 subjects receiving zinc (five men, 21 women; mean age, 61.1 yrs; age range, 41–82 yrs) and 24 subjects receiving placebo (two men, 22 women; mean age, 61.0 yrs; age range, 47–78 yrs). Patients were advised to swallow the drug whole on an empty stomach with ample water. The therapy lasted for 3 mos.
Primary and Secondary Endpoints
The two primary endpoints were the scores of the taste test and self-rated dysgeusia. Gustatory sensitivity was assessed by means of the taste test. To this end, filter paper strips impregnated with 4 different concentrations of 4 taste qualities were placed on the left and right sides of the anterior third of the patient’s tongue, resulting in a total number of 32 paper strips (Müller et al., 2003).
Before each administration of a taste strip, the patient’s mouth was rinsed with water. The taste strips were presented in increasing concentrations. Taste qualities were applied in a randomized fashion at each of the 4 levels of concentration. With the tongue still extended, the subject was asked to identify the taste from a list with the 4 descriptors—i.e., sweet, sour, salty, bitter—and the respective 4 concentrations (sweet = 0.4, 0.2, 0.1, 0.05 g/mL sucrose; sour = 0.3, 0.165, 0.09, 0.05 g/mL citric acid; salty = 0.25, 0.1, 0.04, 0.016 g/mL NaCl; bitter = 0.006, 0.0024, 0.0009, 0.0004 g/mL quinine-hydrochloride). The correlation coefficient for test and re-test in healthy subjects was 0.68 (Müller et al., 2003).
The self-rated impairment due to dysgeusia was recorded by means of a visual analogue scale (10-cm length is equivalent to 100%; no impairment = 0 units; extremely impaired = 10 units).
Secondary endpoints were the results of psychological tests related to depression (Beck Depression Inventory, BDI; Beck et al., 1961) and mood (von Zersen mood scale, ZMS; Heimann et al., 1975). In addition, the levels of zinc, sodium, calcium, potassium, and chloride in both the serum and saliva were analyzed. All measurements were taken before and after therapy.
Based on our clinical experience (Müller et al., 2003), an improvement by 6 points in the taste test can be regarded as substantial, which typically also corresponds to the subjective feeling of an improved sense of taste.
Statistical Analysis
The results were evaluated with the use of SPSS 11 for WindowsTM. For the primary endpoints, an analysis of variance for repeated measurements was performed with the two within-subject factors ‘session’ (before, after therapy) and ‘test’ (taste test, self-rated dysgeusia), and the between-subject factor ‘treatment’ (zinc, placebo). Group comparisons were also performed with t tests for independent samples. For reasons of normalization, differences between the data obtained before and those obtained after therapy were computed. In addition, correlations (Pearson) were calculated between the variables of interest. The alpha level was set at 0.05.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS & METHODSRESULTSDISCUSSIONREFERENCES |
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When the secondary endpoints were reviewed, signs of depression or lowered mood were found to have improved in the zinc group (BDI score, t = 2.60, p = 0.012; ZMS, t = 2.13, p = 0.039). No significant group differences were seen for the other parameters investigated, with the exception of the salivary calcium level, which was higher in zinc patients than in controls (t = 2.18, p = 0.034). Interestingly, treatment with zinc had no significant effect on levels of zinc measured in serum (t = 0.83, p = 0.41) or saliva (t = 0.46, p = 0.65).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS & METHODSRESULTSDISCUSSIONREFERENCES |
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Treatment with zinc in cases of dysgeusia is frequently recommended (Heyneman, 1996), although the results of published studies are equivocal. Reasons for these discrepancies are, among other things, the small sample size, the open trial design, inhomogeneous patient diagnosis involving patients with smell disorder or symptomatic dysgeusia, and the inclusion of zinc-deficient patients (Schechter et al., 1972; Henkin et al., 1976, 1999; Stoll and Oepen, 1994; Sakai et al., 2002). To prevent bias and to ensure that the groups of patients studied were homogeneous, we enrolled only patients with idiopathic dysgeusia and, hence, a normal serum zinc level.
In the study at hand, there was a striking gender imbalance, with more females than males suffering from dysgeusia. This is consistent with the clinical experience of our unit for the care of patients with orofacial diseases (Heckmann et al., 2001). It has been suggested that, among other things, hormonal changes may be responsible for the initiation of this symptom (Levenson, 2002).
No significant increase in serum zinc was found in the zinc group. This may be due to the fact that zinc is a trace element and is rapidly transferred into the cells. Zinc is of particular significance, especially in cells with a high-rate turnover, such as cells of the taste buds (Henkin, 1994; Umeta et al., 2000). Thus, for the zinc dosage used, the insignificant change in serum zinc can be explained.
No side-effects were reported in the present study. At higher dosages, however, several side-effects can occur, such as gastrointestinal or hematological disorders—e.g., anemia, leukopenia, and neutropenia (Salzman et al., 2002)—and zinc intoxication can occur in cases of extreme dosage (Chobanian, 1981).
The presence of elevated salivary calcium in the zinc-treated patients is difficult to interpret. Our speculations center on an increased calcium secretion due to the influence of zinc. In previous studies, a salivary calcium-zinc exchange was observed, whereby the absorption of zinc led to a release of calcium (Ingram et al., 1992).
Several basic scientific studies indicate that zinc is an extremely important factor in gustation. For example, zinc appears to be of significance for the regeneration of taste bud cells (Henkin et al., 1999). Zinc also seems to be crucial in the regulation of metalloprotein expression and, in turn, for the synthesis of growth hormones. Finally, zinc is assumed to influence the activity of carbonic anhydrase VI, and thus, the level of gustin, an important metalloprotein which has been reported to act as a growth factor for taste bud cells (Henkin et al., 1988). However, since the exact role that zinc plays in gustation is not fully understood, further research is necessary to explore the molecular and biological mechanisms underlying the effects of zinc on taste (Seiden, 1997). Nevertheless, from an empirical point of view, analysis of the current data suggests that treatment with zinc is helpful in treating patients with idiopathic dysgeusia.
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ACKNOWLEDGMENTS |
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Received October 1, 2003; Last revision October 4, 2004; Accepted November 1, 2004
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REFERENCES |
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