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Comparative Study of Taste Disturbance by Losartan and Perindopril in Healthy Volunteers

From the Department of Pharmacology, Division of Clinical Pharmacology, Jichi Medical School, Tochigi, Japan.

Address for reprints: Shuichi Tsuruoka, MD, Department of Pharmacology, Division of Clinical Pharmacology, Jichi Medical School, 3311 Yakushiji, Minamikawachi, Kawachi, Tochigi 329-0498, Japan; e-mail: tsuru{at}jichi.ac.jp.

	ABSTRACT

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The aim of this study was to compare the degree of taste disturbance by losartan, an angiotensin II receptor blocker, with that of perindopril, an angiotensin-converting enzyme inhibitor. Perindopril erbumine (2 mg), losartan potassium (25 mg), or vehicle was given to Japanese volunteers (n = 7) for 14 days in a randomized, placebo-controlled, 3-way crossover design with a 14-day washout period. Gustometry by filter-paper test and electrogustometry were performed before and at the end of each trial. Plasma renin activity (PRA) and serum and salivary zinc concentrations were measured. One subject dropped out because of a perindopril-induced dry cough, but no one claimed a taste disturbance. Detection thresholds of 4 basic tastes (sweet, salty, sour, and bitter) by the paper-disc test and electrogustometry were significantly worsened, and plasma renin activity was elevated by the drugs, whereas the deteriorating effects of 2 drugs did not significantly differ. These drugs did not affect zinc concentrations in plasma and saliva. It was concluded that losartan and perindopril similarly alter taste sensitivity during repeated dosing of the drugs.

Key Words: Dysgeusia • angiotensin-converting enzyme inhibitor • angiotensin II receptor blockers • adverse drug reactions • gustometry

Recently, the effectiveness of coadministration of both ARB and ACE was reported in some clinical situations.⁷ The opportunity to prescribe both drugs at the same time may increase in the future. However, it remains uncertain whether quantity and quality of the taste disturbance by ARBs and ACE inhibitors are similar. In this study, we directly compared the effect of the repeated oral dosing of losartan, an ARB, and an ACE inhibitor, perindopril, on taste sensitivity by a randomized, double-blind, placebo-controlled crossover study in healthy volunteers.

	METHODS

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Study Design
Seven healthy Japanese men (29-46 years) were enrolled in this study. Women, smokers, and subjects younger than age 20 or older than age 50 years were excluded. Demographic characteristics of the subjects are listed in Table I. All subjects gave written informed consent. A randomized, double-blind, placebo-controlled, 3-way crossover design with a washout period of 2 weeks was used in this study.⁶ In brief, detection thresholds for tastes were determined and salivary fluid was obtained on day 1 (observation period) at 0800, 1100, 1400, and 2000 hours. Subjects took perindopril erbumine (2 mg of powder plus 98 mg of lactose, wrapped in a wafer), losartan potassium (25 mg of powder plus 75 mg of lactose, wrapped in a wafer), or placebo (100 mg of lactose, wrapped in a wafer) at 0800 hours from days 2 to 15. We have found that these doses do not affect blood pressure after repeated administration in normotensive subjects. On day 15, an evaluation test and samplings of salivary fluid and blood were performed at the same time. On the day of taste evaluation, subjects did not have breakfast, but a similar light meal was served just after the evaluation at 1400 hours. They were prohibited to eat any other food or drink anything except distilled water until the end of the test. After the washout period, an identical protocol was repeated in a cross-over fashion. All protocols were approved by the Ethical Committee of Jichi Medical School.

Samplings of Saliva and Blood
Spontaneously salivated salivary fluid was collected after gargling.⁶ Serum was transferred into special tubes after centrifugation.⁶ All samples were stored at –80°C until the assay. Zinc concentration was measured by atomic absorption spectrophotometry.⁸ Plasma renin activity (PRA) was measured by radioimmunoassay.⁹

Evaluation for Taste Disturbance⁶
Semi-Quantitative Clinical Gustometry Using Filter-Paper Disc
Semi-quantitative clinical gustometry using filter-paper discs (Taste Disc, Sanwa Chemical Laboratory, Japan), which is routinely used in clinical settings,^6,10 was performed. In brief, detection thresholds for 4 basic tastes (sweet, salty, sour, and bitter) were evaluated by using the same chemical solutions (sucrose, NaCl, tartaric acid, and quinine, respectively) that were sequentially diluted with distilled water into 5 grades. Concentration number 1 is the lowest, and 5 is the highest (0.3%, 2.5%, 10%, 20%, and 80% for sucrose; 0.3%, 1.25%, 5%, 10%, and 20% for NaCl; 0.02%, 0.2%, 2%, 4%, and 8% for tartaric acid; and 0.001%, 0.02%, 0.1%, 0.5%, and 4% for quinine). Subjects were asked to gargle with distilled water several times just before each test. A small droplet of each solution was added to filter paper (8 mm diameter), which was placed 2 cm on the left side from the tip of the tongue (ie, locus for left chorda tympani nerve) for a second. The test was started from concentration number 1 and gradually increased. The thresholds were determined by the subjects' answers. The order of the test for 4 basic tastes was randomly chosen. Mean thresholds for normal volunteers were less than 3.¹⁰ The test was performed by the same person (S.T.) throughout the study. We have confirmed that the mean changes among 3 continuous examinations were –0.17 ± 0.05, –0.22 ± 0.07, –0.14 ± 0.05, and –0.19 ± 0.05 for sweet, salty, sour, and bitter, respectively, in healthy subjects (n = 8).⁶ Thus, we think that the reproducibility of the test was extremely acceptable.

Electrogustometer
The electrogustometry was performed by commercially available equipment (TR-06, Rion Co, Ltd, Tokyo, Japan) as previously described.^6,10 In brief, a single-type stimulation rod was placed on the tongue, as done in the filter-paper disc test, and the electrical stimuli were pulsed from the lowest power (–8 dB) and gradually increased. The smallest stimulus that the subjects noticed was regarded as the threshold. Normal range was less than +14 dB.¹⁰ The test was performed following the filter disc test after gargling with distilled water. The test was performed by the same person (S.T.) throughout the study. We have confirmed that the mean change among 3 continuous examinations was +0.8 ± 0.2 dB in healthy subjects (n = 8).⁶ Thus, we think that the reproducibility of the test was extremely acceptable.

Statistics
All data were expressed with mean ± SE. Statistical analysis was performed by analysis of variance. Fisher's protected least significant difference (PLSD) test was used as a post hoc test. P < .05 was regarded as significant.

	RESULTS

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Six subjects completed the protocols, whereas 1 subject dropped out because of a perindopril-induced dry cough. No subject recognized a taste disturbance during the trial. Mean blood pressure just before final dosing was not different among the 3 trials (108 ± 4, 110 ± 5, and 111 ± 5 mm Hg for losartan, perindopril, and placebo, respectively). The recognition threshold of sweetness at the end of the repeated treatment was significantly worse after treatment with the 2 drugs, whereas the increment of the score was not significantly different between the drugs (Figure 1A). The detection thresholds of the other 3 tastes were also significantly (P < .05) worse after repeated treatment with losartan or perindopril but not after placebo (Figure 1B-D). The difference in area under the time-score curve (determined by the trapezoidal method) between drug and placebo is shown in Table II. The decrements of parameters were not different between the 2 drugs. The thresholds of the tastes just before each treatment were not different between the 3 groups (data not shown).

View larger version (18K): [in this window] [in a new window]   Figure 1. Detection thresholds for tastes using the filter-paper disc after repeated dosing of losartan, perindopril, and placebo. Four basic tastes—sweet (A), salty (B), sour (C), and bitter (D)—were evaluated by using chemical solutions before and at the end of each treatment. A similar test was performed just before each protocol, which confirmed that the disturbances completely disappeared after the washout period (data not shown). Mean ± SE, n = 6. Losartan, open circles; perindopril, open squares; placebo, solid circles.

The detection threshold at the end of each trial using an electrogustometer was also worse after losartan or perindopril to the same extent but not after placebo (Figure 2). Differences in area under the time-score curve between the drugs and placebo are shown in Table II. The thresholds before each trial were not significantly different among the 3 groups (data not shown).

View larger version (12K): [in this window] [in a new window]   Figure 2. Detection threshold using the electrogustometer after repeated dosing of losartan, perindopril, and placebo. A similar test was performed just before each protocol, which confirmed that the disturbances completely disappeared after the washout period (data not shown). Mean ± SE, n = 6. Losartan, open circles; perindopril, open squares; placebo, filled circles.

Salivary and serum zinc concentrations and plasma renin activity at the end of the repeated treatment were measured (Figures 3A,B and 4). Differences in area under the time-concentration curve (determined by the trapezoidal method) between drugs and placebo are shown in Table II. Serum zinc concentration at 12 hours after final dosing was significantly lower than other points in each trial (Figure 3B). Plasma renin activity at the end of the repeated treatment was significantly higher in the trial with losartan and perindopril than with placebo (Figure 4). However, no significant differences between the drug-treated groups were observed in these parameters.

View larger version (13K): [in this window] [in a new window]   Figure 3. Salivary (A) and serum (B) zinc concentrations before and after repeated dosing of losartan, perindopril, and placebo. Mean ± SE, n = 6. Losartan, open circles; perindopril, open squares; placebo, filled circles.

View larger version (13K): [in this window] [in a new window]   Figure 4. Plasma renin activity at the end of each treatment. Mean ± SE, n = 6. Losartan, open circles; perindopril, open squares; placebo, filled circles.

	DISCUSSION

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Another important issue in this study is that we directly compared the effect of losartan, an ARB, and perindopril, an ACE inhibitor, on taste sensitivity in healthy subjects with a crossover study and determined their effects. We found that the taste disturbance by the 2 drugs at the dosages used was similar in quality and quantity. It was recently reported that coadministration of ARB and ACE inhibitors has beneficial effects on the preservation of renal function in patients with chronic renal insufficiency.⁷ This study indicates that coadministration of ARB and ACE inhibitors might additively worsen taste. Careful monitoring is needed in this clinical situation.

The mechanisms of the taste disturbances by these drugs remain uncertain. These drugs similarly increased plasma renin activity but did not affect serum and salivary zinc concentrations. Thus, alteration of the renin-angiotensin-system might directly or indirectly affect the taste sensation system. Perindopril causes taste disturbance and possesses strong tissue ACE affinity among ACE inhibitors.¹³ In addition, other ACE inhibitors that possess less affinity to tissue ACE are reported to cause taste disturbances in clinical practice.^1-3 These observations indicate that taste disturbance does not depend on tissue ACE activity. Further studies are needed to evaluate the mechanisms.

The number of subjects who participated in this study was small, which is a major limitation. We could detect the subclinical taste disturbance by the drug in this small population; therefore, the number of patients who have similar subclinical disorders must be very large in the clinical situation. If hypertensive patients with slight taste disturbance receive these drugs, the drug-induced taste disturbance might be clinically obvious.

In this study, drug-induced taste disturbances seemed to be larger for "bitterness" and "sourness" than "salt" and "sweetness." Recent advances in molecular biology have identified some receptors and ion channels on taste cells. Sweet and bitter tastes are mediated by large families of taste receptors, which are G-protein-coupled proteins with 7 transmembrane domains.^14,15 On the other hand, salt and sour tastes are elicited by some ion channels (salt, amiloride-sensitive epithelial Na channel; sour, amiloride-sensitive epithelial Na channels and H⁺-activated cation channels).^14,15 Our results indicate that deteriorating effects of perindopril and losartan on taste depend on these receptors/channels. Further studies with a larger number of subjects are needed to evaluate the precise mechanisms.

In conclusion, we compared the effect of losartan and perindopril on taste in healthy Japanese male volunteers. Both drugs subclinically worsened taste to a similar extent in quality and quantity. Careful monitoring is necessary, especially in the case of coadministration.

DOI: 10.1177/0091270005280445

	REFERENCES

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10. Tomita H, Ikeda M, Okuda Y. Basis and practice of clinical taste examinations. Auris Nasus Larynx. 1986;13(suppl 1): S1-S15.

11. Lees KR, Reid JL. Haemodynamic and humoral effects of oral perindopril, an angiotensin converting enzyme inhibitor, in man. Br J Clin Pharmacol. 1987;23: 159-164.[Web of Science][Medline] [Order article via Infotrieve]

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Request Reprints Citing Articles Citing Articles via ISI Web of Science (3) Citing Articles via Google Scholar Google Scholar Articles by Tsuruoka, S. Articles by Fujimura, A. Search for Related Content PubMed PubMed Citation Articles by Tsuruoka, S. Articles by Fujimura, A. Social Bookmarking                   What's this?