Does Lisinopril Change Your Taste And Smell
Br J Clin Pharmacol. 2004 Jun; 57(vi): 807–812.
Subclinical alteration of taste sensitivity induced by candesartan in salubrious subjects
Received 2003 Jun 17; Accepted 2003 Nov 27.
Abstract
Aims
There have been example reports of taste disturbance for the angiotensin II receptor blockers losartan and valsartan, but not for candesartan. This study was undertaken to examine whether candesartan causes gustatory modality disturbance.
Methods
Candesartan cilexetil (4 mg day−i) or vehicle was given to healthy volunteers (n = 8) for 7 days in a randomized, double-blind, placebo-controlled, cross-over design with a 2-calendar week washout period. Clinical gustometry using the filter-paper disc test and electrogustometry were sequentially performed before and at the end of each trial. Serum and salivary zinc concentrations were also measured.
Results
Detection thresholds of iv basic tastes (sweet, salty, sour and bitter) determined by the paper disc test were significantly (P < 0.05 in all tests) worsened (i.due east. score of test increased) after repeated dosing of the drug, although the subjects did not discover such changes. The mean ± SEM (and 95% CI) scores of the 4 tastes at just before the 7th dosing of candesartan or vehicle was iii.38 ± 0.32 (3.02, 3.74) and 2.63 ± 0.18 (2.18, 3.08) for sugariness, three.63 ± 0.38 (4.49, two.77) and ii.63 ± 0.26 (iii.27, 1.98) for table salt, 4.01 ± 0.42 (3.04, iv.98) and two.61 ± 0.32 (3.35, i.87) for sourness, four.01 ± 0.38 (iii.22, four.lxxx) and 2.99 ± 0.33 (2.24, iii.74) for bitterness, for candesartan and placebo, respectively. Electrogustometry confirmed the candesartan-related taste disturbance. Serum and salivary zinc concentrations were not influenced by candesartan.
Conclusions
These data suggest that candesartan subclinically reduces taste sensitivity after repeated dosing in salubrious subjects. Because similar events are reported for losartan and valsartan in instance reports, this agin outcome might be a form effect of angiotensin-II receptor blockers (ARBs).
Keywords: adverse reactions, angiotensin-II receptor blockers, dysgeusia, gustometry
Introduction
Taste disturbance is acquired by several endogenous and exogenous factors, about 20% of which are drug-related [1–iii]. Antihypertensive drugs have been identified equally potential causes of taste disturbance [two, 3]. L percent of patients with taste disturbance have low serum zinc concentrations and some antihypertensive drugs complex with or chelate zinc. Zinc metalloprotein is present in salivary fluid and is important in the maintenance of sense of taste cells.
Captopril, an ACE inhibitor, induces taste disturbance. The captopril molecule contains a thiol-group (–SH) and has been shown to form chelates with zinc [2–4]. Yet, other ACE inhibitors without the thiol-radical accept been reported to crusade taste disturbance. The ACE enzyme is a zinc-dependent enzyme. Because ACE inhibitors, even without thiol groups, need zinc for reaction, the inhibition of ACE by the drug may bear upon the zinc of the ACE protein in the salivary gland cells, and subsequently may modify gustatory modality.
Angiotensin-2 receptor blockers (ARBs) are relatively new merely widely used antihypertensive agents [5]. ARBs inhibit angiotensin Two-mediated effects and induce haemodynamic changes similar to ACE inhibitors. Moreover, sense of taste disturbance is also reported with the ARBs losartan and valsartan [6–9]. To our cognition, there accept been no case reports on candesartan cilexetil (candesartan), another ARB. Therefore, it is interesting to examine whether sense of taste disturbance is a class effect of ARBs. To address this issue, candesartan or placebo was given orally for vii days in a randomized, double-blind, cantankerous-over design to healthy subjects. Recognition thresholds for four bones tastes (sweet, salty, sour and biting) by filter paper disc test and detection threshold for electrogustometry were determined at the stop of each period.
Methods
Study design
Eight healthy men (29–46 years) were enrolled in this written report. All subjects gave written informed consent. They were not-smokers and did non receive any medications throughout the report. Before the initiation of the study, no otolaryngeal disorders were detected in these subjects. The study was of a randomized, double-blind, placebo-controlled, cross-over blueprint with a 2-week washout period. On day ane (observation period), the detection thresholds for tastes were adamant and salivary fluid was obtained at 09.00 h, 12.00 h, 15.00 h and 21.00 h. Subjects took candesartan cilexetil (Blopress®, Takeda Pharmaceutical Co. Ltd, Tokyo, Nippon, 4 mg, of pulverisation plus lactose, wrapped in a wafer) or placebo (100 mg of lactose, wrapped in a wafer) at 09.00 h for 7 days from solar day 2 to day viii. On solar day 8, an evaluation test and samplings of salivary fluid and blood were performed at 09.00 h, 12.00 h, xv.00 h and 21.00 h for the measurement of zinc and candesartan concentrations. On the day of the taste evaluations, subjects took their breakfast before 07.00 h. For lunch, a similar light meal (sandwich with milk) was served to all subjects only subsequently the evaluation at fifteen.00 h. Subjects were prohibited from taking whatsoever other nutrient or drink (except distilled water) until the finish of the written report at 21.00 h. After the washout menstruum, an identical protocol was repeated in a cross-over fashion (days 23–30). The protocol was canonical by the Ideals Committee of Jichi Medical School.
Samplings of saliva and blood
Spontaneously salivated salivary fluid was collected into a special polyethylene tube after gargling with distilled h2o three times. The plastic tubes were incubated with 1 m HCl for 30 min and washed with distilled water before employ to remove any metals. Blood samples were taken from the cubital vein and serum was transferred into the special tubes after centrifugation. Both salivary fluid and serum were stored at −80 °C until assayed.
Assay
Full zinc concentration was measured by atomic assimilation spectrophotometry [ten]. Salivary and serum concentrations of candesartan and 1000-II, an agile metabolite, were measured by high-operation liquid chromatography [11]. Detection limits for candesartan and K-Two were ane and two ng ml−i, respectively.
Evaluation for taste disturbance
Two types of gustometries were performed in each subject field.
1 Semi-quantitative clinical gustometry using a filter-paper disc
Semi-quantitative clinical gustometry using filter-newspaper discs (the filter-paper disc method; Taste disc®, Sanwa Chemic Laboratory, Nagoya, Japan) were performed. This semiquantitative method is routinely used for the evaluation of dysgeusia in the clinical setting [12–xiv]. In brief, recognition thresholds for iv bones tastes (sweet, salty, sour and bitter) were evaluated using the same chemical solutions (sucrose, NaCl, tartaric acrid and quinine, respectively). The solutions were sequentially diluted with distilled water into five grades. Concentration number 1 is the lowest and five is the highest (0.3, 2.5, x, 20 and lxxx% for sucrose, 0.3, ane.25, 5, ten and 20% for NaCl, 0.02, 0.2, 2, 4 and 8%, for tartaric acid, 0.001, 0.02, 0.1, 0.v and iv% for quinine). Subjects were asked to gargle with distilled water several times just before each exam. A small droplet of each solution was added to filter paper (8 mm diameter), which was placed on the left side of the tongue 2 cm from the tip (i.e. locus for left chorda tympani nerve) of the subjects for 1 s. The test was started from concentration number 1 and gradually increased. Subjects selected a unmarried reply from the following listing; sweet, salty, sour, bitter, unidentifiable taste, or no gustation. Thresholds for bones tastes were determined by their reply. The order of testing for the 4 basic tastes was randomly chosen. The test was performed past the same person (ST) throughout the study. Mean thresholds for normal volunteers were less than three [13, 15]. We have confirmed that the hateful changes among iii 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 (due north = 8). Thus, the reproducibility of the test was adequate.
2 Electrogustrometer
The electrogustometry routinely used for the evaluation of hypogeusia in the oto-rhino-laryngology clinic was performed according to the method of Tomita et al. [12, thirteen, 15] using commercially bachelor equipment (TR-06®, Rion Co., Ltd, Tokyo, Japan). In cursory, a single type stimulation rod was placed on the left side of the tongue 2 cm from the tip (i.east. locus for left chorda tympani nervus) and the electrical stimuli was pulsed from the lowest ability (−eight dB) and gradually increased. The smallest stimulus that the subjects noticed was regarded as the detection threshold. Normal range was less than + 14 dB [12, 13, 15]. The test was performed following the filter disc test after gargling with distilled water. The exam was performed by the aforementioned person (ST) throughout the study. We have previously confirmed that the mean change among three continuous examinations was + 0.8 ± 0.ii dB in healthy subjects (n = viii). Thus, the reproducibility of the test is acceptable.
Statistics
All data are expressed as the mean ± SEM. Statistical analysis was performed past analysis of variance. Fisher's Protected Least Significance Difference (PLSD) test was used every bit a posthoc exam. These analyses were performed using StatView five for Windows (SAS Institute Inc, NC). P < 0.05 was regarded as significant.
Results
All subjects completed the protocol without any complaints of taste disturbance. Hateful claret pressure 24 h earlier final dosing of the drug was not different betwixt candesartan and placebo (108.v ± 6.5 and 112.5 ± 4.2 mmHg, respectively, P = 0.08). Figure 1a–d shows the recognition thresholds for tastes using filter-newspaper disc. During the observation periods (day ane and day 23), the thresholds of iv tastes were inside the normal range in all subjects and did non differ significantly between day 1 and 24-hour interval 23. The detection thresholds of four unlike tastes were significantly (P < 0.05) worsened afterward the repeated treatment with candesartan, but not with placebo. Significant (P < 0.05) differences were observed at every observation betoken between the two trials. Hateful ± SEM (and 95% CI) scores of four tastes at 24 h after the 6th dosing (i.east. only before the last dosing) of candesartan or vehicle, respectively, were 3.38 ± 0.32 (iii.02, 3.74) and 2.63 ± 0.18 (2.xviii, three.08) for sweetness, three.63 ± 0.38 (4.49, 2.77) and 2.63 ± 0.26 (iii.27, 1.98) for saltiness, 4.01 ± 0.42 (3.04, 4.98) and 2.61 ± 0.32 (3.35, 1.87) for sourness, four.01 ± 0.38 (three.22, iv.80) and 2.99 ± 0.33 (2.24, 3.74) for bitterness, respectively. The mean (± SEM) changes of the scores for candesartan and placebo, respectively, were 0.81 ± 0.32 and −0.07 ± 0.21 for sweetness, 0.99 ± 0.39 and 0.07 ± 0.22 for saltiness, ane.35 ± 0.44 and 0.09 ± 0.27 for sourness, 1.02 ± 0.36 and −0.05 ± 0.28 for bitterness. Although the thresholds of sourness in three subjects and bitterness in four subjects were in the abnormal range (i.e. 5 units), the subjects did not notice these changes.
Detection thresholds for tastes using filter-paper disc after repeated dosing of candesartan. Four bones tastes (sugariness (a), salty (b), sour (c) and bitter (d)) were evaluated by using chemical solutions before (mean solar day 1 + twenty-four hours 23) and at the end of each treatment (twenty-four hour period viii + day thirty). Mean ± SEM, due north = 8. Candesartan: before (○), after (•); Placebo: before (□), after (▪)
Detection threshold using an electrogustometer is shown in Figure 2. Compared with the observation period, the threshold was significantly (P < 0.05) worsened later on repeated treatment with candesartan, but not with placebo. Still, all values remained within the normal range. Mean ± SEM (and 95% CI) scores of threshold at 24 h after the thirteenth dosing (i.e. just earlier the terminal dosing) of candesartan or vehicle were +2.75 ± 0.84 (4.72, 0.73) and −0.25 ± 1.28 (ii.02, −two.04), respectively.
Detection threshold using electrogustometer after repeated dosing of candesartan earlier (solar day 1 + twenty-four hours 23) and at the end of each treatment (mean solar day 8 + day 30). Mean ± SEM, n = viii. Candesartan: before (○), after (•); Placebo: before (□), subsequently (▪)
Salivary zinc concentration earlier (day 1, solar day 23) and at the terminate of repeated treatment (day 8, day 30) with candesartan and placebo are shown in Figures 3a and b. At that place were no significant differences in this parameter between the two trials. No significant differences were observed in serum zinc concentrations between the candesartan and placebo trials (Figure 4). Serum, but not salivary candesartan and M-Two were detected subsequently the final dosing of the drug (Figure v).
Salivary zinc concentration before (solar day 1 + twenty-four hours 23) and at the end (mean solar day 8 + twenty-four hours thirty) of the handling. Mean ± SEM, northward = 8. Candesartan: before (○), later on (•); Placebo: before (□), afterward (▪)
Serum zinc concentration at the cease of each treatment. Mean ± SEM, northward = 8. Candesartan (•), placebo (○)
Salivary and serum concentrations of candesartan and Chiliad-II afterward repeated dosing of the drug (4 mg, once daily for vii days). Hateful ± SEM, north = eight. Serum candesartan (•), serum Chiliad-II (○), salivary candesartan (□). Candesartan and Thousand-II were not detected in salivary fluid at any observation betoken
Discussion
The filter-paper disc test is semiquantitative, and the detection thresholds for tastes vary slightly amongst individuals [15]. To avoid such interindividual variation, this written report was performed using a randomized, double-blind, placebo-controlled, cross-over blueprint. Detection threshold was also determined past an electrogustometer.
Previous case reports have shown that the patients noticed a metallic taste or burning feeling on the natural language, and lost all 4 tastes during repeated treatment with losartan [6–viii]. Their taste disturbance disappeared within a few weeks after discontinuation of the drug. Nosotros evaluated the effect of candesartan on four basic tastes (sweetness, salty, sour and bitter) using filter-paper discs. Nosotros found that the drug caused subclinical disturbances for these tastes after repeated dosing in salubrious subjects. Candesartan-induced taste disturbance was besides detected by the electrogustometer. In particular, bitterness and sourness were worsened to a pathological level in virtually half the subjects, although they did not observe the disturbance. Based on these findings together with previous observations, we retrieve that gustation disturbance is not specific for losartan, simply is a class effect of ARBs.
Hypertensive patients noticed the taste disturbance afterwards repeated dosing of losartan and valsartan for 1 calendar week to 3 months [vi–9], which indicates that ARB-induced taste disturbance gradually developed. In addition, the present information suggest that this adverse event persisted for more 24 h after each dosing of candesartan during repeated treatment. However, the detection thresholds at the observation menstruation (day 1, 24-hour interval 23) of the candesartan and placebo trials did non differ significantly. This indicates that the candesartan-induced taste disturbance was reversible within 2 weeks after the discontinuation of the drug.
A diversity of drugs are reported to cause gustation disturbance, including thiamazol, d-penicillamine and captopril [16]. Taste disturbance induced by thiamazol and d-penicillamine has been ascribed to the complexing of zinc past these drugs [17] while captopril caused this agin effect by chelation of zinc [two–4]. Zinc-unrelated taste disturbances have too been reported [two, 3]. In this study, serum and salivary zinc concentrations were non influenced past the repeated dosing of candesartan. Thus, nosotros establish no testify that shows involvement of zinc in candesartan-induced sense of taste disturbance. In salivary fluid, both bound and unbound fractions of zinc were measured. Information technology is therefore uncertain whether the jump fraction of zinc with metalloprotein in the salivary fluid was inverse by the drug. Recent advances in molecular biology take identified receptors and ion channels on taste cells. Sweet and bitter taste receptors are the proteins that couple with Thousand-proteins [18, nineteen]. Coupling and uncoupling to K-protein causes 'taste-on' and 'gustatory modality-off' [ii]. The taste receptors have vii transmembrane domains [18, 19]. Angiotenisin 2 receptor, which is the target molecule of ARB, likewise belongs to the aforementioned category of receptor [xx]. It is possible that ARBs are secreted in salivary fluid, which in plow, bind with taste receptors and consequently disturb the sense of sweet and bitter tastes. On the other hand, salt and sour tastes are elicited by ion channels (salt; amiloride-sensitive epithelial Na channel, sour; amiloride-sensitive epithelial Na channels and H+-activated cation channels [eighteen, 19]. In this instance, salivary ARBs might plug these channels and disturb common salt and sour tastes. Although salivary candesartan and its metabolite were not detected in this study, the higher up-mentioned hypothesis remains to be determined.
In summary, this written report shows that repeated dosing with candesartan subclinically reduces the sensitivity of basic tastes. The effect was reversible after discontinuation of the drug within 2 weeks. Because like events are reported for losartan and valsartan in the clinical setting, taste disturbance might be a class effect of ARBs. Similar events are reported for ACE-I with unknown mechanisms except for captopril. Further studies are needed to determine the frequency and grade of taste disturbance for each ARB.
Acknowledgments
Nosotros give thanks Takeda Pharmaceutical Co, Ltd, for measurement of candesartan and M-II concentrations. Part of this study was supported by a grant from the Ministry building of Health, Welfare and Labor of Japan and the Renal Osteodystrophy Foundation.
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Does Lisinopril Change Your Taste And Smell,
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