Drug-induced Taste Disorders Research Articles

Cellular mechanisms of taste disturbance induced by the non-steroidal anti-inflammatory drug, diclofenac, in mice.

Drug-induced taste disorders are a serious problem in an aging society. This study investigated the mechanisms underlying taste disturbances induced by diclofenac, a non-steroidal anti-inflammatory drug that reduces pain and inflammation by inhibiting the synthesis of prostaglandins by cyclooxygenase enzymes (COX-1 and COX-2). RT-PCR analyses demonstrated the expression of genes encoding arachidonic acid pathway components such as COX-1, COX-2 and prostaglandin synthases in a subset of mouse taste bud cells. Double-staining immunohistochemistry revealed that COX-1 and cytosolic prostaglandin E synthase (cPGES) were co-expressed with taste receptor type-1 member-3 (T1R3), a sweet/umami receptor component, or gustducin, a bitter/sweet/umami-related G protein, in a subset of taste bud cells. Long-term administration of diclofenac reduced the expression of genes encoding COX-1, gustducin and cPGES in mouse taste buds and suppressed both the behavioral and taste nerve responses to sweet and umami taste stimuli but not to other tastants. Furthermore, diclofenac also suppressed the responses of both mouse and human sweet taste receptors (T1R2/T1R3, expressed in HEK293 cells) to sweet taste stimuli. These results suggest that diclofenac may suppress the activation of sweet and umami taste cells acutely via a direct action on T1R2/T1R3 and chronically via inhibition of the COX/prostaglandin synthase pathway inducing down-regulated expression of sweet/umami responsive components. This dual inhibition mechanism may underlie diclofenac-induced taste alterations in humans.

The Antiarrhythmic Drug Flecainide Enhances Aversion to HCl in Mice.

Drug-induced taste disorders reduce quality of life, but little is known about the molecular mechanisms by which drugs induce taste disturbances. In this study, we investigated the short-term and long-term effects of the antiarrhythmic drug flecainide, which is known to cause taste dysfunction. Analyses of behavioral responses (licking tests) revealed that mice given a single intraperitoneal injection of flecainide exhibited a significant reduction in preference for a sour tastant (HCl) but not for other taste solutions (NaCl, quinine, sucrose, KCl and monopotassium glutamate) when compared with controls. Mice administered a single dose of flecainide also had significantly higher taste nerve responses to HCl but not to other taste solutions. Compared with controls, mice administered flecainide once-daily for 30 d showed a reduced preference for HCl without any changes in the behavioral responses to other taste solutions. The electrophysiological experiments using HEK293T cells transiently expressing otopetrin-1 (Otop1; the mouse sour taste receptor) showed that flecainide did not alter the responses to HCl. Taken together, our results suggest that flecainide specifically enhances the response to HCl in mice during short-term and long-term administration. Although further studies will be needed to elucidate the molecular mechanisms, these findings provide new insights into the pathophysiology of drug-induced taste disorders.

Bisphosphonate affects the behavioral responses to HCl by disrupting farnesyl diphosphate synthase in mouse taste bud and tongue epithelial cells.

Little is known about the molecular mechanisms underlying drug-induced taste disorders, which can cause malnutrition and reduce quality of life. One of taste disorders is known adverse effects of bisphosphonates, which are administered as anti-osteoporotic drugs. Therefore, the present study evaluated the effects of risedronate (a bisphosphonate) on taste bud cells. Expression analyses revealed that farnesyl diphosphate synthase (FDPS, a key enzyme in the mevalonate pathway) was present in a subset of mouse taste bud and tongue epithelial cells, especially type III sour-sensitive taste cells. Other mevalonate pathway-associated molecules were also detected in mouse taste buds. Behavioral analyses revealed that mice administered risedronate exhibited a significantly enhanced aversion to HCl but not for other basic taste solutions, whereas the taste nerve responses were not affected by risedronate. Additionally, the taste buds of mice administered risedronate exhibited significantly lower mRNA expression of desmoglein-2, an integral component of desmosomes. Taken together, these findings suggest that risedronate may interact directly with FDPS to inhibit the mevalonate pathway in taste bud and tongue epithelial cells, thereby affecting the expression of desmoglein-2 related with epithelial barrier function, which may lead to alterations in behavioral responses to HCl via somatosensory nerves.

Evaluation of antibiotic-induced taste and smell disorders using the FDA adverse event reporting system database

Adverse effects can occur owing to anorexia, which can reduce treatment compliance and worsen the patients overall condition. One such side effect, namely drug-induced taste and smell disorders, reduces patients quality of life. Although antibiotics can cause taste and smell disorders, a few studies have examined antibiotic-induced taste and smell disorders. Therefore, this study comprehensively analyzed the relationship between taste and smell disorders and antibiotic usage. The side effects of antibiotics were investigated using the FDA Adverse Event Reporting System database (FAERS). The reporting odds ratios between the listed drugs and taste and smell disorders P values were comprehensively calculated. Adjusted odds ratios were calculated to account for patient background. Furthermore, to clarify the feature of this adverse effect, shape parameters indicating the expression pattern were calculated. Signals that induced taste and smell disorders were detected for six antibiotics, including drugs for which this event is not described in the package insert in Japan. Multiple logistic regression analysis suggested an association of taste and smell disorders with gender, hypertension, mental disorder, and cancer. The median time to onset of antibiotic-induced taste and smell disorders was 2–5 days. Six antibiotics could be analyzed, and four of these drugs matched those with detected signals. Our study supported previous findings on gender and age. Furthermore, antibiotic-induced taste and smell disorders are likely to develop in the early stage of treatment. For these reasons, it is important to remember the risk of developing of taste and smell disorders when administering antibiotics. In addition, it is recommended that the patient be monitored carefully for at least 1 week before initiating treatment, and the patients course should be followed for at least 2 months.

Drinking Ice-Cold Water Reduces the Severity of Anticancer Drug-Induced Taste Dysfunction in Mice.

Taste disorders are common adverse effects of cancer chemotherapy that can reduce quality of life and impair nutritional status. However, the molecular mechanisms underlying chemotherapy-induced taste disorders remain largely unknown. Furthermore, there are no effective preventive measures for chemotherapy-induced taste disorders. We investigated the effects of a combination of three anticancer drugs (TPF: docetaxel, cisplatin and 5-fluorouracil) on the structure and function of mouse taste tissues and examined whether the drinking of ice-cold water after TPF administration would attenuate these effects. TPF administration significantly increased the number of cells expressing apoptotic and proliferative markers. Furthermore, TPF administration significantly reduced the number of cells expressing taste cell markers and the magnitudes of the responses of taste nerves to tastants. The above results suggest that anticancer drug-induced taste dysfunction may be due to a reduction in the number of taste cells expressing taste-related molecules. The suppressive effects of TPF on taste cell marker expression and taste perception were reduced by the drinking of ice-cold water. We speculate that oral cryotherapy with an ice cube might be useful for prophylaxis against anticancer drug-induced taste disorders in humans.

Oral adverse effects of drugs: Taste disorders.

ObjectiveOral healthcare professionals are frequently confronted with patients using drugs on a daily basis. These drugs can cause taste disorders as adverse effect. The literature that discusses drug‐induced taste disorders is fragmented. This article aims to support oral healthcare professionals in their decision making whether a taste disorder can be due to use of drugs by providing a comprehensive overview of drugs with taste disorders as an adverse effect.Materials and methodsThe national drug information database for Dutch pharmacists, based on scientific drug information, guidelines, and summaries of product characteristics, was analyzed for drug‐induced taste disorders. “MedDRA classification” and “Anatomic Therapeutical Chemical codes” were used to categorize the results.ResultsOf the 1,645 drugs registered in the database, 282 (17%) were documented with “dysgeusia” and 61 (3.7%) with “hypogeusia.” Drug‐induced taste disorders are reported in all drug categories, but predominantly in “antineoplastic and immunomodulating agents,” “antiinfectives for systemic use,” and “nervous system.” In ~45%, “dry mouth” coincided as adverse effect with taste disorders.ConclusionHealthcare professionals are frequently confronted with drugs reported to cause taste disorders. This article provides an overview of these drugs to support clinicians in their awareness, diagnosis, and treatment of drug‐induced taste disorders.

From the Cover: Drug-Induced Taste Disorders in Clinical Practice and Preclinical Safety Evaluation.

More than 200 medications can induce taste disorders in patients. They not only reduce quality of life for those affected, but can lead to malnutrition, severe dehydration and difficulty in maintaining a therapeutic regimen. Nevertheless, the impact of drug candidates on taste is rarely evaluated in preclinical toxicology studies during the early stage of drug development. Moreover, knowledge about how to investigate these adverse effects is scarce in the toxicology field. Here, we discuss the clinical status of drug-induced taste disorders in patients, with the goal of providing toxicologists with a broad understanding of its prevalence, and how stressful and even dangerous it can be to affected patients. Because taste, smell, and oral trigeminal sensation are highly interdependent, we also address drug-induced changes in olfactory and oral somatosensory perceptions. We then review the biology of the gustatory system (including anatomy and histology), and the latest developments about how taste contributes to flavor perception. Finally, we feature recently optimized preclinical approaches to investigate drug-induced taste change in animal models, including morphological evaluation of taste buds and taste cells, gustatory nerve recording, and behavioral testing. Our goals are to raise awareness of drug-induced taste disorders among toxicologists, share an overview of new approaches and key studies that can be used to identify drug-induced gustatory system toxicity early in the drug development process, and to stimulate further research at this emerging interface of chemosensory disorders with toxicology.

P-407: Drug-induced taste disorders: prescribing analysis in French nursing homes

P-407: Drug-induced taste disorders: prescribing analysis in French nursing homes

Impact of Taste Sensitivity on Lifestyle-related Diseases

Individual taste sensitivity affects one's eating habits, and could thus play a role in the development of lifestyle-related diseases, such as obesity, hypertension and dyslipidemia. However, only a handful of studies have been conducted to investigate these associations. Therefore, we performed taste sensitivity tests on approximately 250 patients with lifestyle-related diseases who were undergoing outpatient treatment at the Department of Internal Medicine, or received a health check-up in order to examine the associations of individual taste sensitivity with their eating habits and lifestyle-related diseases. Our findings showed that sensitivity to sweet or salt taste was significantly lower in patients with cardiovascular diseases, and sensitivity to umami taste was significantly lower in obese patients. These findings suggest that taste sensitivity disorders may be linked not only to eating habits and lifestyle-related diseases, but also to the onset of cardiovascular diseases. Many of the drugs used in the treatment of lifestyle-related diseases and cardiovascular diseases, including antihypertensive agents, statins, fibrates, and allopurinol, are known to form zinc chelates and thereby possibly cause drug-induced taste disorders. Focusing on individual taste sensitivity to improve or maintain intake levels may become a new target for drug development in the areas of lifestyle-related and cardiovascular diseases.

Taste of a Pill

Drug-induced taste disturbance is a common adverse drug reaction often triggered by drug secretion into saliva. Very little is known regarding the molecular mechanisms underlying salivary gland transport of xenobiotics, and most drugs are assumed to enter saliva by passive diffusion. In this study, we demonstrate that salivary glands selectively and highly express OCT3 (organic cation transporter-3), a polyspecific drug transporter in the solute carrier 22 family. OCT3 protein is localized at both basolateral (blood-facing) and apical (saliva-facing) membranes of salivary gland acinar cells, suggesting a dual role of this transporter in mediating both epithelial uptake and efflux of organic cations in the secretory cells of salivary glands. Metformin, a widely used anti-diabetic drug known to induce taste disturbance, is transported by OCT3/Oct3 in vitro. In vivo, metformin was actively transported with a high level of accumulation in the salivary glands of wild-type mice. In contrast, active uptake and accumulation of metformin in salivary glands were abolished in Oct3(-/-) mice. Oct3(-/-) mice also showed altered metformin pharmacokinetics and reduced drug exposure in the heart. These results demonstrate that OCT3 is responsible for metformin accumulation and secretion in salivary glands. Our study uncovered a novel carrier-mediated pathway for drug entry into saliva and sheds new light on the molecular mechanisms underlying drug-induced taste disorders.

味覚障害1,059例の原因と治療に関する検討

Taste disorders are caused by several factors, and there have been few reports concerning the clinical course of taste disorders. In this study, patients with taste disorders were classified into 10 groups according to causes, and they were retrospectively studied in terms of therapeutic effects. In total, 1059 patients (412 men and 647 women, mean age: 60.0 years) who complained of taste disorders were reviewed in our clinic. The patients were asked detailed questions about their history of symptoms, and their emotional status was assessed using a self-rating depression scale. In all subjects, taste functions were measured by electrogustometry (EGM) and filter paper disks (FPD). The grades of their symptoms were assessed with a visual analogue scale (VAS). In addition, the levels of serum iron, copper, and zinc were examined. The patients were treated with zinc sulfate, polaprezinc, iron preparation, herbal medicine, and minor tranquilizers according to the factors causing the taste disorders. The most frequent cause was idiopathic taste disorder (192 cases, 18.2%), the second was psychogenic (186 cases, 17.6%), and the third was drug-induced (179 cases, 16.9%). The recovery rate of the symptoms was 64/92 (70.2%) in post-common cold, 31/35 (88.6%) in iron deficiency, and 85/116 (73.3%) in zinc deficiency. In these groups, the rates of recoveries were better than in the other groups. The recovery period in drug-induced taste disorders was approximately twice as long as the recovery period in the other groups. In the patients who were able to start treatment within 6 months from the onset of taste disorder, the recovery rate was significantly higher and the therapeutic period was significantly shorter than in those who had the disorders for more than 6 months (p<0.05, respectively).

Drug-induced taste disorders

Taste and smell are critical components to a person's overall sense of well-being and quality of life. Taste related problems can cause pain and discomfort and can hinder the maintenance of a satisfying and nutritious diet. Loss of taste interferes with pleasure derived from food and food-related activities. Many drugs can affect this special sense and contribute significantly to the morbidity of the associated illness. This article gives a brief account of this problem and emphasizes the need for more awareness of the clinicians about this problem.

Taste and Appetite Loss in the Aged

Abstract “My father is 93 years old and has stopped eating (except soup) because of lack of taste. He is in CA and is not strong enough to make a cross country trip. His health is deteriorating bec...

Drug-Induced Taste Disorders

Numerous drugs have the potential to adversely influence a patient's sense of taste, either by decreasing function or producing perceptual distortions or phantom tastes. In some cases, such adverse effects are long lasting and cannot be quickly reversed by drug cessation. In a number of cases, taste-related adverse effects significantly alter the patient's quality of life, dietary choices, emotional state and compliance with medication regimens. In this review, we describe common drug-related taste disturbances and review the major classes of medications associated with them, including antihypertensives, antimicrobials and antidepressants. We point out that there is a dearth of scientific information related to this problem, limiting our understanding of the true nature, incidence and prevalence of drug-related chemosensory disturbances. The limited data available suggest that large differences exist among individuals in terms of their susceptibility to taste-related adverse effects, and that sex, age, body mass and genetic variations in taste sensitivity are likely involved. Aside from altering drug usage, management strategies for patients with taste-related adverse effects are sorely needed. Unfortunately, stopping a medication is not always an easy option, particularly when one is dealing with life-threatening conditions such as seizures, cancer, infection, diabetes mellitus and uncontrolled hypertension. Hopefully, the information contained in this review will sensitize physicians, researchers and drug manufacturers to this problem and will result in much more research on this pressing topic.

Statistical Approach to the Drug-Induced Taste Disorders Based on Zinc Chelating Ability

Various drug-induced taste disorders have been ascribed to zinc deficiency in serum. Assuming that the zinc deficiency is caused by the chelating reaction of zinc ions with drugs, the electrode potential of the Zn(2+)/Zn(Hg) system was measured in the presence of drugs in water, ethanol, and N,N-dimethylformamide (DMF). The zinc-chelating ability was estimated based on the potential change Delta E(2) with the addition of a drug. A large potential change suggesting potent chelating ability was observed in penicillamine, furosemide, and ibuprofen in ethanol and in fluorouracil, acetazolamide, and bezafibrate in DMF. Multiple regression analysis was used to evaluate the observed Delta E(2) in mV to represent chelating ability. The regression equation to estimate the frequency of taste disorders was deduced from Delta E(2), and frequency of four drugs appeared in package inserts and interview forms. According to the regression equation, the frequency of taste disorders was successfully estimated for 14 drugs examined in this study. The result was examined in a clinical case.

Drug-Induced Taste and Smell Disorders

Drugs in every major pharmacological category can impair both taste and smell function and do so more commonly than presently appreciated. Impairment usually affects sensory function at a molecular level, causing 2 major behavioural changes--loss of acuity (i.e. hypogeusia and hyposmia) and/or distortion of function (i.e. dysgeusia and dysosmia). These changes can impair appetite, food intake, cause significant lifestyle changes and may require discontinuation of drug administration. Loss of acuity occurs primarily by drug inactivation of receptor function through inhibition of tastant/odorant receptor: (i) binding; (ii) Gs protein function; (iii) inositol trisphosphate function; (iv) channel (Ca++,Na++) activity; (v) other receptor inhibiting effects; or (vi) some combination of these effects. Distortions occur primarily by a drug inducing abnormal persistence of receptor activity (i.e. normal receptor inactivation does not occur) or through failure to activate: (i) various receptor kinases; (ii) Gi protein function; (iii) cytochrome P450 enzymes; or other effects which usually (iv) turn off receptor function; (v) inactivate tastant/odorant receptor binding; or (vi) some combination of these effects. Termination of drug therapy is commonly associated with termination of taste/smell dysfunction, but occasionally effects persist and require specific therapy to alleviate symptoms. Treatment primarily requires restoration of normal sensory receptor growth, development and/or function. Treatment which restores sensory acuity requires correction of steps initiating receptor and other pathology and includes zinc, theophylline, magnesium and fluoride. Treatment which inhibits sensory distortions requires reactivation of biochemical inhibition at the receptor or inactivation of inappropriate stimulus receptor binding and/or correction of other steps initiating pathology including dopaminergic antagonists, gamma-aminobutyric acid (GABA)-ergic agonists, calcium channel blockers and some orally active local anaesthetic, antiarrhythmic drugs.