“A Spoonful of Sugar Helps the Medicine Go Down”: Bitter Masking by Sucrose Among Children and Adults

Chem. Senses 40: 17–25, 2015 doi:10.1093/chemse/bju053 Advance Access publication November 6, 2014 “A Spoonful of Sugar Helps the Medicine Go Down”: Bitter Masking by Sucrose Among Children and Adults Julie A. Mennella, Danielle R. Reed, Phoebe S. Mathew, Kristi M. Roberts and Corrine J. Mansfield Monell Chemical Senses Center, 3500 Market Street, Philadelphia, PA 19104, USA Correspondence to be sent to: Julie A. Mennella, Monell Chemical Senses Center, 3500 Market Street, Philadelphia, PA 19104, USA. e-mail: Accepted September 21, 2014 Abstract Sweeteners are often added to liquid formulations of drugs but whether they merely make them better tasting or actually reduce the perception of bitterness remains unknown. In a group of children and adults, we determined whether adding sucrose to urea, caffeine, denatonium benzoate, propylthiouracil (PROP), and quinine would reduce their bitterness using a forced-choice method of paired comparisons. To better understand individual differences, adults also rated each solution using a more complex test (general Labeled Magnitude Scale [gLMS]) and were genotyped for the sweet taste receptor gene TAS1R3 and the bitter receptor TAS2R38. Sucrose suppressed the bitterness of each agent in children and adults. In adults, sucrose was effective in reducing the bitterness ratings from moderate to weak for all compounds tested, but those with the sensitive form of the sweet receptor reported greater reduction for caffeine and quinine. For PROP, sucrose was most effective for those who were genetically the most sensitive, although this did not attain statistical significance. Not only is the paired comparison method a valid tool to study how sucrose improves the taste of pediatric medicines among children but knowledge gleaned from basic research in bitter taste and how to alleviate it remains an important public health priority. Key words: bitter taste, children, psychophysics, sucrose, TAS1R3 Introduction Drugs given to young children are seldom administered alone but often as part of formulations delivered as liquids, because many children have difficulty swallowing pills or tablets. The resulting liquid formulations are complex mixtures that contain both the drug substance (commonly referred to as the active pharmaceutical ingredient or API) and excipients, including, but not limited to, sweeteners (Pawar and Kumar 2002). Sweeteners are added not just to medications but many products geared for children, for several reasons. First, sweeteners can function as gelling and bulking agents or emulsifiers (Mitchell 2006). Second, they impart a sweet taste that is highly preferred by children (Mennella et al. 2011a) and can drive acceptance of a variety of products, as evidenced by findings from scientific research (Mennella 2008), as well as the widespread use of sweeteners in medicines, foods, and beverages geared for pediatric populations. The liking of sweet-tasting liquids is evident within hours of birth (Desor et al. 1973), remains elevated during periods of maximal growth, and does not decrease to adult levels until mid-adolescence (Mennella et al. 2011a, 2014a). Third, to enhance the palatability of liquid formulations, one must diminish or eliminate the bad tastes of the APIs, since from an early age children have a well-developed ability to detect and reject bitter tastes (Kajiura et al. 1992; Mennella et al. 2003). In adults, the addition of sweeteners can make a formulation taste better not just because they impart sweetness but because they can reduce the bitterness of some APIs, as can salts in adults (Keast and Breslin 2002). Psychophysical studies in adults suggest that the mode of action for bitterness suppression differs between sugars and salts. Sodium salts appear to suppress bitter taste in the periphery (receptor level), and this suppression is compound specific (Breslin and Beauchamp 1995; Keast and Breslin 2002; Keast et al. 2004; Narukawa et al. 2012). Sugars, on the other hand, act along the central gustatory pathway (cognitive level) and have been shown to suppress the bitterness of a range of bitter agents in adults (Lawless 1979; Kroeze and Bartoshuk 1985; Keast et al. 2004). In a landmark study, Kroeze and Bartoshuk (1985) compared © The Author 2014. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: 18 J. Mennella et al. perceptions of bitterness of quinine and salt or quinine and sucrose applied to the entire tongue (thus allowing for interaction at the receptor level) versus quinine applied to one side of the tongue and either salt or sucrose to the other. Because the 2 sides of the tongue are neurally independent prior to the thalamic level, no suppression should occur with the separate applications if sucrose works only in the periphery. Sucrose attenuated the perceive bitterness of quinine when the 2 compounds were applied simultaneously but independently to the 2 sides of the tongue, but sodium salts reduced bitterness only when applied to the same side of the tongue. Tests of bitter tasting have been performed almost exclusively in adults. Because of the importance of taste in adherence and compliance of medication regimens among children (Giacoia et al. 2012), we recently expanded basic research on bitter taste blocking to pediatric populations (Mennella et al. 2003, 2014b). Consistent with studies in adults (Breslin and Beauchamp 1997; Keast and Breslin 2002; Keast et al. 2004), we found that the ability of 2 sodium salts (sodium gluconate [Na gluconate] and monosodium glutamate [MSG]) to block bitter taste was not only compound specific but, as we showed for the first time, also specific to the age of the subject. In general, if the blocker worked for a given bitter in children, it also worked for adults, but not vice versa. The bitterness of propylthiouracil (PROP), a member of one of the most studied class of bitter agents (Guo and Reed 2001), was not reduced by either blocker in either age group, and its ineffectiveness was independent of genotype of the PROP receptor (TAS2R38). Overall, these results suggest that the efficacy of blocking bitter tastes depends on both the age of the subject and the chemical nature of the blocker and bitter agent. In the present study, we evaluated for the first time the efficacy of sucrose to reduce the bitterness of a broad array of bitter-tasting compounds in children. First, we tested the null hypothesis that there would be no systematic differences in the ability of sucrose to reduce bitterness between children and adults. Because of the lesser ability of children to understand complex psychophysical tasks, such as the general Labeled Magnitude Scale (gLMS; Bartoshuk et al. 2004), both age groups were tested with the same forced-choice, paired comparison method validated in previous studies (Mennella et al. 2003, 2014b). This method cannot determine how much the addition of sucrose decreases perceived bittern (...truncated)