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The Bad Taste of Medicines: Overview of Basic Research on Bitter Taste

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. Author manuscript; available in PMC: 2014 Aug 1.

Abstract

Background

Many active pharmaceutical ingredients taste bitter and thus are aversive to children, as well as many adults. Encapsulation of the medicine in pill or tablet form, an effective method for adults to avoid the unpleasant taste, is problematic for children. Many children cannot or will not swallow solid dosage forms.

Objective

This review highlights basic principles of gustatory function, with a special focus on the science of bitter taste, derived from studies of animal models and human psychophysics. We focus on the set of genes that encode the proteins that function as bitter receptors, as well as the cascade of events that lead to multidimensional aspects of taste function, highlighting the role that animal models played in these discoveries. We also summarize psychophysical approaches to studying bitter taste in adult and pediatric populations, highlighting evidence of the similarities and differences in bitter taste perception and acceptance between adults and children and drawing on useful strategies from animal models.

Results

Medicine often tastes bitter, and because children are more bitter sensitive than are adults, this creates problems with compliance. Bitter arises from stimulating receptors in taste receptor cells, with signals processed in the taste bud and relayed to the brain. However, there are many gaps in our understanding of how best to measure bitterness and how to ameliorate it, including whether it is more efficiently addressed at the level of receptor and sensory signaling, at the level of central processing, or by masking techniques. All methods of measuring responsiveness to bitter ligands—in animal models, through human psychophysics, or with “electronic tongues”—have limitations.

Conclusions

Better-tasting medications may enhance pediatric adherence to drug therapy. Sugars, acids, salt, and other substances reduce perceived bitterness of several pharmaceuticals, and although pleasant flavorings may help children consume some medicines, they often are not effective in suppressing bitter tastes. Further development of psychophysical tools for children will help us better understand their sensory worlds. Multiple testing strategies will help us refine methods to assess acceptance and compliance/adherence by various pediatric populations. Research involving animal models, in which the gustatory system can be more invasively manipulated, can elucidate mechanisms, ultimately providing potential targets. These approaches, combined with new technologies and guided by findings from clinical studies, will potentially lead to effective ways to enhance drug acceptance and compliance in pediatric populations.

Keywords: bitter taste, flavor, children, medicines, animal models, receptors, psychophysics, genetics, palatability

1. Introduction

Most children at some point in their lives are prescribed medicine. Some refuse to take it, and they and their parents suffer the consequences. Although children are subject to many of the same ailments and diseases as adults and are treated with the same drugs, most drugs (nearly 75%) available in the United States lack Food and Drug Administration (FDA)-approved pediatric formulations and therefore do not have labeling information about pediatric safety and efficacy.¹ The lack of “child-friendly” formulations leaves an estimated 40% of the world’s children at increased risk for avoidable adverse events, such as suboptimal dosing, lack of adherence to medication regimens, and reduced access to new medicines.² Although recent legislation in the United States and European Union has created incentives for testing drugs in this special population,³ this process is confounded by the requirement that the formulation be suitable for the pediatric patient population—actually a continuum of many smaller populations, such as preterm infants, term infants, infants and toddlers, preschoolers, school-age children, and adolescents.²

2 The Problem: A Matter of Taste

A central challenge of administering medicine to children is a “matter of taste”—drugs, by their very nature, often taste unpleasant, with bitter taste a primary culprit. More than 90% of pediatricians reported that a drug’s taste and palatability were the biggest barriers to completing treatment.²

Most drugs work by interfering with physiological processes within cells, so medicines have the potential to be toxic when ingested in sufficient quantity. Bitter taste is thought to have evolved as a deterrent against ingesting toxic substances,⁴ which may explain why many drugs taste bitter. The basic biology of the child, as reviewed here, explains why children (and adults) reject bitter-tasting drugs. In fact, bitter compounds are effective agents in deterring pediatric poisonings when used in conjunction with other preventive measures, such as child-resistant closures.⁵

Although many solid oral dosage forms (e.g., pills, tablets) have the advantage of masking or encapsulating bitter tastes, such methods are ineffective for many children because they often cannot or will not swallow pills or tablets. The cutoff for needing liquid formulations typically is between 6 and 8 years of age,⁶ but older children (and teenagers and adults) vary greatly in their ability to swallow tablets and capsules.^7,8 In addition, fixed doses are impractical because the dosage often varies according to the size of the child. The Physician Drug and Diagnosis Audit revealed that 6-year-olds were four times as likely as 16-year-olds to not take their medications as oral solids.²

Drugs usually are administered not alone but, rather, as part of formulations that are in either liquid or solid form. Liquid formulations are complex mixtures containing many other components besides the active ingredients; excipients include, but are not limited to, bulk materials, flavorings, sweeteners, buffers, preservatives, and coloring agents.⁹ Because masking the bitter taste of medications is a major challenge in formulating liquid medications, drugs are often combined with more pleasant-tasting compounds, for example, sucrose, high-intensity sweeteners, and flavors popular with children, such as bubble gum. Adding both sugars and acids to medication formulations reduces, but does not completely eliminate, the bitterness of drugs.¹⁰ However, frequent use of sucrose-sweetened medicines has been linked to dental caries in children.^11–15 This concern is responsible, in part, for the general decrease in sugar content in prescription medications in recent decades.^16,17

In contrast, acids remain in frequent use in medicine formulations to improve flavor and to maintain chemical stability.¹⁸ Children like more intense sourness than do adults,¹⁹ so lowering the pH increases the palatability for children, probably more so than for adults, and can contribute to bitter taste masking. Using buffering agents to adjust pH into the acidic range also increases the stability of medications otherwise prone to hydrolysis in liquid formulations.²⁰ However, adding acids to medications has the potential to cause dental erosion (at pH < 5.5).¹⁸ About half of 97 pediatric medication formulations used regularly and over the long term by children have an endogenous pH below 5.5 and thus are capable of damaging tooth enamel.¹⁸ Citric acid was the most frequently used acid, which raises concerns because citric acid has been linked to tooth erosion due to its ability to dissolve the hydroxyapatite of tooth enamel and dentin.^21,22

The need for liquids for some children may be bypassed by newer modalities for delivering medications for children. However, solid oral minitablets were refused, spat out, or chewed by half of children younger than 5 years,²³ and chewables and melting tablets trigger bitter taste responses, limiting the compounds amenable to such formulations. In addition, new research suggests that the ingestion of bitter compounds may also act in the gut to elicit nausea.²⁴ Whether children’s encounters with a relatively novel-tasting medication followed by nausea can result in a long-lasting learned aversion to the flavor²⁵ is an important area for further research.

Although liquid formulations are often the preferred form of oral delivery for infants and young children,^2,20,26 the vast majority of drugs are not commercially available in this form.²⁶ The need for liquid formulations is expected to rise—most newly approved drugs are not yet labeled for use in pediatric patients, and an appropriate formulation usually is not available unless the drug is approved for that population.²⁶

In this article, we draw knowledge from the chemical senses literature, with emphasis on bitter taste research involving animal models and on recent developments in the psychophysical assessment of taste responsiveness in children (see Mennella and Beauchamp 2008²⁷ for an earlier review), to better understand the nature of bitterness and suggest further ways to make medications more acceptable to the pediatric population. We focus on bitter taste but acknowledge that other sensory attributes (e.g., texture, sourness, or bad odors) also play a role in compliance. We review the set of genes that encode for the known proteins that function as bitter receptors, as well as the cascade of events that lead to multidimensional aspects of taste function, highlighting the role that animal models played in these discoveries. We also summarize psychophysical approaches to study bitter taste both in animal models and in pediatric populations, and we compare and contrast bitter taste perception between adults and children and identify gaps in knowledge. When appropriate, we reference review articles to direct the reader to the wider literature.

3. Overview of Bitter Taste

Taste is one of the senses through which humans and other animals perceive their environment. One of the primary taste qualities is bitter, a sensation that arises when specific chemicals are detected by specialized receptors in the tongue, as well as other parts of the oral cavity (e.g., throat). In developing effective strategies for reducing the bitter taste of medications, it is important to consider the basic functional architecture of the gustatory system (illustrated schematically in the Figure). We summarize the state of knowledge about bitter taste, from peripheral receptors to the brain, and link this system with perception.

How Bitter Works: the process of bitter perception. The generation of bitter taste starts when a bitter compound enters the oral cavity, where the ligand binds to a T2R G-protein coupled receptor expressed in the apical membrane of receptor cells found in taste buds, triggering a cascade of signaling events, leading to the release of neurotransmitter that activates an afferent nerve fiber that transmits the signal via the cranial nerve to the brain. Taste buds are distributed in distinct fields in the oral, pharyngeal, and laryngeal epithelia, with each field innervated by a different cranial nerve branch. Only the taste buds on the tongue are depicted in the figure. The taste buds of the laryngeal epithelium are thought to be involved more with protection of the airways. Taste receptors have also been identified in a variety of nongustatory tissues, such as the gut, where they have been proposed to play a role in nutrient and toxin sensing. The taste signals course through the brain and provide input to circuits that subserve various functions, such as oromotor and physiological reflexes, discriminative perception, and affective processing. The figure illustrates the complexity of the mechanisms intervening between the application of the bitter stimulus and the generation of the behavioral response, providing a variety of potential targets for strategies to modulate the bitterness of medications. VPM_PC, ventral posterior medial nucleus, parvocellular subdivision. *The insula/operculum is actually lateral to the sagittal plane of section shown. Cell and molecular segment adapted from Finger and Kinnamon (2011).⁵³

a. Neurobiology of Bitter Taste

i. Peripheral and Central Anatomy of the Gustatory System

The principal sensory organ of gustation is the taste bud, a collection of about 50–100 specialized epithelial cells, some of which serve the role of receptors. Receptor proteins are expressed on the apical membranes of microvilli, which protrude into a pore in the epithelium, where they have access to the oral environment (see segment labeled “Taste Bud” in the Figure). Thus, stimuli must be in solution to adequately reach and stimulate the receptor cells.

The taste buds are bathed in excretions from the sublingual, submaxillary, and parotid salivary glands, as well as from numerous minor salivary glands throughout the oral epithelium. Although there is sufficient evidence that saliva plays a significant role in taste receptor activation by orally applied chemical compounds, its contribution has not been extensively studied. Proline-rich proteins found in saliva can bind with bitter-tasting tannins found in some foods, increasing their acceptability.²⁸ Proline-rich proteins arise from gene clusters that are interleafed with bitter receptor genes, hinting at a common regulatory mechanism and function.²⁹ A better understanding of the function of saliva in taste receptor processes may help us curtail the bitterness of medicines.

Taste buds are distributed in distinct fields in the oral cavity (see “Oral” segment on the Figure).^30,31 In the anterior tongue, taste buds are housed in specialized protrusions called fungiform papillae. In the posterior tongue, the taste buds are found in a series of trench-like structures in the lateral margins, referred to as the foliate papillae, and in moat-like structures in the dorsal surface, referred to as the circumvallate papillae. Extralingual taste buds are also found on the soft palate and in the laryngeal epithelium. Each field is selectively innervated by a specific branch of the seventh, ninth, or tenth cranial nerve, which all project to the rostral nucleus of the solitary tract (NTS) in the medulla, where they terminate in a roughly overlapping orotopic fashion.^32–34

Interestingly, the pathway of gustatory signals through the brain varies somewhat across the mammalian species examined.³⁵ For example, in rodents and lagomorphs (e.g., rabbits and pikas), taste-responsive neurons in the NTS, in addition to contributing to local hindbrain circuits involved with oromotor and autonomic function,^36–38 project to the parabrachial nucleus (PBN). The projections from PBN neurons bifurcate, with one set terminating in ventral forebrain structures associated with homeostatic functions and affective processes, and the other in the parvocellular subdivision of the ventral posterior medial nucleus of the thalamus, from which neurons send their axons to terminate in the insular cortex’s gustatory zone. In primates, the projections of the taste neurons of the NTS bypass the PBN and terminate in the thalamus, whose cells project directly to taste cortex (see Figure, “Central Nervous System”).³⁹ Thus, the ventral forebrain in primates receives its taste input from cortical structures. Many of these pathways are reciprocal, setting the stage for significant feedback to modulate the signals.

Regardless of the different anatomical paths of taste signals through brain in various mammalian orders, the significance of which remains to be understood, in all cases taste signals can be modulated not only in the periphery but also anywhere along the central gustatory pathway. For example, the adage “a spoonful of sugar helps the medicine go down” receives some support from evidence that sucrose can indeed decrease the perceived intensity of quinine, a phenomenon referred to as mixture suppression.^40,41 Although some mixture suppression effects likely have a peripheral origin,^41,42 there are central contributions as well.^40,41 For example, if the sucrose solution is applied to one side of the tongue and the quinine solution to the other, the perceived intensity of the quinine is attenuated despite the stimulation of independent lingual receptor fields.⁴¹ Further, anesthetic block of the nerve that innervates the front of the tongue increases perceived bitterness of quinine applied to the back of the tongue, presumably preventing inhibition arising from anterior lingual taste signals.⁴²

ii. Taste Receptor Mechanisms and the T2R Family

There are two general classes of taste receptor mechanisms: the G-protein-coupled receptors (GPCRs), involved in mediating sweet, bitter, and umami taste, and the ion channel receptors, implicated in salt and sour taste.^43–47 The activities of some of these receptors and/or their downstream transduction intermediaries are thermally sensitive,^48–50 making temperature a candidate strategy for modulating the taste of medicine.

All of these receptor proteins are expressed in a variety of tissues in the body.^51–55 For example, the GPCRs that serve as taste receptors are also found in the gut.^51,52,54 This has led to the term “gut taste,” which is more of a metaphor than a reality: as described below, “taste” results not from the receptors themselves but from the downstream neural consequences of the activation of these receptors. Bitter receptors are also expressed in the ciliated cells of the sinonasal epithelium and can trigger immune responses when stimulated with chemical signals from bacteria.⁵⁶

The GPCRs share certain transduction intermediaries in taste receptor cells, such as α-gustducin, PLCβ₂, and TrpM5, which ultimately lead to release of the neurotransmitter (see the “Cell and Molecular” segment in the Figure).⁵⁷ In some cells, the G-protein subunit α-gustducin helps mediate responses to both bitter- and sweet-tasting ligands.^58,59 Because GPCR transduction signaling components are shared by both bitter and sweet-tasting ligands, they may not be selective targets for decreasing the bitterness of medications. However, although to our knowledge it is untested, the deactivation of these signaling components on a temporary basis could prove useful because even if sweetness is potentially attenuated, the decrease in bitterness could lead to an overall increase in the acceptability of the medicine.

The T2R family of taste receptors was discovered a little more than a decade ago.^60,61 It consists of about 25 GPCRs that serve as the principal receptors for mediating bitter taste. Although many of the receptors remain to be de-orphaned (i.e., determine which ligands activate them), most T2Rs studied have binding profiles that involve several different bitter-tasting ligands.^62,63 Likewise, a given bitter-tasting ligand can activate more than one T2R.^62,63 As might be expected, there are some genetic variants in the receptors within and across species.⁶³ For example, a subset of the population, classified as “nontasters,” cannot detect the presence of the compounds propylthiouracil (PROP) and phenylthiocarbamide (PTC) at moderate concentrations that all others, referred to as “tasters,” find exceptionally bitter.⁶⁴ The nontaster phenotype is due to a haplotype involving polymorphisms at three amino acid positions in the hT2R38 protein, which is known to bind with these compounds.⁶⁵ Likewise, genetic variants within another cluster of bitter receptor genes affect the ability to perceive the bitterness of quinine,⁶⁶ a bitter chemical used in the past to treat malaria. Thus, variation in the compliance of children to ingest particular liquid medications could be attributable to potential polymorphisms in these or other T2Rs that have yet to be revealed.

Developing research indicates that receptors for stimuli generating different taste qualities are not co-expressed in taste bud cells.^{44,45,47,60,67} Thus, if a taste bud cell expresses the T1R2+T1R3 receptor responsible for mediating sweet taste, it will not express any of the T2Rs that serve as the receptors for bitter-tasting ligands. Although rodent studies first indicated that virtually all T2Rs were co-expressed on taste receptor cells responsive to bitter ligands,^60,61 later human studies revealed that most T2R-expressing cells express only a subset of the T2R members.⁶³ Nevertheless, a consistent systematic pattern to this expression has not been identified. This lack of co-expression sets the stage for the flow of taste information that gives rise to different qualitative taste perceptions, although there is plenty of opportunity for convergence in the transmission of the signals through the brain.

iii. Neural Response Profiles to T2R Ligands

In addition to overlap among ligands for receptors and receptors for ligands,^62,63 there is overlapping expression of the T2R members in the subset of taste bud cells responsive to bitter compounds. Surprisingly, however, imaging experiments of intracellular changes in calcium concentration in rat taste bud cells in situ in response to bitter stimuli indicate much narrower tuning properties: of the 374 cells tested, 69 responded to at least one of the five bitter ligands in the test panel, and of these, 45 cells responded to only one and 18 responded to only two.⁶⁸

Because single axons from a taste nerve branch are close to the tongue and innervate more than one taste cell, any selectivity present in taste receptor cells could be lost by early convergence in the system. The extent to which this occurs at the ganglion cell level remains understudied. Most prior studies used only quinine hydrochloride as the bitter stimulus, rather than a diverse set of bitter ligands. Moreover, the vast majority of peripheral and central electrophysiological results in the literature are based on anterior tongue stimulation, reflecting the contribution of only about 15% of the total taste bud population and circumventing the taste receptor field of the posterior tongue, which has the densest expression of T2Rs.⁶⁰ This is due, in part, to the difficulty in effectively perfusing the foliate and circumvallate trenches in the posterior tongue with stimulus solutions in an anesthetized preparation.

Despite these difficulties, two studies stand out in this regard. Frank⁶⁹ published the first comprehensive set of findings detailing the response properties of single fibers in the glossopharyngeal nerve. She inserted a pipette into the circumvallate papilla of the rat (rodent tongues have only one circumvallate papilla, vs. ∼10 in the human tongue) and tested salts, acids, sugars, and quinine. Although in her prior studies quinine-responsive single fibers in the chorda tympani nerve innervating the front of the tongue responded best to acids and other electrolytes,⁷⁰ in this study a set of fibers was identified that responded selectively to quinine and not to the other stimuli. This indicates a segregation of quinine-evoked signals from those of other taste qualities, consistent with the so-called labeled-line model of neural coding, in which activity in a given class of neurons is necessary and sufficient for generating a specific taste quality.⁷¹

In the other study, Dahl and colleagues⁷² recorded single-fiber responses in the chorda tympani nerve (anterior tongue) and the glossopharyngeal nerve (posterior tongue) to a panel of bitter-tasting ligands. Not all ligands stimulated the same fibers, suggesting that signals may be present in the overall peripheral input that permits some discriminability among these particular bitter compounds. This has been taken as evidence for an ensemble or across-neuron model of neural coding.

Once the signals from the peripheral nerves reach the brain, there is opportunity for further anatomical convergence. From a functional standpoint, the pattern of this convergence is key in terms of how the nervous system represents information about chemical compounds contacting the oral epithelium. Indeed, there is evidence that the breadth of tuning of taste-responsive neurons increases in the brain. However, some narrowly tuned neurons are still present in the population, and it is unclear to which taste function a given neuron contributes. Thus, some neurons might be responsive to the affective valence of the stimulus, whereas others might code for taste quality and contribute to stimulus identification.⁷³

The literature on responses of central taste neurons to bitter-tasting stimuli in rodent models is mixed. For many years the bitter stimulus quinine was included in many electrophysiological studies of neuronal taste responses in several central gustatory structures, but despite its potent behavioral effects, neuronal responses were weak or nonexistent—possibly because many studies did not stimulate the posterior tongue. In recent years, however, some more robust responses of neurons in the gustatory zone of the NTS and PBN to a variety of bitter-tasting ligands have been revealed.^74–76 Indeed, a class of neurons has been identified that respond best to bitter compounds and little to compounds associated with other taste qualities.^74,75 Within this class, however, not all bitter compounds are equally effective stimuli for a given neuron. This may be due to idiosyncratic upstream connections originating from the specific T2Rs expressed in the taste receptor cells, or it may represent a fundamental distinction in organizing inputs from subclasses of bitter-tasting ligands. Some of the ionic bitter compounds can also stimulate neurons that respond best to acids and electrolytes, adding another layer of complexity to the unraveling of the neural representation of bitter taste.^74,75

In a set of recent results using a two-photon imaging protocol to measure cellular calcium responses, anatomically distinct clusters of neurons were found in the insular cortex of the mouse that appeared to respond selectively to taste compounds associated with specific basic taste qualities, including a group that responded only to bitter compounds.⁷⁷ The disparity between these findings and the lack of evidence of explicit chemotopy from electrophysiological studies of central neuronal taste responses⁷¹ has yet to be resolved. However, results from an earlier study using a less spatially precise optical imaging technique provide support for some degree of a spatial mapping of taste quality in this cortical region.⁷⁸

From all that we now know about bitter perception and its multiple receptors, it is not surprising that the bitter taste of oral pharmaceuticals is an ongoing formulation problem. The mechanics of bitter taste signaling suggest that it should be amenable to the methods of pharmacology.⁷⁹ However, the large number of bitter-tasting compounds and receptors makes blocking bitterness at the receptor level difficult because medicines may have multiple bitter compounds that stimulate multiple receptors, and each receptor may require its own antagonist. As mentioned above, the blockade of second messenger signaling poses problems because several components of the bitter-taste transduction pathway are shared with those mediating sweet taste, and attenuation both bitterness and sweetness may pose practical problems because sweeteners are a commonly used agents to reduce perceived bitterness. Nonetheless, temporary nonselective blockade of these taste transduction pathways could lead to an overall increase in the acceptability of the medicine.

b. Linking the Neurobiology of Bitter Taste to Perception

The discussion above provides a cursory description of the “hardware” of the gustatory system, with a focus on neural mechanisms underlying bitter taste. Most of what we have learned about the molecular aspects of bitter taste transduction has been from experimental animal models, mostly rodents.

However, without data defining the psychophysical properties of various taste compounds and their mixtures, we cannot link the underlying neurobiology with perception. In this regard, animal models are particularly useful because effects of very selective manipulations of the gustatory system can be studied in a highly systematic and quantitative way, in a wide variety of tissues, including the nervous system, as well as in taste-related behavior. In such efforts, however, it is important to be mindful of several interpretive guidelines.⁷³

First, when most people talk about “taste,” they are actually referring to flavor. Flavor can be considered the perceptual integration of signals from the gustatory, olfactory, and trigeminal systems.⁸⁰ To the specialist, however, taste refers to the behavioral and physiological consequences of stimulating taste receptor cells in the oral cavity. Accordingly, the potential for taste stimuli to activate nongustatory sensory systems, including those of a visceroceptive nature in the cases where the taste solutions are swallowed, must be considered.

Second, perception cannot be measured directly—it must be inferred from behavior. The veracity of that inference depends heavily on the procedure used to measure the behavior, whether studying animals or humans.

Third, taste function is multidimensional. The sensory/discriminative dimension encompasses stimulus identification, including the basic taste qualities sweetness, sourness, saltiness, bitterness, and umami. The affective dimension involves the hedonic evaluation of taste stimuli, ultimately promoting or discouraging ingestion, which is perhaps most relevant to addressing the unpalatable nature of bitter medicines in children. Physiological reflexes are also triggered by taste stimuli, such as salivation triggered by the oral sampling of a lemon. Thus, behavioral outcomes from a given gustatory manipulation need to be interpreted in light of the domain(s) being assessed.

Finally, a neuron’s response to an orally applied chemical stimulus does not, in and of itself, reveal the functional domain(s) to which the cell contributes. In this sense, behavioral observations are indispensable in understanding of the neurobiological mechanisms underlying taste function.

4. Behavioral Assays in Animal Models

Although behavioral procedures involving nonhuman subjects are time-consuming and resource-intensive, their value is indisputable because they link the neurobiology of the gustatory system to behavior and, by inference, perception in the same animal model. Rodents are particularly useful animal models for studying taste perception: they are commensal with humans and thus have a similar sense of taste. Animal models also share other similarities with very young children: for both populations, behavior rather than language communicates important information about their sense of taste. The behavioral outcomes from animal models can then be compared with psychophysical results from similar experiments conducted with human subjects, providing a potential bridge between the animal neurobiological data and human taste perception.

The most common behavioral procedure for assessing taste function in animal models (and in young infants, as described below) remains the two-bottle preference test in which the animal is simultaneously presented with two liquid stimuli (e.g., sucrose solution vs. water) for a specified duration. Although these tests provide a reasonable first approximation of an animal’s taste responsiveness to a given compound and have the virtue of simplicity, their interpretation is limited because intake and choice can be influenced by nongustatory contributions, most notably, those arising from postingestive events (e.g., satiety or nausea). Over the last several decades, however, a variety of behavioral procedures have been developed that assess taste function more selectively.⁸¹ These procedures could have great utility in testing various strategies for screening drugs in their early stages of development or for modulating the bitter taste of a drug based on more fundamental physiological or molecular research. In this section we briefly summarize each of these methodologies in animal models.

a. Brief-Access Test

The brief-access taste test is an effective way to circumvent the limitations of intake tests by presenting small volumes of taste samples and measuring immediate behavioral responses. Generally, various concentrations of a given taste compound are presented in very brief trials, on the order of seconds, and licking responses are measured with the help of specialized testing devices^82–90. This procedure is most commonly used to test rats and mice. With normally preferred taste stimuli, such as sucrose, the animals can be tested in either a nondeprived or a food-deprived state, and a monotonic increase in licking as a function of concentration is generally observed. With aversive stimuli, such as bitter-tasting ligands, animals are tested in a water-deprived state, and a monotonic decrease in licking as a function of concentration generally occurs.

These responses are sensitive to gustatory manipulations. For example, mice in which the gene encoding the GPCR taste transduction intermediaries PLCβ2 and TRPM5 have been knocked out display relatively flat concentration-response curves to sweet and bitter stimuli compared with wild-type controls.^57,91,92 Interestingly, the knockout mice still display some licking avoidance of very high concentrations of certain bitter-tasting compounds, such as quinine or denatonium, suggesting an alternative high-threshold taste transduction pathway(s) for these ligands that is independent of PLCβ₂ and TRPM5.^91,92 Although the brief-access test does not assess taste quality perception per se (e.g., NaCl, citric acid, and quinine all produce decreasing licking functions), it is an effective measure of an animal’s affective responsiveness to a taste stimulus and has great potential utility for testing masking agents and other strategies to attenuate the aversiveness of medicines.

b. Taste Reactivity

Many animals, including rodents and humans, display reflex-like oromotor responses to taste stimuli,⁹³ which has been termed taste reactivity.^94–97 This has been best studied in rats in which taste solutions are delivered directly into the oral cavity through surgically implanted cannulas. Normally preferred taste stimuli, such as sugars, elicit tongue and mouth movements directly proportional to the concentration of the solution. These are collectively referred to as ingestive behaviors. Normally avoided taste stimuli, such as quinine, elicit gapes, chin rubs, forelimb flails, and head shakes directly proportional to the concentration of the solution, and all of these are generally accompanied by active fluid ejection. These are collectively referred to as aversive behaviors. Transection of the glossopharyngeal nerve, which innervates the taste buds of the posterior tongue where T2Rs are densely expressed, virtually eliminates the characteristic aversive oromotor responses to intraorally delivered highly concentrated quinine solutions,^98–100 which return when the nerve regenerates.¹⁰⁰

Although bitter taste stimuli are often aversive, not all aversive tastes are bitter. Accordingly, taste reactivity does not assess taste quality but rather provides information about the acceptability of various taste stimuli. Nonetheless, these procedures could contribute significantly to developing ways to increase medication palatability.

c. Conditioned Taste Generalization and Discrimination

These procedures can more selectively assess taste quality independent of the inherent hedonic characteristics of the stimulus, by establishing a taste stimulus as a conditioned signal. For example, with the conditioned taste aversion procedure, commonly used in rodents,^{86,90,101,102} the ingestion of a specific taste stimulus is paired with administration of an agent that produces temporary visceral malaise (presumably nausea). On subsequent occasions, the animal will avoid ingesting the conditioned stimulus and others that have a similar qualitative taste, a phenomenon called generalization. When the test array includes sucrose, quinine, NaCl, and citric acid, inferences can be made about how sweet, bitter, salty, and sour the conditioned stimulus is. Although intake compared with nonconditioned control animals is often the primary dependent measure, brief-access tests and taste reactivity measures can also be used.

One limitation of the use this paradigm to assess qualitative characteristics of naturally aversive taste stimuli is that they are already unconditionally avoided. However, operant conditioning procedures can circumvent this shortcoming. In these procedures, a small volume of a taste compound serves as a cue in the presence of which a specific response is rewarded or punished. For example, using a specially designed gustometer, Grobe and Spector¹⁰³ trained one group of thirsty rats to lick a specific drinking spout after sampling sucrose (the standard stimulus) and a different spout after sampling quinine, citric acid, or NaCl (the comparison stimuli). If the rats responded correctly, they were rewarded with water; if not, they were punished with a time-out. Three other groups were trained with quinine, citric acid, and NaCl, respectively, as the standard stimulus and the remaining compounds as the comparison stimuli. Concentrations of all stimuli were varied, rendering intensity cues irrelevant. After all four groups learned the task, a test compound was randomly interjected during the taste trials. By observing which spout each animal went to after sampling the test stimulus, the experimenters were able to infer taste quality of the sample using the response profiles across all four groups: sweetness (sucrose standard group), bitterness (quinine standard group), saltiness (NaCl standard group), and sourness (citric acid standard group).

A similar procedure can test how well rats and mice can discriminate between two specific compounds. There has been some debate about whether animals can discriminate among bitter-tasting compounds. As noted above, the co-expression of T2Rs in taste receptor cells, as well as their somewhat broad tuning profiles, predicts poor discriminability, whereas the calcium responses of taste bud cells predict good discriminability. The response profiles for central taste neurons can be used to support either prediction. Spector and Kopka¹⁰⁴ tested whether rats could discriminate between quinine and denatonium, for which calcium imaging suggested a high degree of discriminability. The procedure was similar to the one described above: rats were rewarded for licking one spout when quinine was delivered and for licking the other when denatonium was presented; incorrect responses were punished with a time-out. These rats could not be trained, but did subsequently learn to discriminate quinine from KCl.

A second group of naive rats were first trained to discriminate quinine from KCl; then denatonium was substituted for quinine, and performance remained unperturbed on the very first session, suggesting that denatonium and quinine share similar qualitative properties. To show that any stimulus substitution does not necessarily result in unaltered performance, Spector and Kopka substituted NaCl for denatonium. In this case, performance dropped to chance levels on the first session and then subsequently improved across sessions as the animals learned the new discrimination task. Finally, these same highly trained rats were tested on the quinine vs. denatonium task, and their performance remained at chance over 15 test sessions. Accordingly, if rats can discriminate quinine from denatonium, it is likely very difficult, suggesting that the two compounds produce a unitary qualitative taste perception that one could perhaps call bitterness. Whether other bitter-tasting ligands can be discriminated from one another remains to be tested. On a more conceptual level, failure to discriminate is always more compelling than is success, provided learning and intensity effects can be ruled out, because it suggests that an identity relation exists somewhere along the sensory neuraxis.

5. Behavioral Assays in Children

A major challenge in formulating pharmaceuticals for children’s palates is the identification of methods to assess the acceptance of the taste of the medicines, once they are approved, and to determine in the long term which methods yield data that predict adherence/compliance to medication regimes.¹⁰⁵ When conducting research in children, several methodological issues need to be addressed.

First, young children are more prone to attention lapses and have shorter memory spans compared with adults. Therefore, any method relying on sustained attention that places demands on memory could yield spurious findings. Second, because young children tend to answer questions in the affirmative, a forced-choice categorization procedure is generally preferred. Age-appropriate tasks embedded in the context of a game that are fun for children and minimize the impact of language and the stage of cognitive development, are particularly effective. Third, before actual testing and after a period of acclimation, the experimenter should ascertain whether the child comprehends the task. Training tools are needed to determine whether a given child has the ability to do the task. Reproducibility of the measures over time should be built into the design of the study. All of these special features must be considered when developing sensory methods for children.

A variety of psychophysical methodologies have been employed to assess taste perception and preference throughout infancy, childhood, and adolescence.¹⁰⁶ The method chosen depends on the objective of the study, as well as the age (and, in turn, cognitive and language abilities) of the participants under study. These psychophysical studies on taste provide data relevant to two separate aspects of sensation: (1) the sensitivity of the system to chemical stimuli and (2) the hedonic valence, or pleasantness, of the sensation.^107,108

The century-long legacy of experimental research in taste has revealed that, like the other senses (sounds,¹⁰⁹ smells,^110,111 and irritants¹¹²), children live in different sensory worlds than do adults. These age-related differences are especially striking for taste. Within hours after birth, infants have been shown to prefer sweet and umami tastes^113–115 and to reject bitter-tasting liquids,¹¹⁶ although adult-like sensitivity to salt does not emerge until the infant is approximately four months of age.¹¹⁷ Their dietary likes and dislikes provide further evidence of their stronger liking for foods and beverages that taste sweet,¹¹⁸ salty,¹¹⁹ and, in some cases, sour¹²⁰ and their profound dislike of all that tastes bitter. Children’s heightened liking for sweets and salts, relative to adults, probably reflects the need for energy or minerals, respectively, during periods of maximal growth, since many foods rich in energy (e.g., mother’s milk, fruits) taste sweet. Thus, it is not surprising that many pediatric formulations taste sweet.

The Table provides an overview of some of the psychophysical tools used to study bitter taste in children (for more thorough review that includes the other basic tastes, see Forestell and Mennella 2013¹⁰⁶). For preverbal children, the tools often focus on reflex-like responses (e.g., orofacial responses) or consummatory responses—many of the experimental paradigms for this age group are similar to those used in animal model studies,^{85,94,116,121–123} as reviewed above. Because virtually all of these measures can be associated with acceptance or rejection, they presumably involve a hedonic component. At least for human infants, sensitivity and hedonics are difficult to distinguish.¹⁰⁸ For older children, the psychophysical tools are more complex, but very little research has established at what age children can reliably perform these tasks.

Table.

Examples of types of psychophysical tools used to assess bitter taste and medication palatability in pediatric populations.

Method	Age of Subjects	Measures	Outcome Measures	Key References
Facial reactivity	All ages, but facial reactivity as an indicator becomes less reliable with age¹⁸¹	The number of affective reactions infants express to a taste stimulus is quantified as a measure of the valence and intensity of an affective reaction. Facial expressions are dissected into constituent action units (AUs) via slow-motion video analysis by trained raters.	Bitter solutions elicit upper and midface Aus (including cheek raises (AU 6) and gaping (AU 26 and AU 27)).	Oster and Rosenstein 1988¹¹⁵; Mennella et al. 2009¹²⁸; Forestell and Mennella 2012¹²⁵
Brief-access tests	Infancy (<1 year)	Infants are provided with brief access to two or more bottles in succession containing various bitter-tasting liquids or diluent.	Decreased intake to bitter taste.	Desor et al. 1975¹³²; Kajiura et al. 1992¹³⁰
Brief-access tests, multiple days	Infancy (<1 year)	Infants are fed food on multiple occasions; the days differ in the taste of the food presented.	Decreased intake to bitter-flavored relative to plain cereal.	Mennella et al. 2009¹²⁸
Suckling response	Infancy (<1 year)	Patterning of suckling response measured while infant is feeding tastant versus diluent solutions; transducer may be embedded in nipple of bottle.	Retardation of suckling to bitter taste.	Kajiura et al. 1992¹³⁰
Suprathreshold taste thresholds	Children ≥3 years of age	Subjects tasted (but did not swallow), solutions of PROP in ascending concentrations, rinsing with water before and after each tasting. Subjects are then classified into groups based on which concentration, if any, tasted bitter.	Variation in sensitivity to PROP related to TAS2R38 genotype and children’s food likes.	Anliker et al. 1991¹³⁹; Mennella et al. 2005¹³⁷
Scaling methods	Children ≥3 years of age	A variety of scaling methods are used during taste testing to evaluate children’s hedonic responses after tasting one solution at a time. Typically, the child is presented with a line or other type of scale that contains pictorial (e.g., faces ranging from frowns to smiles) or verbal descriptors to evaluate stimuli in a graded order.	Children (4–11 years) with kidney disease rated the taste of two different pulverized calcium channel blockers on a 5-point hedonic face scale to determine most palatable drug.¹⁴⁸ Children (4–8 years) rated oral suspension of four antibiotics using a 5-point hedonic face scale to determine most preferred drug.¹⁴⁹ Children (5–8 years) rated four antimicrobial agents using a 10-cm line with face labels placed above the line at approximately 0, 2.5, 5, 7.5, and 10 cm to determine the most palatable drug preparation.¹⁴⁵ Caveat: unclear at what age children can comprehend these tasks.¹⁴³	Powers et al. 2000¹⁴⁹; Angelilli et al. 2000¹⁴⁵; Milani et al. 2010¹⁴⁸; Guinard 2001¹⁴³

a. Taste Reactivity

Some of the earliest investigations on taste in infants involved videotaping infants and then characterizing their oromotor reflexes when taste stimuli were placed on the tongue or in the oral cavity.^114–126 In 1988, Oster and Rosenstein¹¹⁵ developed a method for describing orofacial responses with Ekman and Friesen’s¹²⁷ anatomically based Facial Action Coding System (FACS), which can dissect virtually any facial expression into its constituent action units (AUs). Video records are often analyzed in slow motion⁹⁷ to quantify the actual number of affective reactions infants express to a taste stimulus, as a measure of valence and intensity.¹²⁸ This method requires trained individuals (preferably certified in FACS) to analyze the video images and establish reliability across scores,¹²⁵ which can be time-consuming and costly.

b. Brief-Access Tests: Intake and Suckling Methods

Ingestive and suckling responses have been used successfully to study response patterns as a function of individual and age-related differences in taste perception. Methods include delivering small quantities of taste solutions directly to the tongue or providing brief access to multiple bottles in succession that contain various taste or diluent solutions.^{113,129–132} In some cases, a transducer was embedded into the nipple of the bottle to measure the patterning of suckling in response to the tastant.^133,134 In other cases, infants are tested on repeated days for their acceptance of a food (e.g., cereal) that differs in taste quality,^125,128 which requires controlling for a number of variables, including time of day and time since the infant was last fed, and ensuring that appropriate controls are built into the study design. One can then infer from this research that infants detect a bitter taste solution (e.g., urea solutions), and reject it more than the diluent, if they consume less (or suck less) of the bitter taste solution than of the diluent solution.^130,132

c. Forced-Choice Tracking Procedure/Thresholds

Various methods have been used to measure how sensitive a child is to a particular tastant (e.g., taste thresholds) and whether there are individual differences. Perhaps the most widely studied taste trait relates to the genetically determined ability to taste compounds containing an N–C=S (thio) group, such as phenylthiocarbamide (PTC) and its chemical relative propylthiouracil (PROP), in human populations.^10–14 As mentioned above, these chemicals taste bitter to “tasters,” whereas “nontasters” either cannot taste them or require high concentrations to recognize their presence.

A variety of methods have been used to assess sensitivity to PROP and/or PTC.^135–138 Often, these include forced-choice procedures embedded in the context of a game. Based on the procedures of Anliker and colleagues (1991),¹³⁹ children were presented, in succession, with samples of water and then three increasing concentrations of PROP (56, 180, and 560 µM) and were asked to taste the sample without swallowing.^137,140,141 If the solution tasted like “water” or “nothing,” then they were asked to give the sample to Big Bird, a popular television character. If the sample tasted “bad,” “yucky,” or “bitter,” children were asked to give it to Oscar the Grouch so he could throw it in his trash can. Children were grouped by the concentration of the first sample, if any, that was given to Oscar the Grouch. Children who were heterozygous at the TASR38 gene locus—that is, had one “taster” and one “nontaster” allele—were more sensitive to the taste of PROP than were heterozygous adults. The thresholds of heterozygous adolescents were intermediate,¹⁴⁰ and homozygous children and adults showed no difference in threshold.

In other studies, children were presented with a series of pairs of solutions: water paired with an aqueous tastant (i.e., paired comparisons). In some cases the aqueous tastants increased in concentration with each pair presented, and the child was asked to indicate which sample of the pair contained the tastant or tasted stronger. The lowest concentration successfully detected in one or two consecutive trials was recorded as the detection threshold.¹⁴²

d. Scaling Procedures

Various types of scaling methods (i.e., methods in which sensations to varying concentrations of suprathreshold stimuli are quantified) have been used to determine children’s preferences and sensitivity to tastes. Depending on age, children are presented with a line or other type of scale that contains pictorial or verbal descriptors in a graded order. Although there has been no systematic determination of what scaling test is most appropriate for children at what age, some researchers have concluded that use of scales in children younger than age 5 can be problematic because they have not mastered the ability to rank things in order of magnitude.¹⁴³

A variety of methods, including spontaneous verbal reports following dosing, time required for medication intake, 10-cm visual analog scales, and hedonic face scales, are used by pharmaceutical companies, marketing research firms, and other investigators when testing children.¹⁴⁴ Several different 5-point hedonic scales have been developed to assess taste acceptability of pharmaceuticals.^145–149 These scales typically consist of five different facial expressions accompanied by written labels and are used to evaluate children’s hedonic responses after tasting one medication at a time. Davies and Tuleu¹⁵⁰ searched PubMed to identify 30 papers assessing medication palatability in children dating back to 1984 and found that half of the studies used a hedonic scale to rate palatability and that participants included children as young as 3 years. Although 5-point scales typically were used,¹⁴⁹ scales ranged from 2 points¹⁵¹ to 10 points.¹⁵² The use of such scales in young children is potentially problematic, as it is not clear at what age children begin to use the entire scale versus just the two extremes.¹⁰⁵ To date, only a few studies have examined the validity and reliability of hedonic scales in young children. We highlight some of these studies and how their findings provide insight into whether such methods are even valid for pediatric populations.

Sjovall and colleagues¹⁵³ compared spontaneous verbal judgments and a 5-point facial hedonic scale in children given five different penicillin formulations. Although both methods successfully discriminated between pediatric formulations when used with older children, for children 6 years and younger spontaneous verbal assessment discriminated between formulations better than did the facial hedonic scale.

Leon and colleagues¹⁵⁴ examined the reliability and validity of facial hedonic scales in children whose ages ranged from 4 to 10 years. Children in the study tasted biscuits covered with different flavors of jam. Children 4 and 5 years old rated the jams using a 2-point hedonic face scale (like vs. dislike), whereas older children rated them using a 4-point hedonic face scale (like very much, like, dislike, dislike very much). For children younger than 5 years, intersession repeatability of results with the hedonic scale was poor (Kendall correlation = 0.18) and did not correlate with other measures of preference in the same children. In contrast, children older than 5 years could reliably use the 4-point hedonic scale, and results correlated with other measures of preference. These studies illustrate the difficulty of using hedonic scales in young children.

e. Application of Methods to Study Bitter Taste in Children

Some children refuse to take bitter medicines, whereas others comply readily.² Likewise, not every child (or adult) is equally sensitive to the taste of bitter compounds.¹³⁷ Many children are more sensitive to bitter tastes than are adults.^131,137 However, because of the paucity of research on the ontogeny of bitter taste sensitivity, we do not know the full extent of the differences in perception between adults and children and how that relates to individual genotype. We hypothesize that the substantial degree of sequence diversity and variation that exist in taste receptor genes¹⁵⁵ may underlie individual differences in medication adherence in children related to taste. Although these individual differences arise for a variety of reasons (e.g., temperament,¹⁵⁶ experience,¹⁵⁷ ethnicity/race¹⁵⁸), the best-known example is person-to-person genetic variation. As described above, variations in perception of the bitter compound PROP are due in large part to “taster” and “nontaster” alleles of a particular bitter receptor.^65,159 Allele frequencies for this gene differ markedly by race; for example, high sensitivity to the bitterness of PROP and related compounds is more common in African populations.¹⁵⁵

A recent study explored the relationship between genotype of one of the 25 bitter receptor genes (TAS2R38) and medication history.¹⁶⁰ Children younger than 10 years who had at least one taster (P) allele (PP or AP genotype) were more likely to have taken medicine in solid formulation than were nontaster (AA genotype) children. We hypothesized that the resistance to taking bitter liquid formulations may relate to compliance and that bitter-sensitive children may be resistant to taking bitter liquid formulations and motivated to try medicine in pill form as an alternative. Although children were genotyped for only one of the 25 known bitter receptors, alleles of this particular receptor may be a proxy for general taste ability,¹³⁸ or bitter receptor genes may occur in tightly linked clusters⁶⁰ such that genetic variation in this receptor may relate to variation in other receptors. This particular receptor may also respond more broadly than previously understood—drugs commonly used in children’s medications have not been widely tested in assays designed to understand such receptor-ligand interactions. Further study of the relationship between TAS2R38 genotype and liquid formulation intake and compliance is warranted.

Recent research has revealed that cell-based assays are imperfect proxies of the human taste response. For example, TAS2R38 has three variant sites that give rise to several taster and nontaster haplotypes. When cell-based assays¹⁵⁹ of these haplotypes are compared with studies of people with those same haplotypes,¹⁴¹ there is agreement in many cases but not in all, especially for variants that may directly couple with the G protein. This study highlights the need for psychophysical as well as cell-based methods to understand the genotype-phenotype relationship for taste receptors.¹⁴¹

Research to further characterize how taste receptor genotype and other aspects of taste phenotypes relate to pediatric medication formulation and compliance is necessary to help us develop better medicines for pediatric populations. Such research could be incorporated into pediatric clinical trials, to help understand individual compliance during the trial and to expand our understanding of the role of taste genetics in behavioral choices. Because children are more bitter-sensitive than are adults, and age-related changes in bitter perception are more common for people with particular genotypes, we need to study both adults and children and take genetic variation into account when interpreting the results.¹⁶⁰ Although we have studied only a few examples of how bitter receptor genotype can affect bitter perception,^{66,159,161–164} genotype, like age, it is an important determinant of perception and should be considered in all methods to evaluate the taste of medicine and compliance.

Many investigators are developing a new generation of molecules to inhibit bitterness.⁷⁹ However, there are very few peer-reviewed studies on their effectiveness in adults (reviewed in Roy 1997¹⁶⁵), and to our knowledge, only one study, conducted in our laboratory, has examined children.¹⁶⁶ Nevertheless, because of the age-related differences in bitter taste perception, we suggest that research aimed at reducing the bitterness of medicine, such as evaluating the effectiveness of bitter blockers, should directly involve children rather than extrapolating from data collected from adults.

6. Artificial Sensor Systems

There is much debate in the literature on whether artificial sensors can be successful substitutes for the human palate and replace the use of sensory panelists, since use of the latter is problematic in industry “due to the potential toxicity of drugs and subjectivity of taste panelists, problems in recruiting taste panelists, motivation and panel maintenance … when working with unpleasant products.”¹⁶⁷ Furthermore, because FDA-unapproved drugs cannot be taste tested, use of artificial sensors, it has been argued, can provide important data regarding the taste of these drugs.^167,168

These artificial sensory devices typically are arrays of sensors, called “electronic noses” for arrays of gas sensors and “electronic tongues” for arrays of liquid sensors. Often these devices are designed to analyze the levels of various ingredients composing a fluid mixture and in a variety of applications involving product quality control.¹⁶⁹ But in recent years, these devices have been used as an analytical gustatory tool in evaluating pharmaceuticals.^{167,170–173} It has been argued that this approach, whose advantages include its speed, relatively low cost, and lack of risk, will help develop more palatable pediatric formulations.^174–177

Nevertheless, whether such artificial sensory systems will lead to significant insights that will address the heart of the problem in practice remains to be seen. Given the numerous and varied components of peripheral and central mechanisms involved in the mediation of bitter taste (summarized in the Figure), the ability of an artificial sensor to model and predict the properties of this complex biological system is questionable. Thus, the utility of the electronic tongue to offer meaningful guidance in the development of strategies to increase the palatability of pediatric formulations is likely to be limited to simply providing a detailed analysis of the chemical constituents in the mixture. However, it is quite possible that, since this is an active area of research, these devices might be more useful in the future.

8. Conclusions

Like other sensory systems, taste is experienced through a “sensory window” that changes with age and experience and is partially defined by genetics. Children have well-developed sensory systems for detecting tastes, as well as smells and chemical irritants, and their rejection of unpalatable medications reflects their basic biological preferences for sweet, salty, and, to some extent, sour tastes and rejection of bitter tastes. Sugars, salt, acids, and other substances help reduce the perceived bitterness of several pharmaceuticals. Although adding pleasant flavor volatiles such as bubble gum may also help induce children to consume a medicine, such volatile compounds are often not very effective in suppressing the strong bitter tastes associated with many medications.

This aversion to bitter creates a roadblock for oral formulations; undesirable chemosensory characteristics can hinder the acceptance and usefulness of many beneficial, safe, and efficacious drugs. The unpleasant taste of a medicine is often a sensory expression of its pharmacological activity; in many cases, the more potent the drug, the more bitter it will be.¹⁷⁸ The more bitter, the more likely the drug will be rejected. Better-tasting medications may go a long way toward enhancing the ability of pediatric patients to adhere to drug therapy, especially when failure to consume may do harm and, in some cases, be life threatening.¹⁷⁹ Thus, a primary challenge is to reduce the bitterness and other off flavors of pediatric formulations.

Adult panelists who are sensitive to the pediatric palate, new techniques involving animal models, and even electronic detection devices are among the tools that can help evaluate the palatability of medications and predict compliance among pediatric populations. Further development of and consensus regarding which psychophysical tools are valid and appropriate for use with children will provide a better understanding of the sensory world of the child. Testing multiple strategies will help us refine methods that may be used to assess acceptance and compliance/adherence by pediatric populations of varying ages, which will allow for comparisons across studies. These methods then can be applied to clinical trials to obtain data that can help predict initial acceptance versus long-term compliance of a medication, and how medication usage and disease state modify bitter taste perception of the drug in children. While much of the research will by necessity focus on taste testing without swallowing, there are also bitter receptors in the back of the throat¹⁸⁰ that may be engaged primarily during swallowing of the liquid medication. The effect of these receptors on taste acceptance can be studied during clinical trials in which children not only taste but also swallow medicine.

While progress has been made in our current understanding of bitter taste, it is far from complete, and new ways to reduce the bitterness of certain medications may yet be discovered. Most of our knowledge on the neurobiological mechanisms of taste has been derived from animal models in which the gustatory system can be invasively manipulated and studied. As discussed in the preceding pages, a variety of behavioral techniques can be used to link taste perception to its underlying neurobiological processes. Accordingly, these model systems can be exploited to evaluate potential strategies to safely and effectively attenuate bitterness. Such an approach, coupled with psychophysical assessment of taste function in children, and ultimately clinical testing, should increase the chances of finding solutions to what has been the vexing problem of bitter taste reducing drug acceptance and compliance in pediatric populations— understanding bitterness better may take the guesswork out of improving formulations.

ACKNOWLEDGMENT

We acknowledge the valuable discussions with Dr. George Giacoia from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS, as well as other members of the Taste Working Group. Johan Lundström provided guidance about human taste brain areas.

CONFLICT OF INTEREST STATEMENT

Preparation of this article was supported in part by NIH grants R01 DC01187 (JM), P30 DC011735 (DR), and the Washington Dental Service Endowed Professorship (SC). Funding sources had no role in the study design; in the collection, analysis, or interpretation of data; in the writing of the manuscript; or in the decision to submit the manuscript for publication.

Footnotes

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

DEDICATION

We dedicate this review article to the memory of Dr. Barry Davis, past director of the taste and smell program within the National Institute on Deafness and Other Communication Disorders, and a friend and mentor.

Contributor Information

Julie A. Mennella, Monell Chemical Senses Center.

Alan C. Spector, Florida State University.

Danielle R. Reed, Monell Chemical Senses Center.

Susan E. Coldwell, University of Washington.

References

1.Roberts R, Rodriguez W, Murphy D, Crescenzi T. Pediatric drug labeling: improving the safety and efficacy of pediatric therapies. JAMA. 2003;290(7):905–911. doi: 10.1001/jama.290.7.905. [DOI] [PubMed] [Google Scholar]
2.Milne CP, Bruss JB. The economics of pediatric formulation development for off-patent drugs. Clin Ther. 2008;30(11):2133–2145. doi: 10.1016/j.clinthera.2008.11.019. [DOI] [PubMed] [Google Scholar]
3.Giacoia GP, Taylor-Zapata P, Mattison D. Eunice Kennedy Shriver National Institute of Child Health and Human Development Pediatric Formulation Initiative: selected reports from working groups. Clin Ther. 2008;30(11):2097–2101. doi: 10.1016/j.clinthera.2008.11.017. [DOI] [PubMed] [Google Scholar]
4.Glendinning JI. Is the bitter rejection response always adaptive? Physiol Behav. 1994;56(6):1217–1227. doi: 10.1016/0031-9384(94)90369-7. [DOI] [PubMed] [Google Scholar]
5.Rodgers GC, Jr, Tenenbein M. The role of aversive bittering agents in the prevention of pediatric poisonings. Pediatrics. 1994;93(1):68–69. [PubMed] [Google Scholar]
6.Schirm E, Tobi H, de Vries TW, Choonara I, De Jong-van den Berg LT. Lack of appropriate formulations of medicines for children in the community. Acta Paediatr. 2003;92(12):1486–1489. doi: 10.1080/08035250310006728. [DOI] [PubMed] [Google Scholar]
7.Ruark JL, McCullough GH, Peters RL, Moore CA. Bolus consistency and swallowing in children and adults. Dysphagia. 2002;17(1):24–33. doi: 10.1007/s00455-001-0098-0. [DOI] [PubMed] [Google Scholar]
8.Sadrieh N, Brower J, Yu L, et al. Stability, dose uniformity, and palatability of three counterterrorism drugs-human subject and electronic tongue studies. Pharm Res. 2005;22(10):1747–1756. doi: 10.1007/s11095-005-6387-x. [DOI] [PubMed] [Google Scholar]
9.Pawar S, Kumar A. Issues in the formulation of drugs for oral use in children: role of excipients. Paediatr Drugs. 2002;4(6):371–379. doi: 10.2165/00128072-200204060-00004. [DOI] [PubMed] [Google Scholar]
10.Ishizaka T, Okada S, Tokuyama E, Mukai J, Uchida T. Suppression of bitterness and improvement of palatability of commercial prednisolone powder. Chem Pharm Bull. 2008;56(10):1395–1399. doi: 10.1248/cpb.56.1395. [DOI] [PubMed] [Google Scholar]
11.Roberts IF, Roberts GJ. Relation between medicines sweetened with sucrose and dental disease. Br Med J. 1979;2(6181):14–16. doi: 10.1136/bmj.2.6181.14. [DOI] [PMC free article] [PubMed] [Google Scholar]
12.Hobson P. The treatment of medically handicapped children. Int Dent J. 1980;30(1):6–13. [PubMed] [Google Scholar]
13.Feigal RJ, Gleeson MC, Beckman TM, Greenwood ME. Dental caries related to liquid medication intake in young cardiac patients. ASDC J Dent Child. 1984;51(5):360–362. [PubMed] [Google Scholar]
14.Greenwood M, Feigal R, Messer H. Cariogenic potential of liquid medications in rats. Caries Res. 1984;18(5):447–449. doi: 10.1159/000260801. [DOI] [PubMed] [Google Scholar]
15.Manley MC, Calnan M, Sheiham A. A spoonful of sugar helps the medicine go down? Perspectives on the use of sugar in children's medicines. Soc Sci Med. 1994;39(6):833–840. doi: 10.1016/0277-9536(94)90045-0. [DOI] [PubMed] [Google Scholar]
16.Maguire A, Rugg-Gunn AJ. Changes in the prescribing of liquid oral medicines (LOMs) in the northern region of England between 1987 and 1992 with special regard to sugar content and long-term use in children. Community Dent Health. 1997;14(1):31–35. [PubMed] [Google Scholar]
17.Baqir W, Maguire A. Consumption of prescribed and over-the-counter medicines with prolonged oral clearance used by the elderly in the northern region of England, with special regard to generic prescribing, dose form and sugars content. Public Health. 2000;114(5):367–373. doi: 10.1038/sj.ph.1900673. [DOI] [PubMed] [Google Scholar]
18.Maguire A, Baqir W, Nunn JH. Are sugars-free medicines more erosive than sugars-containing medicines? An in vitro study of paediatric medicines with prolonged oral clearance used regularly and long-term by children. Int J Paediatr Dent. 2007;17(4):231–238. doi: 10.1111/j.1365-263X.2007.00826.x. [DOI] [PubMed] [Google Scholar]
19.Liem DG, Mennella JA. Heightened sour preferences during childhood. Chem Senses. 2003;28(2):173–180. doi: 10.1093/chemse/28.2.173. [DOI] [PMC free article] [PubMed] [Google Scholar]
20.Allen LV., Jr Dosage form design and development. Clin Ther. 2008;30(11):2102–2111. doi: 10.1016/j.clinthera.2008.11.015. [DOI] [PubMed] [Google Scholar]
21.Grenby TH, Phillips A, Desai T, Mistry M. Laboratory studies of the dental properties of soft drinks. Br J Nutr. 1989;62:451–464. doi: 10.1079/bjn19890045. [DOI] [PubMed] [Google Scholar]
22.Leung VW-H, Darvell BW. Artificial salivas for in vitro studies of dental materials. J Dent. 1997;25(6):475–484. doi: 10.1016/s0300-5712(96)00068-1. [DOI] [PubMed] [Google Scholar]
23.Thomson SA, Tuleu C, Wong IC, Keady S, Pitt KG, Sutcliffe AG. Minitablets: new modality to deliver medicines to preschool-aged children. Pediatrics. 2009;123(2):e235–e238. doi: 10.1542/peds.2008-2059. [DOI] [PubMed] [Google Scholar]
24.Peyrot des Gachons C, Beauchamp GK, Stern RM, Koch KL, Breslin PA. Bitter taste induces nausea. Curr Biol. 2011;21(7):R247–R248. doi: 10.1016/j.cub.2011.02.028. [DOI] [PubMed] [Google Scholar]
25.Bernstein IL. Learned taste aversions in children receiving chemotherapy. Science. 1978;200(4347):1302–1303. doi: 10.1126/science.663613. [DOI] [PubMed] [Google Scholar]
26.Nahata MC, Allen LV., Jr Extemporaneous drug formulations. Clin Ther. 2008;30(11):2112–2119. doi: 10.1016/j.clinthera.2008.11.020. [DOI] [PubMed] [Google Scholar]
27.Mennella JA, Beauchamp GK. Optimizing oral medications for children. Clin Ther. 2008;30(11):2120–2132. doi: 10.1016/j.clinthera.2008.11.018. [DOI] [PMC free article] [PubMed] [Google Scholar]
28.Glendinning JI. Effect of salivary proline-rich proteins on ingestive responses to tannic acid in mice. Chem Senses. 1992;17:1–12. [Google Scholar]
29.Cabras T, Melis M, Castagnola M, et al. Responsiveness to 6-n-propylthiouracil (PROP) is associated with salivary levels of two specific basic proline-rich proteins in humans. PLoS One. 2012;7(2):e30962. doi: 10.1371/journal.pone.0030962. [DOI] [PMC free article] [PubMed] [Google Scholar]
30.Miller IJ., Jr . Gustatory receptors of the palate. In: Katsuki Y, Sato M, Takagi S, Oomura Y, editors. Food Intake and Chemical Senses. Tokyo: University of Tokyo Press; 1977. pp. 173–186. [Google Scholar]
31.Miller IJ., Jr . Anatomy of the peripheral gustatory system. In: Doty RL, editor. Handbook of Olfaction and Gustation. New York: Dekker; 1995. pp. 521–547. [Google Scholar]
32.Hamilton RB, Norgren R. Central projections of gustatory nerves in the rat. J Comp Neurol. 1984;222(4):560–577. doi: 10.1002/cne.902220408. [DOI] [PubMed] [Google Scholar]
33.May OL, Hill DL. Gustatory terminal field organization and developmental plasticity in the nucleus of the solitary tract revealed through triple-fluorescence labeling. J Comp Neurol. 2006;497(4):658–669. doi: 10.1002/cne.21023. [DOI] [PMC free article] [PubMed] [Google Scholar]
34.Corson J, Aldridge A, Wilmoth K, Erisir A. A survey of oral cavity afferents to the rat nucleus tractus solitarii. J Comp Neurol. 2012;520(3):495–527. doi: 10.1002/cne.22715. [DOI] [PMC free article] [PubMed] [Google Scholar]
35.Lundy RF, Norgren R. The rat nervous system. 3rd ed. New York: Elsevier; 2004. Gustatory system; pp. 891–921. [Google Scholar]
36.Zaidi FN, Todd K, Enquist L, Whitehead MC. Types of taste circuits synaptically linked to a few geniculate ganglion neurons. J Comp Neurol. 2008;511(6):753–772. doi: 10.1002/cne.21869. [DOI] [PMC free article] [PubMed] [Google Scholar]
37.Travers SP, Travers JB. Reflex topography in the nucleus of the solitary tract. Chem Senses. 2005;30(Suppl 1):i180–i181. doi: 10.1093/chemse/bjh173. [DOI] [PubMed] [Google Scholar]
38.Norgren R. Taste and the autonomic nervous system. Chem Senses. 1985;10:143–161. [Google Scholar]
39.Pritchard TC, Norgren R. Gustatory system. In: Paxinos G, Mai J, editors. The Human Nervous System. 2nd ed. New York: Elsevier; 2004. pp. 1171–1195. [Google Scholar]
40.Lawless HT. Evidence for neural inhibition in bittersweet taste mixtures. J Comp Physiol Psychol. 1979;93(3):538–547. doi: 10.1037/h0077582. [DOI] [PubMed] [Google Scholar]
41.Kroeze JH, Bartoshuk LM. Bitterness suppression as revealed by split-tongue taste stimulation in humans. Physiol Behav. 1985;35(5):779–783. doi: 10.1016/0031-9384(85)90412-3. [DOI] [PubMed] [Google Scholar]
42.Formaker BK, MacKinnon BI, Hettinger TP, Frank ME. Opponent effects of quinine and sucrose on single fiber taste responses of the chorda tympani nerve. Brain Res. 1997;772(1–2):239–242. doi: 10.1016/s0006-8993(97)00845-7. [DOI] [PubMed] [Google Scholar]
43.Lehman CD, Bartoshuk LM, Catalanotto FC, Kveton JF, Lowlicht RA. Effect of anesthesia of the chorda tympani nerve on taste perception in humans. Physiol Behav. 1995;57(5):943–951. doi: 10.1016/0031-9384(95)91121-r. [DOI] [PubMed] [Google Scholar]
44.Kinnamon SC. Taste receptor signalling—from tongues to lungs. Acta Physiol (Oxf) 2012;204(2):158–168. doi: 10.1111/j.1748-1716.2011.02308.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
45.Niki M, Jyotaki M, Yoshida R, Ninomiya Y. Reciprocal modulation of sweet taste by leptin and endocannabinoids. Results Probl Cell Differ. 2010;52:101–114. doi: 10.1007/978-3-642-14426-4_9. [DOI] [PubMed] [Google Scholar]
46.Bigiani A, Ghiaroni V, Fieni F. Channels as taste receptors in vertebrates. Prog Biophys Mol Biol. 2003;83(3):193–225. doi: 10.1016/s0079-6107(03)00058-0. [DOI] [PubMed] [Google Scholar]
47.Chandrashekar J, Hoon MA, Ryba NJ, Zuker CS. The receptors and cells for mammalian taste. Nature. 2006;444(7117):288–294. doi: 10.1038/nature05401. [DOI] [PubMed] [Google Scholar]
48.Ninomiya Y, Fukami Y, Yamazaki K, Beauchamp GK. Amiloride inhibition of chorda tympani responses to NaCl and its temperature dependency in mice. Brain Res. 1996;708(1–2):153–158. doi: 10.1016/0006-8993(95)01218-4. [DOI] [PubMed] [Google Scholar]
49.Ohkuri T, Yasumatsu K, Horio N, Jyotaki M, Margolskee RF, Ninomiya Y. Multiple sweet receptors and transduction pathways revealed in knockout mice by temperature dependence and gurmarin sensitivity. Am J Physiol Regul Integr Comp Physiol. 2009;296(4):R960–R971. doi: 10.1152/ajpregu.91018.2008. [DOI] [PMC free article] [PubMed] [Google Scholar]
50.Talavera K, Yasumatsu K, Voets T, et al. Heat activation of TRPM5 underlies thermal sensitivity of sweet taste. Nature. 2005;438(7070):1022–1025. doi: 10.1038/nature04248. [DOI] [PubMed] [Google Scholar]
51.Kokrashvili Z, Mosinger B, Margolskee RF. Taste signaling elements expressed in gut enteroendocrine cells regulate nutrient-responsive secretion of gut hormones. Am J Clin Nutr. 2009;90(3):822S–825S. doi: 10.3945/ajcn.2009.27462T. [DOI] [PMC free article] [PubMed] [Google Scholar]
52.Behrens M, Meyerhof W. Gustatory and extragustatory functions of mammalian taste receptors. Physiol Behav. 2011;105(1):4–13. doi: 10.1016/j.physbeh.2011.02.010. [DOI] [PubMed] [Google Scholar]
53.Finger TE, Kinnamon SC. Taste isn't just for taste buds anymore. F1000 Biol Rep. 2011;3:20. doi: 10.3410/B3-20. [DOI] [PMC free article] [PubMed] [Google Scholar]
54.Rozengurt E, Sternini C. Taste receptor signaling in the mammalian gut. Curr Opin Pharmacol. 2007;7(6):557–562. doi: 10.1016/j.coph.2007.10.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
55.Kellenberger S, Schild L. Epithelial sodium channel/degenerin family of ion channels: a variety of functions for a shared structure. Physiol Rev. 2002;82(3):735–767. doi: 10.1152/physrev.00007.2002. [DOI] [PubMed] [Google Scholar]
56.Lee RJ, Xiong G, Kofonow JM, et al. T2R38 taste receptor polymorphisms underlie susceptibility to upper respiratory infection. J Clin Invest. 2012;122(11):4145–4159. doi: 10.1172/JCI64240. [DOI] [PMC free article] [PubMed] [Google Scholar]
57.Zhang Y, Hoon MA, Chandrashekar J, et al. Coding of sweet, bitter, and umami tastes: different receptor cells sharing similar signaling pathways. Cell. 2003;112(3):293–301. doi: 10.1016/s0092-8674(03)00071-0. [DOI] [PubMed] [Google Scholar]
58.McLaughlin SK, McKinnon PJ, Margolskee RF. Gustducin is a taste-cell-specific G protein closely related to the transducins. Nature. 1992;357(6379):563–569. doi: 10.1038/357563a0. [DOI] [PubMed] [Google Scholar]
59.Wong GT, Gannon KS, Margolskee RF. Transduction of bitter and sweet taste by gustducin. Nature. 1996;381(6585):796–800. doi: 10.1038/381796a0. [DOI] [PubMed] [Google Scholar]
60.Adler E, Hoon MA, Mueller KL, Chandrashekar J, Ryba NJ, Zuker CS. A novel family of mammalian taste receptors. Cell. 2000;100(6):693–702. doi: 10.1016/s0092-8674(00)80705-9. [DOI] [PubMed] [Google Scholar]
61.Chandrashekar J, Mueller KL, Hoon MA, et al. T2Rs function as bitter taste receptors. Cell. 2000;100(6):703–711. doi: 10.1016/s0092-8674(00)80706-0. [DOI] [PubMed] [Google Scholar]
62.Meyerhof W, Batram C, Kuhn C, et al. The molecular receptive ranges of human TAS2R bitter taste receptors. Chem Senses. 2010;35(2):157–170. doi: 10.1093/chemse/bjp092. [DOI] [PubMed] [Google Scholar]
63.Behrens M, Meyerhof W. Mammalian bitter taste perception. Results Probl Cell Differ. 2009;47:203–220. doi: 10.1007/400_2008_5. [DOI] [PubMed] [Google Scholar]
64.Fox AL. The relationship between chemical constitution and taste. Proc Natl Acad Sci USA. 1932;18:115–120. doi: 10.1073/pnas.18.1.115. [DOI] [PMC free article] [PubMed] [Google Scholar]
65.Kim U, Jorgenson E, Coon H, Leppert M, Risch N, Drayna D. Positional cloning of the human quantitative trait locus underlying taste sensitivity to phenylthiocarbamide. Science. 2003;299:1221–1225. doi: 10.1126/science.1080190. [DOI] [PubMed] [Google Scholar]
66.Reed DR, Zhu G, Breslin PA, et al. The perception of quinine taste intensity is associated with common genetic variants in a bitter receptor cluster on chromosome 12. Hum Mol Genet. 2010;19(21):4278–4285. doi: 10.1093/hmg/ddq324. [DOI] [PMC free article] [PubMed] [Google Scholar]
67.Nelson G, Hoon MA, Chandrashekar J, Zhang Y, Ryba NJ, Zuker CS. Mammalian sweet taste receptors. Cell. 2001;106:381–390. doi: 10.1016/s0092-8674(01)00451-2. [DOI] [PubMed] [Google Scholar]
68.Caicedo A, Roper SD. Taste receptor cells that discriminate between bitter stimuli. Science. 2001;291(5508):1557–1560. doi: 10.1126/science.291.5508.1557. [DOI] [PMC free article] [PubMed] [Google Scholar]
69.Frank ME. Taste-responsive neurons of the glossopharyngeal nerve of the rat. J Neurophysiol. 1991;65(6):1452–1463. doi: 10.1152/jn.1991.65.6.1452. [DOI] [PubMed] [Google Scholar]
70.Frank ME, Contreras RJ, Hettinger TP. Nerve fibers sensitive to ionic taste stimuli in chorda tympani of the rat. J Neurophysiol. 1983;50(4):941–960. doi: 10.1152/jn.1983.50.4.941. [DOI] [PubMed] [Google Scholar]
71.Spector AC, Travers SP. The representation of taste quality in the mammalian nervous system. Behav Cogn Neurosci Rev. 2005;4(3):143–191. doi: 10.1177/1534582305280031. [DOI] [PubMed] [Google Scholar]
72.Dahl M, Erickson RP, Simon SA. Neural responses to bitter compounds in rats. Brain Res. 1997;756(1–2):22–34. doi: 10.1016/s0006-8993(97)00131-5. [DOI] [PubMed] [Google Scholar]
73.Spector AC. Linking gustatory neurobiology to behavior in vertebrates. Neurosci Biobehav Rev. 2000;24(4):391–416. doi: 10.1016/s0149-7634(00)00013-0. [DOI] [PubMed] [Google Scholar]
74.Geran LC, Travers SP. Single neurons in the nucleus of the solitary tract respond selectively to bitter taste stimuli. J Neurophysiol. 2006;96(5):2513–2527. doi: 10.1152/jn.00607.2006. [DOI] [PubMed] [Google Scholar]
75.Geran LC, Travers SP. Bitter-responsive gustatory neurons in the rat parabrachial nucleus. J Neurophysiol. 2009;101(3):1598–1612. doi: 10.1152/jn.91168.2008. [DOI] [PMC free article] [PubMed] [Google Scholar]
76.Lemon CH, Smith DV. Neural representation of bitter taste in the nucleus of the solitary tract. J Neurophysiol. 2005;94(6):3719–3729. doi: 10.1152/jn.00700.2005. [DOI] [PubMed] [Google Scholar]
77.Chen X, Gabitto M, Peng Y, Ryba NJ, Zuker CS. A gustotopic map of taste qualities in the mammalian brain. Science. 2011;333(6047):1262–1266. doi: 10.1126/science.1204076. [DOI] [PMC free article] [PubMed] [Google Scholar]
78.Accolla R, Bathellier B, Petersen CC, Carleton A. Differential spatial representation of taste modalities in the rat gustatory cortex. J Neurosci. 2007;27(6):1396–1404. doi: 10.1523/JNEUROSCI.5188-06.2007. [DOI] [PMC free article] [PubMed] [Google Scholar]
79.Palmer RK. The pharmacology and signaling of bitter, sweet, and umami taste sensing. Mol Interv. 2007;7(2):87–98. doi: 10.1124/mi.7.2.9. [DOI] [PubMed] [Google Scholar]
80.Rozin P. “Taste-smell confusions” and the duality of the olfactory sense. Percept Psychophys. 1982;31(4):397–401. doi: 10.3758/bf03202667. [DOI] [PubMed] [Google Scholar]
81.Spector AC. Doty RL. Handbook of Olfaction and Gustation. 2nd ed. New York: Dekker; 2003. Psychophysical evaluation of taste function in non-human mammals; pp. 861–879. [Google Scholar]
82.Davis JD. The effectiveness of some sugars in stimulating licking behavior in the rat. Physiol Behav. 1973;11(1):39–45. doi: 10.1016/0031-9384(73)90120-0. [DOI] [PubMed] [Google Scholar]
83.O'Keefe GB, Schumm J, Smith JC. Loss of sensitivity to low concentrations of NaCl following bilateral chorda tympani nerve sections in rats. Chem Senses. 1994;19(2):169–184. doi: 10.1093/chemse/19.2.169. [DOI] [PubMed] [Google Scholar]
84.St John SJ, Garcea M, Spector AC. Combined, but not single, gustatory nerve transection substantially alters taste-guided licking behavior to quinine in rats. Behav Neurosci. 1994;108(1):131–140. doi: 10.1037//0735-7044.108.1.131. [DOI] [PubMed] [Google Scholar]
85.Glendinning JI, Gresack J, Spector AC. A high-throughput screening procedure for identifying mice with aberrant taste and oromotor function. Chem Senses. 2002;27(5):461–474. doi: 10.1093/chemse/27.5.461. [DOI] [PubMed] [Google Scholar]
86.Treesukosol Y, Smith KR, Spector AC. Behavioral evidence for a glucose polymer taste receptor that is independent of the T1R2+3 heterodimer in a mouse model. J Neurosci. 2011;31(38):13527–13534. doi: 10.1523/JNEUROSCI.2179-11.2011. [DOI] [PMC free article] [PubMed] [Google Scholar]
87.Spector AC. Gustatory parabrachial lesions disrupt taste-guided quinine responsiveness in rats. Behav Neurosci. 1995;109(1):79–90. doi: 10.1037//0735-7044.109.1.79. [DOI] [PubMed] [Google Scholar]
88.Young PT, Trafton CL. Activity contour maps as related to preference in four gustatory stimulus areas of the rat. J Comp Physiol Psychol. 1964;58:68–75. doi: 10.1037/h0044823. [DOI] [PubMed] [Google Scholar]
89.Smith JC. The history of the “Davis Rig.”. Appetite. 2001;36(1):93–98. doi: 10.1006/appe.2000.0372. [DOI] [PubMed] [Google Scholar]
90.Smith JC, Davis JD, O'Keefe GB. Lack of an order effect in brief contact taste tests with closely spaced test trials. Physiol Behav. 1992;52(6):1107–1111. doi: 10.1016/0031-9384(92)90467-g. [DOI] [PubMed] [Google Scholar]
91.Damak S, Rong M, Yasumatsu K, et al. Trpm5 null mice respond to bitter, sweet, and umami compounds. Chem Senses. 2006;31(3):253–264. doi: 10.1093/chemse/bjj027. [DOI] [PubMed] [Google Scholar]
92.Dotson CD, Roper SD, Spector AC. PLCbeta2-independent behavioral avoidance of prototypical bitter-tasting ligands. Chem Senses. 2005;30(7):593–600. doi: 10.1093/chemse/bji053. [DOI] [PMC free article] [PubMed] [Google Scholar]
93.Berridge KC. Measuring hedonic impact in animals and infants: microstructure of affective taste reactivity patterns. Neurosci Biobehav Rev. 2000;24(2):173–198. doi: 10.1016/s0149-7634(99)00072-x. [DOI] [PubMed] [Google Scholar]
94.Grill HJ, Norgren R. The taste reactivity test. I. Mimetic responses to gustatory stimuli in neurologically normal rats. Brain Res. 1978;143(2):263–279. doi: 10.1016/0006-8993(78)90568-1. [DOI] [PubMed] [Google Scholar]
95.Spector AC, Breslin P, Grill HJ. Taste reactivity as a dependent measure of the rapid formation of conditioned taste aversion: a tool for the neural analysis of taste-visceral associations. Behav Neurosci. 1988;102(6):942–952. doi: 10.1037//0735-7044.102.6.942. [DOI] [PubMed] [Google Scholar]
96.Berridge KC. Food reward: brain substrates of wanting and liking. Neurosci Biobehav Rev. 1996;20(1):1–25. doi: 10.1016/0149-7634(95)00033-b. [DOI] [PubMed] [Google Scholar]
97.Grill HJ, Spector AC, Schwartz GJ, Kaplan JM, Flynn FW. Evaluating taste effects on ingestive behavior. In: Toates F, Rowland N, editors. Techniques in the Behavioral and Neural Sciences. Vol. 1. Amsterdam: Elsevier; 1987. pp. 151–188. Feeding and Drinking. [Google Scholar]
98.Travers JB, Grill HJ, Norgren R. The effects of glossopharyngeal and chorda tympani nerve cuts on the ingestion and rejection of sapid stimuli: an electromyographic analysis in the rat. Behav Brain Res. 1987;25(3):233–246. doi: 10.1016/0166-4328(87)90071-4. [DOI] [PubMed] [Google Scholar]
99.Grill HJ, Schwartz GJ, Travers JB. The contribution of gustatory nerve input to oral motor behavior and intake-based preference. I. Effects of chorda tympani or glossopharyngeal nerve section in the rat. Brain Res. 1992;573(1):95–104. doi: 10.1016/0006-8993(92)90117-r. [DOI] [PubMed] [Google Scholar]
100.King CT, Garcea M, Spector AC. Glossopharyngeal nerve regeneration is essential for the complete recovery of quinine-stimulated oromotor rejection behaviors and central patterns of neuronal activity in the nucleus of the solitary tract in the rat. J Neurosci. 2000;20(22):8426–8434. doi: 10.1523/JNEUROSCI.20-22-08426.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
101.Nowlis GH, Frank ME, Pfaffmann C. Specificity of acquired aversions to taste qualities in hamsters and rats. J Comp Physiol Psychol. 1980;94(5):932–942. doi: 10.1037/h0077809. [DOI] [PubMed] [Google Scholar]
102.Tapper DN, Halpern BP. Taste stimuli: a behavioral categorization. Science. 1968;161(3842):708–710. doi: 10.1126/science.161.3842.708. [DOI] [PubMed] [Google Scholar]
103.Grobe CL, Spector AC. Constructing quality profiles for taste compounds in rats: a novel paradigm. Physiol Behav. 2008;95(3):413–424. doi: 10.1016/j.physbeh.2008.07.007. [DOI] [PubMed] [Google Scholar]
104.Spector AC, Kopka SL. Rats fail to discriminate quinine from denatonium: implications for the neural coding of bitter-tasting compounds. J Neurosci. 2002;22(5):1937–1941. doi: 10.1523/JNEUROSCI.22-05-01937.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
105.Chambers E. Commentary: conducting sensory research in children. J Sensory Stud. 2005;20:90–92. [Google Scholar]
106.Forestell CA, Mennella JA. The ontogeny of taste perception and preference throughout childhood. In: Doty RL, editor. Handbook of Olfaction and Gustation. 3rd ed. Boca Raton, FL: CRC Press; in press. [Google Scholar]
107.Cowart BJ. Development of taste perception in humans: sensitivity and preference throughout the life span. Psychol Bull. 1981;90(1):43–73. [PubMed] [Google Scholar]
108.Cowart BJ, Beauchamp GK, Mennella JA. Development of taste and smell in the neonate. In: Polin RA, Fox WW, Abman SH, editors. Fetal and Neonatal Physiology. 3rd ed. Vol. 2. Philadelphia: Saunders; 2004. pp. 1819–1827. [Google Scholar]
109.Schneider BA, Trehub SE, Morrongiello BA, Thorpe LA. Developmental changes in masked thresholds. J Acoust Soc Am. 1989;86(5):1733–1742. doi: 10.1121/1.398604. [DOI] [PubMed] [Google Scholar]
110.Dorries KM, Schmidt HJ, Beauchamp GK, Wysocki CJ. Changes in sensitivity to the odor of androstenone during adolescence. Dev Psychobiol. 1989;22(5):423–435. doi: 10.1002/dev.420220502. [DOI] [PubMed] [Google Scholar]
111.Odeigah PG, Obieze AC. Differences in sodium chloride taste sensitivity in a rural and an urban population in Nigeria: implications for the incidence of hypertension. East Afr Med J. 1986;63(4):236–243. [PubMed] [Google Scholar]
112.Patil S, Maibach HI. Effect of age and sex on the elicitation of irritant contact dermatitis. Contact Dermatitis. 1994;30(5):257–264. doi: 10.1111/j.1600-0536.1994.tb00594.x. [DOI] [PubMed] [Google Scholar]
113.Desor J, Maller O, Turner R. Taste in acceptance of sugars by human infants. J Comp Phys Psychol. 1973;84:496–501. doi: 10.1037/h0034906. [DOI] [PubMed] [Google Scholar]
114.Steiner J. Facial expressions of the neonate infant indicating the hedonics of food-related chemical stimuli. In: Weiffenbach JM, editor. Taste and Development: The Genesis of Sweet Preference. Washington, DC: U.S. Government Printing Office; 1977. pp. 173–188. [Google Scholar]
115.Rosenstein D, Oster H. Differential facial responses to four basic tastes in newborns. Child Dev. 1988;59(6):1555–1568. [PubMed] [Google Scholar]
116.Steiner JE, Glaser D, Hawilo ME, Berridge KC. Comparative expression of hedonic impact: affective reactions to taste by human infants and other primates. Neurosci Biobehav Rev. 2001;25(1):53–74. doi: 10.1016/s0149-7634(00)00051-8. [DOI] [PubMed] [Google Scholar]
117.Beauchamp GK, Cowart BJ, Moran M. Developmental changes in salt acceptability in human infants. Dev Psychobiol. 1986;19(1):17–25. doi: 10.1002/dev.420190103. [DOI] [PubMed] [Google Scholar]
118.Beauchamp GK, Cowart BJ. Development of sweet taste. In: Dobbing J, editor. Sweetness. London: Springer; 1987. pp. 127–138. [Google Scholar]
119.Beauchamp GK, Moran M. Acceptance of sweet and salty tastes in 2-year-old children. Appetite. 1984;5(4):291–305. doi: 10.1016/s0195-6663(84)80002-1. [DOI] [PubMed] [Google Scholar]
120.Liem DG, Mennella JA. Sweet and sour preferences during childhood: role of early experiences. Dev Psychobiol. 2002;41(4):388–395. doi: 10.1002/dev.10067. [DOI] [PMC free article] [PubMed] [Google Scholar]
121.Spector AC, Smith JC, Hollander GR. A comparison of dependent measures used to quantify radiation-induced taste aversion. Physiol Behav. 1981;27(5):887–901. doi: 10.1016/0031-9384(81)90059-7. [DOI] [PubMed] [Google Scholar]
122.Berridge KC, Kringelbach ML. Affective neuroscience of pleasure: reward in humans and animals. Psychopharmacology (Berl) 2008;199(3):457–480. doi: 10.1007/s00213-008-1099-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
123.Boughter JDJ, Bachmanov AA. Behavioral genetics and taste. BMC Neurosci. 2007;8(Suppl 3):S3. doi: 10.1186/1471-2202-8-S3-S3. [DOI] [PMC free article] [PubMed] [Google Scholar]
124.Mennella JA, Griffin CE, Beauchamp GK. Flavor programming during infancy. Pediatrics. 2004;113(4):840–845. doi: 10.1542/peds.113.4.840. [DOI] [PMC free article] [PubMed] [Google Scholar]
125.Forestell CA, Mennella JA. More than just a pretty face. The relationship between infant's temperament, food acceptance, and mothers' perceptions of their enjoyment of food. Appetite. 2012;58(3):1136–1142. doi: 10.1016/j.appet.2012.03.005. [DOI] [PMC free article] [PubMed] [Google Scholar]
126.Forestell CA, Mennella JA. Early determinants of fruit and vegetable acceptance. Pediatrics. 2007;120(6):1247–1254. doi: 10.1542/peds.2007-0858. [DOI] [PMC free article] [PubMed] [Google Scholar]
127.Ekman P, Friesen WV. Facial Action Coding System: A Technique for the Measurement of Facial Movement. Palo Alto, CA: Consulting Psychologists Press; 1978. [Google Scholar]
128.Mennella JA, Forestell CA, Morgan LK, Beauchamp GK. Early milk feeding influences taste acceptance and liking during infancy. Am J Clin Nutr. 2009;90(3):780S–788S. doi: 10.3945/ajcn.2009.27462O. [DOI] [PMC free article] [PubMed] [Google Scholar]
129.Beauchamp GK, Cowart BJ, Mennella JA, Marsh RR. Infant salt taste: developmental, methodological, and contextual factors. Dev Psychobiol. 1994;27(6):353–365. doi: 10.1002/dev.420270604. [DOI] [PubMed] [Google Scholar]
130.Kajiura H, Cowart BJ, Beauchamp GK. Early developmental change in bitter taste responses in human infants. Dev Psychobiol. 1992;25(5):375–386. doi: 10.1002/dev.420250508. [DOI] [PubMed] [Google Scholar]
131.Mennella JA, Lukasewycz LD, Castor SM, Beauchamp GK. The timing and duration of a sensitive period in human flavor learning: a randomized trial. Am J Clin Nutr. 2011;93(5):1019–1024. doi: 10.3945/ajcn.110.003541. [DOI] [PMC free article] [PubMed] [Google Scholar]
132.Desor JA, Maller O, Andrews K. Ingestive responses of human newborns to salty, sour, and bitter stimuli. J Comp Physiol Psychol. 1975;89(8):966–970. doi: 10.1037/h0077171. [DOI] [PubMed] [Google Scholar]
133.Maone TR, Mattes RD, Bernbaum JC, Beauchamp GK. A new method for delivering a taste without fluids to preterm and term infants. Dev Psychobiol. 1990;13:179–191. doi: 10.1002/dev.420230208. [DOI] [PubMed] [Google Scholar]
134.Mennella JA. Infants’ suckling responses to the flavor of alcohol in mothers’ milk. Alcohol Clin Exp Res. 1997;21(4):581–585. [PubMed] [Google Scholar]
135.Harris H, Kalmus H. The measurement of taste sensitivity to phenylthiourea (P.T.C.) Ann Eugenics. 1949;15:24–31. doi: 10.1111/j.1469-1809.1949.tb02419.x. [DOI] [PubMed] [Google Scholar]
136.Tepper BJ, Christensen CM, Cao J. Development of brief methods to classify individuals by PROP taster status. Physiol Behav. 2001;73(4):571–577. doi: 10.1016/s0031-9384(01)00500-5. [DOI] [PubMed] [Google Scholar]
137.Mennella JA, Pepino MY, Reed DR. Genetic and environmental determinants of bitter perception and sweet preferences. Pediatrics. 2005;115(2):e216–e222. doi: 10.1542/peds.2004-1582. [DOI] [PMC free article] [PubMed] [Google Scholar]
138.Bartoshuk LM, Duffy VB, Reed D, Williams A. Supertasting, earaches and head injury: genetics and pathology alter our taste worlds. Neurosci Biobehav Rev. 1996;20(1):79–87. doi: 10.1016/0149-7634(95)00042-d. [DOI] [PubMed] [Google Scholar]
139.Anliker JA, Bartoshuk L, Ferris AM, Hooks LD. Children's food preferences and genetic sensitivity to the bitter taste of 6-n-propylthiouracil (PROP) Am J Clin Nutr. 1991;54(2):316–320. doi: 10.1093/ajcn/54.2.316. [DOI] [PubMed] [Google Scholar]
140.Mennella JA, Pepino MY, Duke FF, Reed DR. Age modifies the genotype-phenotype relationship for the bitter receptor TAS2R38. BMC Genet. 2010;11:60. doi: 10.1186/1471-2156-11-60. [DOI] [PMC free article] [PubMed] [Google Scholar]
141.Mennella JA, Pepino MY, Duke FF, Reed DR. Psychophysical dissection of genotype effects on human bitter perception. Chem Senses. 2011;36(2):161–167. doi: 10.1093/chemse/bjq106. [DOI] [PMC free article] [PubMed] [Google Scholar]
142.James CE, Laing DG, Oram N. A comparison of the ability of 8–9-year-old children and adults to detect taste stimuli. Physiol Behav. 1997;62(1):193–197. doi: 10.1016/s0031-9384(97)00030-9. [DOI] [PubMed] [Google Scholar]
143.Guinard JX. Sensory and consumer testing with children. Trends Food Sci Technol. 2001;11:273–283. [Google Scholar]
144.Baguley D, Lim E, Bevan A, Pallet A, Faust SN. Prescribing for children—taste and palatability affect adherence to antibiotics: a review. Arch Dis Child. 2012;97(3):293–297. doi: 10.1136/archdischild-2011-300909. [DOI] [PubMed] [Google Scholar]
145.Angelilli ML, Toscani M, Matsui DM, Rieder MJ. Palatability of oral antibiotics among children in an urban primary care center. Arch Pediatr Adolesc Med. 2000;154(3):267–270. doi: 10.1001/archpedi.154.3.267. [DOI] [PubMed] [Google Scholar]
146.Cohen R, de La Rocque F, Lecuyer A, Wollner C, Bodin MJ, Wollner A. Study of the acceptability of antibiotic syrups, suspensions, and oral solutions prescribed to pediatric outpatients. Eur J Pediatr. 2009;168(7):851–857. doi: 10.1007/s00431-008-0857-0. [DOI] [PubMed] [Google Scholar]
147.Holas C, Chiu YL, Notario G, Kapral D. A pooled analysis of seven randomized crossover studies of the palatability of cefdinir oral suspension versus amoxicillin/clavulanate potassium, cefprozil, azithromycin, and amoxicillin in children aged 4 to 8 years. Clin Ther. 2005;27(12):1950–1960. doi: 10.1016/j.clinthera.2005.11.017. [DOI] [PubMed] [Google Scholar]
148.Milani G, Ragazzi M, Simonetti GD, et al. Superior palatability of crushed lercanidipine compared with amlodipine among children. Br J Clin Pharmacol. 2010;69(2):204–206. doi: 10.1111/j.1365-2125.2009.03580.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
149.Powers JL, Gooch WM, III, Oddo LP. Comparison of the palatability of the oral suspension of cefdinir vs. amoxicillin/clavulanate potassium, cefprozil and azithromycin in pediatric patients. Pediatr Infect Dis J. 2000;19(12 Suppl):S174–S180. doi: 10.1097/00006454-200012001-00008. [DOI] [PubMed] [Google Scholar]
150.Davies EH, Tuleu C. Medicines for children: a matter of taste. J Pediatr. 2008;153(5):599–604. doi: 10.1016/j.jpeds.2008.06.030. [DOI] [PubMed] [Google Scholar]
151.Motte J, Pedespan JM, Sevestre M, Chiron C. [Acceptability and tolerance of sodium valproate, a new sustained-action granule formulation, in monotherapy for epileptic children from 3 years old] Arch Pediatr. 2005;12(10):1533–1539. doi: 10.1016/j.arcped.2005.07.009. [DOI] [PubMed] [Google Scholar]
152.Guenther Skokan E, Junkins EP, Jr, Corneli HM, Schunk JE. Taste test: children rate flavoring agents used with activated charcoal. Arch Pediatr Adolesc Med. 2001;155(6):683–686. doi: 10.1001/archpedi.155.6.683. [DOI] [PubMed] [Google Scholar]
153.Sjovall J, Fogh A, Huitfeldt B, Karlsson G, Nylen O. Methods for evaluating the taste of paediatric formulations in children: a comparison between the facial hedonic method and the patients’ own spontaneous verbal judgement. Eur J Pediatr. 1984;141(4):243–247. doi: 10.1007/BF00572770. [DOI] [PubMed] [Google Scholar]
154.Leon F, Couronne T, Marcuz MC, Koster EP. Measuring food liking in children: a comparison on non verbal methods. Food Qual Pref. 1999;10:93–100. [Google Scholar]
155.Kim U, Wooding S, Ricci D, Jorde LB, Drayna D. Worldwide haplotype diversity and coding sequence variation at human bitter taste receptor loci. Hum Mutat. 2005;26(3):199–204. doi: 10.1002/humu.20203. [DOI] [PubMed] [Google Scholar]
156.Macht M, Mueller J. Increased negative emotional responses in PROP supertasters. Physiol Behav. 2007;90(2–3):466–472. doi: 10.1016/j.physbeh.2006.10.011. [DOI] [PubMed] [Google Scholar]
157.Mela DJ, Mattes RD, Tanimura S, Garcia-Medina MR. Relationships between ingestion and gustatory perception of caffeine. Pharmacol Biochem Behav. 1992;43(2):513–521. doi: 10.1016/0091-3057(92)90186-j. [DOI] [PubMed] [Google Scholar]
158.Guo SW, Reed DR. The genetics of phenylthiocarbamide perception. Ann Hum Biol. 2001;28(2):111–142. doi: 10.1080/03014460151056310. [DOI] [PMC free article] [PubMed] [Google Scholar]
159.Bufe B, Breslin PA, Kuhn C, et al. The molecular basis of individual differences in phenylthiocarbamide and propylthiouracil bitterness perception. Curr Biol. 2005;15(4):322–327. doi: 10.1016/j.cub.2005.01.047. [DOI] [PMC free article] [PubMed] [Google Scholar]
160.Lipchock SV, Reed DR, Mennella JA. Relationship between bitter-taste receptor genotype and solid medication formulation usage among young children: a retrospective analysis. Clin Ther. 2012;34(3):728–733. doi: 10.1016/j.clinthera.2012.02.006. [DOI] [PMC free article] [PubMed] [Google Scholar]
161.Hayes JE, Wallace MR, Knopik VS, Herbstman DM, Bartoshuk LM, Duffy VB. Allelic variation in TAS2R bitter receptor genes associates with variation in sensations from and ingestive behaviors toward common bitter beverages in adults. Chem Senses. 2010;36(3):311–319. doi: 10.1093/chemse/bjq132. [DOI] [PMC free article] [PubMed] [Google Scholar]
162.Kuhn C, Bufe B, Winnig M, et al. Bitter taste receptors for saccharin and acesulfame K. J Neurosci. 2004;24(45):10260–10265. doi: 10.1523/JNEUROSCI.1225-04.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
163.Wooding S, Gunn H, Ramos P, Thalmann S, Xing C, Meyerhof W. Genetics and bitter taste responses to goitrin, a plant toxin found in vegetables. Chem Senses. 2010;35:685–692. doi: 10.1093/chemse/bjq061. [DOI] [PubMed] [Google Scholar]
164.Roudnitzky N, Bufe B, Thalmann S, et al. Genomic, genetic, and functional dissection of bitter taste responses to artificial sweeteners. Hum Mol Genet. 2011;20(17):3437–3449. doi: 10.1093/hmg/ddr252. [DOI] [PubMed] [Google Scholar]
165.Roy G. Modifying Bitterness: Mechanism, Ingredients, And applications. Boca Raton, FL: CRC Press; 1997. [Google Scholar]
166.Mennella JA, Pepino MY, Beauchamp GK. Modification of bitter taste in children. Dev Psychobiol. 2003;43(2):120–127. doi: 10.1002/dev.10127. [DOI] [PMC free article] [PubMed] [Google Scholar]
167.Latha RS, Lakshmi PK. Electronic tongue: an analytical gustatory tool. J Adv Pharm Technol Res. 2012;3(1):3–8. doi: 10.4103/2231-4040.93556. [DOI] [PMC free article] [PubMed] [Google Scholar]
168.Woertz K, Tissen C, Kleinebudde P, Breitkreutz J. Taste sensing systems (electronic tongues) for pharmaceutical applications. Int J Pharm. 2011;417(1–2):256–271. doi: 10.1016/j.ijpharm.2010.11.028. [DOI] [PubMed] [Google Scholar]
169.Ferreira M, Riul A, Jr, Wohnrath K, Fonseca FJ, Oliveira ON, Jr, Mattoso LH. High-performance taste sensor made from Langmuir-Blodgett films of conducting polymers and a ruthenium complex. Anal Chem. 2003;75(4):953–955. doi: 10.1021/ac026031p. [DOI] [PubMed] [Google Scholar]
170.Zheng JY, Keeney MP. Taste masking analysis in pharmaceutical formulation development using an electronic tongue. Int J Pharm. 2006;310(1–2):118–124. doi: 10.1016/j.ijpharm.2005.11.046. [DOI] [PubMed] [Google Scholar]
171.Kayumba PC, Huyghebaert N, Cordella C, Ntawukuliryayo JD, Vervaet C, Remon JP. Quinine sulphate pellets for flexible pediatric drug dosing: formulation development and evaluation of taste-masking efficiency using the electronic tongue. Eur J Pharm Biopharm. 2007;66(3):460–465. doi: 10.1016/j.ejpb.2006.11.018. [DOI] [PubMed] [Google Scholar]
172.Baldwin EA, Bai J, Plotto A, Dea S. Electronic noses and tongues: applications for the food and pharmaceutical industries. Sensors (Basel) 2011;11(5):4744–4766. doi: 10.3390/s110504744. [DOI] [PMC free article] [PubMed] [Google Scholar]
173.Guhmann M, Preis M, Gerber F, Pollinger N, Breitkreutz J, Weitschies W. Development of oral taste masked diclofenac formulations using a taste sensing system. Int J Pharm. 2012;438(1–2):81–90. doi: 10.1016/j.ijpharm.2012.08.047. [DOI] [PubMed] [Google Scholar]
174.Walsh J, Bickmann D, Breitkreutz J, Chariot-Goulet M. Delivery devices for the administration of paediatric formulations: overview of current practice, challenges and recent developments. Int J Pharm. 2011;415(1–2):221–231. doi: 10.1016/j.ijpharm.2011.05.048. [DOI] [PubMed] [Google Scholar]
175.Breitkreutz J. European perspectives on pediatric formulations. Clin Ther. 2008;30(11):2146–2154. doi: 10.1016/j.clinthera.2008.11.016. [DOI] [PubMed] [Google Scholar]
176.Anand V, Kataria M, Kukkar V, Saharan V, Choudhury PK. The latest trends in the taste assessment of pharmaceuticals. Drug Discov Today. 2007;12(5–6):257–265. doi: 10.1016/j.drudis.2007.01.010. [DOI] [PubMed] [Google Scholar]
177.Cram A, Breitkreutz J, Desset-Brethes S, Nunn T, Tuleu C. Challenges of developing palatable oral paediatric formulations. Int J Pharm. 2009;365(1–2):1–3. doi: 10.1016/j.ijpharm.2008.09.015. [DOI] [PubMed] [Google Scholar]
178.Fischer RA, Griffin F. Pharmacogenetic aspects of gustation. Drug Res. 1964;14:673–686. [PubMed] [Google Scholar]
179.Matsui D. Current issues in pediatric medication adherence. Paediatr Drugs. 2007;9(5):283–288. doi: 10.2165/00148581-200709050-00001. [DOI] [PubMed] [Google Scholar]
180.Miller IJ, Bartoshuk LM. Taste perception, taste bud distribution, and spatial relationship. In: Getchell TV, Bartoshuk LM, Doty RL, Snow JB Jr, editors. Smell and Taste in Health and Disease. New York: Raven Press; 1991. pp. 205–233. [Google Scholar]
181.Fridlund AJ, Gilbert AN, Izard CE, Burdett AN. Emotions and facial expression. Science. 1985;230(4726):607–608. doi: 10.1126/science.4048950. 610, 687. [DOI] [PubMed] [Google Scholar]