Validation of a rat behavioral avoidance model from a drug delivery perspective

Bhat, Meenakshi; Jordt, Raymond M.; Khan, Mubeena; Foley, C. Fritz; Gilbertson, Timothy A.

doi:10.1016/j.ijpharm.2005.06.015

Cited by 15 publications

(9 citation statements)

References 11 publications

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“…Data from BATA experiments are generally displayed by concentration-response curves representing the means of the number of licks or "lick ratios" as a function of the concentrations of the compound tested and the standard error (SE) or standard deviation (SD) obtained with a number n of rats (3,5,7,8,11,12,(15)(16)(17)(18). This way of presenting the results can…”

Section: Discussionmentioning

confidence: 99%

“…Among these approaches, the rodent BATA model has a great potential and has already shown very promising results comparable to human panel data (3,4). The BATA model has been widely used and documented in the literature for different purposes (3)(4)(5)(6)(7)(8)(9). In this animal model, rodents such as mice or rats, are mildly water-deprived and then put into a "lickometer" which records the number of "licks" that the rodents make to different concentrations of the compound under test samples presented in several sipper tubes.…”

Section: Introductionmentioning

confidence: 99%

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Development of a model for robust and exploratory analysis of the rodent brief-access taste aversion data

Soto

Sheng

Standing

et al. 2015

European Journal of Pharmaceutics and Biopharmaceutics

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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 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. DEVELOPMENT OF A MODEL FOR ROBUST AND EXPLORATORY ANALYSIS OF THE RODENT BRIEF-ACCESS TASTE ABSTRACTThe rodent brief-access taste aversion (BATA) model is an efficient in vivo screening tool for taste assessment. A new E max (maximum effect attributable to the drug) model was developed and further investigated in comparison to three previously published models for analysing the rodent BATA data; the robustness of all the models was discussed.The rodent BATA data were obtained from a series of experiments conducted with a bitter reference compound, quinine hydrochloride dihydrate (QHD). A new E max model that could be applied to both "lick numbers" and "lick ratios" was built and three published models that used lick ratios were employed for analysing the BATA data. IC 50 , the concentration that inhibits 50% of the maximum lick numbers, quantified the oral aversiveness of QHD. One thousand bootstrap datasets were generated from the original data. All models were applied to estimate the confidence intervals of the IC 50s without symmetric assumption.The IC 50 value obtained from the new E max model was 0.0496 mM (95% CI 0.0297-0.0857) using the lick numbers for analysis, while an IC 50 of 0.0502 mM (95% CI 0.0267-0.0859) was acquired with the lick ratios. Except from one published model, the IC 50 values have a similar range for the 95% CI.The new E max model enabled the analysis of both "lick numbers" and "lick ratios" whereas other models could only handle data presented as "lick ratios". IC 50s obtained with these two types of datasets showed similarity among all models thereby justified the robustness of the new E max model. KEY WORDSBrief-access taste aversion, lickometer, bitterness, E max model, NONMEM

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Development of a model for robust and exploratory analysis of the rodent brief-access taste aversion data

Soto

Sheng

Standing

et al. 2015

European Journal of Pharmaceutics and Biopharmaceutics

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“…A total of 20 chemicals were tested in oral solutions, including quinine and cycloheximide, two of the most commonly used substances to study bitter taste. We thereby extended earlier work on oral taste aversion (Bhat et al, 2005) in mice to include pharmaceutical compounds from a wide range of drug classes and chemical structures.…”

Section: Discussionmentioning

confidence: 99%

“…To address basic questions regarding tastant molecule potency, efficacy, selectivity, and structure-activity relationships, in-vitro assays have been developed using recombinant cells that express heterologous taste receptors (Bufe et al, 2002;Behrens et al, 2004;Jiang et al, 2004Jiang et al, , 2005Xu et al, 2004). Animal models for studying taste exist (reviewed by Spector, 2002), but only recently they have acquired the semblance of pharmacologic experimental design Spector, 2002, 2003;Bhat et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Quantitative assessment of TRPM5-dependent oral aversiveness of pharmaceuticals using a mouse brief-access taste aversion assay

Devantier¹,

Long²,

Brennan³

et al. 2008

Behavioural Pharmacology

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Many orally administered pharmaceuticals are regarded by humans as aversive, most often described as 'bitter'. Taste aversiveness often leads to patient noncompliance and reduced treatment effectiveness. 'Bitter' taste is mediated by T2R G-protein coupled receptors through a peripheral signaling pathway critically dependent upon function of the TRPM5 ion channel. The brief-access taste aversion (BATA) assay operationally defines aversive taste as suppression of the rate at which a rodent licks from sipper tubes that deliver tastant solutions or suspensions. We have used a mouse BATA assay for rapid quantification of oral aversiveness from a set of 20 active pharmaceutical ingredients (APIs). Robust lick-rate dose-response functions were obtained from both C57BL/6J wild type (WT) and C57BL/6J/TRPM5-/- (TRPM5 knockout) mouse strains, generating reliable determinations of potency and relative maximal oral aversiveness for each API. A subset of APIs was also evaluated in a human bitterness assessment test; effective concentrations for half-maximum responses (EC50s) from both the human test and WT mouse BATA were equivalent. Relative to WT potencies, EC50s from TRPM5 knockout mice were right-shifted more than 10-fold for most APIs. However, APIs were identified for which EC50s were essentially identical in both mouse strains, indicating a TRPM5-independent alternative aversive pathway. Our results suggest the BATA assay will facilitate formulation strategies and taste assessment of late development-phase APIs.

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“…Electronic tongues are, however, limited by their application to assess only aqueous solutions, and the sensor sensitivity can be affected by formulation pH and excipients (13). 4 An in vivo model that exploits the natural defense mechanism in most animals to avert bitter-tasting substances has also been developed for the palatability testing of medicines (14).…”

Section: Introductionmentioning

confidence: 99%

Taste evaluation of a novel midazolam tablet for pediatric patients: In vitro drug dissolution, in vivo animal taste aversion and clinical taste perception profiles

Cheung

Nguyen

Tang

et al. 2018

International Journal of Pharmaceutics

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Harmonized methodologies are urgently required for the taste evaluation of novel pediatric medicines. This study utilized in vitro, in vivo and clinical data to evaluate the palatability of a novel midazolam chocolate tablet. In vitro dissolution experiments showed the crushed tablet to release within 5 min 1.68 mg of midazolam into simulated saliva. This translated to a drug level of 0.84 mg/ml in the oral cavity, which would be higher than the midazolam bitterness detection threshold concentration of 0.03 mg/ml determined in a rat 'brief access taste aversion' (BATA) model. The visual analogue scale scores of patients aged 4-16 years prescribed with midazolam pre-surgery showed a clear preference for the midazolam chocolate tablets (3.35 ± 1.04, n = 20) compared to the control midazolam solution (1.47 ± 0.62, n = 17). The clinical data was in agreement with the in vivo rodent data in showing the novel chocolate tablet matrix to be effective at taste-masking the bitter midazolam.

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Validation of a rat behavioral avoidance model from a drug delivery perspective

Cited by 15 publications

References 11 publications

Development of a model for robust and exploratory analysis of the rodent brief-access taste aversion data

Development of a model for robust and exploratory analysis of the rodent brief-access taste aversion data

Quantitative assessment of TRPM5-dependent oral aversiveness of pharmaceuticals using a mouse brief-access taste aversion assay

Taste evaluation of a novel midazolam tablet for pediatric patients: In vitro drug dissolution, in vivo animal taste aversion and clinical taste perception profiles

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