Peri-threshold Trigeminal Stimulation with Capsaicin Increases Taste Sensitivity in Humans

Introduction Taste perception is affected by trigeminal stimuli, i.e., capsaicin. This has been studied at suprathreshold concentrations. However, little is known about taste perception at threshold level in the presence of low concentration of capsaicin. The aim of the study was to explore whether taste sensitivity for sweet, sour, salt, bitter, and umami is modulated by the presence of capsaicin in the peri-threshold range. Methods Fifty-seven adults (age range 19–85 years; 32 women) with functional gustation participated in the study. Based on their perception of phenylthiocarbamide (PTC), the group was stratified into non-tasters (n = 20) and tasters (n = 37). Threshold for sweet (sucrose), sour (citric acid), salty (sodium chloride), bitter (quinine-hydrochloride), and umami (sodium-glutamate) tastes was estimated using a single-staircase paradigm (3-alternative forced choice; volume per trial 0.1 ml) with or without 0.9-µM capsaicin added. This capsaicin concentration had been determined in pilot studies to be in the range of oral perception thresholds. Results The addition of capsaicin produced lower taste thresholds for sweet, sour, salty, and bitter but not for umami. In contrast, neither PTC taster status nor sex affected these results. Conclusion The current results indicate that a low concentration of capsaicin increases gustatory sensitivity. Implications The current findings provide evidence supporting different effects of capsaicin on taste perception at threshold level. It has implications for boosting taste sensitivity or flavor enjoyment with low concentration of capsaicin.

The endocrine effects of bitter tastant administration in the gastrointestinal system - Intragastric versus intraduodenal administration

Bitter tastants are recently introduced as potential hunger-suppressive compounds, the so-called "Bitter pill". However, the literature about bitter administration lacks consistency in methods and findings. We want to test whether hunger ratings and hormone plasma levels are affected by: 1) the site of administration: intragastrically (IG) or intraduodenally (ID), 2) the bitter tastant itself, quinine hydrochloride (QHCl) or denatonium benzoate (DB), and 3) the timing of infusion. Therefore, 14 healthy, female volunteers participated in a randomized, placebo-controlled six-visit crossover study. After an overnight fast, DB (1µmol/kg), QHCl (10µmol/kg) or placebo were given IG or ID via a nasogastric feeding tube. Blood samples were taken 10 min prior to administration and every 10 min after administration for a period of 2 hours. Hunger was rated at the same timepoints on a visual analogue scale (VAS). ID bitter administration did not affect hunger sensations, motilin or acyl-ghrelin release compared with its PLC infusion. IG QHCl infusion tended to suppress hunger increase, especially between 50-70 minutes after infusion, simultaneously with reduced motilin values. Here, acyl-ghrelin was not affected. IG DB did not affect hunger or motilin, however acyl-ghrelin levels were reduced 50-70 minutes after infusion. Plasma values of glucagon-like peptide 1 and cholecystokinin were too low to be properly detected or to have any physiological relevance. In conclusion, bitter tastants should be infused into the stomach to reduce hunger sensations and orexigenic gut peptides. QHCl has the best potential to reduce hunger sensations, and it should be infused 60 minutes before food intake.

Effective treatment of cutaneous mold infections by antimicrobial blue light that is potentiated by quinine

Background Cutaneous mold infections commonly result from an array of traumatic injuries that involve direct inoculation of contaminated soil into wounds. Here, we explored the use of antimicrobial blue light (aBL; 405 nm wavelength) and the combination of aBL with quinine hydrochloride (aBL + Q-HCL) for the treatment of cutaneous mold infections. Methods Efficacy of aBL and aBL + Q-HCL in killing clinically important pathogenic molds (Aspergillus fumigatus, Aspergillus flavus, and Fusarium oxyprorum) was investigated. Ultra-performance liquid chromatography (UPLC) identified and quantified endogenous porphyrins in the mold conidia. Finally, a mouse model of dermabrasion wound infected with a bioluminescent variant of A. fumigatus was developed to investigate the efficacy of aBL in treating cutaneous mold infections. Results We demonstrated that mold conidia are tolerant to aBL, but Q-HCL enhances efficacy. Transmission electron microscopy revealed intracellular damage by aBL. aBL + Q-HCL resulted in intracellular and cell wall damage. Porphyrins were observed in all mold strains, with A. fumigatus having the highest concentration. aBL and aBL + Q-HCL effectively reduced the burden of A. fumigatus within an established dermabrasion infection that limited recurrence post-treatment. Conclusions aBL and aBL + Q-HCL may offer a novel approach for the treatment of mold infections.

Inhibition of Radiation and Temozolomide-Induced Glioblastoma Invadopodia Activity Using Ion Channel Drugs

Glioblastoma (GBM) is the most prevalent and malignant type of primary brain cancer. The rapid invasion and dissemination of tumor cells into the surrounding normal brain is a major driver of tumor recurrence, and long-term survival of GBM patients is extremely rare. Actin-rich cell membrane protrusions known as invadopodia can facilitate the highly invasive properties of GBM cells. Ion channels have been proposed to contribute to a pro-invasive phenotype in cancer cells and may also be involved in the invadopodia activity of GBM cells. GBM cell cytotoxicity screening of several ion channel drugs identified three drugs with potent cell killing efficacy: flunarizine dihydrochloride, econazole nitrate, and quinine hydrochloride dihydrate. These drugs demonstrated a reduction in GBM cell invadopodia activity and matrix metalloproteinase-2 (MMP-2) secretion. Importantly, the treatment of GBM cells with these drugs led to a significant reduction in radiation/temozolomide-induced invadopodia activity. The dual cytotoxic and anti-invasive efficacy of these agents merits further research into targeting ion channels to reduce GBM malignancy, with a potential for future clinical translation in combination with the standard therapy.

101 Amyotrophic Lateral Sclerosis (ALS) - Not Just a Motor Disease? Isolated Bitter and Sweet Taste Loss in ALS

Study Objective:Specific taste quality deficits in ALS has not heretofore been described.METHOD:Case Study: A 71 year old right handed female presented with a two year course of progressive reduction in strength in her hands, arms and legs with difficulty tying shoe laces, opening jars, writing and walking. She described nocturnal muscle spasms involving all extremities. Gradually, over eight months prior to presentation, all food began to taste bad and horribly bitter. Associated with no appetite and a seven pounds weight loss.RESULTS:Abnormalities in Neurological examination: Cranial Nerve (CN) examination: CN IX and X: Gag absent bilaterally. Motor examination: Bulk: atrophy in thenar and hypothenar eminences and intrinsics in both upper extremities. Percussion induced fasciculation and myotonia in both shoulders and arms. Fasciculation of tongue with percussion myotonia of tongue. Strength: Intrinsic 4/5 in both upper extremities, 3/5 in abductor policis brevis bilaterally, 3/5 right gastrocnemius soleus, 4/5 bilateral anterior tibialis. Drift testing: left abductor digiti minimi sign. Gait: Heel and toe walking unstable with circumduction of left leg. Tandem gait unstable. Cerebellar: Holmes rebound phenomena positive in the left upper extremity. Deep tendon reflexes: 1+ left brachioradialis. 1+ left triceps. 3+ right ankle jerks. 0 left ankle jerk. Positive jaw jerk. Chemosensory Testing: Normosmia to: Alcohol Sniff Test (46), Pocket Smell Test (3/3) and Retronasal Smell Index (9). Taste Quadrant Testing: ageusia in the palate to sodium chloride and citric acid. Ageusia throughout the palate, tongue and whole mouth to sucrose and quinine hydrochloride. Fungiform papillae count: left 18, right 20 (normal). Lip biopsy (normal). MRI: T2 flair in bilateral corticospinal tracts, left greater than right in the spinal cord and the brain. EMG: fibrillation, positive waves with fasciculation in all four extremities. Voluntary contraction with polyphasic unstable motor unit action potentials.CONCLUSION:While Lang found no taste loss in ALS (Lang, 2011), Pelletier found reduction in intensity of taste to all modalities in different sectors of the tongue, but paradoxically demonstrated normogeusia in whole mouth taste perception (Pelletier, 2013). Pathological specimens of those with ALS revealed degeneration in the nucleus parabrachialis medialis and tractus trigeminothalamicus dorsalis (Oyanagi, 2015), suggesting that taste deficit may be due to central white matter abnormalities. Sweet taste is localized in the most posterior and rostral aspect of the right insular cortex, immediately adjacent to bitter (Prinster, 2017), suggesting a neighborhood effect phenomena. Weight loss in ALS may be due to sensory distortion and secondary impairment of appetite. It would be worthwhile to investigate those with ALS for evidence of otherwise overlooked gustatory deficits, correction of which may improve appetite and nutritional state.

Bitter Taste Perception of the Human Tongue Mediated by Quinine and Caffeine Impregnated Taste Strips

Objectives: Tests for gustatory function have become increasingly important in diagnosis and treatment of patients with taste disorders. While caffeine and quinine hydrochloride solutions have been used for global testing of bitter perception, only quinine has been used to test regional bitter perception by means of taste strips. The aim of the present study was to validate caffeine impregnated taste strips as an alternative to quinine taste strips for assessment of regional bitter perception. Methods: A total of 46 healthy volunteers (mean age/range, 23/19-27 years) were included in this study. Quinine and caffeine impregnated taste strips were pairwise presented at different parts of the tongue. Perceived intensity and hedonic dislike were evaluated using labeled magnitude scales. Additionally, gustatory function was assessed using the taste strips test and overall sense of taste was rated using visual analog scales. Results: Assessment of gustatory function demonstrated scores within the normogeusic range in most included subjects (mean/SD, 13.1/2.5). Notably, equally concentrated quinine and caffeine impregnated taste strips placed on different regions of the tongue did not lead to significant differences in perceived intensity or hedonic dislike, whereas quinine and caffeine impregnated taste strips of different concentrations placed on the same region on the tongue led to significant differences of perceived intensity and hedonic dislike. Furthermore, no correlation was found between self-assessment of gustatory function and taste strips scores. Conclusion: Caffeine seems to be a valid bitter compound for regional testing using taste strips and may be used alternatively to quinine.

Repeatability of Taste Recognition Threshold Measurements with QUEST and Quick Yes–No

Taste perception, although vital for nutrient sensing, has long been overlooked in sensory assessments. This can, at least in part, be attributed to challenges associated with the handling of liquid, perishable stimuli, but also with scarce efforts to optimize testing procedures to be more time-efficient. We have previously introduced an adaptive, QUEST-based procedure to measure taste sensitivity thresholds that was quicker than other existing approaches, yet similarly reliable. Despite its advantages, the QUEST procedure lacks experimental control of false alarms (i.e., response bias) and psychometric function slope. Variations of these parameters, however, may also influence the threshold estimate. This raises the question as to whether a procedure that simultaneously assesses threshold, false-alarm rate, and slope might be able to produce threshold estimates with higher repeatability, i.e., smaller variation between repeated measurements. Here, we compared the performance of QUEST with a method that allows measurement of false-alarm rates and slopes, quick Yes–No (qYN), in a test–retest design for citric acid, sodium chloride, quinine hydrochloride, and sucrose recognition thresholds. We used complementary measures of repeatability, namely test–retest correlations and coefficients of repeatability. Both threshold procedures yielded largely overlapping thresholds with good repeatability between measurements. Together the data suggest that participants used a conservative response criterion. Furthermore, we explored the link between taste sensitivity and taste liking or which we found, however, no clear association.

Synthesis of Saponite Based Nanocomposites to Improve the Controlled Oral Drug Release of Model Drug Quinine Hydrochloride Dihydrate

In the present research study, a 2:1 type of smectite clay minerals, namely natural saponite (NSAP) and synthetic saponite (SSAP), was demonstrated for the first time to be controlled drug release host materials for the model drug quinine hydrochloride dihydrate (QU). The popular sol–gel hydrothermal technique was followed for the synthesis of saponite. The QU was ion exchanged and intercalated into an interlayered gallery of synthetic as well as natural saponite matrices. The developed QU-loaded hybrid composite materials along with the pristine materials were characterized by powder X-ray diffraction (PXRD), Fourier transformed infrared spectroscopy (FTIR), thermal gravimetric analysis (TGA), the Brunauer–Emmett–Teller method (BET) for surface area (SA), and scanning electron microscopy (SEM). The characterization of material results using DSC, FTIR and PXRD confirmed the presence of saponite clay mineral phases in the original and the synthesized saponite samples. Similarly, the drug-loaded composites confirmed the successful intercalation of QU drug on the natural and synthesized saponite matrices. The oral drug release performance of both nanocomposites along with pure quinine drug was monitored in sequential buffer environments at 37 ± 0.5 °C. These composite hybrid materials showed the superior controlled release of QU in gastric fluid (pH = 1.2) and intestinal fluid (pH = 7.4). QU release was best fitted in the Korsmeyer–Peppas kinetic model and demonstrated a diffusion-controlled release from nanocomposite layered materials. The observed controlled drug release results suggest that the applied natural/synthetic saponite matrices have the potential to provide critical design parameters for the development of bioengineered materials for controlled drug release.

Evaluation of Specific Administering Devices for Antineoplastic Drugs Compounded in Syringes in Paediatry: Methodology Proposal

Purpose The aims of this study were to propose a simple methodology to assess the rinsing volume of syringe extension sets and to compare several marketed devices. Methods A UV-spectrophotometry assay using quinine hydrochloride as drug substitute was developed. Quinine concentration ranged from 20 to 200 µg/ml. The assay was validated with the accuracy profile method and tested on five different assemblies (device+extension sets) with different dead-space volumes (1.28–2.80 ml) and at two different quinine concentrations (0.3 and 8.0 mg/ml). Rinsing was performed stepwise with water for injection until reaching an undetectable quinine concentration. After fitting the data with a Weibull model, assemblies were compared with an ANOVA performed on ranks (GraphPad, La Jolla, USA). Results The within-day and between-day precision ranges were 0.39–0.81 and 0.48–0.84%, respectively. The lower limit of quantification was 4.26 µg/ml. The volume required to completely rinse the infusion line was different according to the initial drug concentration and to the device assessed: from 6 to 10 ml for a low quinine concentration and from 7 to 17 ml for a high quinine concentration. Conclusion This study shows that a simple, cheap and easy-to-use methodology may be used to assess the rinsing volume of syringe extension sets. The rinsing volume is different according to the tested device.