Randomized placebo controlled trial of phytoterpenes in DMSO for the treatment of plantar fasciitis.

Plantar fasciitis is the most common cause of heel pain in adults with an overall prevalence of 0.85% in the adult population of the US, affecting over 2 million adults annually. Most current treatment modalities are not supported by sufficient evidence to recommend one particular strategy over another. Topical application of analgesics for soft tissue pain is well established, however the plantar fascia presents challenges in this regard due to thick skin, fibrotic tissue, and an often thickened fat pad. Sixty-two patients with plantar fasciitis were randomized to a placebo controlled trial testing the efficacy of a topical solution of plant terpenes containing camphor, menthol, eugenol, eucalyptol, and vanillin. Skin permeation of the mixture was enhanced with 15% dimethylsulfoxide (DMSO), 1% limonene, and rosemary oil. One ml of solution was applied topically twice daily, and pain scores evaluated on Day 0, Day 1, Day 3, and Day 10. Using the validated foot function index 78.1% of patients reported an 85% or greater decrease in their total pain score by day 10 while placebo treatment was without effect (One Way ANOVA, P < 0.01). This study adapts the treatment modality of topical analgesia for soft tissue pain to a problematic area of the body and shows therapeutic promise.ClinicalTrials.gov Identifier: NCT05467631.

Menthol-Modified Quercetin Liposomes with Brain-Targeting Function for the Treatment of Senescent Alzheimer's Disease.

Oxidative stress and neuroinflammation in the aging brain are correlated with the development of neurodegenerative diseases, such as Alzheimer's disease (AD). The blood-brain barrier (BBB) poses a significant challenge to the effective delivery of therapeutics for AD. Prior research has demonstrated that menthol (Men) can augment the permeability of the BBB. Consequently, in the current study, we modified Men on the surface of liposomes to construct menthol-modified quercetin liposomes (Men-Qu-Lips), designed to cross the BBB and enhance quercetin (Qu) concentration in the brain for improved therapeutic efficacy. The experimental findings indicate that Men-Qu-Lips exhibited good encapsulation efficiency and stability, successfully crossed the BBB, improved oxidative stress and neuroinflammation in the brains of aged mice, protected neurons, and enhanced their learning and memory abilities.

[Development of Transdermal Formulation Based on Nanotechnology and Elucidation of Its Drug Delivery Pathways].

Transdermal drug delivery is a formulation in which the drug is absorbed through the skin for systemic action. Its advantages include avoidance of first-pass effects, sustained drug supply, and ease of administration and discontinuation. Drugs administered transdermally transfer into the blood circulation through the stratum corneum, epidermis, and dermis. The stratum corneum on the skin surface plays a barrier function in skin absorption. Therefore, developing of transdermal drug delivery systems requires innovations that overcome the barrier function of the stratum corneum and improve skin permeation. This review examines the usefulness of transdermal formulations based on solid nanoparticles using raloxifene. Milled raloxifene was gelled with (mRal-NPs) or without menthol (Ral-NPs) using Carbopol. The drug release and transdermal penetration were measured using a Franz diffusion cell, and the therapeutic evaluation of osteoporosis was determined in an ovariectomized rat model. Although the raloxifene released from Ral-NPs remained in the nanoparticle state, the skin penetration of raloxifene nanoparticles was prevented by the stratum corneum in rat. The inclusion of menthol in the formulation attenuated the barrier function of the stratum corneum and permitted raloxifene nanoparticles to penetrate through the skin. Moreover, macropinocytosis relates to the formulation's skin penetration, including menthol (mRal-NPs). Applying mRal-NPs attenuated the decreases in calcium level and stiffness of bones of ovariectomized rats. This information can support future studies aimed at designing novel transdermal formulations.

Subchronic inhalation of a novel electronic nicotine delivery system formulation and its corresponding base formulation.

BACKGROUND: Fresh Menthol 3% Nicotine (FM3) is a novel JUUL e-liquid formulation. Its potential toxicity and that of the corresponding base formulation relative to a filtered air (FA) control was studied in a subchronic inhalation study conducted in general accordance with OECD 413. METHODS: Aerosols generated with an intense puffing regime were administered to rats in a nose-only fashion at 1400 µg aerosol collected mass/L on a 6 hour/day basis for 90 days with a 42-day recovery. Exposure atmospheres met target criteria. Systemic exposure was confirmed by plasma measurement of nicotine. RESULTS: No test article-related mortality, clinical signs (other than reversible lower body weight gains in males), clinical pathology or gross findings were noted during this study. No microscopic lesions related to base formulation exposure were identified. Minimal microscopic lesions were observed in the FM3 6-hour exposure group. Microscopic lesions observed in the FM3 6-hour exposure group comprised only minimal laryngeal squamous metaplasia in one male and one female animal. No microscopic lesions related to FM3 exposure remained after the recovery period. CONCLUSION: Exposure atmosphere characterization indicated that conditions were achieved to permit thorough assessment of test articles and results indicate a low order of toxicity for the FM3 Electronic nicotine delivery systems (ENDS) formulation and its base formulation.

Menthol alleviates post-race elevations in muscle soreness and metabolic and respiratory stress during running.

PURPOSE: We evaluated (1) whether participating in middle- and long-distance running races augments muscle soreness, oxygen cost, respiration, and exercise exertion during subsequent running, and (2) if post-race menthol application alleviates these responses in long-distance runners. METHODS: Eleven long-distance runners completed a 1500-m race on day 1 and a 3000-m race on day 2. On day 3 (post-race day), either a 4% menthol solution (Post-race menthol) or a placebo solution (Post-race placebo) serving as a vehicle control, was applied to their lower leg skin, and their perceptual and physiological responses were evaluated. The identical assessment with the placebo solution was also conducted without race participation (No-race placebo). RESULTS: The integrated muscle soreness index increased in the Post-race placebo compared to the No-race placebo (P < 0.001), but this response was absent in the Post-race menthol (P = 0.058). Oxygen uptake during treadmill running tended to be higher (4.3%) in the Post-race placebo vs. No-race placebo (P = 0.074). Oxygen uptake was 5.4% lower in the Post-race menthol compared to the Post-race placebo (P = 0.018). Minute ventilation during treadmill running was 6.7-7.6% higher in the Post-race placebo compared to No-race placebo, whereas it was 6.6-9.0% lower in the Post-race menthol vs. Post-race placebo (all P ≤ 0.001). The rate of perceived exertion was 7.0% lower in the Post-race menthol vs. Post-race placebo (P = 0.007). CONCLUSIONS: Middle- and long-distance races can subsequently elevate muscle soreness and induce respiratory and metabolic stress, but post-race menthol application to the lower legs can mitigate these responses and reduce exercise exertion in long-distance runners.

Stimulus mediation, specificity and impact of menthol in rats trained to discriminate puffs of nicotine e-cigarette aerosol from nicotine-free aerosol.

RATIONALE: It is unclear if e-cigarettes have reduced abuse liability relative to traditional cigarettes, especially when considering advanced devices which deliver nicotine more efficiently. Translatable and predictive animal models are needed to addresses this question. OBJECTIVES: Our goal was to explore the subjective stimulus effects of e-cigarettes by training rats to discriminate puffs of nicotine aerosol from vehicle aerosol using an aerosol delivery system designed to model e-cigarette use patterns in humans. METHODS: Rats were trained to discriminate between ten, 10 s puffs of aerosol generated from 3 mg/ml nicotine e-liquid and nicotine-free e-liquid using a food-reinforced operant procedure. Following acquisition, tests were conducted to determine the specificity of the nicotine aerosol stimulus as well as the impact to the stimulus effects of nicotine resulting from the addition of menthol to e-liquid. RESULTS: Rats learned the nicotine aerosol puff vs vehicle puff discrimination in a mean of 25 training sessions. Injected nicotine fully substituted for the stimulus effects of nicotine aerosol. The stimulus effects of nicotine aerosol were blocked by the nicotinic receptor antagonist mecamylamine. The nicotinic receptor partial agonist, varenicline as well as the stimulant d-amphetamine substituted more robustly for nicotine aerosol puffs than did the NMDA antagonist, ketamine. Menthol enhanced the stimulus effects of nicotine aerosol without altering nicotine blood plasma levels. CONCLUSIONS: Nicotine aerosol puffs can function as a training stimulus in rats. The stimulus effects were CNS-mediated and receptor specific. Menthol appears to enhance the stimulus effects of nicotine aerosol through a pharmacodynamic rather than pharmacokinetic mechanism.

A topographical and physiological exploration of C-tactile afferents and their response to menthol and histamine.

Unmyelinated tactile (C-tactile or CT) afferents are abundant in arm hairy skin and have been suggested to signal features of social affective touch. Here, we recorded from unmyelinated low-threshold mechanosensitive afferents in the peroneal and radial nerves. The most distal receptive fields were located on the proximal phalanx of the third finger for the superficial branch of the radial nerve and near the lateral malleolus for the peroneal nerve. We found that the physiological properties with regard to conduction velocity and mechanical threshold, as well as their tuning to brush velocity, were similar in CT units across the antebrachial (n = 27), radial (n = 8), and peroneal (n = 4) nerves. Moreover, we found that although CT afferents are readily found during microneurography of the arm nerves, they appear to be much more sparse in the lower leg compared with C-nociceptors. We continued to explore CT afferents with regard to their chemical sensitivity and found that they could not be activated by topical application to their receptive field of either the cooling agent menthol or the pruritogen histamine. In light of previous studies showing the combined effects that temperature and mechanical stimuli have on these neurons, these findings add to the growing body of research suggesting that CT afferents constitute a unique class of sensory afferents with highly specialized mechanisms for transducing gentle touch.NEW & NOTEWORHY Unmyelinated tactile (CT) afferents are abundant in arm hairy skin and are thought to signal features of social affective touch. We show that CTs are also present but are relatively sparse in the lower leg compared with C-nociceptors. CTs display similar physiological properties across the arm and leg nerves. Furthermore, CT afferents do not respond to the cooling agent menthol or the pruritogen histamine, and their mechanical response properties are not altered by these chemicals.

Menthol-induced activation of TRPM8 receptors increases cutaneous blood flow across the dermatome.

Topical menthol-based analgesics increase skin blood flow (SkBF) through transient receptor potential melastatin 8 (TRPM8) receptor-dependent activation of sensory nerves and endothelium-derived hyperpolarization factors. It is unclear if menthol-induced TRPM8 activation mediates a reflex change in SkBF across the dermatome in an area not directly treated with menthol. The purpose of this study was to determine the effects of localized topical menthol application on SkBF across a common dermatome. We hypothesized that SkBF would be increased with menthol at the site of application and across the dermatome (contralateral limb) through a spinal reflex mechanism. In a double blind, placebo controlled, cross-over design, 15 healthy participants (7 men; age = 22 ± 1 yrs) were treated with direct application (3 ml over 8 × 13 cm) of 5% menthol gel (Biofreeze™) or placebo gel on the L4 dermatome, separated by 48 h. Red blood cell flux was measured using laser Doppler flowmetry over the area of application, on the contralateral leg of the same dermatome, and in a separate dermatome (L5/S1) to serve as control. Cutaneous vascular conductance was calculated for each measurement site (CVC = flux/MAP). At baseline there were no differences in CVC between menthol and placebo gels, or among sites (all p > 0.05). After 30 ± 6 min, CVC increased at the treated site with menthol (0.12 ± 0.02 vs. 1.36 ± 0.19 flux/mm Hg, p < 0.01) but not the placebo (0.10 ± 0.01 vs. 0.18 ± 0.04 flux/mm Hg, p = 0.91). There was a modest increase in CVC at the contralateral L4 dermatome with menthol gel (0.16 ± 0.04 vs. 0.29 ± 0.06 flux/mm Hg, p < 0.01), but not placebo (0.11 ± 0.02 vs. 0.15 ± 0.03 flux/mm Hg, p = 0.41). There was no effect on SkBF from either treatments at the L5/S1 control dermatome (both, p > 0.05), suggesting the lack of a systemic response. In conclusion, menthol containing topical analgesic gels increased SkBF at the treated site, and modestly throughout the dermatome. These data suggest menthol-induced activation of the TRPM8 receptors induces an increase in SkBF across the area of common innervation through a localized spinal reflex mechanism.

Combination of TRP channel dietary agonists induces energy expending and glucose utilizing phenotype in HFD-fed mice.

BACKGROUND: Bioactive dietary constituents activating Transient receptor potential (TRP) channels have emerged as promising candidates for the prevention of metabolic disorders. OBJECTIVE: The present study is an attempt to evaluate anti-obesity potential of a dietary TRP-based tri-agonist, combination of sub-effective doses of capsaicin (TRPV1 agonist), menthol (TRPM8 agonist), and cinnamaldehyde (TRPA1 agonist) in high-fat diet (HFD)-fed mice. DESIGN: Male C57BL/6 J mice divided into three groups (n = 8), were fed on normal pellet diet (NPD), or high-fat diet (HFD) (60% energy by fat) and HFD + CB (combination of capsaicin 0.4 mg/Kg, menthol 20 mg/Kg, and cinnamaldehyde 2 mg/Kg; p.o) for 12 weeks. Effects on HFD-induced weight gain, biochemical, histological and genomic changes in the WAT, BAT, liver and hypothalamus tissues were studied. RESULTS: Administration of tri-agonist prevented HFD-induced increase in weight gain, improved altered morphometric parameters, glucose homeostasis, and adipose tissue hypertrophy. Tri-agonist supplementation was found to induce browning of white adipose tissue and promote brown adipose tissue activation. Enhanced glucose utilization and prevention of lipid accumulation and insulin resistance in the liver was observed in mice supplemented with a tri-agonist. CONCLUSION: The present work provides evidence that the new approach based on combination of sub-effective doses of TRP channel agonists (TRI-AGONIST) can be employed to develop concept-based functional food for therapeutic and preventive strategies against HFD-associated pathological complications.

The Effect of Isolated and Combined Application of Menthol and Carbohydrate Mouth Rinses on 40 km Time Trial Performance, Physiological and Perceptual Measures in the Heat.

The current study compared mouth swills containing carbohydrate (CHO), menthol (MEN) or a combination (BOTH) on 40 km cycling time trial (TT) performance in the heat (32 °C, 40% humidity, 1000 W radiant load) and investigates associated physiological (rectal temperature (Trec), heart rate (HR)) and subjective measures (thermal comfort (TC), thermal sensation (TS), thirst, oral cooling (OC) and RPE (legs and lungs)). Eight recreationally trained male cyclists (32 ± 9 y; height: 180.9 ± 7.0 cm; weight: 76.3 ± 10.4 kg) completed familiarisation and three experimental trials, swilling either MEN, CHO or BOTH at 10 km intervals (5, 15, 25, 35 km). The 40 km TT performance did not differ significantly between conditions (F2,14 = 0.343; p = 0.715; η2 = 0.047), yet post-hoc testing indicated small differences between MEN and CHO (d = 0.225) and MEN and BOTH (d = 0.275). Subjective measures (TC, TS, RPE) were significantly affected by distance but showed no significant differences between solutions. Within-subject analysis found significant interactions between solution and location upon OC intensity (F28,196 = 2.577; p < 0.001; η2 = 0.269). While solutions containing MEN resulted in a greater sensation of OC, solutions containing CHO experienced small improvements in TT performance. Stimulation of central CHO pathways during self-paced cycling TT in the heat may be of more importance to performance than perceptual cooling interventions. However, no detrimental effects are seen when interventions are combined.

Cooling e-cigarette flavors and the association with e-cigarette use among a sample of high school students.

INTRODUCTION: E-liquid flavor is typically presented by flavor category (e.g. menthol, mint, fruit, dessert). Cooling sensations produced by flavor additives such as menthol enhance appeal of e-cigarettes among youth, but not all e-liquids that produce cooling sensations are labeled as menthol. Sensory experiences produced by flavors may allow for a new way to capture e-cigarette flavor use. This study aims to examine use of flavors that produce cooling sensations among youth and its association with e-cigarette use behaviors. METHODS: A 2019 survey of high school students (n = 4875) examined use of e-cigarette flavors that produced cooling sensations (cooling flavors) among past 30-day e-cigarette users. E-cigarette use behaviors (flavor use, nicotine use, frequency of use) were examined between those who did and did not use cooling flavors. A binary logistic regression was used to examine associations between vaping frequency, nicotine (vs. non-nicotine) use, and vaping cooling flavors while controlling for demographics, number of flavors vaped in the past month, and vaping age of onset. RESULTS: 51.6% (n = 473/916) of the analytic sample endorsed vaping cooling flavors. There were no demographic differences by vaping cooling flavors. Vaping cooling flavors was associated with vaping more frequently (AOR:1.04,95% CI:1.03,1.05) and vaping nicotine (AOR:2.37,95% CI:1.53,3.67). CONCLUSION: Vaping cooling flavors was associated with greater nicotine vaping and frequency of e-cigarette use. Assessing sensory experience, such as cooling, in addition to flavor category may more fully capture e-cigarette flavor use and its impacts on youth e-cigarette use behaviors.

The effect of body surface area exposure to menthol on temperature regulation and perception in men.

INTRODUCTION: In warm conditions topical application of menthol increases cool sensations and influences deep body temperature. The purpose of this experiment was to explore whether different body surface areas (BSA) exposed to menthol influence these responses. It was hypothesized that the forcing function exerted by menthol will be proportionally related to BSA. METHOD: Using a within-participant design, 13 participants underwent three BSA exposures (Small [S; finger]; Medium [M; arm]; Large [L; upper/lower body]) to 4.13% menthol, and one Placebo exposure. During each exposure participants rested supine in a tent (30 °C, 50%rh) for 30-min before their intervention and 30-min thereafter. Measures included thermal sensation, thermal comfort, irritation, skin blood flow (finger SkBF; laser Doppler flowmetry), rectal temperature (Tre), and skin temperature (chest, forearm, thigh, calf). The Area Under the Curve from minute 30 to 60 was calculated and analyzed using a one-way ANOVA or Friedman's test with post-hoc testing (0.05 alpha level). RESULTS: There was no significant difference in any measure of thermometry (p > 0.05), while SKBF was significantly lowered in L, M, and S vs. P respectively (p < 0.05). Participants in L felt cooler vs. P and S (p < 0.05). Losses in thermal comfort were noted in L and M vs. P and S (p < 0.05), along with increased irritation in L vs. S (p < 0.05). CONCLUSIONS: Despite similar skin temperatures, larger BSA's exposed to menthol caused cooler sensations, likely due to the activation of a larger pool of menthol-sensitive neurons. This occurred in the absence of thermal discomfort and without perceptions of irritation exceeding 'weak'. Larger BSA's also exhibited greater alterations in Tre, likely driven by a reduction in SkBF, but despite this mean body temperature was regulated suggesting the thermoregulatory system can cope with the range of BSA exposures studied herein.

Nicotine self-administration with menthol and audiovisual cue facilitates differential packaging of CYP2A6 and cytokines/chemokines in rat plasma extracellular vesicles.

In this study, we investigated whether intravenously self-administered nicotine with menthol and audiovisual cue modulates nicotine-metabolizing CYP2A6, oxidative stress modulators, and cytokines/chemokines in plasma extracellular vesicles (EVs) in rats. We assigned rats to self-administered nicotine with: (a) audiovisual cue (AV), (b) menthol, and (c) menthol and AV cue. We found increased levels of CD9 in plasma EVs after self-administered nicotine with menthol and AV cue. Moreover, expression of CYP2A6 in plasma EVs was significantly increased after self-administered nicotine in response to menthol and AV cue. However, despite an upward trend on SOD1 and catalase, increase was not found to be statistically significant, while total antioxidant capacity was found to be significantly increased in plasma and plasma EVs obtained after self-administered nicotine with menthol and AV cue. Among cytokine and chemokine profiling, we found a significant increase in the levels of MCP-1 after self-administered nicotine with menthol and AV cue and complete packaging of IL-1ß in EVs. Taken together, the study provides evidence that nicotine in response to menthol and AV cues can package altered levels of CYP2A6, and cytokines/chemokines in plasma EVs that may contribute to cell-cell communication, nicotine metabolism, and inflammation upon cigarette smoking.

Advantages of using toothpaste containing propolis and plant oils for gingivitis prevention and oral cavity hygiene in cleft lip/palate patients.

BACKGROUND: The anti-inflammatory and antibacterial action of preparations used during oral hygiene procedures is particularly important in patients with oral cleft. Few reports have been published assessing the influence of natural products on the state of the oral cavity in patients with oral cleft. The aim of this study was to assess the effect of toothpaste containing Polish propolis and plant oils on oral cavity health in patients with oral cleft treated orthodontically. MATERIALS AND METHODS: A total of 50 patients aged 9-16 years old (20 females, 23 males) were selected and randomly assigned into two groups. Group (A) received toothpaste with Polish propolis, tea tree oil, menthol, and rosemary oil. Group (B) received toothpaste without active ingredients (placebo). A baseline assessment was followed by an oral hygiene index (OHI, debris OHI-D, and calculus OHI-C component) and gingival bleeding index (GBI) after 35 days. The methodology of the oral condition assessment included the presence of cleft malformation as a dysmorphic of the anterior maxilla segment. RESULTS: In group A, improvement in oral cavity hygiene assessed for incisors and molars was found (OHI-T p = 0.011). For the gingival condition, a decrease in the gingival bleeding index - total (GBI-T p = 0.002), as well as for the incisors (GBI-I p = 0.007) and molars (GBI-M p = 0.017) was found. CONCLUSIONS: This research confirms the biological effectiveness of toothpaste with Polish propolis and plant oils. These results may be clinically useful for improving preventative oral care and for control of oral infectious diseases during orthodontic treatment in patients with oral cleft.

Cutaneous microbial biofilm formation as an underlying cause of red scrotum syndrome.

BACKGROUND: Red scrotum syndrome is typically described as well-demarcated erythema of the anterior scrotum accompanied by persistent itching and burning. It is chronic and difficult to treat and contributes to significant psychological distress and reduction in quality of life. The medical literature surrounding the condition is sparse, with the prevalence likely under-recognized and the pathophysiology remaining poorly understood. Formation of a cutaneous microbial biofilm has not been proposed as an underlying etiology. Microbial biofilms can form whenever microorganisms are suspended in fluid on a surface for a prolonged time and are becoming increasingly recognized as important contributors to medical disease (e.g., chronic wounds). CASE PRESENTATION: A 26-year-old man abruptly developed well-demarcated erythema of the bilateral scrotum after vaginal secretions were left covering the scrotum overnight. For 14 months, the patient experienced daily scrotal itching and burning while seeking care from multiple physicians and attempting numerous failed therapies. He eventually obtained complete symptomatic relief with the twice daily application of 0.8% menthol powder. Findings in support of a cutaneous microbial biofilm as the underlying etiology include: (1) the condition began following a typical scenario that would facilitate biofilm formation; (2) the demarcation of erythema precisely follows the scrotal hairline, suggesting that hair follicles acted as scaffolding during biofilm formation; (3) despite resolution of symptoms, the scrotal erythema has persisted, unchanged in boundary 15 years after the condition began; and (4) the erythematous skin demonstrates prolonged retention of gentian violet dye in comparison with adjacent unaffected skin, suggesting the presence of dye-avid material on the skin surface. CONCLUSION: The probability that microorganisms, under proper conditions, can form biofilm on intact skin is poorly recognized. This case presents a compelling argument for a cutaneous microbial biofilm as the underlying cause of red scrotum syndrome in one patient, and a review of similarities with other reported cases suggests the same etiology is likely responsible for a significant portion of the total disease burden. This etiology may also be a significant contributor to the disease burden of vulvodynia, a condition with many similarities to red scrotum syndrome.

Protein profiling in the habenula after chronic (-)-menthol exposure in mice.

The identification of proteins that are altered following nicotine/tobacco exposure can facilitate and positively impact the investigation of related diseases. In this report, we investigated the effects of chronic (-)-menthol exposure in 14 murine brain regions for changes in total ß2 subunit protein levels and changes in epibatidine binding levels using immunoblotting and radioligand binding assays. We identified the habenula as a region of interest due to the region's marked decreases in ß2 subunit and nAChR levels in response to chronic (-)-menthol alone. Thus, we further examined the habenula, a brain region associated with both the reward and withdrawal components of addiction, for additional protein level alterations using mass spectrometry. A total of 552 proteins with altered levels were identified after chronic (-)-menthol exposure. Enriched in the proteins with altered levels after (-)-menthol exposure were proteins associated with signaling, immune systems, RNA regulation, and protein transport. The continuation and expansion of the brain region-specific protein profiling in response to (-)-menthol will provide a better understanding of how this common flavorant in tobacco and e-liquid products may affect addiction and general health.

Energy-Dependent Endocytosis Is Responsible for Skin Penetration of Formulations Based on a Combination of Indomethacin Nanoparticles and l-Menthol in Rat and Göttingen Minipig.

We previously designed a Carbopol gel formulation (N-IND/MEN) based on a combination of indomethacin solid nanoparticles (IND-NPs) and l-menthol, and we reported that the N-IND/MEN showed high transdermal penetration. However, the detailed mechanism for transdermal penetration of IND-NPs was not clearly defined. In this study, we investigated whether endocytosis in the skin tissue of rat and Göttingen minipig is related to the transdermal penetration of IND-NPs using pharmacological inhibitors of endocytosis. The pharmacological inhibitors used in this study are as follows: 54 µM nystatin, a caveolae-mediated endocytosis (CavME) inhibitor; 40 µM dynasore, a clathrin-mediated endocytosis (CME) inhibitor; and 2 µM rottlerin, a micropinocytosis (MP) inhibitor. The N-IND/MEN was prepared by a bead mill method, and the particle size of solid indomethacin was 79-216 nm. In both rat and Göttingen minipig skin, skin penetration of approximately 80% IND-NPs was limited by the stratum corneum (SC), although the penetration of SC was improved by the combination of l-menthol. On the other hand, the treatment of nystatin and dynasore decreased the transdermal penetration of indomethacin in rats and Göttingen minipigs treated with N-IND/MEN. Moreover, in addition to nystatin and dynasore, rottlerin attenuated the transdermal penetration of IND-NPs in the Göttingen minipigs' skin. In conclusion, we found that l-menthol enhanced the SC penetration of IND-NPs. In addition, this study suggests that the SC-passed IND-NPs are absorbed into the skin tissue by energy-dependent endocytosis (CavME, CME, and/or MP pathways) on the epidermis under the SC, resulting in an enhancement in transdermal penetration of IND-NPs. These findings provide significant information for the design of nanomedicines in transdermal formulations.

Impact of elevated core temperature on cognition in hot environments within a military context.

PURPOSE: Cognition can be impaired during exercise in the heat, potentially contributing to military casualties. To our knowledge, the independent role of elevated core temperature during exercise has not been determined. The aim of the current study was to evaluate effects of elevated core temperature on cognition during physically encumbering, heated exercise, and to determine whether the perceptual cooling effects of menthol preserves cognition. METHODS: Eight participants complete three trials in randomised order: one normothermic (CON) and two with elevated (38.5°C) core temperature, induced by prior immersion in neutral versus hot water The CON trial and one hot trial (HOT) used a water mouth-rinse following each cognitive task of the trial, (HOT) while the other used a menthol mouth-rinse (MENT). Participants walked in humid heat (33°C, 75% relative humidity) in military clothing, completing a cognitive battery of reaction time, perceptual processing, working memory, executive function, cognitive flexibility, vigilance, and declarative memory. RESULTS: No differences in cognitive performance were observed between any conditions. Near-infrared spectroscopy showed greater oxygenated haemoglobin tissue content in HOT and MENT compared to CON (ΔO2Hb-deO2Hb: 2.3 ± 4.5 µM, p < .024), and lower deoxygenated haemoglobin in MENT than in CON or HOT (p = .017), suggesting higher brain metabolism during the more stressful conditions. CONCLUSION: Moderately elevated core (38.5°C) and skin temperature does not appear to impair cognitive performance during exercise despite mildly elevated cerebral metabolism. The effects of menthol remain undetermined due to the lack of heat-mediated cognitive impairment.

Development of a "Cooling" Menthol Energy Gel for Endurance Athletes: Effect of Menthol Concentration on Acceptability and Preferences.

Menthol is effective at stimulating thermosensitive neurons that evoke pleasant cooling sensations. Internal application of menthol can be ergogenic for athletes, and hence, addition of menthol to sports nutrition products may be beneficial for athletes. The aim of this study was to develop a menthol energy gel for consumption during exercise and to determine acceptability and preferences for gels with different menthol concentrations. With a randomized, crossover, and double-blind placebo-controlled design, 40 endurance athletes (20 females) ingested an energy gel with a menthol additive at a high (0.5%; HIGH) or low concentration (0.1%; LOW), or a mint-flavored placebo (CON), on separate occasions during outdoor endurance training sessions. The athletes rated the gels for cooling sensation, mint flavor intensity, sweetness, and overall experience and provided feedback. Results are reported as median (interquartile range). Both menthol gels successfully delivered a cooling sensation, with a significantly greater response for HIGH (5.0 [4.0-5.0]) compared with LOW (3.5 [3.0-4.0]; p = .022) and CON (1.0 [1.0-2.0]; p < .0005), and LOW compared with CON (p < .0005). Ratings of mint flavor intensity followed the same trend as cooling sensation, while ratings of overall experience were significantly worse for HIGH (2.0 [1.0-3.0]) compared with LOW (4.0 [2.0-4.0]; p = .001) and CON (4.0 [3.0-4.0]; p < .0005). An energy gel with the addition of menthol at 0.1-0.5% provides a cooling sensation for athletes with a dose-response when ingested during exercise. The 0.1% concentration is recommended to maximize the overall experience of the gel.

L-Menthol for Gastrointestinal Endoscopy: A Systematic Review and Meta-Analysis.

INTRODUCTION: In randomized controlled trials, L-menthol inhibits gastrointestinal peristalsis during endoscopy. Our goal was to quantitatively synthesize the available evidence to evaluate the efficacy and safety of L-menthol for gastrointestinal endoscopy. METHODS: We comprehensively searched for relevant studies published up to January 2020 in PubMed, EMBASE, Web of Science, and Cochrane Library. The main outcomes consisted of the proportion of no peristalsis, proportion of no or mild peristalsis, adenoma detection rate, and adverse events. RESULTS: Eight randomized controlled trials analyzing 1,366 subjects were included. According to the pooled data, L-menthol significantly improved the proportion of no peristalsis (odds ratio [OR] = 6.51, 95% confidence interval [CI] = 4.94-8.57, P < 0.00001), and the proportion of no or mild peristalsis (OR = 7.89, 95% CI = 5.03-12.39, P < 0.00001) compared with the placebo, whereas it was not associated with an improvement in the adenoma detection rate (OR = 1.03, 95% CI = 0.54-1.99, P = 0.92). Adverse events did not differ significantly between the 2 groups (OR = 1.40, 95% CI = 0.75-2.59, P = 0.29). DISCUSSION: The findings of this study support the use of L-menthol to suppress gastrointestinal peristalsis during endoscopic procedure.