Exploring the thermally-controlled fentanyl transdermal therapy to provide constant drug delivery by physics-based digital twins.

Transdermal drug delivery is suitable for low-molecular-weight drugs with specific lipophilicity, like fentanyl, which is widely used for cancer-induced pain management. However, fentanyl's transdermal therapy displays high intra-individual variability. Factors like skin characteristics at application sites and ambient temperature contribute to this variation. In this study, we developed a physics-based digital twin of the human body to cope with this variability and propose better adapted setups. This twin includes an in-silico skin model for drug penetration, a pharmacokinetic model, and a pharmacodynamic model. Based on the results of our simulations, applying the patch on the flank (side abdominal area) showed a 15.3 % higher maximum fentanyl concentration in the plasma than on the chest. Additionally, the time to reach this maximum concentration when delivered through the flank was 19.8 h, which was 10.3 h earlier than via the upper arm. Finally, this variation led to an 18 % lower minimum pain intensity for delivery via the flank than the chest. Moreover, the impact of seasonal changes on ambient temperature and skin temperature by considering the activity level was investigated. Based on our result, the fentanyl uptake flux by capillaries increased by up to 11.8 % from an inactive state in winter to an active state in summer. We also evaluated the effect of controlling fentanyl delivery by adjusting the temperature of the patch to alleviate the pain to reach a mild pain intensity (rated three on the VAS scale). By implementing this strategy, the average pain intensity decreased by 1.1 points, and the standard deviation for fentanyl concentration in plasma and average pain intensity reduced by 37.5 % and 33.3 %, respectively. Therefore, our digital twin demonstrated the efficacy of controlled drug release through temperature regulation, ensuring the therapy toward the intended target outcome and reducing therapy outcome variability. This holds promise as a potentially useful tool for physicians.

Nicotine exacerbates exertional heat strain in trained men: a randomized, placebo-controlled, double-blind study.

To determine whether using nicotine exacerbates exertional heat strain through an increased metabolic heat production (Hprod) or decreased skin blood flow (SkBF), 10 nicotine-naïve trained males [37 ± 12 yr; peak oxygen consumption (V̇o2peak): 66 ± 10 mL·min-1·kg-1] completed four trials at 20°C and 30°C following overnight transdermal nicotine (7 mg·24 h-1) and placebo use in a crossover, double-blind design. They cycled for 60 min (55% V̇o2peak) followed by a time trial (∼75% V̇o2peak) during which measures of gastrointestinal (Tgi) and mean weighted skin ([Formula: see text]sk) temperatures, SkBF, Hprod, and mean arterial pressure (MAP) were made. The difference in ΔTgi between nicotine and placebo trials was greater during 30°C (0.4 ± 0.5°C) than 20°C (0.1 ± 0.7°C), with [Formula: see text]sk higher during nicotine than placebo trials (0.5 ± 0.5°C, P = 0.02). SkBF became progressively lower during nicotine than placebo trials (P = 0.01) and progressively higher during 30°C than 20°C trials (P < 0.01); MAP increased from baseline (P < 0.01) and remained elevated in all trials. The difference in Hprod between 30°C and 20°C trials was lower during nicotine than placebo (P = 0.01) and became progressively higher during 30°C than 20°C trials with exercise duration (P = 0.03). Mean power output during the time trial was lower during 30°C than 20°C trials (24 ± 25 W, P = 0.02), and although no effect of nicotine was observed (P > 0.59), two participants (20%) were unable to complete their 30°C nicotine trials as one reached the ethical limit for Tgi (40.0°C), whereas the other withdrew due to "nausea and chills" (Tgi = 39.7°C). These results demonstrate that nicotine use increases thermal strain and risk of exertional heat exhaustion by reducing SkBF.NEW & NOTEWORTHY In naïve participants, acute nicotine use exerts a hyperthermic effect that increases the risk of heat exhaustion during exertional heat strain, which is driven by a blunted skin blood flow response. This has implications for 1) populations that face exertional heat strain and demonstrate high nicotine use (e.g., athletes and military, 25%-50%) and 2) study design whereby screening and exclusion for nicotine use or standardization of prior use (e.g., overnight abstinence) is encouraged.

Menstrual cycle phases and dosage of synthetic hormonal contraceptives influence diurnal rhythm characteristics of distal skin temperature.

This study aimed to explore how natural menstrual cycle phases and dosage of oral hormonal contraceptives (OC) influence the diurnal rhythm of distal skin temperature (DST) under real-life conditions. Participants were 41 healthy females (23.9 ± 2.48 y), comprising 27 females taking monophasic hormonal oral contraceptives (OC users) and 14 females with menstrual cycles (non-OC users). Wrist DST was continuously recorded and averaged over two consecutive 24-hour days during (pseudo)follicular and (pseudo)luteal menstrual phases. Diurnal rhythm characteristics, i.e. acrophase and amplitude, describing timing and strength of the DST rhythm, respectively, were calculated using cosinor analysis. Results show that non-OC users experienced earlier diurnal DST maximum (acrophase, p = 0.019) and larger amplitude (p = 0.016) during the luteal phase than during the follicular phase. This was observed in most (71.4%) but not all individuals. The OC users showed no differences in acrophase or amplitude between pseudoluteal and pseudofollicular phases. OC users taking a higher dosage of progestin displayed a larger amplitude for DST rhythm during the pseudoluteal phase (p = 0.009), while estrogen dosage had no effect. In conclusion, monophasic OC cause changes in diurnal DST rhythm, similar to those observed in the luteal phase of females with menstrual cycles, suggesting that synthetic progestins act in a similar manner on skin thermoregulation as progesterone does.

Nitrate ingestion blunts the increase in blood pressure during cool air exposure: a double-blind, placebo-controlled, randomized, crossover trial.

Cold exposure increases blood pressure (BP) and salivary flow rate (SFR). Increased cold-induced SFR would be hypothesized to enhance oral nitrate delivery for reduction to nitrite by oral anaerobes and to subsequently elevate plasma [nitrite] and nitric oxide bioavailability. We tested the hypothesis that dietary nitrate supplementation would increase plasma [nitrite] and lower BP to a greater extent in cool compared with normothermic conditions. Twelve males attended the laboratory on four occasions. Baseline measurements were completed at 28°C. Subsequently, participants ingested 140 mL of concentrated nitrate-rich (BR; ∼13 mmol nitrate) or nitrate-depleted (PL) beetroot juice. Measurements were repeated over 3 h at either 28°C (Norm) or 20°C (Cool). Mean skin temperature was lowered compared with baseline in PL-Cool and BR-Cool. SFR was greater in BR-Norm, PL-Cool, and BR-Cool than PL-Norm. Plasma [nitrite] at 3 h was higher in BR-Cool (592 ± 239 nM) versus BR-Norm (410 ± 195 nM). Systolic BP (SBP) at 3 h was not different between PL-Norm (117 ± 6 mmHg) and BR-Norm (113 ± 9 mmHg). SBP increased above baseline at 1, 2, and 3 h in PL-Cool but not BR-Cool. These results suggest that BR consumption is more effective at increasing plasma [nitrite] in cool compared with normothermic conditions and blunts the rise in BP following acute cool air exposure, which might have implications for attenuating the increased cardiovascular strain in the cold.NEW & NOTEWORTHY Compared with normothermic conditions, acute nitrate ingestion increased plasma [nitrite], a substrate for oxygen-independent nitric oxide generation, to a greater extent during cool air exposure. Systolic blood pressure was increased during cool air exposure in the placebo condition with this cool-induced blood pressure increase attenuated after acute nitrate ingestion. These findings improve our understanding of environmental factors that influence nitrate metabolism and the efficacy of nitrate supplementation to lower blood pressure.

Short-term cocoa bioflavanol supplementation does not improve cold-induced vasodilation in young healthy adults.

PURPOSE: Cold-induced vasodilation (CIVD) is an oscillatory rise in blood flow to glabrous skin that occurs in cold-exposed extremities. Dietary flavanols increase bioavailable nitric oxide, a proposed mediator of CIVD through active vasodilation and/or withdrawal of sympathetic vascular smooth muscle tone. However, no studies have examined the effects of flavanol intake on extremity skin perfusion during cold exposure. We tested the hypothesis that acute and 8-day flavanol supplementation would augment CIVD during single-digit cold water immersion (CWI). METHODS: Eleven healthy adults (24 ± 6 years; 10 M/1F) ingested cocoa flavanols (900 mg/day) or caffeine- and theobromine-matched placebo for 8 days in a double-blind, randomized, crossover design. On Days 1 and 8, CIVD was assessed 2 h post-treatment. Subjects immersed their 3rd finger in warm water (42 °C) for 15 min before CWI (4 °C) for 30 min, during which nail bed and finger pad skin temperature were measured. RESULTS: Flavanol ingestion had no effect on CIVD frequency (Day 1, Flavanol: 3 ± 2 vs. Placebo: 3 ± 2; Day 8, Flavanol: 3 ± 2 vs. Placebo: 3 ± 1) or amplitude (Day 1, Flavanol: 4.3 ± 1.7 vs. Placebo: 4.9 ± 2.6 °C; Day 8, Flavanol: 3.9 ± 1.9 vs. Placebo: 3.9 ± 2.0 °C) in the finger pad following acute or 8-day supplementation (P > 0.05). Furthermore, average, nadir, and apex finger pad temperatures during CWI were not different between treatments on Days 1 or 8 of supplementation (P > 0.05). Similarly, no differences in CIVD parameters were observed in the nail bed following supplementation (P > 0.05). CONCLUSION: These data suggest that cocoa flavanol ingestion does not alter finger CIVD. Clinical Trial Registration Clinicaltrials.gov Identifier: NCT04359082. April 24, 2020.

Effect of Liothyronine Treatment on Dermal Temperature and Activation of Brown Adipose Tissue in Female Hypothyroid Patients: A Randomized Crossover Study.

Background: Thyroid hormones are essential for the full thermogenic response of brown adipose tissue (BAT) and have been implicated in dermal temperature regulation. Nevertheless, persistent cold-intolerance exists among a substantial proportion of hypothyroid patients on adequate levothyroxine (LT4) substitution. Materials and Methods: To assess if skin temperature and activation of BAT during treatment with liothyronine (LT3) differs from that of LT4 treatment, fifty-nine female hypothyroid patients with residual symptoms on LT4 or LT4/LT3 combination therapy were randomly assigned in a non-blinded crossover study to receive monotherapy with LT4 or LT3 for 12 weeks each. Change in supraclavicular (SCV) skin temperature overlying BAT, and sternal skin temperature not overlying BAT, during rest and cold stimulation were assessed by infrared thermography (IRT). In addition, abundance of exosomal miR-92a, a biomarker of BAT activation, was estimated as a secondary outcome. Results: Cold stimulated skin temperatures decreased less with LT3 vs. LT4 in both SCV (mean 0.009°C/min [95% CI: 0.004, 0.014]; P<0.001) and sternal areas (mean 0.014°C/min [95% CI: 0.008, 0.020]; P<0.001). No difference in serum exosomal miR-92a abundance was observed between the two treatment groups. Conclusion: LT3 may reduce dermal heat loss. Thermography data suggested increased BAT activation in hypothyroid patients with cold-intolerance. However, this finding was not corroborated by assessment of the microRNA biomarker of BAT activation. Clinical Trial Registration: ClinicalTrials.gov, identifier NCT03627611.

Thermoregulatory effects of guava leaf extract-menthol toner application for post-exercise use.

CONTEXT: Psidium guajava L. (Myrtaceae) leaf contains a wide variety of bioactive compounds that contribute valuable effects on human well-being. OBJECTIVE: This study investigates the influence of guava leaf extract-menthol toner on thermoregulation, including perspiration, skin temperature, and recovery heart rate. MATERIALS AND METHODS: This randomised, placebo-controlled clinical trial assessed the effects of the guava leaf extract-menthol toner and placebo with a 1-week washout period. Sixty-four participants were enrolled. The participants exercised on a treadmill until a 75% heart rate reserve was achieved for 5 min, followed by a 5 min post-exercise rest period. The skin temperature and heart rate were then measured before 5 mL of the testing product was sprayed to specific areas of the body, left it for 30 sec before wiped off. Post-exercise perspiration and skin temperatures were collected by sweat patches and measured by the Skin-thermometer ST500, respectively. A 20 min heart rate monitoring period started 10 min after the exercise and measured every 2 min intervals. RESULTS: Use of the toner significantly reduced post-exercise perspiration to approximately half of the baseline and placebo use values (p < 0.05). Furthermore, relative heart rate changes showed no significant differences among the tests (p > 0.05). Skin temperature was also unaffected (p > 0.05). DISCUSSION AND CONCLUSION: Guava leaf extract-menthol toner reduced perspiration by astringent effects but did not influence heat dissipation and did not affect cardiovascular mechanism compared to the controls. Additional cleaning with guava leaf extract-menthol toner could offer better hygiene after a workout.

Associations between peripheral perfusion disorders, mean arterial pressure and dose of norepinephrine administrated in the early phase of septic shock.

The aim of the study was to explore the correlations between peripheral perfusion, mean arterial pressure and the dose-rate of norepinephrine (NE) infused for the treatment of septic shock. The study is retrospective analysis of data acquired prospectively on 57 patients during the first 24 hours after the occurrence of the shock. Clinical and haemodynamic characteristics, skin perfusion parameters (capillary refill time [CRT], mottling score and temperature gradients) and the dose rate of NE infusion were collected. Negative correlations between mean arterial pressure (MAP) and temperature gradients (core-to-toe: P = .03, core-to-index: P = .04) were found and abnormal CRT was associated with lower MAP (P = .02). The dose rate of NE was negatively correlated with temperature gradients (core-to-toe: P = .02, core-to-index: P = .01, forearm-to-index: P = .008) in the overall population. In patients receiving NE for at least 12 hours, the NE dose rate positively was correlated with the mottling score (P = .006), temperature gradients (core-to-toe: P = .04, forearm-to-index: P = .02, core-to-index: P = .005) and CRT (P = .001). The dose of NE administrated was associated with 14-days mortality (odds ration [OR] = 1.21 [1.06-1.38], P = .006) and with 28-days mortality (OR = 1.17 [1.01-1.36], P = 0.04). In conclusion, the study described the presence of correlations between peripheral perfusion and MAP and between peripheral perfusion and the dose rate of NE infusion.

Effects of neurokinin 3 receptor antagonist fezolinetant on hot flash-like symptoms in ovariectomized rats.

The majority of women experience vasomotor symptoms (VMS), such as hot flashes and night sweats, during the menopausal transition. Recent evidence strongly suggests a connection between neurokinin 3 (NK3) receptor signaling and VMS associated with menopause. The NK3 receptor antagonist fezolinetant is currently in phase 3 development for treatment of moderate to severe VMS associated with menopause. We investigated the pharmacological effects of repeated administration of fezolinetant on levels of sex hormones and gonadotropins, neuronal activity in the hypothalamus, and skin temperature as an index of hot flash-like symptoms in ovariectomized rats as a model of menopause. Ovariectomized rats exhibited several typical menopausal symptoms: hyperphagia, increased body weight, significantly decreased plasma estradiol levels, increased luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels, and significantly increased skin temperature. Increased c-Fos expression (an indirect marker of neuronal activity) in median preoptic nucleus (MnPO) hypothalamic neurons was also observed in ovariectomized rats. Repeated oral administration of fezolinetant (1-10 mg/kg, twice daily) for 1 week dose-dependently reduced plasma LH levels without affecting estradiol or FSH levels, inhibited the activation of MnPO neurons, and attenuated hot flash-like symptoms. In addition, fezolinetant dose-dependently reduced hyperphagia and weight gain in ovariectomized rats. These preclinical findings suggest that fezolinetant attenuates hot flash-like symptoms via inhibition of neuronal activity in the MnPO of ovariectomized rats and provides further support for the ongoing clinical development of fezolinetant for the treatment of VMS associated with menopause.

Effects of Norepinephrine Infusion on Cutaneous Surface Temperatures of the Distal Extremities.

OBJECTIVES: The etiology of vasopressor-induced digital necrosis is poorly understood, but the skin changes resemble those of frostbite, and it is known from experience that patients taking vasopressors have decreased digital temperatures. We aimed to examine the effects of norepinephrine use on surface temperatures of the distal extremities because there have been no studies examining this relation. METHODS: Surface temperatures of all digits, palms, and soles were measured using an infrared thermometer in patients receiving different rates of norepinephrine infusion in the intensive care unit and compared with those not receiving any vasopressors. RESULTS: A total of 101 measurements from 41 unique individuals were obtained. Temperature gradients between the core and the fingertips were consistently more pronounced in those receiving norepinephrine compared with those not receiving norepinephrine and increased with increasing rates of norepinephrine infusion, except with high-dose norepinephrine. Temperature gradients were more pronounced in the toes. CONCLUSIONS: Norepinephrine use was associated with greater core-to-fingertip temperature gradients and were more pronounced in the toes compared with the fingers.

Nitrous oxide improves cardiovascular, respiratory, and thermal stability during prolonged isoflurane anesthesia in juvenile guinea pigs.

Anesthesia is frequently used to facilitate physiological monitoring during interventional animal studies. However, its use may induce cardiovascular (central and peripheral), respiratory, and thermoregulatory depression, confounding results in anesthetized animals. Despite the wide utility of guinea pigs as a translational platform, anesthetic protocols remain unstandardized for extended physiological studies in this species. Therefore, optimizing an anesthetic protocol that balances stable anesthesia with intact cardiorespiratory and metabolic function is crucial. To achieve this, 12 age and sex-matched juvenile Dunkin Hartley guinea pigs underwent extended anesthesia (≤150 min) with either (a) isoflurane (ISO: 1.5%), or (b) isoflurane + N2 O (ISO+ N2 O: 0.8% +70%), in this randomized cross-over designed study. Cardiovascular (HR, SBP, peripheral microvascular blood flow), respiratory (respiratory rate, SpO2 ), and thermal (Tre and Tsk ) measures were recorded continuously throughout anesthesia. Blood gas measures pre- and post- anesthesia were performed. Incorporation of 70% N2 O allowed for significant reductions in isoflurane (to 0.8%) while maintaining an effective anesthetic depth for prolonged noninvasive physiological examination in guinea pigs. ISO+N2 O maintained heart rate, peripheral blood flow, respiratory rate, and thermoregulatory function at levels closest to those of conscious animals, especially in females; however, it did not fully rescue anesthesia-induced hypotension. These results suggest that for studies requiring prolonged physiological examination (≤150 min) in guinea pigs, 0.8% isoflurane with a 70% N2 O adjuvant provides adequate anesthesia, while minimizing associated cardiorespiratory depression. The preservation of cardiorespiratory status is most marked throughout the first hour of anesthesia.

Sustained release buprenorphine effectively attenuates postoperative hypersensitivity in an incisional pain model in neonatal rats (Rattus norvegicus).

Despite the need for safe and effective postoperative analgesia in neonates, research regarding pain management in neonatal rodents is relatively limited. Here, we investigate whether sustained release buprenorphine (Bup SR) effectively attenuates thermal hypersensitivity in a neonatal rat model of incisional pain. Male and female postnatal day 3 Sprague Dawley rat pups (n = 34) were randomly assigned to one of four treatment groups: 1) saline (control), 0.1 mL, once subcutaneously (SC); 2) buprenorphine HCl (Bup HCl), 0.05 mg/kg, once SC; 3) low dose Bup SR (low-SR), 0.5 mg/kg, once SC; 4) high dose Bup SR (high-SR), 1 mg/kg, once SC. Pups were anesthetized with sevoflurane and a 0.5-cm long skin incision was made over the left lateral thigh. The underlying muscle was dissected and closed using surgical glue. Thermal hypersensitivity testing was performed at 24 h prior to surgery and subsequently at 1, 4, 8, 24, and 48 h post-surgery using an infrared diode laser. Thermal hypersensitivity was attenuated at 1 h post-surgery in the Bup HCl group, while it was attenuated through the entire postoperative period in both low-SR and high-SR groups. This data suggests that a single dose of low-SR (0.5 mg/kg) or high-SR (1 mg/kg) effectively attenuates thermal hypersensitivity for at least 8 h in neonatal rat pups.

The influence of menthol dose on human temperature regulation and perception.

INTRODUCTION: This study assessed the influence of High (H, 4.13%), Medium (M, 2.0%) and Low (L, 0.1%) doses of menthol on temperature perception and regulation, compared to a Placebo Condition (P). METHOD: Sixteen participants underwent the aforementioned conditions on four separate days. During each test participants rested supine (Environmental conditions: 30 °C, 50% rh) for 30-min before 40 mL of L, M, H or P gel was applied to the anterior upper body, then rested 30-min thereafter. Primary measures included thermal sensation (TS), thermal comfort (TC), irritation (IRR), rectal temperature (Tre), and skin temperature (chest, forearm, thigh, calf), and EMG (trapezius, pectoralis major, sternocleidomastoid). The area under the curve (AUC) from minute 30 to 60 was compared between conditions using relevant non/parametric tests (alpha level = 0.05). RESULTS: A cooling trend in Tre was observed following Placebo gel application, but this significantly (p < 0.05) reversed into a heat storage response in M and H. Both TS and TC significantly differed by condition (p < 0.001) in a dose-dependent manner, with L, M, and H doses eliciting significantly cooler sensations and more discomfort than P (p < 0.05). Irritation significantly differed by condition (p < 0.01) in a dose-dependent manner, with L and M eliciting significantly greater irritation than P (p < 0.01). No other differences were observed. CONCLUSIONS: Menthol exerts perceptual and thermoregulatory effects independent of skin temperature. A menthol dose-dependent perceptual cooling effect was evident with possible saturation at the moderate dose. A dose-dependent alteration in deep body temperature was also evident.

Systemic acyl-ghrelin increases tail skin temperature in rats without affecting their thermoregulatory behavior in a cold environment.

Fasting increases ghrelin that is a peptide hormone with two circulating isoforms, acyl and des-acyl ghrelin. We reported that fasting or des-acyl ghrelin facilitates behavioral thermoregulation in the cold in rats assessed by tail-hiding behavior that was the indicator of rats' thermoregulatory behavior in the cold; however, the effect of acyl-ghrelin on the same process remains to be elucidated. We investigated the effect of acyl-ghrelin on thermoregulatory behavior in the cold in rats. The animals received an intraperitoneal saline or 24 µg acyl-ghrelin injection and were exposed to 27 °C or 15 °C for 2 h, while their body temperature, tail skin temperature, and tail-hiding behavior were constantly monitored. cFos immunoreactive (cFos-IR) cells in the median preoptic area, medial preoptic area, paraventricular nucleus (PVN), and arcuate nucleus were counted. Body temperature and the duration of thermoregulatory behavior did not show a significant difference between the acyl-ghrelin-treated and control groups at 15 °C; however, tail skin temperature in the acyl-ghrelin-treated group was higher than that in the control group. The number of cFos-IR cells in the PVN was greater in the control group than that in the acyl-ghrelin-treated group at 27 °C. These results indicate that acyl-ghrelin did not affect behavioral thermoregulation but might affect tail skin temperature in rats in the cold.

Dietary nitrate supplementation does not influence thermoregulatory or cardiovascular strain in older individuals during severe ambient heat stress.

NEW FINDINGS: What is the central question of this study? Does dietary nitrate supplementation with beetroot juice attenuate thermoregulatory and cardiovascular strain in older adults during severe heat stress? What is the main finding and its importance? A 7-day nitrate supplementation regimen lowered resting mean arterial pressure in thermoneutral conditions. During heat stress, core and mean skin temperatures, vasodilatory responses, sweat loss, heart rate and left ventricular function were unchanged, and mean arterial pressure was only transiently reduced, post-supplementation. These data suggest nitrate supplementation with beetroot juice does not mitigate thermoregulatory or cardiovascular strain in heat-stressed older individuals. ABSTRACT: This study tested the hypothesis that dietary nitrate supplementation with concentrated beetroot juice attenuates thermoregulatory and cardiovascular strain in older individuals during environmental heat stress. Nine healthy older individuals (six females, three males; aged 67 ± 5 years) were exposed to 42.5 ± 0.1°C and 34.0 ± 0.5% relative humidity conditions for 120 min before (CON) and after 7 days of dietary nitrate supplementation with concentrated beetroot juice (BRJ; 280 ml, ∼16.8 mmol of nitrate daily). Core and skin temperatures, body mass changes (indicative of whole-body sweat loss), skin blood flow and cutaneous vascular conductance, forearm blood flow and vascular conductance, heart rate, arterial blood pressures and indices of cardiac function were measured. The 7-day beetroot juice regimen increased plasma nitrate/nitrite levels from 27.4 ± 15.2 to 477.0 ± 102.5 µmol l-1 (P < 0.01) and lowered resting mean arterial pressure from 90 ± 7 to 83 ± 10 mmHg at baseline under thermoneutral conditions (P = 0.02). However, during subsequent heat stress, no differences in core and skin temperatures, skin blood flow and vascular conductance, forearm blood flow and vascular conductance, whole-body sweat loss, heart rate, and echocardiographic indices of systolic function and diastolic filling were evident following nitrate supplementation (all P > 0.05). Mean arterial pressure was lower in BRJ vs. CON during heat stress (treatment-by-time interaction: P = 0.02). Overall, these findings suggest that dietary nitrate supplementation with concentrated beetroot juice does not attenuate thermoregulatory or cardiovascular strain in older individuals exposed to severe ambient heat stress.

Effects of a Standardized Oligomerized-Polyphenol from Litchi chinensis Fruit Extract and Mixed Plant Extract Supplementation on Peripheral Circulation and Cold Sensitivity.

Certain individuals tend to suffer from a cold sensation-particularly in the lower extremities-despite most people not suffering from the same sensation. In Japan, this phenomenon is called "hie-sho" and reduces quality of life for several people, particularly women. A previous study has shown that a standardized oligomerized-polyphenol from Litchi chinensis fruit extract (OPLFE) reportedly causes a significant increase in body surface temperature. The present study aimed to investigate whether supplementation with OPLFE affected peripheral circulation and cold sensitivity. This randomized, double-blind, placebo-controlled trial was performed including 25 participants (age, 45.0±10.4 y; 3 males and 22 females) who were assigned to consume OPLFE, mixed plant extract with OPLFE, or placebo capsules for 14 d. Participants were instructed to relax for 60 min in a temperature-controlled room prior to obtaining measurements. Changes in skin temperature and peripheral blood flow of the middle finger were assessed immediately before and 1, 5, 10, 20, and 30 min after immersion in cold water (10ºC). Participants' height, weight, skin temperature, and blood flow in peripheral tissue were measured; furthermore, their "hie-sho" was measured using the Visual Analog Scale (VAS). Skin temperature and blood flow in peripheral tissue increased in the OPLFE and mixed plant extract with OPLFE groups on day 14 compared with those on day 1. In addition, cold sensitivity in these two groups significantly improved between day 1 and day 14. These findings suggest that OPLFE improves "hie-sho" by increasing peripheral blood flow and skin temperature.

Modeling Temperature-Dependent Dermal Absorption and Clearance for Transdermal and Topical Drug Applications.

A computational model was developed to better understand the impact of elevated skin temperatures on transdermal drug delivery and dermal clearance. A simultaneous heat and mass transport model with emphasis on transdermal delivery system (TDS) applications was developed to address transient and steady-state temperature effects on dermal absorption. The model was tested using representative data from nicotine TDS applied to human skin either in vitro or in vivo. The approximately 2-fold increase of nicotine absorption with a 10°C increase in skin surface temperature was consistent with a 50-65 kJ/mol activation energy for diffusion in the stratum corneum, with this layer serving as the primary barrier for nicotine absorption. Incorporation of a dermal clearance component into the model revealed efficient removal of nicotine via the dermal capillaries at both normal and elevated temperatures. Two-compartment pharmacokinetic simulations yielded systemic drug concentrations consistent with the human pharmacokinetic data. Both in vitro skin permeation and in vivo pharmacokinetics of nicotine delivered from a marketed TDS under normal and elevated temperatures can be satisfactorily described by a simultaneous heat and mass transfer computational model incorporating realistic skin barrier properties and dermal clearance components.

Polydeoxyribonucleotide Exerts Therapeutic Effect by Increasing VEGF and Inhibiting Inflammatory Cytokines in Ischemic Colitis Rats.

Ischemic colitis is resulted from an inadequate blood supply to a segment or entire colon. Polydeoxyribonucleotide (PDRN), extracted from salmon sperm, has been reported to exert anti-inflammatory and anti-ischemic effects through the adenosine A2A receptor (A2AR). We investigated whether PDRN possesses therapeutic effectiveness on ischemic colitis rats. Ischemic colitis was induced by selective devascularization. The skin temperature on the ischemic colitis-induced region was determined. To assess the colonic damage score and collagen deposition, colonic tissue sections were stained with hematoxylin and eosin (H&E), and Masson trichrome staining was performed. Western blot analysis for A2AR, vascular endothelial growth factor (VEGF), cyclooxygenase-2 (COX-2), tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and IL-6, Bax, Bcl-2, and extracellular signal-regulated kinase 1/2 (ERK1/2) was performed. Skin temperature was increased and mucosal damage and collagen deposition were observed in the affected colonic tissues in the ischemic colitis rats. Expressions of inflammatory cytokines (TNF-α, IL-1ß, and IL-6) and inflammatory mediator (COX-2) were upregulated in the ischemic colitis rats. Apoptosis was increased by decreasing the ratio of Bcl-2 to Bax and by suppressing the phosphorylated form of ERK1/2 expression in the ischemic colitis rats. Treatment with PDRN alleviated mucosal damage reduced the expressions of inflammatory cytokines and COX-2 and inhibited apoptosis in the ischemic colitis rats. PDRN treatment more enhanced the expressions of A2AR and VEGF in the ischemic colitis rats. PDRN showed therapeutic effectiveness on ischemic colitis by increasing VEGF expression and inhibiting inflammatory cytokines and COX-2 through enhancing A2AR expression.

Treprostinil Hydrogel Iontophoresis in Systemic Sclerosis-Related Digital Skin Ulcers: A Safety Study.

Digital skin ulcers are a severe complication of systemic sclerosis. The first-line treatment is intravenous iloprost, but it induces dose-limiting adverse effects. Local administration of treprostinil through skin iontophoresis may be a safe alternative. We conducted a 2-stage, randomized, placebo-controlled single-ascending-dose study in healthy volunteers and patients with systemic sclerosis-related digital ulcer. We further explored the effect of the procedure on skin blood flux. In a first group of healthy subjects, treprostinil and placebo iontophoresis were performed at 3 locations (ie, 6 skin sites): the sole of the foot, the leg, and the fingers. We used a 1-mg/mL hydrogel of treprostinil. We then randomly treated systemic sclerosis-related digital ulcers in a 3:1 ratio of treprostinil or placebo. We used concentrations from 0.1 to 1 mg/mL. All adverse events were recorded and rated according to the Common Terminology Criteria for Adverse Events (CTCAE), whereas skin microvascular blood flux was recorded with laser speckle contrast imaging. Among the 12 healthy volunteers, we observed 60 local adverse effects: burns, skin pain, erythema, and pruritus, graded 1 or 2 on the 5-point CTCAE scale. Treprostinil iontophoresis significantly increased skin blood flux on the leg (AUC0-4 h at 88 460% ± 6436% versus 12 730% ± 3397% baseline flux.min respectively; P < .001) and on the sole of the foot (AUC0-3 h at 20 124% ± 6119% versus 3142% ± 3036% baseline flux.min, respectively; P = .018) with a trend on the finger. Among 5 patients with systemic sclerosis-related digital ulcer, 2 resolutive local adverse effects were reported. Iontophoresis of treprostinil hydrogel was safe in systemic sclerosis patients with digital ulcer.

Efficacy and safety of ucha-shinki-hwan on korean patients with cold hypersensitivity in the hands and feet: Study protocol clinical trial (SPIRIT Compliant).

BACKGROUND: Cold hypersensitivity in the hands and feet (CHHF) is a common complaint in Asian female population especially in Korea. Due to the symptoms of CHHF the quality of individual's daily life can be degraded. Ucha-Shinki-Hwan (UCHA) is widely used in the treatment of various diseases including CHHF by harmonizing Yin and Yang, and improving the vitality of whole body. However, the efficacy of UCHA as a treatment option of CHHF has not been assessed in trials. Thus, we aimed to investigate the efficacy and safety of UCHA in Korean women with CHHF through this trial. METHODS: This study will be an exploratory, randomized, double-blind, placebo-controlled, parallel-group, multicenter trial. Korean women aged 19 to 59 years who complaint with CHHF will be enrolled from 5 university affiliated Korean medicine hospitals. A total of 164 subjects will be randomly assigned to a treatment group (UCHA) or a placebo group at a 1:1 ratio. The subjects will receive 2.5 g of either UCHA or placebo three times a day for 8 weeks. The primary outcome will be evaluated with the visual analog scale score of CHHF. The secondary outcome measures will be changes in skin temperature in extremities as measured by using a thermometer and the Korean version of the World Health Organization Quality of Life Scale Abbreviated Version. DISCUSSION: This study will be the first trial to explore the efficacy and safety of UCHA for CHHF patient. This will provide meaningful clinical information on herbal medicine treatment of CHHF and a clinical evidence for planning a full randomized clinical trial. DISCLOSURES AND ACKNOWLEDGMENTS: The authors report no competing interests. TRIAL REGISTRATION: This study is registered at ClinicalTrials.gov, ID: NCT03790033. Registered on (31 December 2018) PROTOCOL VERSION:: The final approved version of the trial protocol is V1.3. (25 January 2019).