Ampliação de uso da dosagem de cloreto no suor para pacientes com fibrose cística a partir de seis anos / Expansion of the use of sweat chloride measurement for patients with cystic fibrosis from six years

INTRODUÇÃO: A Fibrose Cística (FC) é uma doença genética em que se observa desequilíbrio na concentração de cloro e sódio nas células que produzem assecreções do corpo, como muco e suor. Como resultado do acúmulo demuco e consequente proliferação de patógenos, observa-se como principaissintomas:tosse crônica, pneumonia de repetição, diarreia, pólipos nasais, e déficits de peso e estatura. O diagnóstico é feito a partir da sintomatologia apresentada, teste do suor e testagem genética. O novo PCDT de FC encontra-se em fase de atualização. Nele é preconizado o uso do ivacaftor para o tratamento da FC em pacientes com idade ≥ 6 anos e ≥25 kg que apresentam uma das seguintes mutações no gene CFTR: G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, S549R, já incorporado no Sistema Único de Saúde (SUS). CONSIDERAÇÕES FINAIS: Considerando que o medicamento ivacaftor é preconizado para pacientes a partir de seis anos de idade, verifica-se que o procedimento atualmente disponível no SUS não possibilita o atendimento desta população, uma vez que a idade máxima permitida é de dois anos. Ressalta-se que aqueles pacientes que não apresentarem melhora nos níveis de cloro no suor após exposição ao ivacaftor não devem continuar recebendo o medicamento pela baixa chance de apresentarresposta clínica. Portanto, a realização do exame é fundamental para que haja o uso racional domedicamento. Como apresentado sua inclusão possui um baixo impacto financeiro no orçamento total. Dessa forma, entende-se como um procedimento necessário para o completo tratamento da FC aos pacientes atendidos no SUS. RECOMENDAÇÃO PRELIMINAR: Os membros do Plenário presentes na 111ª Reunião Ordinária da Conitec, realizada no dia 04 de agosto de 2022, sem nenhuma declaração de conflito de interesse, deliberaram por unanimidade, encaminhar o tema para consulta pública com recomendação preliminar favorável ampliação de uso da dosagem de cloreto no suor para pacientes com fibrose cística a partir de seis anos. CONSULTA PÚBLICA: Consulta Pública (CP) nº62/2022: Disponibilizada no período de 13 de setembro a 03 de outubro de 2022, recebeu 7 (sete) contribuições ao todo, sendo uma contribuição técnico-científica e 6(seis) contribuições sobre experiência ou opinião. Todas as contribuições se mostraram favoráveis a ampliação do procedimento. Não houve mais ponderações. Todos os presentes declararam não possuir conflitos de interesse. RECOMENDAÇÃO FINAL DA CONITEC: Os membros do plenário, presentes na 113ª Reunião Ordinária, realizada no dia 06 de outubro de 2022, deliberaram por unanimidade recomendar a ampliação de uso, no SUS, da dosagem de cloreto no suor para pacientes com fibrose cística a partir de seis anos. Assim, foi assinado o Registro de Deliberação nº 776/2022. DECISÃO: ampliar o uso, no âmbito do Sistema Único de Saúde - SUS, da dosagem de cloreto no suor para pacientes com fibrose cística a partir de seis anos, conforme a Portaria nº 146, publicada no Diário Oficial da União nº 214, seção1, página 93, em 11 de novembro de 2022.

Optical Measurements of Sweat for in Vivo Quantification of CFTR Function in Individual Sweat Glands.

Optical measurement of CFTR-dependent sweat secretion stimulated by a beta-adrenergic cocktail (C-phase) vs. CFTR-independent sweat secretion induced by methacholine (M-phase) can discriminate cystic fibrosis (CF) patientts from controls and healthy carriers by the ratio of sweat rate in the C-phase vs. the M-phase (C/M ratio). However, image analysis is experimentally demanding and time-consuming. Here, sweat droplet number (SDN) in the C-phase, corresponding to the number of sweat-secreting glands, was a statistically significant predictor for detecting the effects of CFTR-targeted therapy. We show that in 44 non-CF subjects and 110 CF patients, SDN in the C-phase provides a linear readout of CFTR function that is more sensitive than that using the C/M ratio. In CF patients, increased SDN in the C-phase during treatment with (LUMA/IVA) was associated with a trend toward improved lung function (FEV1). Our method is suitable for multicenter monitoring of the effects of CFTR modulators.

In vitro skin model for characterization of sunscreen substantivity upon perspiration.

OBJECTIVE: The resistance of sunscreens to the loss of ultraviolet (UV) protection upon perspiration is important for their practical efficacy. However, this topic is largely overlooked in evaluations of sunscreen substantivity due to the relatively few well-established protocols compared to those for water resistance and mechanical wear. METHODS: In an attempt to achieve a better fundamental understanding of sunscreen behaviour in response to sweat exposure, we have developed a perspiring skin simulator, containing a substrate surface that mimics sweating human skin. Using this perspiring skin simulator, we evaluated sunscreen performance upon perspiration by in vitro sun protection factor (SPF) measurements, optical microscopy, ultraviolet (UV) reflectance imaging and coherent anti-Stokes Raman scattering (CARS) microscopy. RESULTS AND CONCLUSION: Results indicated that perspiration reduced sunscreen efficiency through two mechanisms, namely sunscreen wash-off (impairing the film thickness) and sunscreen redistribution (impairing the film uniformity). Further, we investigated how the sweat rate affected these mechanisms and how sunscreen application dose influenced UV protection upon perspiration. As expected, higher sweat rates led to a large loss of UV protection, while a larger application dose led to larger amounts of sunscreen being washed-off and redistributed but also provided higher UV protection before and after sweating.

OBJECTIF: La résistance des écrans solaires à la perte de protection contre les ultraviolets (UV) à cause de la transpiration est importante quant à leur efficacité pratique. Cependant, ce point est généralement négligé dans les évaluations de la substantivité des écrans solaires en raison du nombre relativement faible de protocoles bien établis, en comparaison avec ceux pour la résistance à l'eau et l'usure mécanique. MÉTHODES: Dans le but de parvenir à une meilleure compréhension fondamentale du comportement des écrans solaires en cas d'exposition à la sueur, nous avons développé un simulateur de peau transpirante, dont la surface de substrat imite la transpiration de la peau humaine. À l'aide de ce simulateur, nous avons évalué les performances des écrans solaires lors de la transpiration par des mesures in vitro du facteur de protection solaire (FPS), par microscopie optique, par imagerie de la réflectance ultraviolette (UV) et par microscopie cohérente de diffusion Raman anti-Stokes (coherent anti-Stokes Raman scattering, CARS). RÉSULTATS ET CONCLUSION: Les résultats ont montré que la transpiration réduisait l'efficacité de l'écran solaire en raison de deux mécanismes, à savoir le lavage de l'écran solaire (altération de l'épaisseur du film) et la redistribution de l'écran solaire (altération de l'uniformité du film). De plus, nous avons étudié comment le taux de transpiration affectait ces mécanismes et comment la dose d'application d'écran solaire influençait la protection UV en cas de transpiration. Comme l'on pouvait s'y attendre, des taux de sueur plus élevés ont entraîné une perte importante de protection contre les UV, tandis qu'une dose d'application plus importante a conduit à des quantités plus importantes d'écran solaire lavé et redistribué, mais a également fourni une protection contre les UV plus élevée avant et après la transpiration.

Females with cystic fibrosis have a larger decrease in sweat chloride in response to lumacaftor/ivacaftor compared to males.

AIM: To explore which patient-related factors influence sweat test response to CFTR modulators, as well as examining the correlation between the sweat chloride response and ppFEV1 or BMI response, using systematically collected real-life clinical data. METHODS: 160 CF patients were identified who had used lumacaftor/ivacaftor for at least six months. Of these patients, age, sweat chloride levels, ppFEV1 weight and BMI at the start of treatment and after 6 months were collected retrospectively. Pearson and Spearman tests were performed to assess correlations. RESULTS: Females compared to males in this group showed a larger response in sweat chloride (mean difference 10.6 mmol/l, 95% CI: 5.7-15.4) and BMI (mean difference 0.27 kg/m2, 95% CI: 0.01-0.54). A modest but significant correlation was found between patient weight and sweat chloride response (Pearson R = 0.244, p = 0.001), which diminished upon correction for the other factors. The correlation between sex and sweat chloride response remained; R = 0.253, p = 0.001. Sweat chloride response did not correlate with ppFEV1 change or BMI change at 6 months after start of therapy. CONCLUSION: Sweat chloride response is larger in females compared to males, which also explains the negative correlation of weight with the response in sweat chloride concentration after start of lumacaftor/ivacaftor. Sweat chloride response does not correlate with the responses in ppFEV1 and BMI. This information may help the interpretation of sweat test results acquired for the follow up and evaluation of CFTR modulating treatments, and warrants further investigation into the underlying mechanisms of sex differences in response to CFTR modulators.

Aluminium salt-based antiperspirant coated prosthesis liners do not suppress local sweating during moderate intensity exercise in hot and temperate conditions.

OBJECTIVE: To determine whether coating prosthesis liners with a 5% aluminium zirconium tetrachlorohydrate antiperspirant solution (AZCH) reduces local sweating on the thigh. DESIGN: Double-blinded counter-balanced crossover design METHODS: Fourteen able-bodied participants (age: 28±5 y; body mass: 73.9±7.9kg, height: 1.73±0.09m; peak oxygen consumption [VO2peak]: 50.7±9.1 mlO2⋅kg-1⋅min-1) simultaneously wore a prosthesis liner on each leg, one treated with AZCH and one untreated, for four days prior to running at 50% of VO2peak for 60min in a temperate (23.7±0.7°C and 42.2±2.6% relative humidity) or hot (34.0±1.6°C and 40.8±6.1% relative humidity) environment. Rectal temperature (Tre) and whole-body sweat rates (WBSR) were measured to characterize thermal strain. Local sweat rate (LSR) was measured bilaterally underneath the liners, continuously, and heat-activated-sweat gland density (HASGD) was measured bilaterally every 15min. RESULTS: In temperate condition, the mean change in Tre was 1.2±0.4°C and WBSR was 723±129g⋅h-1, whereas in the hot condition, change in Tre was 1.2±0.5°C and WBSR was 911±231g⋅h-1. In the temperate condition, AZCH treatment did not alter LSR (treated: 0.50±0.17 mg·cm-2min-1, untreated: 0.50±0.17 mg·cm-2min-1; P=0.87) or HASGD (treated: 54±14 glands·cm-2, untreated 55±14 glands·cm-2; P=0.38). In the hot condition, AZCH treatment paradoxically increased LSR (treated: 0.88±0.38 mg·cm-2min-1, untreated: 0.74±0.28 mg·cm-2min-1; P=0.04) but not HASGD (treated: 52±17 glands·cm-2, untreated: 48±19 glands·cm-2; P=0.77). CONCLUSION: These results indicate coating prosthesis liners with 5% AZCH is ineffective at reducing local sweating.

TEA-sensitive K+ channels and human eccrine sweat gland output.

Cholinergic-activated sweating depends on an influx of Ca2+ from extracellular fluid. It is thought that the opening of K+ channels on secretory epithelial cells facilitates Ca2+ entry. We examined the hypothesis that tetraethylammonium (TEA)-sensitive K+ channels participate in sweat production. We used a pre-post experimental design and initiated cholinergic-mediated sweating with intradermal electrical stimulation, monitored local sweat rate (SR) with a small sweat capsule mounted on the skin, and delivered 50 mM TEA via intradermal microdialysis. Local SR was activated by intradermal stimulation frequencies of 0.2-64 Hz, and we generated a sigmoid-shaped stimulus-response curve by plotting the area under the SR-time curve versus log10 stimulus frequency. Peak local SR was reduced from 0.372 ± 0.331 to 0.226 ± 0.190 mg·min-1·cm-2 (P = 0.0001) during application of 50 mM TEA, whereas the EC50 and Hill slopes were not altered. The global sigmoid-shaped stimulus-response curves for control and 50 mM TEA were significantly different (P < 0.0001), and the plateau region was significantly reduced (P = 0.0023) with the TEA treatment. The effect of TEA on peak local SR was similar in male and female subjects. However, we did note a small effect of sex on the shape of the stimulus-response curves during intradermal electrical stimulation. Overall, these data support the hypothesis that cholinergic control of sweat gland activity is modulated by the presence of TEA-sensitive K+ channels in human sweat gland epithelial cells.NEW & NOTEWORTHY The contribution of various potassium channels to the process of cholinergic-mediated human eccrine sweat production is unclear. Using a novel model for cholinergic-mediated sweating in humans, we provide evidence that tetraethylammonium-sensitive K+ channels (KCa1.1 and Kv channels) contribute to eccrine sweat production.

A phase 3 study of tezacaftor in combination with ivacaftor in children aged 6 through 11 years with cystic fibrosis.

BACKGROUND: Tezacaftor/ivacaftor is a new treatment option in many regions for patients aged ≥12 years who are homozygous (F/F) or heterozygous for the F508del-CFTR mutation and a residual function (F/RF) mutation. This Phase 3, 2-part, open-label study evaluated the pharmacokinetics (PK), safety, tolerability, and efficacy of tezacaftor/ivacaftor in children aged 6 through 11 years with these mutations. METHODS: Part A informed weight-based tezacaftor/ivacaftor dosages for part B. The primary objective of part B was to evaluate the safety and tolerability of tezacaftor/ivacaftor through 24 weeks; the secondary objective was to evaluate efficacy based on changes from baseline in percentage predicted forced expiratory volume in 1 s (ppFEV1), growth parameters, sweat chloride, and the Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score. RESULTS: After PK analysis in part A, 70 children received ≥1 dose of tezacaftor/ivacaftor in part B; 67 children completed treatment. Exposures in children aged 6 through 11 years were within the target range for those observed in patients aged ≥12 years. The safety profile of tezacaftor/ivacaftor was generally similar to prior studies in patients aged ≥12 years. One child discontinued treatment for a serious adverse event of constipation. Tezacaftor/ivacaftor treatment improved sweat chloride levels and CFQ-R respiratory domain scores, mean ppFEV1 remained stable in the normal range, and growth parameters remained stable over 24 weeks. CONCLUSIONS: Tezacaftor/ivacaftor was generally safe and well tolerated, and improved CFTR function in children aged 6 through 11 years with CF with F/F and F/RF genotypes, supporting tezacaftor/ivacaftor use in this age group. NCT02953314.

CFTR activity is enhanced by the novel corrector GLPG2222, given with and without ivacaftor in two randomized trials.

BACKGROUND: Several treatment approaches in cystic fibrosis (CF) aim to correct CF transmembrane conductance regulator (CFTR) function; the efficacy of each approach is dependent on the mutation(s) present. A need remains for more effective treatments to correct functional deficits caused by the F508del mutation. METHODS: Two placebo-controlled, phase 2a studies evaluated GLPG2222, given orally once daily for 29 days, in subjects homozygous for F508del (FLAMINGO) or heterozygous for F508del and a gating mutation, receiving ivacaftor (ALBATROSS). The primary objective of both studies was to assess safety and tolerability. Secondary objectives included assessment of pharmacokinetics, and of the effect of GLPG2222 on sweat chloride concentrations, pulmonary function and respiratory symptoms. RESULTS: Fifty-nine and 37 subjects were enrolled into FLAMINGO and ALBATROSS, respectively. Treatment-related treatment-emergent adverse events (TEAEs) were reported by 29.2% (14/48) of subjects in FLAMINGO and 40.0% (12/30) in ALBATROSS; most were mild to moderate in severity and comprised primarily respiratory, gastrointestinal, and infection events. There were no deaths or discontinuations due to TEAEs. Dose-dependent decreases in sweat chloride concentrations were seen in GLPG2222-treated subjects (maximum decrease in FLAMINGO: -17.6 mmol/L [GLPG2222 200 mg], p < 0.0001; ALBATROSS: -7.4 mmol/L [GLPG2222 300 mg], p < 0.05). No significant effects on pulmonary function or respiratory symptoms were reported. Plasma GLPG2222 concentrations in CF subjects were consistent with previous studies in healthy volunteers and CF subjects. CONCLUSIONS: GLPG2222 was well tolerated. Sweat chloride reductions support on-target enhancement of CFTR activity in subjects with F508del mutation(s). Significant improvements in clinical endpoints were not demonstrated. Observed safety results support further evaluation of GLPG2222, including in combination with other CFTR modulators. FUNDING: Galapagos NV. Clinical trial registration numbers FLAMINGO, NCT03119649; ALBATROSS, NCT03045523.

An open-label extension study of ivacaftor in children with CF and a CFTR gating mutation initiating treatment at age 2-5 years (KLIMB).

BACKGROUND: KIWI (NCT01705145) was a 24-week, single-arm, pharmacokinetics, safety, and efficacy study of ivacaftor in children aged 2 to 5 years with cystic fibrosis (CF) and a CFTR gating mutation. Here, we report the results of KLIMB (NCT01946412), an 84-week, open-label extension of KIWI. METHODS: Children received age- and weight-based ivacaftor dosages for 84 weeks. The primary outcome was safety. Other outcomes included sweat chloride, growth parameters, and measures of pancreatic function. RESULTS: All 33 children who completed KIWI enrolled in KLIMB; 28 completed 84 weeks of treatment. Most adverse events were consistent with those reported during KIWI. Ten (30%) children had transaminase elevations >3 × upper limit of normal (ULN), leading to 1 discontinuation in a child with alanine aminotransferase >8 × ULN. Improvements in sweat chloride, weight, and body mass index z scores and fecal elastase-1 observed during KIWI were maintained during KLIMB; there was no further improvement in these parameters. CONCLUSIONS: Ivacaftor was generally well tolerated for up to 108 weeks in children aged 2 to 5 years with CF and a gating mutation, with safety consistent with the KIWI study. Improvements in sweat chloride and growth parameters during the initial 24 weeks of treatment were maintained for up to an additional 84 weeks of treatment. Prevalence of raised transaminases remained stable and did not increase with duration of exposure during the open-label extension.

Sunscreen or simulated sweat minimizes the impact of acute ultraviolet radiation on cutaneous microvascular function in healthy humans.

NEW FINDINGS: What is the central question of this study? Are ultraviolet radiation (UVR)-induced increases in skin blood flow independent of skin erythema? Does broad-spectrum UVR exposure attenuate NO-mediated cutaneous vasodilatation, and does sunscreen or sweat modulate this response? What are the main findings and their importance? Erythema and vascular responses to UVR are temporally distinct, and sunscreen prevents both responses. Exposure to UVR attenuates NO-mediated vasodilatation in the cutaneous microvasculature; sunscreen or simulated sweat on the skin attenuates this response. Sun over-exposure may elicit deleterious effects on human skin that are separate from sunburn, and sunscreen or sweat on the skin may provide protection. ABSTRACT: Exposure to ultraviolet radiation (UVR) may result in cutaneous vascular dysfunction independent of erythema (skin reddening). Two studies were designed to differentiate changes in erythema from skin vasodilatation throughout the 8 h after acute broad-spectrum UVR exposure with (+SS) or without SPF-50 sunscreen (study 1) and to examine NO-mediated cutaneous vasodilatation after acute broad-spectrum UVR exposure with or without +SS or simulated sweat (+SW) on the skin (study 2). In both studies, laser-Doppler flowmetry was used to measure red cell flux, and cutaneous vascular conductance (CVC) was calculated (CVC = flux/mean arterial pressure). In study 1, in 14 healthy adults (24 ± 4 years old; seven men and seven women), the skin erythema index and CVC were measured over two forearm sites (UVR only and UVR+SS) before, immediately after and every 2 h for 8 h post-exposure (750 mJ cm-2 ). The erythema index began to increase immediately post-UVR (P < 0.05 at 4, 6 and 8 h), but CVC did not increase above baseline for the first 4-6 h (P ≤ 0.01 at 6 and 8 h); +SS prevented both responses. In study 2, in 13 healthy adults (24 ± 4 years old; six men and seven women), three intradermal microdialysis fibres were placed in the ventral skin of the forearm [randomly assigned to UVR (450 mJ cm-2 ), UVR+SS or UVR+SW], and one fibre (non-exposed control; CON) was placed in the contralateral forearm. After UVR, a standardized local heating (42°C) protocol quantified the percentage of NO-mediated vasodilatation (%NO). The UVR attenuated %NO compared with CON (P = 0.01). The diminished %NO was prevented by +SS (P < 0.01) and +SW (P < 0.01). Acute broad-spectrum UVR attenuates NO-dependent dilatation in the cutaneous microvasculature, independent of erythema. Sunscreen protects against both inflammatory and heating-induced endothelial dysfunction, and sweat might prevent UVR-induced reductions in NO-dependent dilatation.

Assessment of exposure risk of irinotecan and its active metabolite, SN-38, through perspiration during chemotherapy.

BACKGROUND: Irinotecan (CPT-11) is the key drug used in chemotherapy for many malignant tumors. CPT-11 has cholinergic activity and induces perspiration during intravenous administration. In this study, concentrations of CPT-11 and its active metabolite, SN-38, released during perspiration were measured and risk of exposure of these drugs was assessed. METHOD: Beads of sweat were collected using a dropper from four patients undergoing a chemotherapy regimen involving intravenous administration of CPT-11. The concentrations of CPT-11 and SN-38 in sweat were measured using liquid chromatography tandem mass spectrometry. RESULT: Chemotherapy regimens were capecitabine and irinotecan plus bevacizumab (n = 1), CPT-11 monotherapy (n = 1), and oxaliplatin-irinotecan-leucovorin-5-fluorouracil (n = 2). Uridine diphosphate-glucuronosyltransferase 1A1 phenotypes were *6 homo-type (n = 1), *6 hetero-type (n = 1), and wild type (n = 2). CPT-11 dose was 292.3 ± 75.5 mg/body weight (mean ± standard deviation). CPT-11 was detected in sweat secreted by all the four patients, and its mean (±standard deviation) concentration was 252.6 (±111.9) ng/ml. SN-38 was detected in only one of the patients who received oxaliplatin-irinotecan-leucovorin-5-fluorouracil treatment and who had the wild-type uridine diphosphate-glucuronosyltransferase 1A1 phenotype at a concentration of 74.37 ng/ml. CONCLUSION: CPT-11 and SN-38 are detected in sweat released during intravenous CPT-11 administration. Beads of sweat or linen clothes that absorb the sweat might be the source of CPT-11 and SN-38 exposure.

Sweaty feet in adolescents-Early use of botulinum type A toxin in juvenile plantar hyperhidrosis.

BACKGROUND/OBJECTIVES: Plantar hyperhidrosis can have severe social effects on children and adolescents. Therapeutic options include antiperspirants and surgical interventions (eg, sympathectomy). Botulinum type A toxin is approved for axillary hyperhidrosis in adults only. The aim of the study was the determination of effect and safety of botulinum type A toxin in plantar hyperhidrosis in juvenile patients. METHODS: Children and adolescents with idiopathic focal plantar hyperhidrosis were treated with 50-100 U of botulinum type A toxin per sole. Local anesthesia was provided using topical eutectic mixture of local anesthetics cream and ice, in combination with midazolam as an anxiolytic. RESULTS: Fifteen patients (aged 12-17) were included in the study. Best results were achieved with a dose of 75-100 U of botulinum type A toxin per sole. Two patients did not benefit from the therapy, and 11 (73%) were satisfied with the results. Nine patients (60%) experienced pain at the injection site for a maximum duration of 3 days. One patient reported transient focal weakness for 4 weeks. CONCLUSION: Botulinum type A toxin seems to be a safe secondary treatment option for plantar hyperhidrosis in adolescents aged 12 and older. A dose of 75-100 U per sole resulted in a good therapeutic effect of variable duration in most patients. There were no severe side effects.

Effect of topiramate on sweat chloride level while screening for cystic fibrosis.

Cystic fibrosis is the most common life-limiting genetic condition in Caucasians caused by Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene mutations. Sweat chloride is the current gold standard for diagnosis where values >60 mmol/L are diagnostic and values >30 mmol/L are indeterminate. There is limited literature on the effect of medications on the sweat chloride values. We report a case of topiramate being responsible for false-positive testing which resulted in overutilisation of medical resources and psychosocial stress on the family. Topiramate should be considered during the interpretation of the gold standard testing as one of the cause of false-positive sweat tests.

Ivacaftor-induced sweat chloride reductions correlate with increases in airway surface liquid pH in cystic fibrosis.

BACKGROUND: Disruption of cystic fibrosis transmembrane conductance regulator (CFTR) anion channel function causes cystic fibrosis (CF), and lung disease produces most of the mortality. Loss of CFTR-mediated HCO3- secretion reduces the pH of airway surface liquid (ASL) in vitro and in neonatal humans and pigs in vivo. However, we previously found that, in older children and adults, ASL pH does not differ between CF and non-CF. Here, we tested whether the pH of CF ASL increases with time after birth. Finding that it did suggested that adaptations by CF airways increase ASL pH. This conjecture predicted that increasing CFTR activity in CF airways would further increase ASL pH and also that increasing CFTR activity would correlate with increases in ASL pH. METHODS: To test for longitudinal changes, we measured ASL pH in newborns and then at 3-month intervals. We also studied people with CF (bearing G551D or R117H mutations), in whom we could acutely stimulate CFTR activity with ivacaftor. To gauge changes in CFTR activity, we measured changes in sweat Cl- concentration immediately before and 48 hours after starting ivacaftor. RESULTS: Compared with that in the newborn period, ASL pH increased by 6 months of age. In people with CF bearing G551D or R117H mutations, ivacaftor did not change the average ASL pH; however reductions in sweat Cl- concentration correlated with elevations of ASL pH. Reductions in sweat Cl- concentration also correlated with improvements in pulmonary function. CONCLUSIONS: Our results suggest that CFTR-independent mechanisms increase ASL pH in people with CF. We speculate that CF airway disease, which begins soon after birth, is responsible for the adaptation. FUNDING: Vertex Inc., the NIH (P30DK089507, 1K08HL135433, HL091842, HL136813, K24HL102246), the Cystic Fibrosis Foundation (SINGH17A0 and SINGH15R0), and the Burroughs Wellcome Fund.

[Factors Affecting Development of Cholinergic Symptoms after Irinotecan Administration].

Upon administration of irinotecan(CPT-11), cholinergic symptoms, such as perspiration and abdominal pain, may develop. These symptoms are reported to increase with higher doses of CPT-11. However, to date, in Japan, factors influencing cholinergic symptoms, such as dosage of CPT-11, regular medications, and laboratory values indicating liver function, have not been studied. Therefore, to assess such factors, we conducted a retrospective investigation. Cholinergic symptoms occurred in 74(40.4%)of 183 patients. Moreover, of these 74 patients, cholinergic symptoms occurred in 45 patients(60.8%)in the first course, and sweating was the most common symptom in these patients. According to binomial logistic regression analysis, the most significant factor affecting cholinergic symptom expression was a single dose(per body surface area)(odds ratio: 1.03, 95% confidence interval: 1.02-1.05, p<0.01), and the cut-off value in the receiver operating characteristic curve was 137mg/m2. By detecting cholinergic symptoms at an early stage after the administration of a single dose of CPT-11, the discontinuation of therapy administration can be avoided, and cholinergic symptoms can be alleviated.

Update: Efficacy of Military Fluid Intake Guidance.

BACKGROUND: Fluid intake during military training is prescribed based on the interactions among work rates, environmental conditions, and uniform configurations. The efficacy of this guidance has not been empirically assessed in over a decade. To determine the acceptability of the fluid intake guidance, sweat losses were measured in a variety of conditions with modern uniform/body armor configurations and were then compared to prescribed fluid intakes for each condition (workload, environment, clothing). METHODS: Whole body sweat losses of 324 Soldiers and 14 model simulations were measured under a variety of work intensities ((Watts) easy, moderate, hard), work durations (2-25 h), environmental conditions (White-Black flag), and uniform configurations (including Army Combat Uniform and body armor). Whole body sweat losses were then calculated relative to 4 h drinking guidance and in accordance with TB MED 507 recommended work/rest ratios. The differences between the prescribed fluid intake and sweat loss were calculated and expressed as a percent loss or gain of body weight. Values within a threshold of ±2% body water flux (BWF) were deemed an acceptable conservative starting point for performance and health concerns. FINDINGS: Values within ±2% BWF numbered 309/338; 25 of 338 observations exceeded the +2% BWF while 4 of 338 observations exceeded the -2% BWF. When total fluid restriction was simulated, all experienced body weight loss with 151 of 338 observations exceeding the -2% BWF. DISCUSSION: When calculated using actual measured sweating rates from the laboratory and model simulations, current fluid intake guidance appears to predict with 91.4% accuracy the volume of fluid required to maintain a proper euhydrated state (±2%) during 4 h of exercise. Simulations of total fluid restriction support the necessity for fluid intake guidance so that the Warfighter's performance does not degrade. It is recommended that the current military fluid intake guidance focuses on methods for accurately tracking fluid intakes.

Evidence for ß-adrenergic modulation of sweating during incremental exercise in habitually trained males.

The aim of the present study was to determine the ß-adrenergic contribution to sweating during incremental exercise in habitually trained males. Nine habitually trained and 11 untrained males performed incremental cycling until exhaustion (20 W/min). Bilateral forearm sweat rates (ventilated capsule) were measured at two skin sites that were transdermally administered via iontophoresis with either 1% propranolol (Propranolol, a nonselective ß-adrenergic receptor antagonist) or saline (Control). The sweat rate was evaluated as a function of both relative (percentage of maximum workload) and absolute exercise intensities. The sweat rate at the Propranolol site was lower than the control during exercise at 80 (0.57 ± 0.21 and 0.45 ± 0.19 mg·cm-2·min-1 for Control and Propranolol, respectively) and 90% (0.74 ± 0.22 and 0.65 ± 0.17 mg·cm-2·min-1, respectively) of maximum workload in trained males (all P < 0.05). By contrast, no between-site differences in sweat rates were observed in untrained counterparts (all P > 0.05). At the same absolute intensity, higher sweat rates on the control site were observed in trained males relative to the untrained during exercise at 160 (0.23 ± 0.20 and 0.04 ± 0.05 mg·cm-2·min-1 for trained and untrained, respectively) and 180 W (0.40 ± 0.20 and 0.13 ± 0.13 mg·cm-2·min-1, respectively) (all P < 0.05), whereas this between-group difference was not observed at the Propranolol site (all P > 0.05). We show that the ß-adrenergic mechanism does modulate sweating during exercise at a submaximal high relative intensity in habitually trained males. The ß-adrenergic mechanism may in part contribute to the greater sweat production in habitually trained males than in untrained counterparts during exercise.NEW & NOTEWORTHY We demonstrated for the first time that the ß-adrenergic mechanism does modulate sweating (i.e., ß-adrenergic sweating) during exercise using a localized ß-adrenoceptor blockade in humans in vivo. ß-Adrenergic sweating was evident in habitually trained individuals during exercise at a submaximal high relative intensity (80-90% maximal work). This observation advances our understanding of human thermoregulation during exercise and of the mechanism that underlies sweat gland adaptation to habitual exercise training.

In vivo and in vitro ivacaftor response in cystic fibrosis patients with residual CFTR function: N-of-1 studies.

RATIONALE: Ivacaftor, a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator, decreases sweat chloride concentration, and improves pulmonary function in 6% of cystic fibrosis (CF) patients with specific CFTR mutations. Ivacaftor increases chloride transport in many other CFTR mutations in non-human cells, if CFTR is in the epithelium. Some CF patients have CFTR in the epithelium with residual CFTR function. The effect of ivacaftor in these patients is unknown. METHODS: This was a series of randomized, crossover N-of-1 trials of ivacaftor and placebo in CF patients ≥8 years old with potential residual CFTR function (intermediate sweat chloride concentration, pancreatic sufficient, or mild bronchiectasis on chest CT). Human nasal epithelium (HNE) was obtained via nasal brushing and cultured. Sweat chloride concentration change was the in vivo outcome. Chloride current change in HNE cultures with ivacaftor was the in vitro outcome. RESULTS: Three subjects had decreased sweat chloride concentration (-14.8 to -40.8 mmol/L, P < 0.01). Two subjects had unchanged sweat chloride concentration. Two subjects had increased sweat chloride concentration (+23.8 and +27.3 mmol/L, P < 0.001); both were heterozygous for A455E and pancreatic sufficient. Only subjects with decreased sweat chloride concentration had increased chloride current in HNE cultures. CONCLUSIONS: Some CF patients with residual CFTR function have decreased sweat chloride concentration with ivacaftor. Increased chloride current in HNE cultures among subjects with decreased sweat chloride concentrations may predict clinical response to ivacaftor. Ivacaftor can increase sweat chloride concentration in certain mutations with unclear clinical effect. Pediatr Pulmonol. 2017;52:472-479. © 2017 Wiley Periodicals, Inc.

Nicotinic receptor activation augments muscarinic receptor-mediated eccrine sweating but not cutaneous vasodilatation in young males.

NEW FINDINGS: What is the central question of this study? Acetylcholine released from cholinergic nerves can activate both muscarinic and nicotinic receptors. Although each receptor can independently induce cutaneous vasodilatation and eccrine sweating, it remains to be elucidated whether the two receptors interact in order to mediate these responses. What is the main finding and its importance? We show that although nicotinic receptor activation does not modulate muscarinic cutaneous vasodilatation, it lowers the muscarinic receptor agonist threshold at which onset for eccrine sweating (augmentation of muscarinic eccrine sweating) occurs in young men in normothermic resting conditions. These results provide new insights into the physiological significance of nicotinic receptors in the regulation of cutaneous perfusion and eccrine sweating. Acetylcholine released from cholinergic nerves can activate both muscarinic and nicotinic receptors; each is known independently to induce cutaneous vasodilatation and eccrine sweating in humans. However, it is not known whether the two receptors interact in order to mediate cutaneous vasodilatation and eccrine sweating. In 10 young men (27 ± 6 years old), cutaneous vascular conductance and sweat rate were evaluated at intradermal microdialysis sites that were continuously perfused with either lactated Ringer's solution (control) or three different concentrations of nicotine (0.1, 1 and 10 mm), a nicotinic receptor agonist. Co-administration of methacholine, a muscarinic receptor agonist, was performed at all skin sites in a dose-proportional fashion (0.0125, 0.25, 5, 100 and 2000 mm, each for 25 min). Administration of nicotine alone caused dose-dependent transient increases in cutaneous vascular conductance and sweat rate (all P ≤ 0.05), which thereafter returned to pre-nicotine levels, except that a portion of transient responses remained with continuous administration of 10 mm nicotine (both P ≤ 0.05). Cutaneous vascular conductance was increased by administration of ≥0.25 mm methacholine at the control site, and this response was likewise observed in the presence of co-administration of all doses of nicotine used (all P ≤ 0.05). Sweat rate at the control site was increased by administration of ≥0.25 mm methacholine, but the lowest dose of methacholine (0.0125 mm) was able to increase sweat rate in the presence of 10 mm nicotine (P ≤ 0.05). We conclude that nicotinic receptor activation lowers the muscarinic receptor agonist threshold for eccrine sweating (augmentation of muscarinic sweating) but does not affect muscarinic cutaneous vasodilatation in young men in normothermic resting conditions.

Baroreceptor unloading does not limit forearm sweat rate during severe passive heat stress.

This study tested the hypothesis that sweat rate during passive heat stress is limited by baroreceptor unloading associated with heat stress. Two protocols were performed in which healthy subjects underwent passive heat stress that elicited an increase in intestinal temperature of ∼1.8°C. Upon attaining this level of hyperthermia, in protocol 1 (n = 10, 3 females) a bolus (19 ml/kg) of warm (∼38°C) isotonic saline was rapidly (5-10 min) infused intravenously to elevate central venous pressure (CVP), while in protocol 2 (n = 11, 5 females) phenylephrine was infused intravenously (60-120 µg/min) to return mean arterial pressure (MAP) to normothermic levels. In protocol 1, heat stress reduced CVP from 3.9 ± 1.9 mmHg (normothermia) to -0.6 ± 1.4 mmHg (P < 0.001), while saline infusion returned CVP to normothermic levels (5.1 ± 1.7 mmHg; P > 0.999). Sweat rate was elevated by heat stress (1.21 ± 0.44 mg·cm(-2)·min(-1)) but remained unchanged during rapid saline infusion (1.26 ± 0.47 mg·cm(-2)·min(-1), P = 0.5), whereas cutaneous vascular conductance increased from 77 ± 10 to 101 ± 20% of local heating max (P = 0.029). In protocol 2, MAP was reduced with heat stress from 85 ± 7 mmHg to 76 ± 8 mmHg (P = 0.048). Although phenylephrine infusion returned MAP to normothermic levels (88 ± 7 mmHg; P > 0.999), sweat rate remained unchanged during phenylephrine infusion (1.39 ± 0.22 vs. 1.41 ± 0.24 mg·cm(-2)·min(-1); P > 0.999). These data indicate that both cardiopulmonary and arterial baroreceptor unloading do not limit increases in sweat rate during passive heat stress.