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Kappa opioid agonists in the treatment of itch: just scratching the surface? Kappa 阿片受体激动剂治疗瘙痒:仅仅是表面现象?
Pub Date : 2023-10-01 Epub Date: 2023-12-06 DOI: 10.1097/itx.0000000000000072
Tyler C Beck, Elena M Wilson, Erik Wilkes, Lara Wine Lee, Russell Norris, Manuel Valdebran

Chronic pruritus is a debilitating condition affecting 23-44 million Americans. Recently, kappa opioid agonists (KOAs) have emerged as a novel class of potent antipruritic agents. In 2021, the Food and Drug Administration approved difelikefalin (Korsuva) for the treatment of moderate-to-severe pruritus associated with chronic kidney disease in adults undergoing hemodialysis. Difelikefalin is a potent, peripherally restricted KOA that is intravenously available. Although promising, difelikefalin is currently available as an intravenous composition only, limiting the scope of use. Oral formulations of difelikefalin did not meet the primary endpoint criteria in recent phase 2 clinical trials; however, additional clinical studies are ongoing. The future for KOAs in the treatment of pruritus is encouraging. Orally active pathway-biased KOAs, such as triazole 1.1, may serve as viable alternatives with broader applications. Extended-release compositions, such as the TP-2021 ProNeura subdermal implant, may circumvent the pharmacokinetic issues associated with peptide-based KOAs. Lastly, dual-acting kappa opioid receptor agonist/mu opioid receptor antagonists are orally bioavailable and may be useful in the treatment of various forms of chronic itch. In this review, we summarize the results of KOAs in clinical and preclinical trials and discuss future directions of drug development.

慢性瘙痒症是一种使人衰弱的疾病,影响着 2,300 万至 4,400 万美国人。最近,卡巴阿片受体激动剂(KOAs)成为一类新型的强效止痒药物。2021 年,美国食品和药物管理局批准了地非利凯法林(Korsuva),用于治疗接受血液透析的成人慢性肾病相关的中度至重度瘙痒症。地匹福林是一种强效的外周限制性 KOA,可静脉注射。尽管前景看好,但地非利凯法林目前仅作为静脉注射成分供应,限制了其使用范围。在最近的二期临床试验中,地匹福林的口服制剂没有达到主要终点标准;不过,更多的临床研究正在进行中。KOAs 在治疗瘙痒症方面的前景令人鼓舞。三唑 1.1 等口服活性途径型 KOA 可作为可行的替代品,具有更广泛的应用前景。TP-2021 ProNeura皮下植入物等缓释组合物可以避免与多肽类 KOA 相关的药代动力学问题。最后,双效卡巴阿片受体激动剂/缪阿片受体拮抗剂具有口服生物利用度,可用于治疗各种形式的慢性瘙痒。在这篇综述中,我们总结了 KOAs 在临床和临床前试验中的结果,并讨论了药物开发的未来方向。
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引用次数: 0
Real-world clinical efficacy of nemolizumab in Japanese patients with atopic dermatitis 奈莫单抗在日本特应性皮炎患者中的实际临床疗效
Pub Date : 2023-10-01 DOI: 10.1097/itx.0000000000000071
Yoshinori Watanabe, Yozo Ishiuji, Minako Ogawa-Tominaga, Michie Katsuta, Akihiko Asahina
Nemolizumab was approved in Japan in August 2022 to treat patients with atopic dermatitis (AD). The study objective was to evaluate its effectiveness in controlling AD symptoms in the real world postmarketing. Eleven Japanese patients with AD treated with nemolizumab were assessed at 12 weeks for clinical manifestations, AD scores Visual Analog Scale and Eczema Area and Severity Index, and serum biomarkers. Visual Analog Scale and Eczema Area and Severity Index scores were significantly decreased by 80% and 66.4%, showing nemolizumab improved both itch and skin lesions. However, several serum AD biomarkers did not change during treatment with nemolizumab.
Nemolizumab于2022年8月在日本被批准用于治疗特应性皮炎(AD)患者。该研究的目的是评估其在上市后控制阿尔茨海默病症状的有效性。11名接受奈莫单抗治疗的日本AD患者在12周时进行临床表现、AD评分、视觉模拟量表、湿疹面积和严重程度指数以及血清生物标志物的评估。视觉模拟量表和湿疹面积和严重程度指数评分显着降低了80%和66.4%,表明奈莫单抗改善了瘙痒和皮肤病变。然而,一些血清AD生物标志物在奈莫单抗治疗期间没有改变。
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引用次数: 0
Oral administration of 4′-demethyl nobiletin inhibits dry skin-induced mechanical alloknesis 口服4′-去甲基皂素可抑制皮肤干燥引起的机械变形
Pub Date : 2023-07-01 DOI: 10.1097/itx.0000000000000069
S. Toyama, M. Tominaga, E. Komiya, S. Kusano, T. Kaneko, K. Takamori
Mechanical alloknesis develops with dry skin and reduces the quality of life of people afflicted. Nobiletin (NOB) is a major citrus flavonoid with various health benefits. We investigated whether oral administration of NOB or 4’-demethyl NOB inhibits dry skin-induced alloknesis in a mouse model. As a result, both treatments were effective to inhibit mechanical alloknesis. These compounds may be promising candidates to lead to the development of therapeutic agents for mechanical alloknesis.
皮肤干燥会导致机械性异病,降低患者的生活质量。Nobiletin(NOB)是一种主要的柑橘类黄酮,具有多种健康益处。我们在小鼠模型中研究了口服NOB或4’-去甲基NOB是否抑制干燥皮肤诱导的同种异体病。结果,这两种治疗方法都能有效抑制机械性异速症。这些化合物可能是开发用于机械性异症的治疗剂的有希望的候选者。
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引用次数: 0
The effect of repetitive topical applications of local anesthetics (EMLA) on experimental pain and itch (histaminergic and nonhistaminergic) 反复局部应用局部麻醉剂(EMLA)对实验性疼痛和瘙痒(组胺能和非组胺能)的影响
Pub Date : 2023-04-01 DOI: 10.1097/itx.0000000000000070
Giulia Erica Aliotta, S. L. Vecchio, J. Elberling, L. Arendt-Nielsen
Background: The effects of repeated topical applications of local anesthetics are poorly investigated as they may, in addition to analgesia, impact peripheral nerve endings in a cumulative manner. In the present study, the effects of 6 repetitive applications of eutectic mixture of lidocaine (EMLA 2.5% and prilocaine 2.5%) were investigated on experimentally induced pain, histaminergic and nonhistaminergic itch, and neurogenic inflammation. Methods: Four skin areas on the forearms of 24 subjects were randomized to receive 3 hours of application of EMLA or placebo twice a day for 3 consecutive days. After each application, superficial blood perfusion (SBP), mechanical (mechanically evoked itch, mechanical pain threshold, and mechanical pain sensitivity), and thermal sensitivity (warm detection threshold, heat pain threshold, and suprathreshold heat sensitivity) were assessed. After the last application of EMLA/placebo, histamine and cowhage was applied (2 areas each) and itch and pain intensity and SBP were assessed. Results: After 3 hours of EMLA application, significant mechanical and thermal hypoalgesia were found with no cumulative efficacy over the 3 days. EMLA alone had no effect on SBP. Significantly increased SBP, reduced cowhage-induced itch, but the unaffected histamine-induced itch was found when applying EMLA ahead of histamine and cowhage. Conclusions: EMLA induced a reduction of mechanical and thermal sensitivity without a cumulative-dose effect. EMLA reduced nonhistaminergic itch and pain but not the experimentally provoked histaminergic itch. Selective action of EMLA on polymodal C-fibers could explain these effects.
背景:局部麻醉剂的反复局部应用的效果研究很少,因为除了镇痛作用外,它们还可能以累积的方式影响周围神经末梢。在本研究中,我们研究了利多卡因共混物(EMLA 2.5%和prilocaine 2.5%) 6次重复应用对实验性疼痛、组胺性和非组胺性瘙痒以及神经源性炎症的影响。方法:24例受试者前臂4个皮肤区域随机接受3小时EMLA或安慰剂应用,每天2次,连续3天。每次应用后,评估浅表血流灌注(SBP)、机械(机械诱发瘙痒、机械痛阈和机械痛敏感性)和热敏性(热检测阈、热痛阈和超阈热敏性)。最后一次应用EMLA/安慰剂后,应用组胺和奶牛(各2个区域),评估瘙痒、疼痛强度和收缩压。结果:EMLA应用3小时后,发现明显的机械和热痛觉减退,3天内无累积效果。单独使用EMLA对收缩压无影响。在组胺和奶牛之前使用EMLA可显著增加收缩压,减少奶牛诱导的瘙痒,但组胺诱导的瘙痒未受影响。结论:EMLA诱导机械和热敏性降低,无累积剂量效应。EMLA减少了非组胺性瘙痒和疼痛,但没有实验引起的组胺性瘙痒。EMLA对多模c -纤维的选择性作用可以解释这些效应。
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引用次数: 0
Potential antipruritic neuronal targets of nalfurafine in the murine spinal dorsal horn 纳氟萘芬在小鼠脊髓背角的潜在抗瘙痒神经元靶点
Pub Date : 2023-01-01 DOI: 10.1097/itx.0000000000000066
K. Honda, M. Tominaga, F. Kusube, K. Takamori
Introduction: Itch is an unpleasant sensation that evokes a scratching behavior which often damages the skin. Nalfurafine is a kappa opioid receptor (KOR) agonist known as an effective drug used to control the intractable itch. Mechanistically, the spinal cord is a target of nalfurafine, however, little is known about the specific sites important to the antipruritic effects of nalfurafine. Therefore, the aim of this study was an investigation to uncover the sites of action of nalfurafine in the spinal neuronal pathway of itch. Materials and Methods: To reveal the antipruritic action of nalfurafine in the murine spinal dorsal horn, we conducted in vivo electrophysiology, behavioral experiments, and high-sensitive in situ hybridization (ISH) using normal C57BL/6J mice. Results: Behavioral analyses indicated that intrathecal injection of nalfurafine reduced, but not entirely eliminated the gastrin-releasing peptide (GRP)-evoked scratching bouts. In vivo electrophysiological recordings revealed that nalfurafine administration suppressed chloroquine (CQ)-responsive dorsal horn neurons in 15.8% (3/19) of mice. In fact, only 1 of 3 nalfurafine-suppressed mice responded to GRP. ISH in 3 sections of the spinal cord showed that 24.8% (154/623) were double-positive for GRP and KOR and 13.6% (68/431) for GRP receptor (GRPR) and KOR in total KOR+ cells. Most KOR+ cells were negative for GRP and GRPR. Intrathecal injection of dynorphin-saporin did not change the number of scratching bouts caused by GRP. However, it reduced the number of scratching bouts evoked by intradermal injection of CQ. Discussion: In conclusion, our data suggest that nalfurafine targets both GRP+ KOR+ and GRPR+ KOR+ cells which are present in a 2:1 ratio and suppresses CQ-induced itch in the spinal dorsal horn. These findings suggest that GRP+ KOR- or GRPR+ KOR- cells may function as interneurons in the spinal neuronal pathway of itch.
简介:瘙痒是一种令人不快的感觉,会引起抓挠行为,通常会损伤皮肤。纳呋胺是一种κ阿片受体(KOR)激动剂,是一种用于控制顽固性瘙痒的有效药物。从机制上讲,脊髓是萘呋胺的靶点,然而,对萘呋芬的止痒作用重要的特定部位知之甚少。因此,本研究的目的是揭示萘呋胺在瘙痒脊髓神经元通路中的作用位点。材料和方法:为了揭示萘呋胺对小鼠脊髓背角的止痒作用,我们使用正常C57BL/6J小鼠进行了体内电生理、行为实验和高灵敏度原位杂交(ISH)。结果:行为分析表明,鞘内注射呋喃西林减少了但并没有完全消除胃泌素释放肽(GRP)引起的抓挠发作。体内电生理记录显示,在15.8%(3/19)的小鼠中,给予萘呋胺抑制了氯喹(CQ)反应性背角神经元。事实上,只有三分之一的受纳呋胺抑制的小鼠对GRP有反应。在3个脊髓切片中ISH显示,在总的KOR+细胞中,24.8%(154/623)的GRP和KOR双重阳性,13.6%(68/431)的GRPR受体和KOR。大多数KOR+细胞对GRP和GRPR呈阴性。鞘内注射强啡肽saporin不会改变GRP引起的抓挠次数。然而,它减少了皮内注射CQ引起的抓挠次数。讨论:总之,我们的数据表明,萘呋胺靶向GRP+KOR+和GRPR+KOR*细胞,这两种细胞以2:1的比例存在,并抑制CQ诱导的脊髓背角瘙痒。这些发现表明GRP+KOR-或GRPR+KOR-细胞可能在瘙痒的脊髓神经元通路中起中间神经元的作用。
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引用次数: 1
Therapeutics in chronic pruritus of unknown origin 不明原因慢性瘙痒症的治疗
Pub Date : 2023-01-01 DOI: 10.1097/itx.0000000000000064
T. Ju, A. Labib, A. Vander Does, G. Yosipovitch
Chronic pruritus of unknown origin (CPUO) is a common condition that is underrecognized and underdiagnosed. Patients suffer from 6 or more weeks of pruritus with no identified cause, or with multiple potential causes, of which the primary cause cannot be determined. Despite being a common condition and prevalent in nearly 30% of the elderly in certain populations, most patients suffer from CPUO for years from inadequate treatments for itch and are made to undergo extensive diagnostics. There is no FDA-approved treatment for CPUO, and providers are often tasked to treat CPUO patients with limited knowledge and guidance on CPUO and its treatments. However, recent breakthroughs in antipruritic therapeutics have led to an increase in therapies available for CPUO patients. These include a variety of both pharmacological and nonpharmacological interventions, as well as topical and systemic therapies. Newer therapies such as biologics and Janus kinase inhibitors are currently under investigation due to their therapeutic effects in other pruritic diseases and are promising for treating CPUO. Here, we review the various therapeutic options that are currently available or are on the horizon, with a special emphasis on the therapies antipruritic mechanism, available clinical evidence of efficacy and safety, and the appropriate contexts for their application. By doing so, we hope to educate clinicians on the known treatments for pruritus and their applicability to CPUO to guide optimal management of this highly prevalent disease.
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引用次数: 0
The effect of escalating heat stimulation on top of anesthetized skin 在麻醉皮肤上不断升级的热刺激的效果
Pub Date : 2023-01-01 DOI: 10.1097/itx.0000000000000065
D. Riccio, S. Lo Vecchio, L. Arendt-Nielsen
The relationship between itch and heat pain has been vastly explored. A 70-year-old study, showed the development of paradoxical itch following heat stimulation of anesthetized skin. The aim of this study was to re-evaluate, with more modern technologies and systematic approaches, this paradoxical itch effect. Escalating heat stimuli were applied to the local anesthetized skin of 19 healthy subjects, itch, and pain intensities were continuously assessed during the stimulation. As expected, pain sensation was significantly reduced by local intradermal anesthesia, however, no paradoxical itch sensations were observed for any of the stimulation temperatures.
瘙痒和热痛之间的关系已被广泛探索。一项70年前的研究表明,对麻醉皮肤进行热刺激后会产生矛盾的瘙痒。本研究的目的是用更现代的技术和系统的方法来重新评估这种矛盾的瘙痒效应。对19名健康受试者局部麻醉后的皮肤施加逐步升温的热刺激,在刺激过程中持续评估瘙痒和疼痛强度。正如预期的那样,局部皮内麻醉显著降低了疼痛感觉,然而,在任何刺激温度下都没有观察到矛盾的瘙痒感觉。
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引用次数: 0
Pruritic eruptions in older adults: characterization of a patch test negative cohort 老年人瘙痒性皮疹:斑贴试验阴性队列的特征
Pub Date : 2023-01-01 DOI: 10.1097/itx.0000000000000067
S. Sreekantaswamy, Jane Tully, N. Botto, Carina M. Woodruff, D. Butler
{"title":"Pruritic eruptions in older adults: characterization of a patch test negative cohort","authors":"S. Sreekantaswamy, Jane Tully, N. Botto, Carina M. Woodruff, D. Butler","doi":"10.1097/itx.0000000000000067","DOIUrl":"https://doi.org/10.1097/itx.0000000000000067","url":null,"abstract":"","PeriodicalId":73523,"journal":{"name":"Itch (Philadelphia, Pa.)","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45879308","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Role of antioxidants in itch treatment: lessons learned from pain management 抗氧化剂在瘙痒治疗中的作用:从疼痛管理中获得的经验教训
Pub Date : 2023-01-01 DOI: 10.1097/itx.0000000000000068
Georgia Biazus Soares, O. Mahmoud, G. Yosipovitch
Chronic pain and chronic pruritus are both debilitating conditions that cause a significant burden to patients. Oxidative stress—driven by an imbalance between reactive oxygen species and antioxidants—has been shown to play a role both in pain disorders and conditions in which chronic itch is a prominent symptom. Antioxidants can be useful in treating oxidative stress-driven diseases and have shown promise in treating chronic pain conditions such as fibromyalgia and osteoarthritis. However, their role in treating pruritus and pruritic conditions such as psoriasis and atopic dermatitis remains unclear. Many of the current treatments for chronic itch are costly, associated with side effects, and have limited efficacy. Therefore, further controlled studies exploring antioxidants as a potential therapeutic option for chronic pruritus are warranted.
慢性疼痛和慢性瘙痒都是使人衰弱的疾病,对患者造成重大负担。氧化应激由活性氧和抗氧化剂之间的不平衡所驱动,已被证明在疼痛障碍和慢性瘙痒是一个突出症状的条件下发挥作用。抗氧化剂可用于治疗氧化应激引起的疾病,并在治疗慢性疼痛如纤维肌痛和骨关节炎方面显示出前景。然而,它们在治疗瘙痒和瘙痒性疾病(如牛皮癣和特应性皮炎)中的作用尚不清楚。目前许多治疗慢性瘙痒的方法都很昂贵,有副作用,而且疗效有限。因此,进一步的对照研究探索抗氧化剂作为慢性瘙痒的潜在治疗选择是必要的。
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引用次数: 1
Severity stages of chronic nodular prurigo: analysis of associated itch intensity and quality of life impairment 慢性结节性瘙痒症的严重程度分期:相关瘙痒强度和生活质量损害的分析
Pub Date : 2022-10-01 DOI: 10.1097/itx.0000000000000061
C. Zeidler, M. Pereira, M. Storck, Aysenur Suer, S. Ständer
Introduction: Chronic nodular prurigo (CNPG) is a pruritic neuroinflammatory skin disease characterized by the presence of multiple pruriginous nodules. Previous psychometric analyzes showed the presence of moderate to severe pruritus and a considerable impairment of quality of life. A detailed study of these parameters in relation to the severity of the disease defined by the number of lesions is lacking. Methods: A total of 131 adult patients with CNPG were included. The number of pruriginous lesions and disease stage was determined by using the Prurigo Activity and Severity (PAS) scale and the prurigo-specific Investigator’s Global Assessment (IGA) scale. Patient-reported outcomes comprised pruritus intensity (worst itch intensity of the previous 24 h using the numerical rating scale; WI-NRS/24 h) and the impairment of quality of life (ItchyQol, Dermatology Life Quality Index; DLQI). Results: The counted and estimated number of pruriginous nodules correlated strongly with each other (r=0.82; P<0.001), moderately with the WI-NRS/24 h (counted number: r=0.44, P<0.001; estimated number: r=0.45, P<0.001) and with the DLQI score (counted number: r=0.40, P<0.001; estimated number: r=0.38, P<0.001). The severity groups of the CNPG, as defined by the IGA scale, correlated strongly with the WINRS/24 h and DLQI scores. With increasing severity of CNPG, increasing pruritus intensity and DLQI/ItchyQoL scores were recorded. Conclusion: The correlation between objective (disease stage) and subjective (itch intensity, quality of life) CNPG disease parameters argues for a representative disease severity characterization via physician assessments using either PAS or IGA.
慢性结节性痒疹(CNPG)是一种瘙痒性神经炎症性皮肤病,其特征是存在多个瘙痒性结节。先前的心理测量分析显示存在中度至重度瘙痒和相当大的生活质量损害。缺乏对这些参数与由病变数量定义的疾病严重程度的关系的详细研究。方法:131例成人CNPG患者。使用痒疹活性和严重程度(PAS)量表和痒疹特异性研究者全局评估(IGA)量表确定痒疹病变数量和疾病分期。患者报告的结果包括瘙痒强度(使用数值评定量表的前24小时最严重瘙痒强度;WI-NRS/24 h)和生活质量损害(ItchyQol, Dermatology life quality Index;DLQI)。结果:原疹性结节的计数与估计值之间有很强的相关性(r=0.82;P<0.001),与WI-NRS/24 h呈正相关(统计次数:r=0.44, P<0.001;估计数:r=0.45, P<0.001)与DLQI评分(计数数:r=0.40, P<0.001;估计数:r=0.38, P<0.001)。由IGA量表定义的CNPG的严重程度组与WINRS/24 h和DLQI评分密切相关。随着CNPG严重程度的增加,瘙痒强度和DLQI/ItchyQoL评分也随之增加。结论:客观(疾病分期)和主观(瘙痒强度、生活质量)CNPG疾病参数之间的相关性表明,通过使用PAS或IGA进行医生评估,具有代表性的疾病严重程度表征。
{"title":"Severity stages of chronic nodular prurigo: analysis of associated itch intensity and quality of life impairment","authors":"C. Zeidler, M. Pereira, M. Storck, Aysenur Suer, S. Ständer","doi":"10.1097/itx.0000000000000061","DOIUrl":"https://doi.org/10.1097/itx.0000000000000061","url":null,"abstract":"Introduction: Chronic nodular prurigo (CNPG) is a pruritic neuroinflammatory skin disease characterized by the presence of multiple pruriginous nodules. Previous psychometric analyzes showed the presence of moderate to severe pruritus and a considerable impairment of quality of life. A detailed study of these parameters in relation to the severity of the disease defined by the number of lesions is lacking. Methods: A total of 131 adult patients with CNPG were included. The number of pruriginous lesions and disease stage was determined by using the Prurigo Activity and Severity (PAS) scale and the prurigo-specific Investigator’s Global Assessment (IGA) scale. Patient-reported outcomes comprised pruritus intensity (worst itch intensity of the previous 24 h using the numerical rating scale; WI-NRS/24 h) and the impairment of quality of life (ItchyQol, Dermatology Life Quality Index; DLQI). Results: The counted and estimated number of pruriginous nodules correlated strongly with each other (r=0.82; P<0.001), moderately with the WI-NRS/24 h (counted number: r=0.44, P<0.001; estimated number: r=0.45, P<0.001) and with the DLQI score (counted number: r=0.40, P<0.001; estimated number: r=0.38, P<0.001). The severity groups of the CNPG, as defined by the IGA scale, correlated strongly with the WINRS/24 h and DLQI scores. With increasing severity of CNPG, increasing pruritus intensity and DLQI/ItchyQoL scores were recorded. Conclusion: The correlation between objective (disease stage) and subjective (itch intensity, quality of life) CNPG disease parameters argues for a representative disease severity characterization via physician assessments using either PAS or IGA.","PeriodicalId":73523,"journal":{"name":"Itch (Philadelphia, Pa.)","volume":"7 1","pages":"e61 - e61"},"PeriodicalIF":0.0,"publicationDate":"2022-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47657189","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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Itch (Philadelphia, Pa.)
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