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Carreño F, Mehta R, de Souza AR, Collins J, Swift B. Analysis of C4 Concentrations to Predict Impact of Patient-Reported Diarrhea Associated With the Ileal Bile Acid Transporter Inhibitor Linerixibat. CPT Pharmacometrics Syst Pharmacol 2025; 14:596-605. [PMID: 39945351 PMCID: PMC11919258 DOI: 10.1002/psp4.13300] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Revised: 11/25/2024] [Accepted: 12/13/2024] [Indexed: 03/20/2025] Open
Abstract
Linerixibat, an ileal bile acid transporter (IBAT) inhibitor, is being evaluated for the treatment of pruritus in primary biliary cholangitis (PBC). Diarrhea is commonly reported with this drug class as IBAT inhibition redirects bile acids (BA) to the colon. Serum 7-alpha-hydroxy-4-cholesten-3-one (C4) measurement is a validated method to identify BA diarrhea. To inform dose selection, we characterized the relationship between linerixibat dose, C4 levels, and patient-reported bother on the gastrointestinal symptom rating scale (GSRS) diarrhea question. A kinetic-pharmacodynamic model was developed using data from five Phase 1/2 trials, to describe the effect of linerixibat dose (1-180 mg) and regimen (once/twice daily) on C4 concentrations over time. GSRS data from patients with PBC and pruritus in the Phase 2b GLIMMER study (NCT02966834) were used to develop a proportional odds model to predict the probability of a score of 1-7 (no-very severe discomfort) to the question "Have you been bothered by diarrhea during the past week?" in relation to linerixibat dose. The two models were linked to describe the linerixibat dose-C4-diarrhea bother relationship. Models were validated using graphical and numerical assessment and visual predictive checks. Linerixibat caused dose-dependent increases in C4 until saturation (~180 mg total daily dose). Increased C4 concentrations trended with increased GSRS diarrhea scores. Simulations demonstrated increases in moderate-to-very severe (≥ 4) diarrhea scores with increasing linerixibat dose. Increases in patient-reported diarrhea scores were linerixibat dose-dependent. Selecting an optimal dose that maximizes linerixibat's ability to improve pruritus while minimizing patient-reported diarrhea bother is important to support treatment adherence.
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Guo W, Zhong W, He L, Wei X, Hao L, Dong H, Yue R, Sun X, Yin X, Zhao J, Zhang X, Zhou Z. Reversal of hepatic accumulation of nordeoxycholic acid underlines the beneficial effects of cholestyramine on alcohol-associated liver disease in mice. Hepatol Commun 2024; 8:e0507. [PMID: 39082957 DOI: 10.1097/hc9.0000000000000507] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Accepted: 05/31/2024] [Indexed: 08/30/2024] Open
Abstract
BACKGROUND Dysregulation of bile acids (BAs) has been reported in alcohol-associated liver disease. However, the causal relationship between BA dyshomeostasis and alcohol-associated liver disease remains unclear. The study aimed to determine whether correcting BA perturbation protects against alcohol-associated liver disease and elucidate the underlying mechanism. METHODS BA sequestrant cholestyramine (CTM) was administered to C57BL/6J mice fed alcohol for 8 weeks to assess its protective effect and explore potential BA targets. The causal relationship between identified BA metabolite and cellular damage was examined in hepatocytes, with further manipulation of the detoxifying enzyme cytochrome p450 3A11. The toxicity of the BA metabolite was further validated in mice in an acute study. RESULTS We found that CTM effectively reversed hepatic BA accumulation, leading to a reversal of alcohol-induced hepatic inflammation, cell death, endoplasmic reticulum stress, and autophagy dysfunction. Specifically, nordeoxycholic acid (NorDCA), a hydrophobic BA metabolite, was identified as predominantly upregulated by alcohol and reduced by CTM. Hepatic cytochrome p450 3A11 expression was in parallel with NorDCA levels, being upregulated by alcohol and reduced by CTM. Moreover, CTM reversed alcohol-induced gut barrier disruption and endotoxin translocation. Mechanistically, NorDCA was implicated in causing endoplasmic reticulum stress, suppressing autophagy flux, and inducing cell injury, and such deleterious effects could be mitigated by cytochrome p450 3A11 overexpression. Acute NorDCA administration in mice significantly induced hepatic inflammation and injury along with disrupting gut barrier integrity, leading to subsequent endotoxemia. CONCLUSIONS Our study demonstrated that CTM treatment effectively reversed alcohol-induced liver injury in mice. The beneficial effects of BA sequestrant involve lowering toxic NorDCA levels. NorDCA not only worsens hepatic endoplasmic reticulum stress and inhibits autophagy but also mediates gut barrier disruption and systemic translocation of pathogen-associated molecular patterns in mice.
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Affiliation(s)
- Wei Guo
- Center for Translational Biomedical Research
| | - Wei Zhong
- Center for Translational Biomedical Research
- Department of Nutrition, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC, USA
| | - Liqing He
- Department of Chemistry, University of Louisville, Louisville, Kentucky, USA
| | - Xiaoyuan Wei
- Department of Animal Science, Division of Agriculture, University of Arkansas, Fayetteville, AR, USA
| | - Liuyi Hao
- Center for Translational Biomedical Research
| | - Haibo Dong
- Center for Translational Biomedical Research
| | - Ruichao Yue
- Center for Translational Biomedical Research
| | - Xinguo Sun
- Center for Translational Biomedical Research
| | - Xinmin Yin
- Department of Chemistry, University of Louisville, Louisville, Kentucky, USA
| | - Jiangchao Zhao
- Department of Animal Science, Division of Agriculture, University of Arkansas, Fayetteville, AR, USA
| | - Xiang Zhang
- Department of Chemistry, University of Louisville, Louisville, Kentucky, USA
| | - Zhanxiang Zhou
- Center for Translational Biomedical Research
- Department of Nutrition, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC, USA
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Marani M, Madan V, Le TK, Deng J, Lee KK, Ma EZ, Kwatra SG. Dysregulation of the Skin-Liver Axis in Prurigo Nodularis: An Integrated Genomic, Transcriptomic, and Population-Based Analysis. Genes (Basel) 2024; 15:146. [PMID: 38397136 PMCID: PMC10887737 DOI: 10.3390/genes15020146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Revised: 01/06/2024] [Accepted: 01/18/2024] [Indexed: 02/25/2024] Open
Abstract
Pruritus has long been linked to hepatic dysfunction; however, there are limited data characterizing the association between liver disease and prurigo nodularis (PN), a chronic inflammatory skin disease featuring severe pruritis. We thus conducted a cross-sectional analysis of hepatic comorbidities in PN patients using TriNetX, a large global health research network. This analysis revealed that PN patients had a higher risk (p < 0.001) of developing liver cirrhosis, acute and subacute hepatic failure, inflammatory liver disease, chronic hepatitis, nonalcoholic steatohepatitis, portal hypertension, fatty liver, chronic passive congestion of the liver, and hepatocellular carcinoma compared with healthy controls. The cumulative incidence of liver disease was about three times higher in PN patients compared with healthy controls. These findings provided the basis for translational studies to investigate a genetic mechanism for this association. Cutaneous transcriptomic analysis performed on PN patients revealed the dysregulation of genes related to hepatic failure in lesional PN compared with both nonlesional PN and control skin. Similarly, gene set variation analysis (GSVA) revealed a significantly increased (p < 0.05) activation of liver metabolism, chronic hepatic failure, acute hepatic failure, cholestatic liver disease, polycystic liver disease, and hepatocellular carcinoma pathways in lesional PN compared with control skin. A subsequent genome-wide association study (GWAS) identified shared single-nucleotide polymorphisms (SNPs) in the genes AR, EDIL3, MACROD2, PCSK5, RUNX1T1, TENM4, and ZEB2 between PN and liver disease from the FinnGen cohort. Significant dysregulation of the skin-liver axis in PN patients may explain the increased incidence and severity of hepatic comorbidities and help identify future therapeutic targets for PN.
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Affiliation(s)
| | | | | | | | | | | | - Shawn G. Kwatra
- Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
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Pathogenesis and Treatment of Pruritus Associated with Chronic Kidney Disease and Cholestasis. Int J Mol Sci 2023; 24:ijms24021559. [PMID: 36675074 PMCID: PMC9864517 DOI: 10.3390/ijms24021559] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Revised: 01/07/2023] [Accepted: 01/11/2023] [Indexed: 01/14/2023] Open
Abstract
Itching is an unpleasant sensation that provokes the desire to scratch. In general, itching is caused by dermatologic diseases, but it can also be caused by systemic diseases. Since itching hampers patients' quality of life, it is important to understand the appropriate treatment and pathophysiology of pruritus caused by systemic diseases to improve the quality of life. Mechanisms are being studied through animal or human studies, and various treatments are being tested through clinical trials. We report current trends of two major systemic diseases: chronic kidney disease and cholestatic liver disease. This review summarizes the causes and pathophysiology of systemic diseases with pruritus and appropriate treatments. This article will contribute to patients' quality of life. Further research will help understand the mechanisms and develop new strategies in the future.
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Huang L, Wei W, Huang X, Li X, Liu H, Gui L, Jiang J, Wan L, Zhou X, Ding J, Jiang X, Zhang B, Lan K. High-fat diets enhance and delay ursodeoxycholic acid absorption but elevate circulating hydrophobic bile salts. Front Pharmacol 2023; 14:1168144. [PMID: 37138846 PMCID: PMC10149867 DOI: 10.3389/fphar.2023.1168144] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Accepted: 03/20/2023] [Indexed: 05/05/2023] Open
Abstract
Background: Ursodeoxycholic acid (UDCA) is a natural drug essential for the treatment of cholestatic liver diseases. The food effects on the absorption of UDCA and the disposition of circulating bile salts remain unclear despite its widespread global uses. This study aims to investigate the effects of high-fat (HF) diets on the pharmacokinetics of UDCA and disclose how the circulated bile salts were simultaneously perturbed. Methods: After an overnight fast, a cohort of 36 healthy subjects received a single oral dose (500 mg) of UDCA capsules, and another cohort of 31 healthy subjects received the same dose after consuming a 900 kcal HF meal. Blood samples were collected from 48 h pre-dose up to 72 h post-dose for pharmacokinetic assessment and bile acid profiling analysis. Results: The HF diets significantly delayed the absorption of UDCA, with the Tmax of UDCA and its major metabolite, glycoursodeoxycholic acid (GUDCA), changing from 3.3 h and 8.0 h in the fasting study to 4.5 h and 10.0 h in the fed study, respectively. The HF diets did not alter the Cmax of UDCA and GUDCA but immediately led to a sharp increase in the plasma levels of endogenous bile salts including those hydrophobic ones. The AUC0-72h of UDCA significantly increased from 25.4 μg h/mL in the fasting study to 30.8 μg h/mL in the fed study, while the AUC0-72h of GUDCA showed no difference in both studies. As a result, the Cmax of total UDCA (the sum of UDCA, GUDCA, and TUDCA) showed a significant elevation, while the AUC0-72h of total UDCA showed a slight increase without significance in the fed study compared to the fasting study. Conclusion: The HF diets delay UDCA absorption due to the extension of gastric empty time. Although UDCA absorption was slightly enhanced by the HF diets, the beneficial effect may be limited in consideration of the simultaneous elevation of circulating hydrophobic bile salts.
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Affiliation(s)
- Liang Huang
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, China
- West China Second University Hospital, Sichuan University, Chengdu, China
| | - Wei Wei
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, China
| | - Xiaomei Huang
- Department of Phase1 Clinical Trial Research Center, Xiangya Boai Rehabilitation Hospital, Changsha, China
| | - Xuejing Li
- Chengdu Cynogen Bio-pharmaceutical Tech Co, Ltd., Chengdu, China
| | - Haisha Liu
- Department of Phase1 Clinical Trial Research Center, Xiangya Boai Rehabilitation Hospital, Changsha, China
| | - Lanlan Gui
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, China
- Chengdu Cynogen Bio-pharmaceutical Tech Co, Ltd., Chengdu, China
| | - Jinping Jiang
- Chengdu Cynogen Bio-pharmaceutical Tech Co, Ltd., Chengdu, China
| | - Linfei Wan
- Chengdu Cynogen Bio-pharmaceutical Tech Co, Ltd., Chengdu, China
| | - Xiangxiang Zhou
- Chengdu Cynogen Bio-pharmaceutical Tech Co, Ltd., Chengdu, China
| | - Jingsong Ding
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, China
| | - Xuehua Jiang
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, China
| | - Bikui Zhang
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China
- *Correspondence: Ke Lan, ; Bikui Zhang,
| | - Ke Lan
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, China
- Chengdu Cynogen Bio-pharmaceutical Tech Co, Ltd., Chengdu, China
- *Correspondence: Ke Lan, ; Bikui Zhang,
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Transient Receptor Potential Channels and Itch. Int J Mol Sci 2022; 24:ijms24010420. [PMID: 36613861 PMCID: PMC9820407 DOI: 10.3390/ijms24010420] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 12/20/2022] [Accepted: 12/22/2022] [Indexed: 12/28/2022] Open
Abstract
Transient Receptor Potential (TRP) channels are multifunctional sensory molecules that are abundant in the skin and are involved in the sensory pathways of itch, pain, and inflammation. In this review article, we explore the complex physiology of different TRP channels, their role in modulating itch sensation, and their contributions to the pathophysiology of acute and chronic itch conditions. We also cover small molecule and topical TRP channel agents that are emerging as potential anti-pruritic treatments; some of which have shown great promise, with a few treatments advancing into clinical trials-namely, TRPV1, TRPV3, TRPA1, and TRPM8 targets. Lastly, we touch on possible ethnic differences in TRP channel genetic polymorphisms and how this may affect treatment response to TRP channel targets. Further controlled studies on the safety and efficacy of these emerging treatments is needed before clinical use.
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Mitochondrial Reactive Oxygen Species Elicit Acute and Chronic Itch via Transient Receptor Potential Canonical 3 Activation in Mice. Neurosci Bull 2022; 38:373-385. [PMID: 35294713 PMCID: PMC9068852 DOI: 10.1007/s12264-022-00837-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Accepted: 12/13/2021] [Indexed: 02/08/2023] Open
Abstract
Mitochondrial reactive oxygen species (mROS) that are overproduced by mitochondrial dysfunction are linked to pathological conditions including sensory abnormalities. Here, we explored whether mROS overproduction induces itch through transient receptor potential canonical 3 (TRPC3), which is sensitive to ROS. Intradermal injection of antimycin A (AA), a selective inhibitor of mitochondrial electron transport chain complex III for mROS overproduction, produced robust scratching behavior in naïve mice, which was suppressed by MitoTEMPO, a mitochondria-selective ROS scavenger, and Pyr10, a TRPC3-specific blocker, but not by blockers of TRPA1 or TRPV1. AA activated subsets of trigeminal ganglion neurons and also induced inward currents, which were blocked by MitoTEMPO and Pyr10. Besides, dry skin-induced chronic scratching was relieved by MitoTEMPO and Pyr10, and also by resveratrol, an antioxidant. Taken together, our results suggest that mROS elicit itch through TRPC3, which may underlie chronic itch, representing a potential therapeutic target for chronic itch.
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Meinel K, Szabo D, Dezsofi A, Pohl S, Strini T, Greimel T, Aguiriano-Moser V, Haidl H, Wagner M, Schlagenhauf A, Jahnel J. The Covert Surge: Murine Bile Acid Levels Are Associated With Pruritus in Pediatric Autoimmune Sclerosing Cholangitis. Front Pediatr 2022; 10:903360. [PMID: 35633951 PMCID: PMC9130722 DOI: 10.3389/fped.2022.903360] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Accepted: 04/25/2022] [Indexed: 11/13/2022] Open
Abstract
OBJECTIVES The exact etiology of pruritus in chronic cholestasis is unknown. Pruritus intensity does not correlate with common biochemical indices and there is a lack of biomarkers guiding diagnosis and treatment. We explored profiles of bile acids (BA) and muricholic acids (MCA) as well as autotaxin (ATX) antigen levels as potential circulating biomarkers of pruritus in pediatric patients. METHODS In 27 pediatric cholestatic patients [autoimmune sclerosing cholangitis (ASC) n = 20 (with pruritus n = 6, without pruritus n = 14); progressive familial intrahepatic cholestasis (PFIC) n = 7 (with pruritus n = 5, without pruritus n = 2)] and 23 age-matched controls pruritus was assessed by a visual analog scale of pruritus (PVAS). We obtained profiles of serum human BA including MCA using a mass-spectrometry assay and ATX antigen levels with a commercial ELISA. RESULTS PFIC and ASC patients exhibited significantly higher BA-, and MCA levels, than healthy controls, but only PFIC patients showed elevated ATX antigen levels higher [median: 1,650 ng/ml, interquartile rang (IQR): 776.9-3,742] compared to controls (median: 315.9 ng/ml, IQR: 251.1-417.2; PFIC p = 0.0003). ASC patients with pruritus showed only a minor increase in total BA (tBA) levels (median: 76.5 μmol/L, IQR: 54.7-205), but strikingly higher T-conjugated BA (median: 16.4 μmol/L, IQR: 8.9-41.4) and total MCA (tMCA) (median: 1.15 μmol/L, IQR: 0.77-2.44) levels compared to ASC patients without pruritus (tBA median: 24.3 μmol/L, IQR: 16.2-80.8; p < 0.0408; T-conjugated BA median: 1.3 μmol/L, IQR: 0.8-4.9; p = 0.0023; tMCA median: 0.30 μmol/L, IQR: 0.13-0.64, p = 0.0033). BA/MCA profiles distinctly differed depending on presence/absence of pruritus. Different from PFIC patients, ATX antigen levels were not significantly elevated in ASC patients with (median: 665.8 ng/ml, IQR: 357.8-1,203) and without pruritus (median: 391.0 ng/ml, IQR: 283.2-485.6). In ASC patients, tBA, tMCA, and ATX antigen levels did not correlate with pruritus severity. CONCLUSION Despite the same underlying disease, pediatric ASC patients with pruritus exhibit significantly altered BA profiles and MCA levels compared to ASC patients without pruritus. ATX antigen levels seem to have little diagnostic or prognostic meaning in ASC patients. An increased ATX activity alone seems not to be causal for pruritus genesis in ASC patients. CLINICAL TRIAL REGISTRATION [www.drks.de], identifier [DRKS00026913].
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Affiliation(s)
- Katharina Meinel
- Division of General Pediatrics, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria
| | - Doloresz Szabo
- First Department of Pediatrics, Semmelweis University, Budapest, Hungary
| | - Antal Dezsofi
- First Department of Pediatrics, Semmelweis University, Budapest, Hungary
| | - Sina Pohl
- Division of General Pediatrics, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria
| | - Tanja Strini
- Division of General Pediatrics, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria
| | - Theresa Greimel
- Division of General Pediatrics, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria
| | - Victor Aguiriano-Moser
- Division of General Pediatrics, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria
| | - Harald Haidl
- Division of General Pediatrics, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria
| | - Martin Wagner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Axel Schlagenhauf
- Division of General Pediatrics, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria
| | - Jörg Jahnel
- Division of General Pediatrics, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria
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McCain JD, Chascsa DM, Lindor KD. Assessing and managing symptom burden and quality of life in primary sclerosing cholangitis patients. Expert Opin Orphan Drugs 2021. [DOI: 10.1080/21678707.2021.1898370] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Affiliation(s)
- Josiah D. McCain
- Department of Gastroenterology and Hepatology, Mayo Clinic, Phoenix, Arizona, USA
| | - David M. Chascsa
- Department of Gastroenterology and Hepatology, Mayo Clinic, Phoenix, Arizona, USA
- Department of Transplant Center, Mayo Clinic, Phoenix, Arizona, USA
| | - Keith D. Lindor
- Office of University Provost, Arizona State University, Arizona, USA
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Yoshikawa S, Asano T, Morino M, Matsumoto K, Kashima H, Koito Y, Miura T, Takahashi Y, Tsuboi R, Ishii T, Otake H, Fujiwara J, Sekine M, Uehara T, Yuhashi K, Matsumoto S, Asabe S, Miyatani H, Mashima H. Pruritus is common in patients with chronic liver disease and is improved by nalfurafine hydrochloride. Sci Rep 2021; 11:3015. [PMID: 33542298 PMCID: PMC7862656 DOI: 10.1038/s41598-021-82566-w] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2020] [Accepted: 01/20/2021] [Indexed: 02/06/2023] Open
Abstract
Pruritus is known to be a common complication in hepatitis patients, but the exact frequency and degree are not fully elucidated. Thus, we evaluated pruritus of 450 patients with chronic liver disease at our hospital. Pruritus was observed in 240 (53%) of the patients. Pruritus was significantly associated with males (OR = 1.51, P = 0.038) and patients with alkaline phosphatase (ALP) ≥ 200 U/L (OR = 1.56, P = 0.0495) and was significantly less in HBsAg-positive patients (OR = 0.449, P = 0.004). Seasonally, there was no difference in the frequency of pruritus between summer and winter. Of the 24 refractory pruritus patients treated with nalfurafine, 17 (71%) indicated improvement of itch, which is defined as a decrease in the visual analog scale score ≥ 30 mm. Pruritus was improved by nalfurafine both during daytime and nighttime in the Kawashima's scores evaluation. All patients who received nalfurafine exhibited improved Kawashima's scores ≥ 1 point during the daytime or nighttime. In conclusion, pruritus occurred in > 50% of patients with chronic liver disease, and predictors of pruritus were males and ALP ≥ 200 U/L. Nalfurafine may be useful for pruritus, regardless of whether daytime or nighttime.
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Affiliation(s)
- Shuhei Yoshikawa
- Department of Gastroenterology, Saitama Medical Center, Jichi Medical University, 1-847 Amanuma-cho, Omiya-ku, Saitama, 330-8503, Japan
| | - Takeharu Asano
- Department of Gastroenterology, Saitama Medical Center, Jichi Medical University, 1-847 Amanuma-cho, Omiya-ku, Saitama, 330-8503, Japan.
| | - Mina Morino
- Department of Gastroenterology, Saitama Medical Center, Jichi Medical University, 1-847 Amanuma-cho, Omiya-ku, Saitama, 330-8503, Japan
| | - Keita Matsumoto
- Department of Gastroenterology, Saitama Medical Center, Jichi Medical University, 1-847 Amanuma-cho, Omiya-ku, Saitama, 330-8503, Japan
| | - Hitomi Kashima
- Department of Gastroenterology, Saitama Medical Center, Jichi Medical University, 1-847 Amanuma-cho, Omiya-ku, Saitama, 330-8503, Japan
| | - Yudai Koito
- Department of Gastroenterology, Saitama Medical Center, Jichi Medical University, 1-847 Amanuma-cho, Omiya-ku, Saitama, 330-8503, Japan
| | - Takaya Miura
- Department of Gastroenterology, Saitama Medical Center, Jichi Medical University, 1-847 Amanuma-cho, Omiya-ku, Saitama, 330-8503, Japan
| | - Yuko Takahashi
- Department of Gastroenterology, Saitama Medical Center, Jichi Medical University, 1-847 Amanuma-cho, Omiya-ku, Saitama, 330-8503, Japan
| | - Rumiko Tsuboi
- Department of Gastroenterology, Saitama Medical Center, Jichi Medical University, 1-847 Amanuma-cho, Omiya-ku, Saitama, 330-8503, Japan
| | - Takehiro Ishii
- Department of Gastroenterology, Saitama Medical Center, Jichi Medical University, 1-847 Amanuma-cho, Omiya-ku, Saitama, 330-8503, Japan
| | - Haruka Otake
- Department of Gastroenterology, Saitama Medical Center, Jichi Medical University, 1-847 Amanuma-cho, Omiya-ku, Saitama, 330-8503, Japan
| | - Junichi Fujiwara
- Department of Gastroenterology, Saitama Medical Center, Jichi Medical University, 1-847 Amanuma-cho, Omiya-ku, Saitama, 330-8503, Japan
| | - Masanari Sekine
- Department of Gastroenterology, Saitama Medical Center, Jichi Medical University, 1-847 Amanuma-cho, Omiya-ku, Saitama, 330-8503, Japan
| | - Takeshi Uehara
- Department of Gastroenterology, Saitama Medical Center, Jichi Medical University, 1-847 Amanuma-cho, Omiya-ku, Saitama, 330-8503, Japan
| | - Kazuhito Yuhashi
- Department of Gastroenterology, Saitama Medical Center, Jichi Medical University, 1-847 Amanuma-cho, Omiya-ku, Saitama, 330-8503, Japan
| | - Satohiro Matsumoto
- Department of Gastroenterology, Saitama Medical Center, Jichi Medical University, 1-847 Amanuma-cho, Omiya-ku, Saitama, 330-8503, Japan
| | - Shinichi Asabe
- Department of Gastroenterology, Saitama Medical Center, Jichi Medical University, 1-847 Amanuma-cho, Omiya-ku, Saitama, 330-8503, Japan
| | - Hiroyuki Miyatani
- Department of Gastroenterology, Saitama Medical Center, Jichi Medical University, 1-847 Amanuma-cho, Omiya-ku, Saitama, 330-8503, Japan
| | - Hirosato Mashima
- Department of Gastroenterology, Saitama Medical Center, Jichi Medical University, 1-847 Amanuma-cho, Omiya-ku, Saitama, 330-8503, Japan
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Abstract
Despite efforts to develop new antibiotics, antibacterial resistance still develops too fast for drug discovery to keep pace. Often, resistance against a new drug develops even before it reaches the market. This continued resistance crisis has demonstrated that resistance to antibiotics with single protein targets develops too rapidly to be sustainable. Most successful long-established antibiotics target more than one molecule or possess targets, which are encoded by multiple genes. This realization has motivated a change in antibiotic development toward drug candidates with multiple targets. Some mechanisms of action presuppose multiple targets or at least multiple effects, such as targeting the cytoplasmic membrane or the carrier molecule bactoprenol phosphate and are therefore particularly promising. Moreover, combination therapy approaches are being developed to break antibiotic resistance or to sensitize bacteria to antibiotic action. In this Review, we provide an overview of antibacterial multitarget approaches and the mechanisms behind them.
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Affiliation(s)
- Declan Alan Gray
- Newcastle University
Biosciences Institute, Newcastle University, NE2 4HH Newcastle
upon Tyne, United Kingdom
| | - Michaela Wenzel
- Division of Chemical
Biology, Department of Biology and Biological Engineering, Chalmers University of Technology, 412 96 Gothenburg, Sweden
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12
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Chapman MH, Thorburn D, Hirschfield GM, Webster GGJ, Rushbrook SM, Alexander G, Collier J, Dyson JK, Jones DE, Patanwala I, Thain C, Walmsley M, Pereira SP. British Society of Gastroenterology and UK-PSC guidelines for the diagnosis and management of primary sclerosing cholangitis. Gut 2019; 68:1356-1378. [PMID: 31154395 PMCID: PMC6691863 DOI: 10.1136/gutjnl-2018-317993] [Citation(s) in RCA: 178] [Impact Index Per Article: 29.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2018] [Revised: 02/21/2019] [Accepted: 03/24/2019] [Indexed: 12/11/2022]
Abstract
These guidelines on the management of primary sclerosing cholangitis (PSC) were commissioned by the British Society of Gastroenterology liver section. The guideline writing committee included medical representatives from hepatology and gastroenterology groups as well as patient representatives from PSC Support. The guidelines aim to support general physicians, gastroenterologists and surgeons in managing adults with PSC or those presenting with similar cholangiopathies which may mimic PSC, such as IgG4 sclerosing cholangitis. It also acts as a reference for patients with PSC to help them understand their own management. Quality of evidence is presented using the AGREE II format. Guidance is meant to be used as a reference rather than for rigid protocol-based care as we understand that management of patients often requires individual patient-centred considerations.
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Affiliation(s)
- Michael Huw Chapman
- GI Division, UCL Hospitals NHS Foundation Trust, London, UK
- Liver Unit, Royal Free London NHS Foundation Trust, London, UK
| | | | - Gideon M Hirschfield
- Toronto Centre for Liver Disease, University Health Network and University of Toronto, Toronto, Canada
| | | | - Simon M Rushbrook
- Department of Hepatology, Norfolk and Norwich University Hospitals NHS Trust, Norwich, UK
| | | | | | - Jessica K Dyson
- Hepatology, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle, UK
- Institute of Cellular Medicine, Newcastle University, Newcastle, UK
| | - David Ej Jones
- Institute of Cellular Medicine, Newcastle University, Newcastle, UK
| | - Imran Patanwala
- Gastroenterology, Royal Liverpool and Broadgreen University Hospitals NHS Trust, Liverpool, UK
- University of Liverpool, Liverpool, UK
| | | | | | - Stephen P Pereira
- GI Division, UCL Hospitals NHS Foundation Trust, London, UK
- Institute for Liver & Digestive Health, University College London, London, UK
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13
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Ataei S, Kord L, Larki A, Yasrebifar F, Mehrpooya M, Seyedtabib M, Hasanzarrini M. Comparison of Sertraline with Rifampin in the treatment of Cholestatic Pruritus: A Randomized Clinical Trial. Rev Recent Clin Trials 2019; 14:217-223. [PMID: 30919782 DOI: 10.2174/1574887114666190328130720] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2018] [Revised: 03/07/2019] [Accepted: 03/22/2019] [Indexed: 12/28/2022]
Abstract
BACKGROUND Pruritus is one of the most common and disabling symptoms of liver disease such as Primary Sclerosing Cholangitis and Primary Biliary Cholangitis. Cholestyramine, rifampin, opioid antagonists, antihistaminic agents and SSRIs are used for the management of pruritus. Due to rifampin drug interactions as well as its serious side effects such as hepatotoxicity, clinicians are endeavoruing to find a safer and a more effective substitution. OBJECTIVE The purpose of this study was to compare the efficacy and safety of sertraline with rifampin in the management of cholestatic pruritus. METHODS In a single-blinded randomized clinical trial a total of 36 patients of PSC and PBC were divided into two equal groups, one group received 100 mg/day sertraline and the other group received rifampin 300 mg/day for 4 weeks. Visual analog scale was used to record pruritus severity at baseline and 4 weeks after drug intervention, also, ALT, AST, ALP and total bilirubin of all patients were measured at three different time points. RESULTS Over the follow-up period, pruritus had relieved in both groups, but there was no significant differences between sertraline and rifampin in pruritus management (pvalue=0.740), also there was no significant difference between the two intervention strategies (A versus B) in total bilirubin level (pvalue=0.106). Moreover, the ALT, AST and ALP levels were found to be significantly different between the two groups (Pvalue˂0.01). CONCLUSION There is no difference between sertraline and rifampin in pruritus improvement, but sertraline has less adverse effects on hepatobiliary enzyme levels, so it seems to be safer than rifampin.
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Affiliation(s)
- Sara Ataei
- Department of Clinical Pharmacy, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Leila Kord
- Department of Clinical Pharmacy, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Amir Larki
- Department of Pharmacology and Toxicology, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Fatemeh Yasrebifar
- Department of Clinical Pharmacy, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Maryam Mehrpooya
- Department of Clinical Pharmacy, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Maryam Seyedtabib
- Department of Epidemiology and Biostatistics, School of Public Health, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Maryam Hasanzarrini
- Department of Internal Medicine, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
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14
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Affiliation(s)
- Aluko A. Hope
- RS Morrison (corresponding author) Department of Geriatrics and Palliative Medicine, and Hertzberg Palliative Care Institute, Mount Sinai School of Medicine, 1 Gustave Levy Place, Box 1070, New York, New York, USA
| | - R. Sean Morrison
- Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, and Department of Geriatrics and Palliative Medicine, Mount Sinai School of Medicine, New York, New York, USA
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15
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TRP Channels as Drug Targets to Relieve Itch. Pharmaceuticals (Basel) 2018; 11:ph11040100. [PMID: 30301231 PMCID: PMC6316386 DOI: 10.3390/ph11040100] [Citation(s) in RCA: 59] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Revised: 09/26/2018] [Accepted: 10/03/2018] [Indexed: 12/14/2022] Open
Abstract
Although acute itch has a protective role by removing irritants to avoid further damage, chronic itch is debilitating, significantly impacting quality of life. Over the past two decades, a considerable amount of stimulating research has been carried out to delineate mechanisms of itch at the molecular, cellular, and circuit levels. There is growing evidence that transient receptor potential (TRP) channels play important roles in itch signaling. The purpose of this review is to summarize our current knowledge about the role of TRP channels in the generation of itch under both physiological and pathological conditions, thereby identifying them as potential drug targets for effective anti-itch therapies.
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16
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Abstract
Chronic pruritus (>6 week's duration) in the geriatric population (≥65 years old), is an increasing health care problem. The pathophysiologic predisposing factors are abnormalities of the epidermal barrier, immune system, and nervous system. Causes can be dichotomized into histaminergic and nonhistaminergic pruritus. Topical treatments are generally safe. Systemic treatments are chosen depending on the condition, comorbid diseases, and drug interactions. Treatment options are limited. Progress has been made in identifying itch-selective mediators over the last decade. Numerous new medications are currently undergoing clinical trials and they are anticipated to enter the clinics in the near future.
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17
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Pearson HJ, Mosser JL, Jacks SK. The triad of pruritus, xanthomas, and cholestasis: Two cases and a brief review of the literature. Pediatr Dermatol 2017; 34:e305-e308. [PMID: 29144045 DOI: 10.1111/pde.13306] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
Abstract
When encountered in children, xanthomas are most commonly associated with a group of disorders known as familial hyperlipidemias. Aside from cosmetic concerns, these xanthomas are typically asymptomatic, but when generalized pruritus is a prominent associated symptom, clinicians should consider a different set of diagnoses that includes cholestasis of the liver. In this article we present two illustrative cases of children with cholestatic disease, pruritus, and xanthomas and discuss other disorders that may include this triad.
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Affiliation(s)
| | - Joy L Mosser
- Nationwide Children's Hospital, Columbus, OH, USA
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18
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Stauber RE, Fauler G, Rainer F, Leber B, Posch A, Streit A, Spindelboeck W, Stadlbauer V, Kessler HH, Mangge H. Anti-HCV treatment with ombitasvir/paritaprevir/ritonavir ± dasabuvir is associated with increased bile acid levels and pruritus. Wien Klin Wochenschr 2017; 129:848-851. [DOI: 10.1007/s00508-017-1268-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2017] [Accepted: 08/30/2017] [Indexed: 11/24/2022]
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19
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Jarido V, Kennedy L, Hargrove L, Demieville J, Thomson J, Stephenson K, Francis H. The emerging role of mast cells in liver disease. Am J Physiol Gastrointest Liver Physiol 2017; 313:G89-G101. [PMID: 28473331 PMCID: PMC5582878 DOI: 10.1152/ajpgi.00333.2016] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2016] [Revised: 04/12/2017] [Accepted: 04/24/2017] [Indexed: 01/31/2023]
Abstract
The depth of our knowledge regarding mast cells has widened exponentially in the last 20 years. Once thought to be only important for allergy-mediated events, mast cells are now recognized to be important regulators of a number of pathological processes. The revelation that mast cells can influence organs, tissues, and cells has increased interest in mast cell research during liver disease. The purpose of this review is to refresh the reader's knowledge of the development, type, and location of mast cells and to review recent work that demonstrates the role of hepatic mast cells during diseased states. This review focuses primarily on liver diseases and mast cells during autoimmune disease, hepatitis, fatty liver disease, liver cancer, and aging in the liver. Overall, these studies demonstrate the potential role of mast cells in disease progression.
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Affiliation(s)
- Veronica Jarido
- Baylor Scott & White Health and Medicine, Temple, Texas; and
| | - Lindsey Kennedy
- Research, Central Texas Veterans Health Care System, Temple, Texas
- Texas A & M Health Science Center, Temple, Texas
| | | | | | - Joanne Thomson
- Research, Central Texas Veterans Health Care System, Temple, Texas
| | | | - Heather Francis
- Research, Central Texas Veterans Health Care System, Temple, Texas;
- Baylor Scott & White Health and Medicine, Temple, Texas; and
- Texas A & M Health Science Center, Temple, Texas
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20
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Haydek CG, Love E, Mollanazar NK, Valdes Rodriguez R, Lee H, Yosipovitch G, Tharp MD, Hanifin JM, Chen KH, Chen SC. Validation and Banding of the ItchyQuant: A Self-Report Itch Severity Scale. J Invest Dermatol 2017; 137:57-61. [DOI: 10.1016/j.jid.2016.06.633] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2015] [Revised: 05/24/2016] [Accepted: 06/21/2016] [Indexed: 10/21/2022]
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21
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Boyer JL. Treatment of chronic cholestasis: What we know and what we will know? Clin Liver Dis (Hoboken) 2016; 8:140-144. [PMID: 31041082 PMCID: PMC6490239 DOI: 10.1002/cld.591] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2016] [Revised: 09/22/2016] [Accepted: 09/25/2016] [Indexed: 02/04/2023] Open
Affiliation(s)
- James L. Boyer
- Department of Internal MedicineYale University School of MedicineNew HavenCT
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22
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Kittanamongkolchai W, El-Zoghby ZM, Eileen Hay J, Wiesner RH, Kamath PS, LaRusso NF, Watt KD, Cramer CH, Leung N. Charcoal hemoperfusion in the treatment of medically refractory pruritus in cholestatic liver disease. Hepatol Int 2016; 11:384-389. [DOI: 10.1007/s12072-016-9775-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2016] [Accepted: 11/09/2016] [Indexed: 01/01/2023]
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Abstract
Cirrhosis is the end result of nearly all forms of progressive liver disease. The diffuse hepatic process can be characterized as a state of inflammation progressing to fibrosis and resulting in nodular regeneration, ultimately leading to disorganized liver architecture and function. The underlying etiology of cirrhosis in children may often differ from adults owing to specific disease processes that manifest in childhood, including biliary atresia, galactosemia, and neonatal hepatitis. Although basic management strategies in children are similar to those in adults, the care given to children with cirrhosis must keep the child's growth and development of paramount importance. [Pediatr Ann. 2016;45(12):e427-e432.].
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24
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Siemens W, Xander C, Meerpohl JJ, Buroh S, Antes G, Schwarzer G, Becker G, Cochrane Pain, Palliative and Supportive Care Group. Pharmacological interventions for pruritus in adult palliative care patients. Cochrane Database Syst Rev 2016; 11:CD008320. [PMID: 27849111 PMCID: PMC6734122 DOI: 10.1002/14651858.cd008320.pub3] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND This is an update of the original Cochrane review published in 2013 (Issue 6). Pruritus occurs in patients with disparate underlying diseases and is caused by different pathologic mechanisms. In palliative care patients, pruritus is not the most prevalent but is one of the most puzzling symptoms. It can cause considerable discomfort and affects patients' quality of life. OBJECTIVES To assess the effects of different pharmacological treatments for preventing or treating pruritus in adult palliative care patients. SEARCH METHODS For this update, we searched CENTRAL (the Cochrane Library), and MEDLINE (OVID) up to 9 June 2016 and Embase (OVID) up to 7 June 2016. In addition, we searched trial registries and checked the reference lists of all relevant studies, key textbooks, reviews and websites, and we contacted investigators and specialists in pruritus and palliative care regarding unpublished data. SELECTION CRITERIA We included randomised controlled trials (RCTs) assessing the effects of different pharmacological treatments, compared with a placebo, no treatment, or an alternative treatment, for preventing or treating pruritus in palliative care patients. DATA COLLECTION AND ANALYSIS Two review authors independently assessed the identified titles and abstracts, performed data extraction and assessed the risk of bias and methodological quality. We summarised the results descriptively and quantitatively (meta-analyses) according to the different pharmacological interventions and the diseases associated with pruritus. We assessed the evidence using GRADE (Grading of Recommendations Assessment, Development and Evaluation) and created 10 'Summary of findings' tables. MAIN RESULTS In total, we included 50 studies and 1916 participants in the review. We added 10 studies with 627 participants for this update. Altogether, we included 39 different treatments for pruritus in four different patient groups.The overall risk of bias profile was heterogeneous and ranged from high to low risk. However, 48 studies (96%) had a high risk of bias due to low sample size (i.e. fewer than 50 participants per treatment arm). Using GRADE criteria, we downgraded our judgement on the quality of evidence to moderate in seven and to low in three comparisons for our primary outcome (pruritus), mainly due to imprecision and risk of bias.In palliative care participants with pruritus of different nature, the treatment with the drug paroxetine, a selective serotonin reuptake inhibitor, reduced pruritus by 0.78 points (numerical analogue scale from 0 to 10; 95% confidence interval (CI) -1.19 to -0.37; one RCT, N = 48, quality of evidence: moderate) compared to placebo.For participants suffering from uraemic pruritus (UP), gabapentin was more effective than placebo (visual analogue scale (VAS): 0 to 10), mean difference (MD) -5.91, 95% CI -6.87 to -4.96; two RCTs, N = 118, quality of evidence: moderate). The κ-opioid receptor agonist nalfurafine showed amelioration of UP (VAS 0 to 10, MD -0.95, 95% CI -1.32 to -0.58; three RCTs, N = 422, quality of evidence: moderate) and only few adverse events. Moreover, cromolyn sodium relieved UP participants from pruritus by 2.94 points on the VAS (0 to 10) (95% CI -4.04 to -1.83; two RCTs, N = 100, quality of evidence: moderate) compared to placebo.In participants with cholestatic pruritus (CP), data favoured rifampin (VAS: 0 to 100, MD -24.64, 95% CI -31.08 to -18.21; two RCTs, N = 42, quality of evidence: low) and flumecinol (RR > 1 favours treatment group; RR 1.89, 95% CI 1.05 to 3.39; two RCTs, N = 69, quality of evidence: low) and showed a low incidence of adverse events in comparison with placebo. The opioid antagonist naltrexone reduced pruritus for participants with CP (VAS: 0 to 10, MD -2.26, 95% CI -3.19 to -1.33; two RCTs, N = 52, quality of evidence: moderate) compared to placebo. However, effects in participants with UP were inconclusive (percentage difference -12.30%, 95% CI -25.82% to 1.22%, one RCT, N = 32). Furthermore, large doses of opioid antagonists (e.g. naltrexone) could be inappropriate in palliative care patients because of the risk of reducing analgesia.For participants with HIV-associated pruritus, it is uncertain whether drug treatment with hydroxyzine hydrochloride, pentoxifylline, triamcinolone or indomethacin reduces pruritus because the evidence was of very low quality (e.g. small sample size, lack of blinding). AUTHORS' CONCLUSIONS Different interventions tended to be effective for CP and UP. However, therapies for patients with malignancies are still lacking. Due to the small sample sizes in most meta-analyses and the heterogeneous methodological quality of the included trials, the results should be interpreted cautiously in terms of generalisability.
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Affiliation(s)
- Waldemar Siemens
- Faculty of Medicine, University of Freiburg, GermanyClinic for Palliative Care, Medical Center ‐ University of FreiburgRobert‐Koch‐Straße 3FreiburgGermany
| | - Carola Xander
- Faculty of Medicine, University of Freiburg, GermanyClinic for Palliative Care, Medical Center ‐ University of FreiburgRobert‐Koch‐Straße 3FreiburgGermany
| | - Joerg J Meerpohl
- Medical Center ‐ University of FreiburgCochrane GermanyBreisacher Straße 153FreiburgGermany79110
| | - Sabine Buroh
- University Medical CenterLibrary of the Center of SurgeryHugstetterstrasse 55FreiburgBaden‐WürttembergGermany79115
| | - Gerd Antes
- Medical Center ‐ University of FreiburgCochrane GermanyBreisacher Straße 153FreiburgGermany79110
| | - Guido Schwarzer
- Medical Center ‐ University of FreiburgCenter for Medical Biometry and Medical InformaticsStefan‐Meier‐Str. 26FreiburgGermanyD‐79104
| | - Gerhild Becker
- Faculty of Medicine, University of Freiburg, GermanyClinic for Palliative Care, Medical Center ‐ University of FreiburgRobert‐Koch‐Straße 3FreiburgGermany
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25
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Pradhan S, Madke B, Kabra P, Singh AL. Anti-inflammatory and Immunomodulatory Effects of Antibiotics and Their Use in Dermatology. Indian J Dermatol 2016; 61:469-81. [PMID: 27688434 PMCID: PMC5029230 DOI: 10.4103/0019-5154.190105] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Antibiotics (antibacterial, antiviral, and antiparasitic) are class of drugs which result in either killing or inhibiting growth and multiplication of infectious organisms. Antibiotics are commonly prescribed by all specialties for treatment of infections. However, antibiotics have hitherto immunomodulatory and anti-inflammatory properties and can be exploited for various noninfectious dermatoses. Dermatologists routinely prescribe antibiotics in treatment of various noninfectious disorders. This study will review anti-inflammatory and immunomodulatory effects of antibiotics and their use in dermatology.
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Affiliation(s)
- Swetalina Pradhan
- Department of Dermatology, STD and Leprosy, All India Institute of Medical Sciences, Bhubaneswar, Odisha, India
| | - Bhushan Madke
- Department of Dermatology, Venereology and Leprosy, Jawaharlal Nehru Medical College and AVBR Hospital, Wardha, Maharashtra, India
| | - Poonam Kabra
- Department of Dermatology, Venereology and Leprosy, Jawaharlal Nehru Medical College and AVBR Hospital, Wardha, Maharashtra, India
| | - Adarsh Lata Singh
- Department of Dermatology, Venereology and Leprosy, Jawaharlal Nehru Medical College and AVBR Hospital, Wardha, Maharashtra, India
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26
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Tsai CF, Chu CJ, Wang YP, Liu PY, Huang YH, Lin HC, Lee FY, Lu CL. Increased serum interleukin-6, not minimal hepatic encephalopathy, predicts poor sleep quality in nonalcoholic cirrhotic patients. Aliment Pharmacol Ther 2016; 44:836-45. [PMID: 27518472 DOI: 10.1111/apt.13765] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2016] [Revised: 03/07/2016] [Accepted: 07/24/2016] [Indexed: 12/13/2022]
Abstract
BACKGROUND Sleep-wake disturbances are common in patients with cirrhosis and have a considerable effect on health-related quality of life; however, the underlying mechanism behind the phenomenon is unclear. Cytokines are involved in the mediation of signalling pathways regulating fibrogenesis, leading to cirrhosis. In addition, increased cytokines could contribute to sleep disturbances. AIM To determine the relationship between pro-inflammatory cytokines and sleep disturbance in cirrhotic patients. METHODS Ninety-eight nonalcoholic cirrhotic patients without overt hepatic encephalopathy were enrolled in this cross-sectional study. The Pittsburgh Sleep Quality Index (PSQI) was used to assess sleep quality. The Psychometric Hepatic Encephalopathy Score (PHES) was used to examine cognitive performance and define minimal hepatic encephalopathy (MHE). The Hospital Anxiety and Depression Scale (HADS) was used to evaluate the mood status of the patients. Pro-inflammatory cytokines that include interleukin 6 (IL-6) and tumour necrosis factor-α, as well as HBV-DNA or HCV-RNA levels were determined in patients. RESULTS A total of 56 (57%) cirrhotic patients were identified as 'poor' sleepers (PSQI > 5). After multivariate analysis, IL-6 (P = 0.001) and HADS scores (P = 0.002) were found to be independent predictive factors of poor sleep quality. No significant relationships were observed between the sleep indices and the presence of MHE. HCV-RNA, but not HBV-DNA, viraemia was associated with sleep disturbance in cirrhotic patients. CONCLUSIONS Sleep disturbance is found commonly in cirrhotic patients and a high serum IL-6 level is predictive of poor sleep quality. Minimal hepatic encephalopathy by itself may not contribute to sleep dysfunction in cirrhotic patients.
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Affiliation(s)
- C-F Tsai
- Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan.,Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.,Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan
| | - C-J Chu
- Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.,Division of Gastroenterology, Taipei Veterans General Hospital, Taipei, Taiwan.,Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Y-P Wang
- Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan.,Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.,Division of Gastroenterology, Taipei Veterans General Hospital, Taipei, Taiwan.,Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - P-Y Liu
- Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan
| | - Y-H Huang
- Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.,Division of Gastroenterology, Taipei Veterans General Hospital, Taipei, Taiwan.,Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - H-C Lin
- Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.,Division of Gastroenterology, Taipei Veterans General Hospital, Taipei, Taiwan.,Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - F-Y Lee
- Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.,Division of Gastroenterology, Taipei Veterans General Hospital, Taipei, Taiwan.,Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - C-L Lu
- Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan. , .,Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan. , .,Division of Gastroenterology, Taipei Veterans General Hospital, Taipei, Taiwan. , .,Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan. ,
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27
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Gabapentin and pregabalin for the treatment of chronic pruritus. J Am Acad Dermatol 2016; 75:619-625.e6. [DOI: 10.1016/j.jaad.2016.02.1237] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2015] [Revised: 02/26/2016] [Accepted: 02/26/2016] [Indexed: 01/23/2023]
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28
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Belghiti M, Agusti A, Hernandez-Rabaza V, Cabrera-Pastor A, Llansola M, Felipo V. Sildenafil Treatment Eliminates Pruritogenesis and Thermal Hyperalgesia in Rats with Portacaval Shunts. Neurochem Res 2016; 42:788-794. [PMID: 27321307 DOI: 10.1007/s11064-016-1980-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2016] [Revised: 06/11/2016] [Accepted: 06/13/2016] [Indexed: 11/24/2022]
Abstract
Pruritus is a common symptom in chronic liver diseases, which may also alter thermal sensitivity. The underlying mechanisms remain unclear and treatments are not satisfactory. Portal-systemic shunting has been proposed to alter thermal sensitivity in cirrhotics. Inflammation-induced enhanced activity of the Transient Receptor Potential Vanilloid 1 (TRPV1) may contribute to pruritus and thermal hyperalgesia. Sildenafil reduces neuroinflammation in portacaval shunt (PCS) rats. The aims were to assess whether: (1) PCS rats show enhanced scratching or thermal sensitivity; (2) TRPV1 activity is enhanced in PCS rats; (3) treatment with sildenafil reduces TRPV1 activation, scratching and thermal hyperalgesia. Rats were treated with sildenafil beginning 3 weeks after surgery. The number of scratches performed were counted. Thermal hyperalgesia was analyzed using the Hargreaves' Plantar Test. TRPV1 activation by measuring the increase in Ca2+ induced by capsaicin in dorsal root ganglia neurons. PCS rats show enhanced scratching behavior, reaching 66 ± 5 scratches/h (p < 0.01) at 21 days after surgery, while controls show 37 ± 2 scratches/h. PCS rats show thermal hyperalgesia. Paw withdrawal latency was reduced (p < 0.05) to 10 ± 1 s compared to controls (21 ± 2 s). Capsaicin-induced calcium increase was higher in dorsal root ganglia cultures from PCS rats, indicating TRPV1functional increase. PCS rats show enhanced scratching behavior and thermal sensitivity and are a good model to study these alterations in chronic liver diseases. Enhanced sensitivity and activity of TRPV1 channel underlies these alterations. Treatment with sildenafil reduces TRPV1 channel sensitivity and activity and normalizes scratching behavior and thermal sensitivity.
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Affiliation(s)
- Majedeline Belghiti
- Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Eduardo Primo Yufera, 3, 46012, Valencia, Spain
| | - Ana Agusti
- Instituto de Investigación Sanitaria INCLIVA, Valencia, Spain
| | - Vicente Hernandez-Rabaza
- Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Eduardo Primo Yufera, 3, 46012, Valencia, Spain
| | - Andrea Cabrera-Pastor
- Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Eduardo Primo Yufera, 3, 46012, Valencia, Spain
| | - Marta Llansola
- Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Eduardo Primo Yufera, 3, 46012, Valencia, Spain
| | - Vicente Felipo
- Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Eduardo Primo Yufera, 3, 46012, Valencia, Spain.
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29
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Abstract
Itch is a unique sensation associated with the scratch reflex. Although the scratch reflex plays a protective role in daily life by removing irritants, chronic itch remains a clinical challenge. Despite urgent clinical need, itch has received relatively little research attention and its mechanisms have remained poorly understood until recently. The goal of the present review is to summarize our current understanding of the mechanisms of acute as well as chronic itch and classifications of the primary itch populations in relationship to transient receptor potential (Trp) channels, which play pivotal roles in multiple somatosensations. The convergent involvement of Trp channels in diverse itch signaling pathways suggests that Trp channels may serve as promising targets for chronic itch treatments.
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Affiliation(s)
- Shuohao Sun
- The Solomon H. Snyder Department of Neuroscience, Center for Sensory Biology, Johns Hopkins University, School of Medicine, Baltimore, MD, 21205, USA
| | - Xinzhong Dong
- The Solomon H. Snyder Department of Neuroscience, Center for Sensory Biology, Johns Hopkins University, School of Medicine, Baltimore, MD, 21205, USA.
- Howard Hughes Medical Institute, Johns Hopkins University, School of Medicine, Baltimore, MD, 21205, USA.
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Hegade VS, Krawczyk M, Kremer AE, Kuczka J, Gaouar F, Kuiper EMM, van Buuren HR, Lammert F, Corpechot C, Jones DEJ. The safety and efficacy of nasobiliary drainage in the treatment of refractory cholestatic pruritus: a multicentre European study. Aliment Pharmacol Ther 2016; 43:294-302. [PMID: 26526892 DOI: 10.1111/apt.13449] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2015] [Revised: 09/08/2015] [Accepted: 10/07/2015] [Indexed: 01/05/2023]
Abstract
BACKGROUND Pruritus is a common symptom associated with cholestatic liver diseases. To date only small single centre case series have suggested efficacy of nasobiliary drainage in relieving cholestatic pruritus. AIM To perform a multicentre study to evaluate the safety and efficacy of nasobiliary drainage in cholestatic pruritus. METHODS This was a retrospective study of all patients treated with nasobiliary drainage for refractory cholestatic pruritus between 2006 and 2015 at five European centres. Pruritus was quantified using a visual analogue scale (VAS) and liver enzymes, serum bilirubin and total serum bile salts (TBS) were measured before (pre-NBD) and after nasobiliary drainage (post-NBD). We analysed the duration of treatment response and associated complications. RESULTS In total, 27 patients (59% females) underwent 29 nasobiliary drainage procedures. The median duration of NBD was 7 days. NBD decreased pruritus in 89.6% of cases (VAS from 10.0 to 0.3, P < 0.0001). The median percentage decline in pruritus VAS was 94% and 33% of patients were free of pruritus within 24 h of starting drainage. The duration of treatment response was independent of duration of drainage (P = 0.12) and bile output. Significant improvements were seen in the median levels of serum alkaline phosphatase (P = 0.001) and serum bilirubin (P = 0.03) but not in serum TBS (P = 0.07). Mild post-endoscopic retrograde cholangiopancreatography pancreatitis (31%) was the most frequent complication. CONCLUSIONS Nasobiliary drainage is effective in relieving cholestatic pruritus in most patients and has favourable effect on biomarkers of cholestasis. Nasobiliary drainage may be associated with high risk of adverse events, especially pancreatitis. Prospective studies are needed to confirm our findings.
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Affiliation(s)
- V S Hegade
- Freeman Hospital, The Newcastle upon Tyne NHS Foundation Trust and Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
| | - M Krawczyk
- Department of Medicine II, Saarland University Medical Center, Homburg, Germany.,Laboratory of Metabolic Liver Diseases, Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
| | - A E Kremer
- Department of Medicine I, Friedrich-Alexander-University of Erlangen, Erlangen, Germany
| | - J Kuczka
- Department of Medicine I, Friedrich-Alexander-University of Erlangen, Erlangen, Germany
| | - F Gaouar
- Service d'Hépatologie, Centre de référence des Maladies Inflammatoires des voies biliaires, Hôpital Saint-Antoine, Paris, France
| | - E M M Kuiper
- Department of Gastroenterology and Hepatology, Erasmus MC, Rotterdam, The Netherlands
| | - H R van Buuren
- Department of Gastroenterology and Hepatology, Erasmus MC, Rotterdam, The Netherlands
| | - F Lammert
- Department of Medicine II, Saarland University Medical Center, Homburg, Germany
| | - C Corpechot
- Service d'Hépatologie, Centre de référence des Maladies Inflammatoires des voies biliaires, Hôpital Saint-Antoine, Paris, France
| | - D E J Jones
- Freeman Hospital, The Newcastle upon Tyne NHS Foundation Trust and Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
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32
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Abstract
The burden of chronic pruritus is increasingly recognized as significant worldwide. As wet-laboratory researchers investigate the pathophysiology of chronic pruritus, epidemiologists and health services researchers are quantifying the impact of pruritus by incidence, prevalence, and quality of life measures. Outcomes researchers are also investigating factors that may predict chronic pruritus incidence and severity. Such efforts will direct resources for research, public health intervention, and clinical care.
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33
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Cipriani S, Renga B, D’Amore C, Simonetti M, De Tursi AA, Carino A, Monti MC, Sepe V, Zampella A, Fiorucci S. Impaired Itching Perception in Murine Models of Cholestasis Is Supported by Dysregulation of GPBAR1 Signaling. PLoS One 2015; 10:e0129866. [PMID: 26177448 PMCID: PMC4503431 DOI: 10.1371/journal.pone.0129866] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2014] [Accepted: 05/13/2015] [Indexed: 02/07/2023] Open
Abstract
Background & Aims In cholestatic syndromes, body accumulation of bile acids is thought to cause itching. However, the mechanisms supporting this effect remain elusive. Recently, GPBAR1 (TGR5) a G-protein coupled receptor has been shown to mediate itching caused by intradermal administration of DCA and LCA. 6α-ethyl-3α, 7α-dihydroxy-24-nor-5β-cholan-23-ol (BAR502) is a non-bile acid dual ligand for FXR and GPBAR1. Methods Cholestasis was induced in wild type and GPBAR1-/- mice by administration of α-naphthyl-isothiocyanate (ANIT) or 17α-ethynylestradiol. Results. In naïve mice skin application of DCA, TLCA, 6-ECDCA, oleanolic and betulinic acid induces a GPBAR1 dependent pruritogenic response that could be desensitized by re-challenging the mice with the same GPBAR1 agonist. In wild type and GPBAR1-/- mice cholestasis induced by ANIT fails to induce spontaneous itching and abrogates scratching behavior caused by intradermal administration of DCA. In this model, co-treatment with BAR502 increases survival, attenuates serum alkaline phosphatase levels and robustly modulates the liver expression of canonical FXR target genes including OSTα, BSEP, SHP and MDR1, without inducing pruritus. Betulinic acid, a selective GPBAR1 ligand, failed to rescue wild type and GPBAR1-/- mice from ANIT cholestasis but did not induced itching. In the 17α-ethynylestradiol model BAR502 attenuates cholestasis and reshapes bile acid pool without inducing itching. Conclusions The itching response to intradermal injection of GPBAR1 agonists desensitizes rapidly and is deactivated in models of cholestasis, explain the lack of correlation between bile acids levels and itching severity in cholestatic syndromes. In models of non-obstructive cholestasis, BAR502 attenuates liver injury without causing itching.
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Affiliation(s)
| | - Barbara Renga
- Department of Surgery and Biomedical Sciences, University of Perugia, Perugia, Italy
| | - Claudio D’Amore
- Department of Surgery and Biomedical Sciences, University of Perugia, Perugia, Italy
| | - Michele Simonetti
- Department of Surgery and Biomedical Sciences, University of Perugia, Perugia, Italy
| | | | - Adriana Carino
- Department of Surgery and Biomedical Sciences, University of Perugia, Perugia, Italy
| | | | - Valentina Sepe
- Department of Pharmacy, University of Naples “Federico II”, Naples, Italy
| | - Angela Zampella
- Department of Pharmacy, University of Naples “Federico II”, Naples, Italy
| | - Stefano Fiorucci
- Department of Surgery and Biomedical Sciences, University of Perugia, Perugia, Italy
- * E-mail:
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Bassari R, Koea JB. Jaundice associated pruritis: A review of pathophysiology and treatment. World J Gastroenterol 2015; 21:1404-1413. [PMID: 25663760 PMCID: PMC4316083 DOI: 10.3748/wjg.v21.i5.1404] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2014] [Revised: 10/19/2014] [Accepted: 11/19/2014] [Indexed: 02/06/2023] Open
Abstract
To review the underlying pathophysiology and currently available treatments for pruritis associated with jaundice. English language literature was reviewed using MEDLINE, PubMed, EMBASE and clinicaltrials.gov for papers and trails addressing the pathophysiology and potential treatments for pruritis associated with jaundice. Recent advances in the understanding of the peripheral anatomy of itch transmission have defined a histamine stimulated pathway and a cowhage stimulated pathway with sensation conveyed centrally via the contralateral spinothalamic tract. Centrally, cowhage and histamine stimulated neurons terminate widely within the thalamus and sensorimotor cortex. The causative factors for itch in jaundice have not been clarified although endogenous opioids, serotonin, steroid and lysophosphatidic acid all play a role. Current guidelines for the treatment of itching in jaundice recommend initial management with biliary drainage where possible and medical management with ursodeoxycholic acid, followed by cholestyramine, rifampicin, naltrexone and sertraline. Other than biliary drainage no single treatment has proved universally effective. Pruritis associated with jaundice is a common but poorly understood condition for which biliary drainage is the most effective therapy. Pharmacological therapy has advanced but remains variably effective.
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35
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Abstract
Histamine is one of the best-characterized pruritogens in humans. It is known to play a role in pruritus associated with urticaria as well as ocular and nasal allergic reactions. Histamine mediates its effect via four receptors. Antihistamines that block the activation of the histamine H₁receptor, H₁R, have been shown to be effective therapeutics for the treatment of pruritus associated with urticaria, allergic rhinitis, and allergic conjunctivitis. However, their efficacy in other pruritic diseases such as atopic dermatitis and psoriasis is limited. The other histamine receptors may also play a role in pruritus, with the exception of the histamine H₂receptor, H₂R. Preclinical evidence indicates that local antagonism of the histamine H₃receptor, H₃R, can induce scratching perhaps via blocking inhibitory neuronal signals. The histamine H₄receptor, H₄R, has received a significant amount of attention as to its role in mediating pruritic signals. Indeed, it has now been shown that a selective H₄R antagonist can inhibit histamine-induced itch in humans. This clinical result, in conjunction with efficacy in various preclinical pruritus models, points to the therapeutic potential of H₄R antagonists for the treatment of pruritus not controlled by antihistamines that target the H₁R.
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Affiliation(s)
- Robin L Thurmond
- Janssen Research and Development, L.L.C., San Diego, CA, 92121, USA,
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36
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Lieu T, Jayaweera G, Zhao P, Poole DP, Jensen D, Grace M, McIntyre P, Bron R, Wilson YM, Krappitz M, Haerteis S, Korbmacher C, Steinhoff MS, Nassini R, Materazzi S, Geppetti P, Corvera CU, Bunnett NW. The bile acid receptor TGR5 activates the TRPA1 channel to induce itch in mice. Gastroenterology 2014; 147:1417-28. [PMID: 25194674 PMCID: PMC4821165 DOI: 10.1053/j.gastro.2014.08.042] [Citation(s) in RCA: 168] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2014] [Revised: 08/19/2014] [Accepted: 08/26/2014] [Indexed: 12/11/2022]
Abstract
BACKGROUND & AIMS Patients with cholestatic disease have increased systemic concentrations of bile acids (BAs) and profound pruritus. The G-protein-coupled BA receptor 1 TGR5 (encoded by GPBAR1) is expressed by primary sensory neurons; its activation induces neuronal hyperexcitability and scratching by unknown mechanisms. We investigated whether the transient receptor potential ankyrin 1 (TRPA1) is involved in BA-evoked, TGR5-dependent pruritus in mice. METHODS Co-expression of TGR5 and TRPA1 in cutaneous afferent neurons isolated from mice was analyzed by immunofluorescence, in situ hybridization, and single-cell polymerase chain reaction. TGR5-induced activation of TRPA1 was studied in in HEK293 cells, Xenopus laevis oocytes, and primary sensory neurons by measuring Ca(2+) signals. The contribution of TRPA1 to TGR5-induced release of pruritogenic neuropeptides, activation of spinal neurons, and scratching behavior were studied using TRPA1 antagonists or Trpa1(-/-) mice. RESULTS TGR5 and TRPA1 protein and messenger RNA were expressed by cutaneous afferent neurons. In HEK cells, oocytes, and neurons co-expressing TGR5 and TRPA1, BAs caused TGR5-dependent activation and sensitization of TRPA1 by mechanisms that required Gβγ, protein kinase C, and Ca(2+). Antagonists or deletion of TRPA1 prevented BA-stimulated release of the pruritogenic neuropeptides gastrin-releasing peptide and atrial natriuretic peptide B in the spinal cord. Disruption of Trpa1 in mice blocked BA-induced expression of Fos in spinal neurons and prevented BA-stimulated scratching. Spontaneous scratching was exacerbated in transgenic mice that overexpressed TRG5. Administration of a TRPA1 antagonist or the BA sequestrant colestipol, which lowered circulating levels of BAs, prevented exacerbated spontaneous scratching in TGR5 overexpressing mice. CONCLUSIONS BAs induce pruritus in mice by co-activation of TGR5 and TRPA1. Antagonists of TGR5 and TRPA1, or inhibitors of the signaling mechanism by which TGR5 activates TRPA1, might be developed for treatment of cholestatic pruritus.
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Affiliation(s)
- TinaMarie Lieu
- Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia
| | - Gihan Jayaweera
- Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia
| | - Peishen Zhao
- Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia
| | - Daniel P. Poole
- Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia,Department of Anatomy and Neuroscience, University of Melbourne, Parkville, Victoria, Australia
| | - Dane Jensen
- Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia
| | - Megan Grace
- Health Innovations Research Institute and School of Medical Sciences, RMIT University, Bundoora, Victoria, Australia
| | - Peter McIntyre
- Health Innovations Research Institute and School of Medical Sciences, RMIT University, Bundoora, Victoria, Australia
| | - Romke Bron
- Department of Anatomy and Neuroscience, University of Melbourne, Parkville, Victoria, Australia
| | - Yvette M. Wilson
- Department of Anatomy and Neuroscience, University of Melbourne, Parkville, Victoria, Australia
| | - Matteus Krappitz
- Institut für Zelluläre und Molekulare Physiologie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Silke Haerteis
- Institut für Zelluläre und Molekulare Physiologie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Christoph Korbmacher
- Institut für Zelluläre und Molekulare Physiologie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Martin S. Steinhoff
- Charles Institute for Translational Dermatology, University College Dublin, Dublin, Ireland
| | - Romina Nassini
- Department of Health Sciences, Clinical Pharmacology Unit, University of Florence, Florence, Italy
| | - Serena Materazzi
- Department of Health Sciences, Clinical Pharmacology Unit, University of Florence, Florence, Italy
| | - Pierangelo Geppetti
- Department of Health Sciences, Clinical Pharmacology Unit, University of Florence, Florence, Italy
| | - Carlos U. Corvera
- Department of Surgery, University of California, San Francisco, San Francisco, California
| | - Nigel W. Bunnett
- Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia,Department of Pharmacology, University of Melbourne, Parkville, Victoria, Australia
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Johannesdottir S, Farkas D, Vinding G, Pedersen L, Lamberg A, Sørensen H, Olesen A. Cancer incidence among patients with a hospital diagnosis of pruritus: a nationwide Danish cohort study. Br J Dermatol 2014; 171:839-46. [DOI: 10.1111/bjd.13157] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/25/2014] [Indexed: 11/28/2022]
Affiliation(s)
- S.A. Johannesdottir
- Department of Clinical Epidemiology Aarhus University Hospital P.P. Ørumsgade 11 Aarhus C 8000 Denmark
| | - D.K. Farkas
- Department of Clinical Epidemiology Aarhus University Hospital P.P. Ørumsgade 11 Aarhus C 8000 Denmark
| | - G.R. Vinding
- Department of Dermatology Roskilde Hospital Health Sciences Faculty University of Copenhagen Roskilde Denmark
| | - L. Pedersen
- Department of Clinical Epidemiology Aarhus University Hospital P.P. Ørumsgade 11 Aarhus C 8000 Denmark
| | - A. Lamberg
- Department of Clinical Epidemiology Aarhus University Hospital P.P. Ørumsgade 11 Aarhus C 8000 Denmark
- Department of Dermatology Aarhus University Hospital P.P. Ørumsgade 11 Aarhus C 8000 Denmark
| | - H.T. Sørensen
- Department of Clinical Epidemiology Aarhus University Hospital P.P. Ørumsgade 11 Aarhus C 8000 Denmark
| | - A.B. Olesen
- Department of Dermatology Aarhus University Hospital P.P. Ørumsgade 11 Aarhus C 8000 Denmark
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Singhal R, Harrill AH, Menguy-Vacheron F, Jayyosi Z, Benzerdjeb H, Watkins PB. Benign elevations in serum aminotransferases and biomarkers of hepatotoxicity in healthy volunteers treated with cholestyramine. BMC Pharmacol Toxicol 2014; 15:42. [PMID: 25086653 PMCID: PMC4130124 DOI: 10.1186/2050-6511-15-42] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2014] [Accepted: 07/03/2014] [Indexed: 12/16/2022] Open
Abstract
Background There are currently no serum biomarkers capable of distinguishing elevations in serum alanine aminotransferase (ALT) that portend serious liver injury potential from benign elevations such as those occurring during cholestyramine treatment. The aim of the research was to test the hypothesis that newly proposed biomarkers of hepatotoxicity would not significantly rise in serum during elevations in serum ALT associated with cholestyramine treatment, which has never been associated with clinically relevant liver injury. Methods In a double-blind placebo-controlled trial, cholestyramine (8g) was administered for 11 days to healthy adult volunteers. Serum from subjects with elevations in alanine aminotransferase (ALT) exceeding three-fold the upper limit of normal (ULN) were utilized for biomarker quantification. Results In 11 of 67 subjects, cholestyramine treatment resulted in ALT elevation by >3x ULN (mean 6.9 fold; range 3–28 fold). In these 11 subjects, there was a 22.4-fold mean increase in serum levels of miR-122 relative to baseline, supporting a liver origin of the serum ALT. Significant elevations were noted in mean levels of necrosis biomarkers sorbitol dehydrogenase (8.1 fold), cytokeratin 18 (2.1 fold) and HMGB1 (1.7 fold). Caspase-cleaved cytokeratin 18, a biomarker of apoptosis was also significantly elevated (1.7 fold). A rise in glutamate dehydrogenase (7.3 fold) may support mitochondrial dysfunction. Conclusion All toxicity biomarkers measured in this study were elevated along with ALT, confirming the liver origin and reflecting both hepatocyte necrosis and apoptosis. Since cholestyramine treatment has no clinical liver safety concerns, we conclude that interpretation of the biomarkers studied may not be straightforward in the context of assessing liver safety of new drugs.
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Affiliation(s)
| | | | | | | | | | - Paul B Watkins
- The Hamner-University of North Carolina Institute for Drug Safety Sciences, 6 Davis Drive, Research Triangle Park, NC 27709, USA.
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39
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Abstract
The itch-scratch reflex serves as a protective mechanism in everyday life. However, chronic persistent itching can be devastating. Despite the clinical importance of the itch sensation, its mechanism remains elusive. In the past decade, substantial progress has been made to uncover the mystery of itching. Here, we review the molecules, cells, and circuits known to mediate the itch sensation, which, coupled with advances in understanding the pathophysiology of chronic itching conditions, will hopefully contribute to the development of new anti-itch therapies.
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Affiliation(s)
- Liang Han
- The Solomon H. Snyder Department of Neuroscience, Center for Sensory Biology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205;
| | - Xinzhong Dong
- The Solomon H. Snyder Department of Neuroscience, Center for Sensory Biology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205;
- Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205;
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Management of cholestatic pruritus in paediatric patients with alagille syndrome: the King's College Hospital experience. J Pediatr Gastroenterol Nutr 2013; 57:149-54. [PMID: 23619030 DOI: 10.1097/mpg.0b013e318297e384] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
OBJECTIVES The aims of the study were to perform a retrospective observational review of the present management and outcome of cholestatic pruritus in children with Alagille syndrome (AGS) at King's College Hospital and to use results to inform appropriate guidelines. METHODS A retrospective review of 62 patients diagnosed as having AGS from January 1995 to November 2010 treated at King's College Hospital was performed. The departmental database of the Paediatric Liver Centre was searched to identify all patients and the clinical records were then analysed. RESULTS Fifty-one (82.3%) patients experienced pruritus and 50 (80.6%) received antipruritic medication. Ursodeoxycholic acid was the most prescribed drug (n = 40). Other drugs prescribed were rifampicin (n = 39), cholestyramine (n = 18), naltrexone (n = 14), alimemazine (n = 13), nonsedating antihistamine agents (n = 7), ondansetron (n = 5), and phenobarbitone (n = 1). Albumin dialysis using the molecular adsorbent recirculation system was used in 1 patient. Sixteen patients (25.8%) were listed for liver transplantation, and 11 had undergone transplantation by November 2010. Patient survival was high at 95.2%. Pruritus resolved permanently in 39.2% (n = 20) of patients. Fifty-five percent (n = 11) of such patients had undergone liver transplantation. Pruritus was controlled by medication in 41.2% (n = 21). Itching remained a significant problem, affecting quality of life in 19.6% of patients (n = 10). CONCLUSIONS The management of cholestatic pruritus in AGS is difficult and often suboptimal. Pruritus may remain intractable even with combination medical treatment, and at this stage, surgery or liver transplantation is indicated. At our centre, pruritus was successfully treated in 80.4% of patients with medical and surgical management.
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Xander C, Meerpohl JJ, Galandi D, Buroh S, Schwarzer G, Antes G, Becker G. Pharmacological interventions for pruritus in adult palliative care patients. Cochrane Database Syst Rev 2013:CD008320. [PMID: 23749733 DOI: 10.1002/14651858.cd008320.pub2] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Pruritus is not the most prevalent but one of the most puzzling symptoms in palliative care patients. It can cause considerable discomfort and has a major impact on patients' quality of life. In the field of palliative care, pruritus is a symptom occurring in patients with disparate underlying diseases and based on different pathologic mechanisms but ending in the same phenomenon. The pathogenesis of pruritus is complex and not fully elucidated. Thus, it is still very difficult to treat pruritus effectively. Evidence-based treatment approaches are needed. OBJECTIVES The objective was to evaluate the efficacy of different pharmacological treatments for preventing or treating pruritus in adult palliative care patients. SEARCH METHODS A systematic literature search up to January 2012 was performed and it was updated in August 2012. The following databases were searched: The Cochrane Library (CENTRAL, DARE, CDSR) (2012, issue 8 of 12); MEDLINE (1950 to August 2012); EMBASE (1980 to August 2012) and three other databases. In addition, we searched trials registries and checked the reference lists of all relevant studies, key textbooks, reviews, and websites, and contacted investigators and specialists in pruritus and palliative care regarding unpublished data. SELECTION CRITERIA We included randomised controlled trials assessing the effects of different pharmacological treatments on preventing or treating pruritus in palliative care patients. DATA COLLECTION AND ANALYSIS Two review authors independently assessed identified titles and abstracts. Three independent review authors performed assessment of all potentially relevant studies, data extraction, assessment of risk of bias and methodological quality. Results were summarised descriptively according to the different pharmacological interventions and the type of underlying pruritus. Where possible, results were presented in meta-analyses. MAIN RESULTS In total, 38 reports comprising 40 studies and 1286 participants were included in the review. Altogether, 30 different treatments for pruritus in four different patient groups were included.The findings of this review indicated that the treatment of pruritus for palliative care patients is challenging and requires an individualistic approach. Results showed that effective therapeutic choices have to be guided by the pathophysiology of the pruritus. Various forms of pruritus occur, especially in the field of palliative care, and sometimes the origin of the pruritus is difficult to determine. Therefore, identifying the underlying cause of pruritus is of prime importance in order to develop tailored treatment plans, even if in palliative care the treatment is focused towards the symptom and not necessarily the underlying disease.Results show that in palliative care patients with pruritus of different natures, treatment with the drug paroxetine, a selective serotonin reuptake inhibitor, may be beneficial. For patients suffering from pruritus associated with HIV infection, indomethacin was described as the most effective drug, although the evidence was weak. For patients suffering from chronic kidney disease-associated pruritus, gabapentin may be an option. An alternative treatment for this patient group seems to be the κ-opioid receptor agonist nalfurafine, which has shown significant amelioration of pruritus and acceptable adverse effects. As they have exhibited a low incidence of adverse effects, rifampicin and flumecinol may be recommended for patients with cholestatic pruritus. The opioid antagonist naltrexone has been shown to offer a therapeutic alternative for patients suffering from uraemic or cholestatic pruritus. However, these drugs are often inappropriate in the palliative population because of the risk of reducing analgesia when giving high doses of naltrexone. AUTHORS' CONCLUSIONS The findings of this review indicate that the number of systemic and topical drugs used for the different subforms of pruritus is increasing. Different interventions have been shown to be effective in the treatment of pruritus of different origins. Nevertheless, an optimal therapy for pruritus is constrained due to the limited understanding of crucial itch mediators and receptors in the various subforms of itch. Ideal antipruritic therapies are still lacking, especially for palliative care patients.This systematic review also indicates that there is insufficient evidence to give any concrete recommendations regarding treatment of pruritus in palliative care patients. Due to the very small sample sizes and poor methodological quality of the majority of studies that were included, the results of this review need to be interpreted with caution. Furthermore, the generalizability is questionable. Additional studies, and particularly carefully designed treatment trials, are needed to provide valid evidence for adequate treatment of pruritus in palliative care patients.
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Affiliation(s)
- Carola Xander
- German Cochrane Centre, Institute of Medical Biometry and Medical Informatics, University Medical Center Freiburg, Freiburg,Germany.
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Alemi F, Kwon E, Poole DP, Lieu T, Lyo V, Cattaruzza F, Cevikbas F, Steinhoff M, Nassini R, Materazzi S, Guerrero-Alba R, Valdez-Morales E, Cottrell GS, Schoonjans K, Geppetti P, Vanner SJ, Bunnett NW, Corvera CU. The TGR5 receptor mediates bile acid-induced itch and analgesia. J Clin Invest 2013; 123:1513-30. [PMID: 23524965 DOI: 10.1172/jci64551] [Citation(s) in RCA: 284] [Impact Index Per Article: 23.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2012] [Accepted: 01/17/2013] [Indexed: 12/23/2022] Open
Abstract
Patients with cholestatic disease exhibit pruritus and analgesia, but the mechanisms underlying these symptoms are unknown. We report that bile acids, which are elevated in the circulation and tissues during cholestasis, cause itch and analgesia by activating the GPCR TGR5. TGR5 was detected in peptidergic neurons of mouse dorsal root ganglia and spinal cord that transmit itch and pain, and in dermal macrophages that contain opioids. Bile acids and a TGR5-selective agonist induced hyperexcitability of dorsal root ganglia neurons and stimulated the release of the itch and analgesia transmitters gastrin-releasing peptide and leucine-enkephalin. Intradermal injection of bile acids and a TGR5-selective agonist stimulated scratching behavior by gastrin-releasing peptide- and opioid-dependent mechanisms in mice. Scratching was attenuated in Tgr5-KO mice but exacerbated in Tgr5-Tg mice (overexpressing mouse TGR5), which exhibited spontaneous pruritus. Intraplantar and intrathecal injection of bile acids caused analgesia to mechanical stimulation of the paw by an opioid-dependent mechanism. Both peripheral and central mechanisms of analgesia were absent from Tgr5-KO mice. Thus, bile acids activate TGR5 on sensory nerves, stimulating the release of neuropeptides in the spinal cord that transmit itch and analgesia. These mechanisms could contribute to pruritus and painless jaundice that occur during cholestatic liver diseases.
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Affiliation(s)
- Farzad Alemi
- Department of Surgery, UCSF, San Francisco, California 94121, USA
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Belghiti M, Estévez-Herrera J, Giménez-Garzó C, González-Usano A, Montoliu C, Ferrer-Montiel A, Felipo V, Planells-Cases R. Potentiation of the transient receptor potential vanilloid 1 channel contributes to pruritogenesis in a rat model of liver disease. J Biol Chem 2013; 288:9675-9685. [PMID: 23408423 DOI: 10.1074/jbc.m113.455162] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023] Open
Abstract
Persistent pruritus is a common disabling dermatologic symptom associated with different etiologic factors. These include primary skin conditions, as well as neuropathic, psychogenic, or systemic disorders like chronic liver disease. Defective clearance of potential pruritogenic substances that activate itch-specific neurons innervating the skin is thought to contribute to cholestatic pruritus. However, because the underlying disease-specific pruritogens and itch-specific neuronal pathways and mechanism(s) are unknown, symptomatic therapeutic intervention often leads to no or only limited success. In the current study, we aimed to first validate rats with bile duct ligation (BDL) as a model for hepatic pruritus and then to evaluate the contribution of inflammation, peripheral neuronal sensitization, and specific signaling pathways and subpopulations of itch-responsive neurons to scratching behavior and thermal hypersensitivity. Chronic BDL rats displayed enhanced scratching behavior and thermal hyperalgesia indicative of peripheral neuroinflammation. BDL-induced itch and hypersensitivity involved a minor contribution of histaminergic/serotonergic receptors, but significant activation of protein-activated receptor 2 (PAR2) receptors, prostaglandin PGE2 formation, and potentiation of transient receptor potential vanilloid 1 (TRPV1) channel activity. The sensitization of dorsal root ganglion nociceptors in BDL rats was associated with increased surface expression of PAR2 and TRPV1 proteins and an increase in the number of PAR2- and TRPV1-expressing peptidergic neurons together with a shift of TRPV1 receptor expression to medium sized dorsal root ganglion neurons. These results suggest that pruritus and hyperalgesia in chronic cholestatic BDL rats are associated with neuroinflammation and involve PAR2-induced TRPV1 sensitization. Thus, pharmacological modulation of PAR2 and/or TRPV1 may be a valuable therapeutic approach for patients with chronic liver pruritus refractory to conventional treatments.
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Affiliation(s)
| | | | | | | | - Carmina Montoliu
- Fundación Investigación Hospital Clínico de Valencia, INCLIVA, 46010 Valencia, Spain
| | - Antonio Ferrer-Montiel
- Instituto de Biología Molecular y Celular, Universidad Miguel Hernández, 03202 Elche, Spain
| | - Vicente Felipo
- Centro de Investigación Príncipe Felipe, 46012 Valencia, Spain
| | - Rosa Planells-Cases
- Centro de Investigación Príncipe Felipe, 46012 Valencia, Spain; Leibniz-Institut für Molekulare Pharmakologie (FMP) and Max-Delbrück-Centrum für Molekulare Medizin (MDC), 13125 Berlin, Germany.
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Huesmann M, Huesmann T, Osada N, Phan NQ, Kremer AE, Ständer S. Cholestatic pruritus: a retrospective analysis on clinical characteristics and treatment response. J Dtsch Dermatol Ges 2012. [PMID: 23190476 DOI: 10.1111/j.1610-0387.2012.08028.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Chronic cholestatic pruritus (ChP) is caused by various hepatobiliary disorders. This retrospective study describes the distribution of underlying diseases, clinical characteristics and treatment efficacy in a consecutive collective of patients with ChP. PATIENTS AND METHODS Extensive data from 60 patients with ChP (30 women, 30 men; mean age: 58.0 ± 17.0 years) were retrospectively statistically analyzed concerning demographic data, pruritus characteristics, and response to therapy. RESULTS In this study population, 40.0% of the patients suffered from hepatitis B or C. Regarding the overall population, pruritus started in 50% of patients after diagnosis of the underlying hepatobiliary disorder. Only in patients with immune-mediated liver diseases did pruritus more often occur before diagnosis (p < 0.05). Only 23.3% of the patients reported an initial palmoplantar pruritus. Along with other drugs, anticonvulsants proved to be an effective treatment regime. CONCLUSIONS In this study, viral pathogenesis was the most common cause of ChP. Other underlying diseases were represented to a lower extent in the total study population. Overall, the collected clinical parameters in each group were comparable. Thus, it was difficult to draw conclusions on the pathogenesis.
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Affiliation(s)
- Mario Huesmann
- Competence Center Chronic Pruritus and Department of Dermatology, University Hospital Münster, Germany
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Imam MH, Gossard AA, Sinakos E, Lindor KD. Pathogenesis and management of pruritus in cholestatic liver disease. J Gastroenterol Hepatol 2012; 27:1150-1158. [PMID: 22413872 DOI: 10.1111/j.1440-1746.2012.07109.x] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Patients with cholestatic liver diseases such as primary biliary cirrhosis, primary sclerosing cholangitis and intrahepatic cholestasis of pregnancy commonly complain of pruritus. The underlying pathogenesis remains obscure with several mediators possibly playing an important role; these include lysophosphatidic acid, bile salts, opioids, histamine and progesterone metabolites. We describe in this review novel insights into the pathogenesis and management of pruritus in patients with cholestasis.
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Affiliation(s)
- Mohamad H Imam
- Division of Gastroenterology and Hepatology, Mayo Clinic Rochester, Rochester, MN 55905, USA
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Abstract
Pruritus is a troublesome complication in patients with cholestatic liver disease. Several links to its pathogenesis have been proposed, including the role of bile acids, endogenous opioid and serotonins, and lysophosphatidic acid. The management of pruritus in cholestasis is challenging. Medical treatment of the underlying cholestatic condition may provide benefit. Extracorporeal albumin dialysis can be pursued for those who have a poor quality of life and failed the various therapeutic interventions, while awaiting liver transplantation. Experimental interventions, and the management of pruritus in certain conditions such as intrahepatic cholestasis of pregnancy and benign recurrent intrahepatic cholestasis, are also briefly reviewed.
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Affiliation(s)
- Chalermrat Bunchorntavakul
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Pennsylvania, Philadelphia, USA
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Leckie P, Tritto G, Mookerjee R, Davies N, Jones D, Jalan R. 'Out-patient' albumin dialysis for cholestatic patients with intractable pruritus. Aliment Pharmacol Ther 2012; 35:696-704. [PMID: 22260552 DOI: 10.1111/j.1365-2036.2012.04994.x] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2011] [Revised: 11/21/2011] [Accepted: 01/01/2012] [Indexed: 12/15/2022]
Abstract
BACKGROUND Intractable pruritus is a major problem for some patients with cholestasis. Albumin dialysis has been shown to ameliorate pruritus, but long-term outcome data are limited. AIM To evaluate the safety and efficacy of 'out-patient' albumin dialysis using the molecular adsorbent recirculating system (MARS) in the treatment of intractable pruritus in cholestatic patients referred for liver transplantation for symptomatic relief. METHODS Fifteen patients who failed to respond to standard medical therapy to control pruritus were included. Three MARS (6 h) sessions were performed per admission, and were repeated, if necessary. The intensity and severity of itch was quantified using itch severity and visual analogue scales (ISS and VAS). RESULTS Molecular adsorbent recirculating system treatment was safe and associated with immediate and complete response in 11 patients; two patients had a partial response and two patients had no response. Thirty-four treatments were performed during a follow-up period of 15.7 months (3-46) with patients requiring a mean of two admissions (1-6). The mean VAS and ISS improved significantly (both P < 0.001) with improvement in the patient's perception of their quality of life. The duration of acceptable relief in responders was 3.3 months (range 2-5). No serious adverse events were recorded, but the platelet count and haemoglobin were reduced significantly. CONCLUSION Molecular adsorbent recirculating system therapy delivered in an 'out-patient' setting is safe and effective with a high degree of patient acceptability. Albumin dialysis can be considered a viable therapeutic option for patients with severe intractable pruritus, in whom, the only other effective treatment option is liver transplantation.
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Affiliation(s)
- P Leckie
- Liver Failure Group, UCL Hepatology, University College London Medical School, Royal Free Hospital, Rowland Hill Street, London, UK
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Dogra S, Jindal R. Cutaneous manifestations of common liver diseases. J Clin Exp Hepatol 2011; 1:177-84. [PMID: 25755383 PMCID: PMC3940632 DOI: 10.1016/s0973-6883(11)60235-1] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2011] [Accepted: 11/25/2011] [Indexed: 02/06/2023] Open
Abstract
Skin functions as a window to our overall health and a number of systemic diseases result in various cutaneous changes. Knowledge of these manifestations helps in suspecting an underlying systemic illness. Cutaneous abnormalities are quite common in patients with liver diseases and this article aims to focus on these dermatoses. Cutaneous manifestations seen in patients with liver disease though common are nonspecific. They can also be seen in patients without liver diseases and generally do not indicate about a specific underlying hepatic disorder. The presence of a constellation of signs and symptoms is more useful in pointing toward an underlying hepatobiliary condition. The commonest symptom in patients with liver disease is pruritus which is often protracted and disabling. Other common features include spider angiomas, palmar erythema, paper money skin, xanthelasmas, pigmentary changes, and nutritional deficiencies. In this article, first the common cutaneous manifestations that may be associated with liver disorders are discussed and then common liver diseases with their specific cutaneous findings are discussed. Cutaneous abnormalities may be the first clue to the underlying liver disease. Identifying them is crucial for early diagnosis and better management.
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Affiliation(s)
- Sunil Dogra
- Address for correspondence: Sunil Dogra, Associate Professor, Department of Dermatology, Venereology and Leprology, Postgraduate Institute of Medical Education and Research, Chandigarh - 160012, India
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Abstract
Several hepatobiliary abnormalities have been described in association with inflammatory bowel disease (IBD), including primary sclerosing cholangitis (PSC), small duct PSC, chronic hepatitis, cryptogenic cirrhosis, cholangiocarcinoma, and cholelithiasis. PSC is the most common biliary condition in patients with IBD, with an incidence ranging from 2.5% to 7.5%. PSC usually progresses insidiously and eventually leads to cirrhosis independent of inflammatory bowel disease activity. There is a very high incidence of cholangiocarcinoma and an elevated risk for developing colon cancer in patients with PSC. Medical therapy has not proven successful in slowing disease progression or prolonging survival. Treatment of symptoms due to cholestasis, such as pruritis and steatorrhea, is an important aspect of the medical care of patients with PSC. Our preferred treatment of pruritis due to cholestasis is with bile acid binding exchange resins, such as cholestyramine or colestipol. Endoscopic manipulation is recommended for treating complications of recurrent cholangitis or worsening jaundice in the setting of a dominant stricture, but endoscopic approaches have not been conclusively demonstrated to improve survival or decrease the need for liver transplantation. Liver transplantation remains the only effective treatment of advanced PSC, and should be considered in patients with complications of cirrhosis or intractable pruritis or fatigue.
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Affiliation(s)
- David R Lichtenstein
- Section of Gastroenterology, Boston University School of Medicine, Boston Medical Center, Boston, MA, USA.
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Javelle E, Paule P, Chabrillat Y, Lightburn E, Coton T, Morand JJ. Un prurit traité par implantation d’un pacemaker. Presse Med 2011; 40:885-6. [DOI: 10.1016/j.lpm.2011.03.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2010] [Revised: 01/26/2011] [Accepted: 03/08/2011] [Indexed: 11/29/2022] Open
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