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Izumi Y, Koyama Y. Nrf2-Independent Anti-Inflammatory Effects of Dimethyl Fumarate: Challenges and Prospects in Developing Electrophilic Nrf2 Activators for Neurodegenerative Diseases. Antioxidants (Basel) 2024; 13:1527. [PMID: 39765855 PMCID: PMC11727036 DOI: 10.3390/antiox13121527] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2024] [Revised: 11/26/2024] [Accepted: 12/03/2024] [Indexed: 01/15/2025] Open
Abstract
The NF-E2-related factor 2 (Nrf2)-antioxidant response element (ARE) pathway is a potential therapeutic target for central nervous system diseases. This review emphasizes the role of oxidative stress and neuroinflammation in neurodegenerative diseases, highlighting the therapeutic potential of Nrf2 activators such as dimethyl fumarate (DMF). DMF, initially administered for treating psoriasis, has demonstrated efficacy in multiple sclerosis and is metabolized to monomethyl fumarate, which may exert significant therapeutic effects. DMF activates the Nrf2-ARE pathway, and recent studies have indicated that its anti-inflammatory effects occur through Nrf2-independent mechanisms. Electrophilic Nrf2 activators, such as DMF, covalently bind to cysteine residues in proteins and modulate their function. We discuss the implications of cysteine residue modifications by DMF, which may cause both therapeutic benefits and potential off-target effects. Furthermore, we propose a chemical proteomics-based drug discovery approach to achieve desired therapeutic effects by selectively covalently modifying cysteines in target proteins. These findings advocate for a broader understanding of the Nrf2-independent mechanisms of electrophilic Nrf2 activators, thereby improving drug discovery strategies that target neurodegenerative diseases while minimizing toxicity.
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Affiliation(s)
- Yasuhiko Izumi
- Laboratory of Pharmacology, Kobe Pharmaceutical University, 4-19-1 Motoyamakita-machi, Higashinada-ku, Kobe 658-8558, Japan;
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Chen J, Cao Y, Jia O, Wang X, Luo Y, Cheuk YC, Zhu T, Zhu D, Zhang Y, Wang J. Monomethyl fumarate prevents alloimmune rejection in mouse heart transplantation by inducing tolerogenic dendritic cells. Acta Biochim Biophys Sin (Shanghai) 2023. [PMID: 37184280 DOI: 10.3724/abbs.2023088] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/16/2023] Open
Abstract
Dendritic cells (DCs) are important targets for eliciting allograft rejection after transplantation. Previous studies have demonstrated that metabolic reprogramming of DCs can transform their immune functions and induce their differentiation into tolerogenic DCs. In this study, we aim to investigate the protective effects and mechanisms of monomethyl fumarate (MMF), a bioactive metabolite of fumaric acid esters, in a mouse model of allogeneic heart transplantation. Bone marrow-derived DCs are harvested and treated with MMF to determine the impact of MMF on the phenotype and immunosuppressive function of DCs by flow cytometry and T-cell proliferation assays. RNA sequencing and Seahorse analyses are performed for mature DCs and MMF-treated DCs (MMF-DCs) to investigate the underlying mechanism. Our results show that MMF prolongs the survival time of heart grafts and inhibits the activation of DCs in vivo. MMF-DCs exhibit a tolerogenic phenotype and function in vitro. RNA sequencing and Seahorse analyses reveal that MMF activates the Nrf2 pathway and mediates metabolic reprogramming. Additionally, MMF-DC infusion prolongs cardiac allograft survival, induces regulatory T cells, and inhibits T-cell activation. MMF prevents allograft rejection in mouse heart transplantation by inducing tolerogenic DCs.
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Affiliation(s)
- Juntao Chen
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Shanghai Key Laboratory of Organ Transplantation, Shanghai 200032, China
| | - Yirui Cao
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Shanghai Key Laboratory of Organ Transplantation, Shanghai 200032, China
| | - Ouyang Jia
- Nursing Department of Huashan Hospital Affiliated to Fudan University, Shanghai 200031, China
| | - Xuanchuan Wang
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Shanghai Key Laboratory of Organ Transplantation, Shanghai 200032, China
| | - Yongsheng Luo
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Shanghai Key Laboratory of Organ Transplantation, Shanghai 200032, China
| | - Yin Celeste Cheuk
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Shanghai Key Laboratory of Organ Transplantation, Shanghai 200032, China
| | - Tongyu Zhu
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Shanghai Key Laboratory of Organ Transplantation, Shanghai 200032, China
| | - Dong Zhu
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Shanghai Key Laboratory of Organ Transplantation, Shanghai 200032, China
- Department of Urology, Zhongshan Hospital, Fudan University (Xiamen branch), Xiamen 361015, China
| | - Yi Zhang
- Shanghai Key Laboratory of Organ Transplantation, Shanghai 200032, China
- Biomedical Research Center, Institute for Clinical Sciences, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Jina Wang
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Shanghai Key Laboratory of Organ Transplantation, Shanghai 200032, China
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Gnesotto L, Mioso G, Bardazzi F, Filippi F, Di Lernia V, Motolese A, Di Nuzzo S, Conti A, Arginelli F, Corazza M, Odorici G, Borghi A, Gisondi P, Naldi L, Dapavo P, Parodi A, Burlando M, Piaserico S. Dimethyl Fumarate Treatment in Patients with Moderate-to-Severe Psoriasis: A 52-week Real-life Study. Acta Derm Venereol 2023; 103:adv4526. [PMID: 36987538 PMCID: PMC10077142 DOI: 10.2340/actadv.v103.4526] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Accepted: 01/17/2023] [Indexed: 03/30/2023] Open
Abstract
Abstract is missing (Short communication)
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Affiliation(s)
- Laura Gnesotto
- Dermatology Unit, Department of Medicine, University of Padova, Via Cesare Battisti 206, IT-35128 Padua, Italy
| | - Guido Mioso
- Dermatology Unit, Department of Medicine, University of Padova, Via Cesare Battisti 206, IT-35128 Padua, Italy.
| | - Federico Bardazzi
- Department of Experimental, Diagnostic and Specialty Medicine- Division of Dermatology, University of Bologna, Bologna, Italy
| | - Federica Filippi
- Department of Experimental, Diagnostic and Specialty Medicine- Division of Dermatology, University of Bologna, Bologna, Italy
| | - Vito Di Lernia
- Dermatology Unit, Arcispedale S. Maria Nuova, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy
| | - Alberico Motolese
- Dermatology Unit, Arcispedale S. Maria Nuova, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy
| | - Sergio Di Nuzzo
- Dermatology, Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Andrea Conti
- Section of Dermatology, Department of Specialized Medicine, University of Modena and Reggio Emilia, Modena, Italy
| | - Federica Arginelli
- Section of Dermatology, Department of Specialized Medicine, University of Modena and Reggio Emilia, Modena, Italy
| | - Monica Corazza
- Section of Dermatology and Infectious Diseases, Department of Medical Sciences, University of Ferrara, Ferrara, Italy
| | - Giulia Odorici
- Section of Dermatology and Infectious Diseases, Department of Medical Sciences, University of Ferrara, Ferrara, Italy
| | - Alessandro Borghi
- Section of Dermatology and Infectious Diseases, Department of Medical Sciences, University of Ferrara, Ferrara, Italy
| | - Paolo Gisondi
- Section of Dermatology, Department of Medicine, University of Verona, Verona, Italy
| | - Luigi Naldi
- Dermatology Unit, San Bortolo Hospital, Vicenza, Italy
| | - Paolo Dapavo
- Section of Dermatology, Department of Medical Sciences, University of Turin, Turin, Italy
| | - Aurora Parodi
- University of Genova, DiSSal Section of Dermatology, San Martino Polyclinic Hospital IRCCS, Largo R. Benzi 10 16132 Genova, Italy
| | - Martina Burlando
- University of Genova, DiSSal Section of Dermatology, San Martino Polyclinic Hospital IRCCS, Largo R. Benzi 10 16132 Genova, Italy
| | - Stefano Piaserico
- Dermatology Unit, Department of Medicine, University of Padova, Padova, Italy
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Di Cesare A, Ricceri F, Rosi E, Fastame MT, Prignano F. Therapy of PsO in Special Subsets of Patients. Biomedicines 2022; 10:2879. [PMID: 36359399 PMCID: PMC9687729 DOI: 10.3390/biomedicines10112879] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 10/17/2022] [Accepted: 10/27/2022] [Indexed: 01/02/2024] Open
Abstract
Psoriasis is a chronic, inflammatory skin disease that may occur at any age, with a bimodal peak of incidence around the age of 16-20 years of age (early onset) and 57-60 years (late-onset). It is estimated that roughly 70% of patients develop the disease before the age of 40, which coincides with the reproductive years. Moreover, psoriasis is a chronic disease, meaning that, with increased life-duration expectancy, the number of patients affected with psoriasis aged over 65 years is going to increase and represent a big therapeutic challenge. Actually, no specific drug recommendation is available, based only on the age of the patients, while therapeutic prescription should take into account that elderly patients have more comorbidities than younger patients, with polypharmacy and an increased risk of drug interactions. Women with psoriasis are more likely to report a worse influence of the disease on their quality of life, and they are more susceptible to the development of depression. Furthermore, pregnancy and lactation represent a major contraindication to several systemic agents, and only a few studies exist providing the safety of certain drugs during these periods of life of a woman, such as certolizumab pegol. In this paper, we discuss systemic therapeutic strategies, including conventional and biological therapies, in a special subset of patients affected with moderate-to-severe psoriasis focusing on elderly patients and on female patients in fertile age, pregnancy, and lactation.
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Affiliation(s)
| | | | | | | | - Francesca Prignano
- Department of Health Sciences, Section of Dermatology, University of Florence, 50125 Florence, Italy
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Campione E, Mazzilli S, Di Prete M, Dattola A, Cosio T, Lettieri Barbato D, Costanza G, Lanna C, Manfreda V, Gaeta Schumak R, Prignano F, Coniglione F, Ciprani F, Aquilano K, Bianchi L. The Role of Glutathione-S Transferase in Psoriasis and Associated Comorbidities and the Effect of Dimethyl Fumarate in This Pathway. Front Med (Lausanne) 2022; 9:760852. [PMID: 35211489 PMCID: PMC8863102 DOI: 10.3389/fmed.2022.760852] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Accepted: 01/05/2022] [Indexed: 12/12/2022] Open
Abstract
Psoriasis vulgaris is a chronic inflammatory skin disease characterized by well-demarcated scaly plaques. Oxidative stress plays a crucial role in the psoriasis pathogenesis and is associated with the disease severity. Dimethyl fumarate modulates the activity of the pro-inflammatory transcription factors. This is responsible for the downregulation of inflammatory cytokines and an overall shift from a pro-inflammatory to an anti-inflammatory/regulatory response. Both steps are necessary for the amelioration of psoriatic inflammation, although additional mechanisms have been proposed. Several studies reported a long-term effectiveness and safety of dimethyl fumarate monotherapy in patients with moderate-to-severe psoriasis. Furthermore, psoriasis is a chronic disease often associated to metabolic comorbidities, as obesity, diabetes, and cardiovascular diseases, in which glutathione-S transferase deregulation is present. Glutathione-S transferase is involved in the antioxidant system. An increase of its activity in psoriatic epidermis in comparison with the uninvolved and normal epidermal biopsies has been reported. Dimethyl fumarate depletes glutathione-S transferase by formation of covalently linked conjugates. This review investigates the anti-inflammatory role of dimethyl fumarate in oxidative stress and its effect by reducing oxidative stress. The glutathione-S transferase regulation is helpful in treating psoriasis, with an anti-inflammatory effect on the keratinocytes hyperproliferation, and in modulation of metabolic comorbidities.
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Affiliation(s)
- Elena Campione
- Dermatology Unit, University of Rome Tor Vergata, Rome, Italy
| | - Sara Mazzilli
- Italy State Police Health Service Department, Ministry of Interior, Rome, Italy
| | - Monia Di Prete
- Anatomic Pathology Unit, University of Rome Tor Vergata, Rome, Italy.,Anatomic Pathology, Santa Maria di Ca' Foncello Hospital, Treviso, Italy
| | | | - Terenzio Cosio
- Dermatology Unit, University of Rome Tor Vergata, Rome, Italy
| | - Daniele Lettieri Barbato
- Department of Biology, University of Rome Tor Vergata, Rome, Italy.,Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Fondazione Santa Lucia, Rome, Italy
| | | | - Caterina Lanna
- Dermatology Unit, University of Rome Tor Vergata, Rome, Italy
| | | | | | - Francesca Prignano
- Unit of Dermatology, Department of Surgery and Translational Medicine, University of Florence, Florence, Italy
| | - Filadelfo Coniglione
- Department of Surgical Sciences, University Nostra Signora del Buon Consiglio, Tirana, Albania
| | - Fabrizio Ciprani
- Italy State Police Health Service Department, Ministry of Interior, Rome, Italy
| | - Katia Aquilano
- Department of Biology, University of Rome Tor Vergata, Rome, Italy
| | - Luca Bianchi
- Dermatology Unit, University of Rome Tor Vergata, Rome, Italy
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Repurposing approved therapeutics for new indication: Addressing unmet needs in psoriasis treatment. CURRENT RESEARCH IN PHARMACOLOGY AND DRUG DISCOVERY 2021; 2:100041. [PMID: 34909670 PMCID: PMC8663928 DOI: 10.1016/j.crphar.2021.100041] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Revised: 06/04/2021] [Accepted: 06/04/2021] [Indexed: 02/06/2023] Open
Abstract
Psoriasis is a chronic inflammatory autoimmune condition manifested by the hyperproliferation of keratinocytes with buildup of inflammatory red patches and scales on skin surfaces. The available treatment options for the management of psoriasis have various drawbacks, and the clinical need for effective therapeutics for this disease remain unmet; therefore, the approaches of drug repurposing or drug repositioning could potentially be used for treating indications of psoriasis. The undiscovered potential of drug repurposing or repositioning compensates for the limitations and hurdles in drug discovery and drug development processes. Drugs initially approved for other indications, including anticancer, antidiabetic, antihypertensive, and anti-arthritic activities, are being investigated for their potential in psoriasis management as a new therapeutic indication by using repurposing strategies. This article envisages the potential of various therapeutics for the management of psoriasis.
Psoriasis is an autoimmune inflammatory skin disorder with complex physiology. Conventional treatments for psoriasis cause severe adverse effects; therefore an unmet need remains for safer and more effective therapies for psoriasis. Various drugs that effectively decrease the inflammation and proliferation of skin cells can be repurposed for the management of psoriasis. Repurposed drugs provide various incentives to the pharmaceutical industry.
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Ricceri F, Bardazzi F, Buggiani G, Burlando M, Campione E, Corazza M, Cuccia A, Dapavo P, Filippi F, Zichichi L, Parodi A, Prignano F. Efficacy and safety of dimethylfumarate in elderly psoriasis patients: a multicentric Italian study. J DERMATOL TREAT 2021; 33:2000-2003. [PMID: 34315343 DOI: 10.1080/09546634.2021.1962000] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
The number of psoriatic elderly patients is steadily increasing in the Western world, nevertheless they are frequently excluded from clinical trials and described as a high-risk group for adverse events.We conducted a retrospective multicentric study of DMF use in elderly (>65 years) psoriatic patients. DMF efficacy was evaluated up to 24 weeks by Psoriasis Area and Severity Index (PASI) score. We also evaluated drug maintenance and safety.Our study population included 81 elderly psoriatic patients treated with DMF up to 24 weeks. The PASI score at the baseline (week 0) ranged from 3,7-24 (mean ± SD, 9,8 ± 4,1), which changed after DMF administration to 4,3 ± 3,2 at week 16 and 2,7 ± 3,2 at week 24. Among 81 elderly psoriatic patients 59 (72,8%) adverse events were reported during the observation period. The most common were gastrointestinal complaints (n = 24, 29,6%) and flushes (n = 10, 12,3%). Lymphocytopenia (n = 10, 12,35%) was frequently observed.In daily practice, DMF seems to be efficacy and well tolerated in elderly psoriatic patients. DMF may be a first-line systemic treatment option to manage elderly psoriasis, provided that also the long-term safety data are closely monitored, in particular lymphocytopenia.
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Affiliation(s)
- Federica Ricceri
- Department of Health Sciences, Section of Dermatology, University of Florence, Florence, Italy
| | - Federico Bardazzi
- Dermatology Unit -IRCCS Policlinico di Sant'Orsola, Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy
| | | | - Martina Burlando
- DISSAL, Dermatologic Clinic, San Martino Policlinic Hospital, Genoa, Italy
| | - Elena Campione
- Department of Systems Medicine, Dermatologic Unit, University of Rome Tor Vergata, Rome, Italy
| | - Monica Corazza
- Department of Medical Sciences, Section of Dermatology and Infectious Diseases, University of Ferrara, Ferrara, Italy
| | - Aldo Cuccia
- Unit of Dermatology, San Donato Hospital, Arezzo, Italy
| | - Paolo Dapavo
- Department of Biomedical Science and Human Oncology, Second Dermatologic Clinic, University of Turin, Turin, Italy
| | - Federica Filippi
- Dermatology Unit -IRCCS Policlinico di Sant'Orsola, Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy
| | | | - Aurora Parodi
- DISSAL, Dermatologic Clinic, San Martino Policlinic Hospital, Genoa, Italy
| | - Francesca Prignano
- Department of Health Sciences, Section of Dermatology, University of Florence, Florence, Italy
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Biolato M, Bianco A, Lucchini M, Gasbarrini A, Mirabella M, Grieco A. The Disease-Modifying Therapies of Relapsing-Remitting Multiple Sclerosis and Liver Injury: A Narrative Review. CNS Drugs 2021; 35:861-880. [PMID: 34319570 PMCID: PMC8354931 DOI: 10.1007/s40263-021-00842-9] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/28/2021] [Indexed: 02/08/2023]
Abstract
In this narrative review, we analyze pre-registration and post-marketing data concerning hepatotoxicity of all disease-modifying therapies (DMTs) available for the treatment of relapsing-remitting multiple sclerosis, including beta interferon, glatiramer acetate, fingolimod, teriflunomide, dimethyl fumarate, cladribine, natalizumab, alemtuzumab, and ocrelizumab. We review the proposed causal mechanisms described in the literature and we also address issues like use of DMTs in patients with viral hepatitis or liver cirrhosis. Most data emerged in the post-marketing phase by reports to national pharmacovigilance agencies and published case reports or case series. Serious liver adverse events are rare, but exact incidence is largely unknown, as are predictive factors. Unfortunately, none of the DMTs currently available for the treatment of multiple sclerosis is free of potential hepatic toxic effects. Cases of acute liver failure have been reported for beta-interferon, fingolimod, natalizumab, alemtuzumab, and ocrelizumab by different mechanisms (idiosyncratic reaction, autoimmune hepatitis, or viral reactivation). Patients with multiple sclerosis should be informed about possible hepatic side effects of their treatment. Most cases of liver injury are idiosyncratic and unpredictable. The specific monitoring schedule for each DMT has been reviewed and the clinician should be ready to recognize clinical symptoms suggestive for liver injury. Not all DMTs are indicated in cirrhotic patients. For some DMTs, screening for hepatitis B virus and hepatitis C virus is required before starting treatment and a monitoring or antiviral prophylaxis schedule has been established. Beta interferon, glatiramer acetate, natalizumab, and alemtuzumab are relatively contraindicated in autoimmune hepatitis due to the risk of disease exacerbation.
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Affiliation(s)
- Marco Biolato
- Department of Medical and Surgical Sciences, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Largo A. Gemelli 8, 00168, Rome, Italy.
- Institute of Internal Medicine, Catholic University of Sacred Heart, 00168, Rome, Italy.
- Centro di ricerca per la Sclerosi Multipla (CERSM), Università Cattolica del Sacro Cuore, 00168, Rome, Italy.
| | - Assunta Bianco
- Multiple Sclerosis Center, Department of Department of Aging, Neurological, Orthopedic and Head and Neck Sciences, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168, Rome, Italy
| | - Matteo Lucchini
- Multiple Sclerosis Center, Department of Department of Aging, Neurological, Orthopedic and Head and Neck Sciences, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168, Rome, Italy
- Centro di ricerca per la Sclerosi Multipla (CERSM), Università Cattolica del Sacro Cuore, 00168, Rome, Italy
| | - Antonio Gasbarrini
- Department of Medical and Surgical Sciences, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Largo A. Gemelli 8, 00168, Rome, Italy
- Institute of Internal Medicine, Catholic University of Sacred Heart, 00168, Rome, Italy
| | - Massimiliano Mirabella
- Multiple Sclerosis Center, Department of Department of Aging, Neurological, Orthopedic and Head and Neck Sciences, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168, Rome, Italy
- Centro di ricerca per la Sclerosi Multipla (CERSM), Università Cattolica del Sacro Cuore, 00168, Rome, Italy
| | - Antonio Grieco
- Department of Medical and Surgical Sciences, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Largo A. Gemelli 8, 00168, Rome, Italy
- Institute of Internal Medicine, Catholic University of Sacred Heart, 00168, Rome, Italy
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Corazza M, Odorici G, Conti A, Di Lernia V, Motolese A, Bardazzi F, Di Nuzzo S, Monti A, Arginelli F, Filippi F, Valpiani G, Morotti C, Borghi A. Dimethyl fumarate treatment for psoriasis in a real-life setting: A multicentric retrospective study. Dermatol Ther 2021; 34:e15066. [PMID: 34291547 PMCID: PMC9286462 DOI: 10.1111/dth.15066] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Revised: 07/07/2021] [Accepted: 07/18/2021] [Indexed: 12/01/2022]
Abstract
Dimethyl fumarate (DMF) is a fumaric acid esters derivate approved for plaque psoriasis as first‐line systemic therapy. It has been available in Italy since 2017 and an increasing number of patients are treated with this drug. To evaluate DMF effectiveness, side effects and drug survival in a dermatological real‐life setting. We performed a retrospective multi‐center study in five dermatologic clinics in Emilia‐Romagna, Northern Italy, which included all consecutive patients affected by moderate–severe psoriasis treated with DMF. We assessed effectiveness (in terms of PASI50 and PASI75 in an intention to treat observation) and safety (occurrence of side effects) of DMF and their association with demographic and disease characteristics, mean daily dose taken and treatment discontinuation. We included 103 patients, 78 (75.72%) had at least one comorbidity including 19 (18.44%) with a history of cancer; the mean treatment duration was 23.61 ± 17.99 weeks (min 4, max 130) and the mean daily dose was 262.13 ± 190.94 mg. Twenty‐four patients (23.30%) reached PASI75 at week 12, while a further 18 patients (17.47%) reached it at week 26. Side effects occurred in 63 patients (61.16%), the most frequent were diarrhea, epigastric discomfort, nausea, and flushing. Sixteen patients (15.53%) showed an alteration of laboratory tests. In some cases side effects were transitory, while in 53 patients (51.45%) they led to cessation of therapy. The median daily dose showed a direct association with PASI50 achievement and an indirect association with treatment discontinuation. Our study shows the peculiarities of DMF in a real‐world setting: effectiveness is often reached after 12 weeks of treatment and side effects could limit the continuation of the therapy but, at the same time, DMF has no major contraindications and, due to the wide range of dosage, it can allow both to manage side effects and to personalize the prescription for each patient.
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Affiliation(s)
- Monica Corazza
- Department of Medical Sciences, Section of Dermatology and Infectious Diseases University of Ferrara, Ferrara, Italy
| | - Giulia Odorici
- Department of Medical Sciences, Section of Dermatology and Infectious Diseases University of Ferrara, Ferrara, Italy
| | - Andrea Conti
- Department of Surgical, Medical, Dental and Morphological Sciences with Interest transplant, Oncological and Regenerative Medicine; Dermatology Unit; University of Modena and Reggio Emilia, Modena, Italy
| | - Vito Di Lernia
- Department of Medical Specialities, Dermatology Unit, Arcispedale Santa Maria Nuova, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy
| | - Alberico Motolese
- Department of Medical Specialities, Dermatology Unit, Arcispedale Santa Maria Nuova, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy
| | - Federico Bardazzi
- Dermatology Unit -IRCCS Policlinico di Sant'Orsola, Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy
| | - Sergio Di Nuzzo
- Dermatology Unit, Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Alberto Monti
- Department of Medical Sciences, Section of Dermatology and Infectious Diseases University of Ferrara, Ferrara, Italy
| | - Federica Arginelli
- Department of Surgical, Medical, Dental and Morphological Sciences with Interest transplant, Oncological and Regenerative Medicine; Dermatology Unit; University of Modena and Reggio Emilia, Modena, Italy
| | - Federica Filippi
- Dermatology Unit -IRCCS Policlinico di Sant'Orsola, Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy
| | - Giorgia Valpiani
- Research Innovation Offic, S. Anna University Hospital of Ferrara, Ferrara, Italy
| | - Chiara Morotti
- Research Innovation Offic, S. Anna University Hospital of Ferrara, Ferrara, Italy
| | - Alessandro Borghi
- Department of Medical Sciences, Section of Dermatology and Infectious Diseases University of Ferrara, Ferrara, Italy
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10
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Lee YS, Gupta DP, Park SH, Yang HJ, Song GJ. Anti-Inflammatory Effects of Dimethyl Fumarate in Microglia via an Autophagy Dependent Pathway. Front Pharmacol 2021; 12:612981. [PMID: 34025399 PMCID: PMC8137969 DOI: 10.3389/fphar.2021.612981] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Accepted: 04/19/2021] [Indexed: 01/22/2023] Open
Abstract
Dimethyl fumarate (DMF), which has been approved by the Food and Drug Administration for the treatment of relapsing-remitting multiple sclerosis, is considered to exert anti-inflammatory and antioxidant effects. Microglia maintain homeostasis in the central nervous system and play a key role in neuroinflammation, while autophagy controls numerous fundamental biological processes, including pathogen removal, cytokine production, and clearance of toxic aggregates. However, the role of DMF in autophagy induction and the relationship of this effect with its anti-inflammatory functions in microglia are not well known. In the present study, we investigated whether DMF inhibited neuroinflammation and induced autophagy in microglia. First, we confirmed the anti-neuroinflammatory effect of DMF in mice with streptozotocin-induced diabetic neuropathy. Next, we used in vitro models including microglial cell lines and primary microglial cells to examine the anti-inflammatory and neuroprotective effects of DMF. We found that DMF significantly inhibited nitric oxide and proinflammatory cytokine production in lipopolysaccharide-stimulated microglia and induced the switch of microglia to the M2 state. In addition, DMF treatment increased the expression levels of autophagy markers including microtubule-associated protein light chain 3 (LC3) and autophagy-related protein 7 (ATG7) and the formation of LC3 puncta in microglia. The anti-inflammatory effect of DMF in microglia was significantly reduced by pretreatment with autophagy inhibitors. These data suggest that DMF leads to the induction of autophagy in microglia and that its anti-inflammatory effects are partially mediated through an autophagy-dependent pathway.
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Affiliation(s)
- Young-Sun Lee
- Department of Medical Science, College of Medicine, Catholic Kwandong University, Gangneung, Korea.,Translational Brain Research Center, International St. Mary's Hospital, Catholic Kwandong University, Incheon, Korea
| | - Deepak Prasad Gupta
- Department of Medical Science, College of Medicine, Catholic Kwandong University, Gangneung, Korea
| | - Sung Hee Park
- Department of Medical Science, College of Medicine, Catholic Kwandong University, Gangneung, Korea
| | - Hyun-Jeong Yang
- Department of Integrative Biosciences, University of Brain Education, Cheonan, Korea
| | - Gyun Jee Song
- Department of Medical Science, College of Medicine, Catholic Kwandong University, Gangneung, Korea.,Translational Brain Research Center, International St. Mary's Hospital, Catholic Kwandong University, Incheon, Korea
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11
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Zhu J, Yang T, Tang M, Yang Z, Pei H, Ye H, Tang Y, Cheng Z, Lin P, Chen L. Studies on the anti-psoriasis effects and its mechanism of a dual JAK2/FLT3 inhibitor flonoltinib maleate. Biomed Pharmacother 2021; 137:111373. [PMID: 33761599 DOI: 10.1016/j.biopha.2021.111373] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Revised: 01/25/2021] [Accepted: 02/02/2021] [Indexed: 02/08/2023] Open
Abstract
Psoriasis is a chronic, inflammatory autoimmune disease mediated by T cells, and characterized with abnormal proliferation and differentiation of keratinocytes, and inflammatory infiltration. The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway has been identified to play essential roles in mediating various of biological processes, and is closely related to autoimmune diseases. Dendritic cells (DCs) are important antigen presenting cells and play an important regulatory role in T cells. The proliferation, differentiation and function of DCs are regulated by JAK and FMS-like tyrosine kinase 3 (FLT3) signal pathways. Flonoltinib maleate (FM), a high selectivity dual JAK2/FLT3 inhibitor with IC50 values of 0.8 nM and 15 nM for JAK2 and FLT3, respectively, was developed by our laboratory. Moreover, FM was a potent JAK2 inhibitor with 863-fold and 696-fold selectivity over JAK1 and JAK3, respectively. In this study, the anti-psoriasis activity of FM was evaluated both in vitro and in vivo. FM effectively inhibited the proliferation of HaCaT, the inflammatory keratinocyte induced by M5 and markedly suppressed the generation and differentiation of DCs from bone marrow (BM), and inhibited the expression of FLT3 in DCs in vitro. FM effectively inhibited the ear thickening and improved the pathological changes of the ear in interleukin (IL)-23-induced psoriasis-like acanthosis mouse model. Further in keratin 14-vascular endothelial growth factor (K14-VEGF) transgenic homozygous mice model, FM could obviously improve the psoriatic symptom and pathological changes, significantly inhibit the generations of Th1 and Th17 cells in the spleen, and the accumulations of DCs in the ears. FM could also significantly reduce the expression of various inflammatory factors both in C57BL/6 and K14-VEGF mice ears, and the serum of K14-VEGF mice. Mechanism revealed that FM effectively suppressed the phosphorylation of JAK2, STAT3 and STAT5 in inflammatory keratinocytes and the mice ears of C57BL/6 and K14-VEGF, as well as the phosphorylation of FLT3 in K14-VEGF mice ears. In conclusion, FM plays an excellent anti-psoriasis activity, including inhibiting keratinocyte proliferation and regulating inflammatory response through inhibiting JAK2 and FLT3 signaling pathway.
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Affiliation(s)
- Jiali Zhu
- State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China
| | - Tao Yang
- State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China
| | - Minghai Tang
- State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China
| | - Zhuang Yang
- State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China
| | - Heying Pei
- State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China
| | - Haoyu Ye
- State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China
| | - Yu Tang
- State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China
| | - Zhixuan Cheng
- State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China
| | - Ping Lin
- State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China
| | - Lijuan Chen
- State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China.
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12
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Zeng T, Tang Z, Liang L, Suo D, Li L, Li J, Yuan Y, Guan XY, Li Y. PDSS2-Del2, a new variant of PDSS2, promotes tumor cell metastasis and angiogenesis in hepatocellular carcinoma via activating NF-κB. Mol Oncol 2020; 14:3184-3197. [PMID: 33064899 PMCID: PMC7718950 DOI: 10.1002/1878-0261.12826] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Revised: 09/08/2020] [Accepted: 09/25/2020] [Indexed: 12/28/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is among the leading causes of cancer‐related mortality worldwide. Our previous study identified a novel alternative splicing variant of prenyl diphosphate synthase subunit 2 (PDSS2) in HCC characterized by a deletion of exon 2, named PDSS2‐Del2, which is devoid of the tumor‐suppressive function of full‐length PDSS2 (PDSS2‐FL). To better understand the clinical significance of PDSS2‐Del2, we performed a BaseScope™ assay on an HCC tissue microarray and found that positive staining for PDSS2‐Del2 predicted a worse overall survival in patients with HCC (P = 0.02). PDSS2‐Del2 levels correlated significantly with microvessel counts in HCC tumor tissues. Importantly, PDSS2‐Del2 overexpression functionally promoted HCC metastasis, as demonstrated by in vitro and in vivo migration assays. In vivo assays also demonstrated that PDSS2‐Del2 increased angiogenesis in xenografts. Furthermore, we discovered that elevated PDSS2‐Del2 expression in HCC tumor cells decreased fumarate levels and activated the canonical nuclear factor‐κB pathway. The epithelial‐to‐mesenchymal transition (EMT) and WNT/β‐catenin signaling pathways were also activated by overexpression. Dimethyl fumarate (DMF), a fumaric acid ester, effectively reduced the metastasis induced by PDSS2‐Del2 as observed with in vivo spleen‐liver metastasis animal experiments. DMF is a prescribed oral therapy for multiple sclerosis and it might be a potential treatment for metastasis of patients with HCC. Early clinical trials are needed to validate its potential in this context.
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Affiliation(s)
- Tingting Zeng
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Zhi Tang
- School of Public Health, Guangdong Medical University, Dongguan, China
| | - Lili Liang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Daqin Suo
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Lei Li
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.,Department of Clinical Oncology, The University of Hong Kong, China
| | - Jiangchao Li
- Vascular Biology Research Institute, Guangdong Pharmaceutical University, Guangzhou, China
| | - Yunfei Yuan
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Xin-Yuan Guan
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.,Department of Clinical Oncology, The University of Hong Kong, China
| | - Yan Li
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
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13
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Dello Russo C, Scott KA, Pirmohamed M. Dimethyl fumarate induced lymphopenia in multiple sclerosis: A review of the literature. Pharmacol Ther 2020; 219:107710. [PMID: 33091427 DOI: 10.1016/j.pharmthera.2020.107710] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/15/2020] [Indexed: 12/13/2022]
Abstract
Dimethyl fumarate (DMF) is a first line medication for multiple sclerosis. It has a favourable safety profile, however, there is concern regarding the occurrence of moderate-severe and sustained lymphopenia and the associated risk of progressive multifocal leukoencephalopathy. We carried out an extensive literature review to understand the molecular mechanisms underlying this adverse reaction. Dynamic changes in certain components of the immune system are likely to be important for the therapeutic effects of DMF, including depletion of memory T cells and decrease in activated T cells together with expansion of naïve T cells. Similar modifications were reported for the B cell components. CD8+ T cells are particularly susceptible to DMF-induced cell death, with marked reductions observed in lymphopenic subjects. The reasons underlying such increased sensitivity are not known, nor it is known how expansion of other lymphocyte subsets occurs. Understanding the molecular mechanisms underlying DMF action is challenging: in vivo DMF is rapidly metabolized to monomethyl fumarate (MMF), a less potent immunomodulator in vitro. Pharmacokinetics indicate that MMF is the main active species in vivo. However, the relative importance of DMF and MMF in toxicity remains unclear, with evidence presented in favour of either of the compounds as toxic species. Pharmacogenetic studies to identify genetic predictors of DMF-induced lymphopenia are limited, with inconclusive results. A role of the gut microbiome in the pharmacological effects of DMF is emerging. It is clear that further investigations are necessary to understand the mechanisms of DMF-induced lymphopenia and devise preventive strategies. Periodic monitoring of absolute lymphocyte counts, currently performed in clinical practise, allows for the early detection of lymphopenia as a risk-minimization strategy.
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Affiliation(s)
- Cinzia Dello Russo
- MRC Centre for Drug Safety Science and Wolfson Centre for Personalised Medicine, Institute of Systems, Molecular and Integrative Biology (ISMIB), University of Liverpool, Liverpool, UK; Dept. of Healthcare Surveillance and Bioethics, Section of Pharmacology, Fondazione Policlinico Universitario A. Gemelli IRCCS - Università Cattolica del Sacro Cuore, Rome, Italy
| | - Kathryn Anne Scott
- MRC Centre for Drug Safety Science and Wolfson Centre for Personalised Medicine, Institute of Systems, Molecular and Integrative Biology (ISMIB), University of Liverpool, Liverpool, UK
| | - Munir Pirmohamed
- MRC Centre for Drug Safety Science and Wolfson Centre for Personalised Medicine, Institute of Systems, Molecular and Integrative Biology (ISMIB), University of Liverpool, Liverpool, UK.
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14
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Kourakis S, Timpani CA, de Haan JB, Gueven N, Fischer D, Rybalka E. Dimethyl Fumarate and Its Esters: A Drug with Broad Clinical Utility? Pharmaceuticals (Basel) 2020; 13:ph13100306. [PMID: 33066228 PMCID: PMC7602023 DOI: 10.3390/ph13100306] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2020] [Revised: 10/08/2020] [Accepted: 10/12/2020] [Indexed: 12/11/2022] Open
Abstract
Fumaric acid esters (FAEs) are small molecules with anti-oxidative, anti-inflammatory and immune-modulating effects. Dimethyl fumarate (DMF) is the best characterised FAE and is approved and registered for the treatment of psoriasis and Relapsing-Remitting Multiple Sclerosis (RRMS). Psoriasis and RRMS share an immune-mediated aetiology, driven by severe inflammation and oxidative stress. DMF, as well as monomethyl fumarate and diroximel fumarate, are commonly prescribed first-line agents with favourable safety and efficacy profiles. The potential benefits of FAEs against other diseases that appear pathogenically different but share the pathologies of oxidative stress and inflammation are currently investigated.
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Affiliation(s)
- Stephanie Kourakis
- College of Health and Biomedicine, Victoria University, Melbourne, VIC 8001, Australia;
| | - Cara A. Timpani
- Institute for Health and Sport, Victoria University, Melbourne, VIC 8001, Australia;
- Australian Institute for Musculoskeletal Science, Victoria University, St Albans, VIC 3021, Australia
| | - Judy B. de Haan
- Oxidative Stress Laboratory, Baker Heart and Diabetes Institute, Basic Science Domain, Melbourne, VIC 3004, Australia;
- Department of Physiology, Anatomy and Microbiology, La Trobe University, Melbourne, VIC 3083, Australia
| | - Nuri Gueven
- School of Pharmacy and Pharmacology, University of Tasmania, Hobart, TAS 7005, Australia;
| | - Dirk Fischer
- Division of Developmental- and Neuropediatrics, University Children’s Hospital Basel, University of Basel, 4056 Basel, Switzerland;
| | - Emma Rybalka
- Institute for Health and Sport, Victoria University, Melbourne, VIC 8001, Australia;
- Australian Institute for Musculoskeletal Science, Victoria University, St Albans, VIC 3021, Australia
- Correspondence: ; Tel.: +61-383-958-226
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15
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Balak DMW, Gerdes S, Parodi A, Salgado-Boquete L. Long-term Safety of Oral Systemic Therapies for Psoriasis: A Comprehensive Review of the Literature. Dermatol Ther (Heidelb) 2020; 10:589-613. [PMID: 32529393 PMCID: PMC7367959 DOI: 10.1007/s13555-020-00409-4] [Citation(s) in RCA: 60] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Indexed: 01/10/2023] Open
Abstract
Oral systemic therapies are important treatment options for patients with moderate-to-severe psoriasis, either as monotherapy or in therapy-recalcitrant cases as combination therapy with phototherapy, other oral systemics or biologics. Long-term treatment is needed to maintain sufficient disease control in psoriasis, but continuous use of systemic treatments is limited by adverse events (AEs) and cumulative toxicity risks. The primary aim of this comprehensive literature review was to examine the long-term safety profiles of oral agents commonly used in the treatment of adults with psoriasis. Searches were conducted in EMBASE and PubMed up to November 2018, and 157 relevant publications were included. Long-term treatment with acitretin could be associated with skeletal toxicity and hepatotoxicity, although evidence for skeletal toxicity is mixed and hepatotoxicity is rare, particularly at low doses. Other safety issues include hyperlipidaemia and potential for teratogenicity up to 2-3 years after discontinuation of treatment. There is a paucity of data on long-term treatment with apremilast. Continued exposure to apremilast does not seem to increase the incidence of common AEs, such as gastrointestinal (GI) AEs, upper respiratory tract infections and headache, while the long-term risks for depression, suicidal thoughts and weight loss are unknown. Long-term ciclosporin treatment is associated with renal toxicity, hypertension, non-melanoma skin cancer, neurological AEs and GI AEs. Long-term methotrexate treatment is associated with hepatotoxicity, GI AEs, haematological toxicity, renal toxicity and alopecia. Finally, long-term treatment with fumaric acid esters (FAE) is associated with GI AEs, flushing, lymphocytopenia, proteinuria and elevated liver enzymes. Median drug survival estimates varied considerably: ~ 2.9-9.7 months for apremilast; ~ 5.4 months for ciclosporin; ~ 8.6 months for acitretin; ~ 12.1-21.6 months for methotrexate; and ~ 54.8 months for FAE. These long-term safety profiles may help to guide clinicians to select the optimal oral systemic treatment for the long-term treatment of psoriasis in adults.
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Affiliation(s)
- Deepak M W Balak
- Department of Dermatology, LangeLand Ziekenhuis, Zoetermeer, the Netherlands.
| | - Sascha Gerdes
- Department of Dermatology, Psoriasis-Center, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany
| | - Aurora Parodi
- DiSSal Section of Dermatology, University of Genoa-Ospedale-Policlinico San Martino IRCCS, Genoa, Italy
| | - Laura Salgado-Boquete
- Department of Dermatology, Complejo Hospitalario Universitario de Pontevedra, Pontevedra, Spain
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16
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Sangineto M, Grabherr F, Adolph TE, Grander C, Reider S, Jaschke N, Mayr L, Schwärzler J, Dallio M, Moschen AR, Moschetta A, Sabbà C, Tilg H. Dimethyl fumarate ameliorates hepatic inflammation in alcohol related liver disease. Liver Int 2020; 40:1610-1619. [PMID: 32306456 PMCID: PMC7383968 DOI: 10.1111/liv.14483] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Revised: 03/25/2020] [Accepted: 04/14/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Alcohol-related liver disease (ALD) comprises different liver disorders which impose a health care issue. ALD and particularly alcoholic steatohepatitis, an acute inflammatory condition, cause a substantial morbidity and mortality as effective treatment options remain elusive. Inflammation in ALD is fuelled by macrophages (Kupffer cells [KCs]) which are activated by intestinal pathogen associated molecular patterns, eg lipopolysaccharide (LPS), disseminated beyond a defective intestinal barrier. We hypothesized that the immunomodulator dimethyl-fumarate (DMF), which is approved for the treatment of human inflammatory conditions such as multiple sclerosis or psoriasis, ameliorates the course of experimental ALD. METHODS Dimethyl-fumarate or vehicle was orally administered to wild-type mice receiving a Lieber-DeCarli diet containing 5% ethanol for 15 days. Liver injury, steatosis and inflammation were evaluated by histology, biochemical- and immunoassays. Moreover, we investigated a direct immunosuppressive effect of DMF on KCs and explored a potential impact on ethanol-induced intestinal barrier disruption. RESULTS Dimethyl-fumarate protected against ethanol-induced hepatic injury, steatosis and inflammation in mice. Specifically, we observed reduced hepatic triglyceride and ALT accumulation, reduced hepatic expression of inflammatory cytokines (Tnf-α, Il-1β, Cxcl1) and reduced abundance of neutrophils and macrophages in ethanol-fed and DMF-treated mice when compared to vehicle. DMF protected against ethanol-induced barrier disruption and abrogated systemic LPS concentration. In addition, DMF abolished LPS-induced cytokine responses of KCs. CONCLUSIONS Dimethyl-fumarate counteracts ethanol-induced barrier dysfunction, suppresses inflammatory responses of KCs and ameliorates hepatic inflammation and steatosis, hallmarks of experimental ALD. Our data indicates that DMF treatment might be beneficial in human ALD and respective clinical trials are eagerly awaited.
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Affiliation(s)
- Moris Sangineto
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & MetabolismMedical University InnsbruckInnsbruckAustria,Department of Interdisciplinary MedicineUniversity of BariBariItaly
| | - Felix Grabherr
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & MetabolismMedical University InnsbruckInnsbruckAustria
| | - Timon E. Adolph
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & MetabolismMedical University InnsbruckInnsbruckAustria
| | - Christoph Grander
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & MetabolismMedical University InnsbruckInnsbruckAustria
| | - Simon Reider
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & MetabolismMedical University InnsbruckInnsbruckAustria,Christian Doppler Laboratory for Mucosal ImmunologyMedical University InnsbruckInnsbruckAustria
| | - Nikolai Jaschke
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & MetabolismMedical University InnsbruckInnsbruckAustria
| | - Lisa Mayr
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & MetabolismMedical University InnsbruckInnsbruckAustria
| | - Julian Schwärzler
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & MetabolismMedical University InnsbruckInnsbruckAustria
| | - Marcello Dallio
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & MetabolismMedical University InnsbruckInnsbruckAustria,Department of Precision MedicineUniversity of Campania “L. Vanvitelli”NaplesItaly
| | - Alexander R. Moschen
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & MetabolismMedical University InnsbruckInnsbruckAustria,Christian Doppler Laboratory for Mucosal ImmunologyMedical University InnsbruckInnsbruckAustria
| | | | - Carlo Sabbà
- Department of Interdisciplinary MedicineUniversity of BariBariItaly
| | - Herbert Tilg
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & MetabolismMedical University InnsbruckInnsbruckAustria
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17
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Kastrati I, Joosten SEP, Semina SE, Alejo LH, Brovkovych SD, Stender JD, Horlings HM, Kok M, Alarid ET, Greene GL, Linn SC, Zwart W, Frasor J. The NF-κB Pathway Promotes Tamoxifen Tolerance and Disease Recurrence in Estrogen Receptor-Positive Breast Cancers. Mol Cancer Res 2020; 18:1018-1027. [PMID: 32245803 PMCID: PMC7335344 DOI: 10.1158/1541-7786.mcr-19-1082] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Revised: 02/19/2020] [Accepted: 03/31/2020] [Indexed: 01/14/2023]
Abstract
The purpose of this study was to identify critical pathways promoting survival of tamoxifen-tolerant, estrogen receptor α positive (ER+) breast cancer cells, which contribute to therapy resistance and disease recurrence. Gene expression profiling and pathway analysis were performed in ER+ breast tumors of patients before and after neoadjuvant tamoxifen treatment and demonstrated activation of the NF-κB pathway and an enrichment of epithelial-to mesenchymal transition (EMT)/stemness features. Exposure of ER+ breast cancer cell lines to tamoxifen, in vitro and in vivo, gives rise to a tamoxifen-tolerant population with similar NF-κB activity and EMT/stemness characteristics. Small-molecule inhibitors and CRISPR/Cas9 knockout were used to assess the role of the NF-κB pathway and demonstrated that survival of tamoxifen-tolerant cells requires NF-κB activity. Moreover, this pathway was essential for tumor recurrence following tamoxifen withdrawal. These findings establish that elevated NF-κB activity is observed in breast cancer cell lines under selective pressure with tamoxifen in vitro and in vivo, as well as in patient tumors treated with neoadjuvant tamoxifen therapy. This pathway is essential for survival and regrowth of tamoxifen-tolerant cells, and, as such, NF-κB inhibition offers a promising approach to prevent recurrence of ER+ tumors following tamoxifen exposure. IMPLICATIONS: Understanding initial changes that enable survival of tamoxifen-tolerant cells, as mediated by NF-κB pathway, may translate into therapeutic interventions to prevent resistance and relapse, which remain major causes of breast cancer lethality.
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Affiliation(s)
- Irida Kastrati
- Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, Illinois
| | - Stacey E P Joosten
- Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Svetlana E Semina
- Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, Illinois
| | - Luis H Alejo
- Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, Illinois
| | - Svitlana D Brovkovych
- Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, Illinois
| | - Joshua D Stender
- Department of Cellular and Molecular Medicine, University of California San Diego, San Diego, California
| | - Hugo M Horlings
- Division of Molecular Pathology, Department of Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Marleen Kok
- Department of Medical Oncology, Division of Tumor Biology & Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Elaine T Alarid
- Department of Oncology, University of Wisconsin-Madison, Madison, Wisconsin
| | - Geoffrey L Greene
- The Ben May Department for Cancer Research, University of Chicago, Chicago, Illinois
| | - Sabine C Linn
- Division of Molecular Pathology, Department of Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Wilbert Zwart
- Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
| | - Jonna Frasor
- Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, Illinois.
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18
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Selman M, Ou P, Rousso C, Bergeron A, Krishnan R, Pikor L, Chen A, Keller BA, Ilkow C, Bell JC, Diallo JS. Dimethyl fumarate potentiates oncolytic virotherapy through NF-κB inhibition. Sci Transl Med 2019; 10:10/425/eaao1613. [PMID: 29367345 DOI: 10.1126/scitranslmed.aao1613] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2017] [Accepted: 11/22/2017] [Indexed: 12/24/2022]
Abstract
Resistance to oncolytic virotherapy is frequently associated with failure of tumor cells to get infected by the virus. Dimethyl fumarate (DMF), a common treatment for psoriasis and multiple sclerosis, also has anticancer properties. We show that DMF and various fumaric and maleic acid esters (FMAEs) enhance viral infection of cancer cell lines as well as human tumor biopsies with several oncolytic viruses (OVs), improving therapeutic outcomes in resistant syngeneic and xenograft tumor models. This results in durable responses, even in models otherwise refractory to OV and drug monotherapies. The ability of DMF to enhance viral spread results from its ability to inhibit type I interferon (IFN) production and response, which is associated with its blockade of nuclear translocation of the transcription factor nuclear factor κB (NF-κB). This study demonstrates that unconventional application of U.S. Food and Drug Administration-approved drugs and biological agents can result in improved anticancer therapeutic outcomes.
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Affiliation(s)
- Mohammed Selman
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, Ontario K1H 8L6, Canada.,Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada
| | - Paula Ou
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, Ontario K1H 8L6, Canada.,Faculty of Science, University of Ottawa, Ottawa, Ontario K1N 6N5, Canada
| | - Christopher Rousso
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, Ontario K1H 8L6, Canada.,Faculty of Science, University of Ottawa, Ottawa, Ontario K1N 6N5, Canada
| | - Anabel Bergeron
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, Ontario K1H 8L6, Canada.,Faculty of Science, University of Ottawa, Ottawa, Ontario K1N 6N5, Canada
| | - Ramya Krishnan
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, Ontario K1H 8L6, Canada.,Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada
| | - Larissa Pikor
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, Ontario K1H 8L6, Canada
| | - Andrew Chen
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, Ontario K1H 8L6, Canada
| | - Brian A Keller
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, Ontario K1H 8L6, Canada.,Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada
| | - Carolina Ilkow
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, Ontario K1H 8L6, Canada.,Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada
| | - John C Bell
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, Ontario K1H 8L6, Canada.,Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada
| | - Jean-Simon Diallo
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, Ontario K1H 8L6, Canada. .,Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada
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The footprints of mitochondrial impairment and cellular energy crisis in the pathogenesis of xenobiotics-induced nephrotoxicity, serum electrolytes imbalance, and Fanconi's syndrome: A comprehensive review. Toxicology 2019; 423:1-31. [PMID: 31095988 DOI: 10.1016/j.tox.2019.05.002] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2019] [Revised: 04/29/2019] [Accepted: 05/09/2019] [Indexed: 12/19/2022]
Abstract
Fanconi's Syndrome (FS) is a disorder characterized by impaired renal proximal tubule function. FS is associated with a vast defect in the renal reabsorption of several chemicals. Inherited and/or acquired conditions seem to be connected with FS. Several xenobiotics including many pharmaceuticals are capable of inducing FS and nephrotoxicity. Although the pathological state of FS is well described, the exact underlying etiology and cellular mechanism(s) of xenobiotics-induced nephrotoxicity, serum electrolytes imbalance, and FS are not elucidated. Constant and high dependence of the renal reabsorption process to energy (ATP) makes mitochondrial dysfunction as a pivotal mechanism which could be involved in the pathogenesis of FS. The current review focuses on the footprints of mitochondrial impairment in the etiology of xenobiotics-induced FS. Moreover, the importance of mitochondria protecting agents and their preventive/therapeutic capability against FS is highlighted. The information collected in this review may provide significant clues to new therapeutic interventions aimed at minimizing xenobiotics-induced renal injury, serum electrolytes imbalance, and FS.
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Dickel H, Bruckner T, Höxtermann S, Dickel B, Trinder E, Altmeyer P. Fumaric acid ester-induced T-cell lymphopenia in the real-life treatment of psoriasis. J Eur Acad Dermatol Venereol 2019; 33:893-905. [PMID: 30680823 PMCID: PMC6593701 DOI: 10.1111/jdv.15448] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2018] [Accepted: 12/19/2018] [Indexed: 12/31/2022]
Abstract
BACKGROUND Fumaric acid esters (FAEs) are used to treat psoriasis and are known to cause lymphopenia in roughly 60% of the patients. Much remains to be elucidated about the biological effects of FAEs on lymphocytes. OBJECTIVE To evaluate the influence of long-term FAE (Fumaderm® ) treatment on peripheral blood CD4+ and CD8+ T cells, CD19+ B cells and CD56+ natural killer (NK) cells in psoriasis. METHODS In this single-centre retrospective observational subcohort study, we obtained leucocyte and lymphocyte subset counts before initiating FAE therapy in 371 psoriasis patients (mean age, 47.8 years; 63.3% males) and monitored them during treatment (mean treatment duration, 2.9 years). Multiparametric flow cytometry was used for immunophenotyping. RESULTS FAEs significantly reduced the numbers of CD4+ T, CD8+ T, CD19+ B and CD56+ NK cells. Among lymphocyte subsets, the mean percentage reduction from baseline was always highest for CD8+ T cells, with a peak of 55.7% after 2 years of therapy. The risk of T-cell lymphopenia increased significantly with the age of the psoriasis patients at the time that FAE therapy was initiated. It was significantly decreased for the combination therapy with methotrexate and folic acid (vitamin B9) supplementation. Supporting evidence was found suggesting that T-cell lymphopenia enhances the effectiveness of FAE therapy. CONCLUSIONS Monitoring distinct T-cell subsets rather than just absolute lymphocyte counts may provide more meaningful insights into both the FAE treatment safety and efficacy. We therefore suggest optimizing pharmacovigilance by additionally monitoring CD4+ and CD8+ T-cell counts at regular intervals, especially in patients of middle to older age. Thus, further prospective studies are needed to establish evidence-based recommendations to guide dermatologists in the management of psoriasis patients who are taking FAEs and who develop low absolute T-cell counts.
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Affiliation(s)
- H. Dickel
- Department of Dermatology, Venereology and AllergologyRuhr University BochumBochumGermany
| | - T. Bruckner
- Institute of Medical Biometry and Informatics (IMBI)University Hospital HeidelbergHeidelbergGermany
| | - S. Höxtermann
- Department of Dermatology, Venereology and AllergologyRuhr University BochumBochumGermany
| | - B. Dickel
- Dermatology Practice Peter WenzelMDHattingenGermany
| | - E. Trinder
- Department of Dermatology, Venereology and AllergologyRuhr University BochumBochumGermany
| | - P. Altmeyer
- Department of Dermatology, Venereology and AllergologyRuhr University BochumBochumGermany
- Dermatology Practice at City ParkBochumGermany
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21
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Bertinaria M, Gastaldi S, Marini E, Giorgis M. Development of covalent NLRP3 inflammasome inhibitors: Chemistry and biological activity. Arch Biochem Biophys 2018; 670:116-139. [PMID: 30448387 DOI: 10.1016/j.abb.2018.11.013] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2018] [Revised: 11/12/2018] [Accepted: 11/14/2018] [Indexed: 12/12/2022]
Abstract
The NOD-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome is the best recognized and most widely implicated regulator of caspase-1 activation. It is a key regulator of innate immune response and is involved in many pathophysiological processes. Recent evidences for its inappropriate activation in autoinflammatory, autoimmune, as well as in neurodegenerative diseases attract a growing interest toward the development of small molecules NLRP3 inhibitors. Based on the knowledge of biochemical and structural aspects of NLRP3 activation, one successful strategy in the identification of NLRP3 inhibitors relies on the development of covalent irreversible inhibitors. Covalent inhibitors are reactive electrophilic molecules able to alkylate nucleophiles in the target protein. These inhibitors could ensure good efficacy and prolonged duration of action both in vitro and in vivo. In spite of these advantages, effects on other signalling pathways, prone to alkylation, may occur. In this review, we will illustrate the chemistry and the biological action of the most studied covalent NLRP3 inhibitors developed so far. A description of what we know about their mechanism of action will address the reader toward a critical understanding of NLRP3 inhibition by electrophilic compounds.
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Affiliation(s)
- Massimo Bertinaria
- Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, Via P. Giuria 9, 10125, Torino, Italy.
| | - Simone Gastaldi
- Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, Via P. Giuria 9, 10125, Torino, Italy
| | - Elisabetta Marini
- Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, Via P. Giuria 9, 10125, Torino, Italy
| | - Marta Giorgis
- Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, Via P. Giuria 9, 10125, Torino, Italy
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22
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Dickel H, Bruckner T, Altmeyer P. Long-term real-life safety profile and effectiveness of fumaric acid esters in psoriasis patients: a single-centre, retrospective, observational study. J Eur Acad Dermatol Venereol 2018; 32:1710-1727. [PMID: 29705996 PMCID: PMC6221124 DOI: 10.1111/jdv.15019] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2017] [Accepted: 04/04/2018] [Indexed: 12/19/2022]
Abstract
BACKGROUND Fumaric acid esters (FAEs) are an established systemic treatment for moderate-to-severe psoriasis. However, the long-term clinical safety and effectiveness of continuous FAE monotherapy and combination therapy have not been established. OBJECTIVE To examine the long-term safety and effectiveness of FAEs as monotherapy and in combination with phototherapy or methotrexate in patients with psoriasis treated at a single centre in Germany. METHODS This monocentric, retrospective observational study, with a follow-up period of up to 32.5 years, included 859 patients: 626 received FAE monotherapy, 123 received FAEs with concomitant phototherapy and 110 received FAEs with methotrexate. RESULTS Approximately half of patients (49.0%) reported adverse events (566 total events), most of which involved the gastrointestinal tract. Serious adverse events were reported in 2.3% of patients, but none were deemed to have a causal relationship with any of the treatment regimens. Adverse events leading to treatment discontinuation were observed in 12.9% of patients. A median duration of 1 year was observed in all three treatment subcohorts (P = 0.70) from initiation of FAE treatment to a 50% response rate, where response was defined as achieving a cumulative static Physician's Global Assessment (PGA) score of 'light' and at least a 2-point reduction in baseline PGA. A 50% response rate for the cumulative Psoriasis Area and Severity Index 75 was achieved in the FAE monotherapy subcohort after a median of 3 years of treatment, in the FAEs + phototherapy subcohort after 6.7 years and in the FAEs + methotrexate subcohort after 8.1 years (P = 0.001). CONCLUSION According to our data, FAEs as monotherapy or in combination with phototherapy or methotrexate are safe and beneficial for long-term clinical use. However, multicentre, randomized controlled trials are required to establish the clinical value of monotherapy versus combination therapy and the optimal treatment duration.
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Affiliation(s)
- H. Dickel
- Department of Dermatology, Venereology and AllergologyRuhr University BochumBochumGermany
| | - T. Bruckner
- Institute of Medical Biometry and Informatics (IMBI)University Hospital HeidelbergHeidelbergGermany
| | - P. Altmeyer
- Department of Dermatology, Venereology and AllergologyRuhr University BochumBochumGermany
- Dermatology Practice at City ParkBochumGermany
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Mrowietz U, Barker J, Boehncke WH, Iversen L, Kirby B, Naldi L, Reich K, Tanew A, van de Kerkhof P, Warren R. Clinical use of dimethyl fumarate in moderate-to-severe plaque-type psoriasis: a European expert consensus. J Eur Acad Dermatol Venereol 2018; 32 Suppl 3:3-14. [DOI: 10.1111/jdv.15218] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2018] [Accepted: 08/24/2018] [Indexed: 02/06/2023]
Affiliation(s)
- U. Mrowietz
- Psoriasis-Centre at the Department of Dermatology; University Medical Centre Schleswig-Holstein; Kiel Germany
| | - J. Barker
- St John's Institute of Dermatology; King's College London; London UK
| | - W.-H. Boehncke
- Division of Dermatology and Venereology; Geneva University Hospitals; Geneva Switzerland
- Department of Pathology and Immunology; Faculty of Medicine; University of Geneva; Geneva Switzerland
| | - L. Iversen
- Department of Dermatology; Aarhus University Hospital; Aarhus Denmark
| | - B. Kirby
- Department of Dermatology; St. Vincent's University Hospital; Dublin Ireland
| | - L. Naldi
- Centro Studi GISED; Bergamo Italy
- Department of Dermatology; Ospedale san Bortolo di Vicenza; Vicenza Italy
| | - K. Reich
- Dermatologikum Berlin and SCIderm Research Institute; Hamburg Germany
| | - A. Tanew
- Department of Dermatology; Medical University of Vienna; Vienna Austria
| | - P.C.M. van de Kerkhof
- Department of Dermatology; Radboud University Nijmegen Medical Centre; Nijmegen The Netherlands
| | - R.B. Warren
- Dermatology Centre; Salford Royal NHS Foundation Trust; Salford UK
- Manchester Academic Health Science Centre; Manchester NIHR Biomedical Research Centre; The University of Manchester; Manchester UK
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Li QQ, Li LJ, Wang XY, Sun YY, Wu J. Research Progress in Understanding the Relationship Between Heme Oxygenase-1 and Intracerebral Hemorrhage. Front Neurol 2018; 9:682. [PMID: 30177908 PMCID: PMC6109777 DOI: 10.3389/fneur.2018.00682] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2018] [Accepted: 07/30/2018] [Indexed: 01/14/2023] Open
Abstract
Intracerebral hemorrhage (ICH) is a fatal acute cerebrovascular disease, with a high morbidity and mortality. Following ICH, erythrocytes release heme and several of its metabolites, thereby contributing to brain edema and secondary brain damage. Heme oxygenase is the initial and rate-limiting enzyme of heme catabolism, and the expression of heme oxygenase-1 (HO-1) is rapidly induced following acute brain injury. As HO-1 exerts it effects via various metabolites, its role during ICH remains complex. Therefore, in-depth studies regarding the role of HO-1 in secondary brain damage following ICH may provide a theoretical basis for neuroprotective function after ICH. The present review aims to summarize recent key studies regarding the effects of HO-1 following ICH, as well as its influence on ICH prognosis.
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Affiliation(s)
- Qian-Qian Li
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Lan-Jun Li
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Xin-Yu Wang
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Yu-Ying Sun
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Jun Wu
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
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Dimethyl Fumarate Prevents HIV-Induced Lysosomal Dysfunction and Cathepsin B Release from Macrophages. J Neuroimmune Pharmacol 2018; 13:345-354. [PMID: 29987592 DOI: 10.1007/s11481-018-9794-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2017] [Accepted: 05/28/2018] [Indexed: 12/17/2022]
Abstract
HIV-associated neurocognitive disorders (HAND) are prevalent despite combined antiretroviral therapy, affecting nearly half of HIV-infected patients worldwide. During HIV infection of macrophages secretion of the lysosomal protein, cathepsin B, is increased. Secreted cathepsin B has been shown to induce neurotoxicity. Oxidative stress is increased in HIV-infected patients, while antioxidants are decreased in monocytes from patients with HIV-associated dementia (HAD). Dimethyl fumarate (DMF), an antioxidant, has been reported to decrease HIV replication and neurotoxicity mediated by HIV-infected macrophages. Thus, we hypothesized that DMF will decrease cathepsin B release from HIV-infected macrophages by preventing oxidative stress and enhancing lysosomal function. Monocyte-derived macrophages (MDM) were isolated from healthy donors, inoculated with HIV-1ADA, and treated with DMF following virus removal. After 12 days post-infection, HIV-1 p24 and total cathepsin B levels were measured from HIV-infected MDM supernatants using ELISA; intracellular reactive oxygen and nitrogen species (ROS/RNS) were measured from MDM lysates, and functional lysosomes were assessed using a pH-dependent lysosomal dye. Neurons were incubated with serum-free conditioned media from DMF-treated MDM and neurotoxicity was determined using TUNEL assay. Results indicate that DMF reduced HIV-1 replication and cathepsin B secretion from HIV-infected macrophages in a dose-dependent manner. Also, DMF decreased intracellular ROS/RNS levels, and prevented HIV-induced lysosomal dysfunction and neuronal apoptosis. In conclusion, the improvement in lysosomal function with DMF treatment may represent the possible mechanism to reduce HIV-1 replication and cathepsin B secretion. DMF represents a potential therapeutic strategy against HAND.
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Kumar P, Sharma G, Gupta V, Kaur R, Thakur K, Malik R, Kumar A, Kaushal N, Raza K. Preclinical Explorative Assessment of Dimethyl Fumarate-Based Biocompatible Nanolipoidal Carriers for the Management of Multiple Sclerosis. ACS Chem Neurosci 2018; 9:1152-1158. [PMID: 29357233 DOI: 10.1021/acschemneuro.7b00519] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Multiple sclerosis (MS) is a neurodegenerative disease in which myelin sheath damage occurs due to internal and external factors. MS especially affects the young population. Dimethyl fumarate (DMF) is a promising agent for MS treatment, although it is associated with concerns such as poor brain permeation, multiple dosing, and gastrointestinal flushing. The present study attempts to evaluate the preclinical performance of specially designed DMF-based lipoidal nanoparticles in a cuprizone-induced demyelination model in rodents. The studies proved the efficacy of lipid-based nanoparticles containing DMF in a once-a-day dosage regimen over that of thrice-a-day plain DMF administration on crucial parameters like motor coordination, grip strength, mortality, body weight, and locomotor activity. However, neither blank lipid nor blank neuroprotective (vitamins A, D, and E) loaded nanoparticles were able to elicit any desirable behavioral response. Histopathological studies showed that the designed once-a-day DMF nanomedicines were well tolerated and rejuvenated the myelin sheath vis-à-vis the plain DMF thrice-a-day regimen. These findings provide proof of concept for a biocompatible nanomedicine for MS with tremendous promise for effective brain delivery and patient compliance on the grounds of a reduction in the dosage frequency.
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Affiliation(s)
- Pramod Kumar
- Department of Pharmacy, School of Chemical Sciences and Pharmacy , Central University of Rajasthan , Bandar Sindri , Distt. Ajmer , Rajasthan , India 305817
| | - Gajanand Sharma
- Division of Pharmaceutics, University Institute of Pharmaceutical Sciences , Panjab University , Chandigarh , India 160014
| | - Varun Gupta
- Pharmacology Division, University Institute of Pharmaceutical Sciences , UGC Centre of Advanced Studies (UGC-CAS), Panjab University , Chandigarh , India 160014
| | - Ramanpreet Kaur
- Department of Biophysics , Panjab University , Chandigarh , India 160014
| | - Kanika Thakur
- Division of Pharmaceutics, University Institute of Pharmaceutical Sciences , Panjab University , Chandigarh , India 160014
| | - Ruchi Malik
- Department of Pharmacy, School of Chemical Sciences and Pharmacy , Central University of Rajasthan , Bandar Sindri , Distt. Ajmer , Rajasthan , India 305817
| | - Anil Kumar
- Pharmacology Division, University Institute of Pharmaceutical Sciences , UGC Centre of Advanced Studies (UGC-CAS), Panjab University , Chandigarh , India 160014
| | - Naveen Kaushal
- Department of Biophysics , Panjab University , Chandigarh , India 160014
| | - Kaisar Raza
- Department of Pharmacy, School of Chemical Sciences and Pharmacy , Central University of Rajasthan , Bandar Sindri , Distt. Ajmer , Rajasthan , India 305817
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Chen-Roetling J, Regan RF. Targeting the Nrf2-Heme Oxygenase-1 Axis after Intracerebral Hemorrhage. Curr Pharm Des 2018; 23:2226-2237. [PMID: 27799046 DOI: 10.2174/1381612822666161027150616] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2016] [Revised: 10/16/2016] [Accepted: 10/22/2016] [Indexed: 12/25/2022]
Abstract
BACKGROUND Injury to cells adjacent to an intracerebral hemorrhage (ICH) is likely mediated at least in part by toxins released from the hematoma that initiate complex and interacting injury cascades. Pharmacotherapies targeting a single toxin or pathway, even if consistently effective in controlled experimental models, have a high likelihood of failure in a variable clinical setting. Nuclear factor erythroid-2 related factor 2 (Nrf2) regulates the expression of heme oxygenase-1 (HO-1) and multiple other proteins with antioxidant and antiinflammatory effects, and may be a target of interest after ICH. METHODS Studies that tested the effect of HO and Nrf2 in models relevant to ICH are summarized, with an effort to reconcile conflicting data by consideration of methodological limitations. RESULTS In vitro studies demonstrated that Nrf2 activators rapidly increased HO-1 expression in astrocytes, and reduced their vulnerability to hemoglobin or hemin. Modulating HO-1 expression via genetic approaches yielded similar results. Systemic treatment with small molecule Nrf2 activators increased HO-1 expression in perivascular cells, particularly astrocytes. When tested in mouse or rat ICH models, Nrf2 activators were consistently protective, improving barrier function and attenuating edema, inflammation, neuronal loss and neurological deficits. These effects were mimicked by selective astrocyte HO-1 overexpression in transgenic mice. CONCLUSION Systemic treatment with Nrf2 activators after ICH is protective in rodents. Two compounds, dimethyl fumarate and hemin, are currently approved for treatment of multiple sclerosis and acute porphyria, respectively, and have acceptable safety profiles over years of clinical use. Further development of these drugs as ICH therapeutics seems warranted.
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Affiliation(s)
- Jing Chen-Roetling
- Department of Emergency Medicine, Thomas Jefferson University, 1025 Walnut Street, College Building Room 813, Philadelphia, PA 19107, United States
| | - Raymond F Regan
- Department of Emergency Medicine, Thomas Jefferson University, 1025 Walnut Street, College Building Room 813, Philadelphia, PA 19107, United States
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Bouwes Bavinck J, van Zuuren E. Light on fumaric acid esters therapy for psoriasis. Br J Dermatol 2018; 178:586-587. [DOI: 10.1111/bjd.16272] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Affiliation(s)
- J.N. Bouwes Bavinck
- Department of Dermatology; Leiden University Medical Centre; Albinusdreef 2 2333 ZA Leiden the Netherlands
| | - E.J. van Zuuren
- Department of Dermatology; Leiden University Medical Centre; Albinusdreef 2 2333 ZA Leiden the Netherlands
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Tzaneva S, Geroldinger A, Trattner H, Tanew A. Fumaric acid esters in combination with a 6-week course of narrowband ultraviolet B provides an accelerated response compared with fumaric acid esters monotherapy in patients with moderate-to-severe plaque psoriasis: a randomized prospective clinical stud. Br J Dermatol 2018; 178:682-688. [DOI: 10.1111/bjd.16106] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/31/2017] [Indexed: 02/06/2023]
Affiliation(s)
- S. Tzaneva
- Department of Dermatology; Division of General Dermatology and Dermato-Oncology; Medical University of Vienna; Vienna Austria
| | - A. Geroldinger
- Center for Medical Statistics, Informatics and Intelligent Systems; Section for Clinical Biometrics; Medical University of Vienna; Vienna Austria
| | - H. Trattner
- Department of Dermatology; Division of General Dermatology and Dermato-Oncology; Medical University of Vienna; Vienna Austria
| | - A. Tanew
- Department of Dermatology; Division of General Dermatology and Dermato-Oncology; Medical University of Vienna; Vienna Austria
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Update on monitoring and adverse effects of approved second-generation disease-modifying therapies in relapsing forms of multiple sclerosis. Curr Opin Neurol 2018; 29:278-85. [PMID: 27027553 DOI: 10.1097/wco.0000000000000321] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
PURPOSE OF REVIEW There has been a considerable increase in the number of disease-modifying therapies (DMTs) in recent years. It appears that the number of approved DMTs is going to continue to increase in the coming years. The growing number of DMTs has provided a challenge to the clinician to tailor their therapeutic recommendations based on patients' needs and preferences. To choose between these DMTs, knowledge of side-effect profiles is imperative. RECENT FINDINGS Alemtuzumab, a humanized recombinant monoclonal antibody, was recently approved for the management of relapsing forms of multiple sclerosis. Its use seems to be limited by significant adverse effects and regular monitoring requirement. In 2014, the first case of progressive multifocal leukoencephalopathy (PML) was diagnosed in a patient with relapsing remitting multiple sclerosis who received extended dimethyl fumarate without any significant confounding factors. Among patients receiving fingolimod after previous natalizumab treatment, there have been 17 suspected cases of PML. There have also been three confirmed cases of PML in individuals who received fingolimod without previous natalizumab treatment. SUMMARY In this review, we outline the potential adverse effects and recommended laboratory studies as part of the monitoring strategy following initiation of various DMTs.
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Müller S, Smatlik N, Burian M, Ghoreschi K, Röcken M, Yazdi AS. Differential induction of ATF3 and HO-1 in myeloid cells and keratinocytes via Dimethylfumarate or Cyclosporine A. J Dermatol Sci 2017. [PMID: 28633807 DOI: 10.1016/j.jdermsci.2017.06.005] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND Chronic inflammatory skin diseases are characterized by controlled proliferation of keratinocytes. Here, activating transcription factor 3 (ATF3) might play a fundamental role. In these inflammatory diseases, proliferation is controlled and only rarely leads to cancer development which can be supported by an inflammatory microenvironment. ATF3 is a dual function protein as it suppresses pro-inflammatory IL-6 and IL-8, but also acts as a pro-oncogenic factor by the suppression of p53. We therefore analyzed ATF3 expression comparing myeloid cells with keratinocytes. OBJECTIVE To dissect the bi-modal role of ATF3 we pharmacologically induced ATF3 and analyzed its influence on cytokine expression and secretion in a cell type specific manner. METHODS Since inflammatory skin diseases can be treated systemically with Cyclosporin A or Dimethylfumarate we stimulated myeloid cells and primary human keratinocytes with these drugs and analyzed gene expression by quantitative real-time PCR. Cytokine secretion was measured by ELISA. RESULTS In the present study, we could show that ATF3 is induced in PBMCs by DMF and weakly by Ebselen, while CsA is the most prominent inducer of ATF3 in keratinocytes without enhancing HO-1 transcription. Further we could show that induction of stress by LPS treatment elevates IL-1β and IL-6 and weakly ATF3 transcription in PBMCs. While transcription of both cytokines is elevated, LPS treatment mediates IL-6 secretion with only little IL-1β secretion. Treatment with DMF dampens LPS-induced transcription. CONCLUSIONS Taken together, our results shed light into the different carcinogenic potential of CsA and DMF, which both target ATF3. Collectively our data demonstrate that CsA strongly induces pro-carcinogenic ATF3 in keratinocytes, whereas ATF3 induction by DMF in myeloid cells acts anti-inflammatory.
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Affiliation(s)
- Stefanie Müller
- Department of Dermatology, Eberhard Karls University, Liebermeisterstr. 25, D-72076 Tübingen, Germany
| | - Nikola Smatlik
- Department of Dermatology, Eberhard Karls University, Liebermeisterstr. 25, D-72076 Tübingen, Germany
| | - Marc Burian
- Department of Dermatology, Eberhard Karls University, Liebermeisterstr. 25, D-72076 Tübingen, Germany
| | - Kamran Ghoreschi
- Department of Dermatology, Eberhard Karls University, Liebermeisterstr. 25, D-72076 Tübingen, Germany
| | - Martin Röcken
- Department of Dermatology, Eberhard Karls University, Liebermeisterstr. 25, D-72076 Tübingen, Germany
| | - Amir S Yazdi
- Department of Dermatology, Eberhard Karls University, Liebermeisterstr. 25, D-72076 Tübingen, Germany.
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Gieselbach RJ, Muller-Hansma AH, Wijburg MT, de Bruin-Weller MS, van Oosten BW, Nieuwkamp DJ, Coenjaerts FE, Wattjes MP, Murk JL. Progressive multifocal leukoencephalopathy in patients treated with fumaric acid esters: a review of 19 cases. J Neurol 2017; 264:1155-1164. [PMID: 28536921 DOI: 10.1007/s00415-017-8509-9] [Citation(s) in RCA: 65] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2017] [Revised: 05/03/2017] [Accepted: 05/05/2017] [Indexed: 11/25/2022]
Abstract
Progressive multifocal leukoencephalopathy (PML) is a rare and potentially fatal condition caused by a brain infection with JC polyomavirus (JCV). PML develops almost exclusively in immunocompromised patients and has recently been associated with use of fumaric acid esters (FAEs), or fumarates. We reviewed the literature and the Dutch and European pharmacovigilance databases in order to identify all available FAE-associated PML cases and distinguish possible common features among these patients. A total of 19 PML cases associated with FAE use were identified. Five cases were associated with FAE use for multiple sclerosis and 14 for psoriasis. Ten patients were male and nine were female. The median age at PML diagnosis was 59 years. The median duration of FAE therapy to PML symptom onset or appearance of first PML lesion on brain imaging was 31 months (range 6-110). In all cases a certain degree of lymphocytopenia was reported. The median duration of lymphocytopenia to PML symptom onset was 23 months (range 6-72). The median lymphocyte count at PML diagnosis was 414 cells/µL. CD4 and CD8 counts were reported in ten cases, with median cell count of 137 and 39 cells/µL, respectively. Three patients died (16% mortality). The association between occurrence of PML in patients with low CD4 and CD8 counts is reminiscent of PML cases in the HIV population and suggests that loss of T cells is the most important risk factor.
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Affiliation(s)
- Robbert-Jan Gieselbach
- Department of Medical Microbiology and Infection Control, University Medical Center Utrecht, Utrecht, The Netherlands
| | | | - Martijn T Wijburg
- Department of Neurology, Neuroscience Amsterdam, VUmc MS Center Amsterdam, VU University Medical Center, Amsterdam, The Netherlands
- Department of Radiology and Nuclear Medicine, Neuroscience Amsterdam, VUmc MS Center Amsterdam, VU University Medical Center, Amsterdam, The Netherlands
| | | | - Bob W van Oosten
- Department of Neurology, Neuroscience Amsterdam, VUmc MS Center Amsterdam, VU University Medical Center, Amsterdam, The Netherlands
| | - Dennis J Nieuwkamp
- Department of Neurology, Jeroen Bosch Hospital, 's-Hertogenbosch, The Netherlands
| | - Frank E Coenjaerts
- Department of Medical Microbiology and Infection Control, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Mike P Wattjes
- Department of Radiology and Nuclear Medicine, Neuroscience Amsterdam, VUmc MS Center Amsterdam, VU University Medical Center, Amsterdam, The Netherlands
| | - Jean-Luc Murk
- Laboratory of Medical Microbiology and Immunology, St. Elisabeth Hospital Tilburg, Tilburg, The Netherlands.
- Laboratory of Medical Microbiology and Immunology, St. Elisabeth TweeSteden ziekenhuis (ETZ), Hilvarenbeekseweg 60, 5022 GC, Tilburg, The Netherlands.
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Balak DMW, Hajdarbegovic E, Bramer WM, Neumann HAM, Thio HB. Progressive multifocal leukoencephalopathy associated with fumaric acid esters treatment in psoriasis patients. J Eur Acad Dermatol Venereol 2017; 31:1475-1482. [PMID: 28322482 DOI: 10.1111/jdv.14236] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2016] [Accepted: 02/27/2017] [Indexed: 12/23/2022]
Abstract
BACKGROUND Fumaric acid esters (FAEs) are a systemic treatment for psoriasis considered to have a favourable long-term safety profile without an increased risk for immunosuppression. However, progressive multifocal leukoencephalopathy (PML), a rare, opportunistic viral infection of the central nervous system, has been linked anecdotally to FAE treatment. OBJECTIVE To assess clinical features and outcomes of FAE-associated PML cases. METHODS Systematic literature search in multiple databases up to 25th February 2016 for reports of PML in psoriasis patients treated with FAEs. RESULTS Eight cases (four male, four female) of FAE-associated PML were identified. Median age was 64 years (range 42-74 years); median FAE treatment duration was 3 years (range 1.5-5 years). Six patients were treated with a formulation containing dimethyl fumarate (DMF) and monoethyl fumarates, and two patients with a DMF formulation. Patients exhibited neurological symptoms, such as aphasia, hemiparesis and dysarthria. PML diagnosis was based on MRI findings and presence of JC virus in cerebrospinal fluid and/or brain tissue. All cases were linked to moderate-to-severe reductions in absolute lymphocyte counts, with nadirs ranging from 200 to 792 cells per mm3 . Median exposure to lymphocytopenia was 2 years (range 1-5 years). In all cases, FAE treatment was discontinued; PML was treated with mefloquine plus mirtazapine. Three patients improved, two had stable disease, two had residual symptoms, and one patient died to an immune reconstitution inflammatory syndrome. CONCLUSION Progressive multifocal leukoencephalopathy is infrequently linked to FAE treatment, but underreporting cannot be excluded. Physicians treating patients with FAEs should be vigilant for the occurrence of PML, and both clinicians and patients should be alert for onset of new neurological symptoms. Periodic monitoring of lymphocyte counts and FAE discontinuation in case of moderate-to-severe lymphocytopenia is recommended to minimize the risk for PML.
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Affiliation(s)
- D M W Balak
- Department of Dermatology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
| | - E Hajdarbegovic
- Department of Dermatology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
| | - W M Bramer
- Medical Library, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
| | - H A M Neumann
- Department of Dermatology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
| | - H B Thio
- Department of Dermatology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
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Kastrati I, Siklos MI, Brovkovych SD, Thatcher GRJ, Frasor J. A Novel Strategy to Co-target Estrogen Receptor and Nuclear Factor κB Pathways with Hybrid Drugs for Breast Cancer Therapy. Discov Oncol 2017; 8:135-142. [PMID: 28396978 DOI: 10.1007/s12672-017-0294-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2017] [Accepted: 03/22/2017] [Indexed: 12/11/2022] Open
Abstract
Nearly 75% of breast tumors express estrogen receptor (ER), and will be treated with endocrine therapy, such as selective estrogen receptor modulator (SERM), tamoxifen, or aromatase inhibitors. Despite their proven success, as many as 40-50% of ER+ tumors fail to respond to endocrine therapy and eventually recur as aggressive, metastatic cancers. Therefore, preventing and/or overcoming endocrine resistance in ER+ tumors remains a major clinical challenge. Deregulation or activation of the nuclear factor κB (NFκB) pathway has been implicated in endocrine resistance and poor patient outcome in ER+ tumors. As a consequence, one option to improve on existing anti-cancer treatment regimens may be to introduce additional anti-NFκB activity to endocrine therapy drugs. Our approach was to design and test SERM-fumarate co-targeting hybrid drugs capable of simultaneously inhibiting both ER, via the SERM, raloxifene, and the NFκB pathway, via fumarate, in breast cancer cells. We find that the hybrid drugs display improved anti-NFκB pathway inhibition compared to either raloxifene or fumarate. Despite some loss in potency against the ER pathway, these hybrid drugs maintain anti-proliferative activity in ER+ breast cancer cells. Furthermore, these drugs prevent clonogenic growth and mammosphere formation of ER+ breast cancer cells. As a proof-of-principle, the simultaneous inhibition of ER and NFκB via a single bifunctional hybrid drug may represent a viable approach to improve the anti-inflammatory activity and prevent therapy resistance of ER-targeted anti-cancer drugs.
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Affiliation(s)
- Irida Kastrati
- Department of Physiology and Biophysics, College of Medicine, University of Illinois at Chicago, 835 S. Wolcott, E202 MSB, MC90, Chicago, IL, 60612, USA.
| | - Marton I Siklos
- Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, IL, 60612, USA
| | - Svitlana D Brovkovych
- Department of Physiology and Biophysics, College of Medicine, University of Illinois at Chicago, 835 S. Wolcott, E202 MSB, MC90, Chicago, IL, 60612, USA
| | - Gregory R J Thatcher
- Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, IL, 60612, USA
| | - Jonna Frasor
- Department of Physiology and Biophysics, College of Medicine, University of Illinois at Chicago, 835 S. Wolcott, E202 MSB, MC90, Chicago, IL, 60612, USA.
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Popova EV, Boyko AN, Orlova EV. [Dimethylfumarate in the treatment of relapsing-remitting multiple sclerosis]. Zh Nevrol Psikhiatr Im S S Korsakova 2017; 116:68-72. [PMID: 28139614 DOI: 10.17116/jnevro201611610268-72] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
This review includes results of experimental and clinical studies of dimethyl fumarate, a new oral drug for pathogenetic treatment of multiple sclerosis (MS). The mechanism of action, data from clinical trials, including MRI-results related to tolerability and safety of the drug are reviewed. The risk management plan for possible adverse events and a place of dimethyl fumarate in the current pathogenetic treatment of MS are discussed.
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Affiliation(s)
- E V Popova
- City Clinical Hospital #24, Moscow, Russia; Pirogov Russian National Resaerch Medical University, Moscow, Russia
| | - A N Boyko
- City Clinical Hospital #24, Moscow, Russia; Pirogov Russian National Resaerch Medical University, Moscow, Russia
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Eminel S, Jin N, Rostami M, Dibbert S, Mrowietz U, Suhrkamp I. Dimethyl- and monomethylfumarate regulate indoleamine 2,3-dioxygenase (IDO) activity in human immune cells. Exp Dermatol 2016; 26:685-690. [DOI: 10.1111/exd.13138] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/29/2016] [Indexed: 12/31/2022]
Affiliation(s)
- Sevgi Eminel
- Psoriasis-Center; Department of Dermatology; University Medical Center Schleswig- Holstein; Kiel Germany
| | - Na Jin
- Psoriasis-Center; Department of Dermatology; University Medical Center Schleswig- Holstein; Kiel Germany
| | - Martin Rostami
- Psoriasis-Center; Department of Dermatology; University Medical Center Schleswig- Holstein; Kiel Germany
| | - Stefan Dibbert
- Psoriasis-Center; Department of Dermatology; University Medical Center Schleswig- Holstein; Kiel Germany
| | - Ulrich Mrowietz
- Psoriasis-Center; Department of Dermatology; University Medical Center Schleswig- Holstein; Kiel Germany
| | - Ina Suhrkamp
- Psoriasis-Center; Department of Dermatology; University Medical Center Schleswig- Holstein; Kiel Germany
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Mrowietz U, Szepietowski J, Loewe R, van de Kerkhof P, Lamarca R, Ocker W, Tebbs V, Pau-Charles I. Efficacy and safety of LAS41008 (dimethyl fumarate) in adults with moderate-to-severe chronic plaque psoriasis: a randomized, double-blind, Fumaderm®- and placebo-controlled trial (BRIDGE). Br J Dermatol 2016; 176:615-623. [DOI: 10.1111/bjd.14947] [Citation(s) in RCA: 80] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/09/2016] [Indexed: 01/05/2023]
Affiliation(s)
- U. Mrowietz
- Psoriasis Center at the Department of Dermatology; University Medical Center Schleswig-Holstein, Campus Kiel; Schittenhelmstraße 7 24105 Kiel Germany
| | - J.C. Szepietowski
- Department of Dermatology, Venereology and Allergology; Wroclaw Medical University; Wroclaw Poland
| | - R. Loewe
- Department of Dermatology; Medical University of Vienna; Vienna Austria
| | - P. van de Kerkhof
- Department of Dermatology; Radboud University Medical Center; Nijmegen the Netherlands
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Jüngst C, Kim YJ, Lammert F. Severe drug-induced liver injury related to therapy with dimethyl fumarate. Hepatology 2016; 64:1367-9. [PMID: 27228386 DOI: 10.1002/hep.28652] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2016] [Accepted: 05/08/2016] [Indexed: 12/07/2022]
Affiliation(s)
- Christoph Jüngst
- Department of Medicine II, Saarland University Medical Center, Homburg, Germany.
| | - Yoo-Jin Kim
- Institute of Pathology, Saarland University, Saarland University Medical Center, Homburg, Germany
| | - Frank Lammert
- Department of Medicine II, Saarland University Medical Center, Homburg, Germany
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van Bezooijen JS, Balak DMW, van Doorn MBA, Looman CWN, Schreurs MWJ, Koch BCP, van Gelder T, Prens EP. Combination Therapy of Etanercept and Fumarates versus Etanercept Monotherapy in Psoriasis: A Randomized Exploratory Study. Dermatology 2016; 232:407-14. [PMID: 27576483 DOI: 10.1159/000448135] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2016] [Accepted: 07/02/2016] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Biologics are a safe and efficacious therapy for psoriasis. The drug survival of biologics may be disappointing, primarily due to loss of efficacy. Therefore, safe combination treatments are sought to improve their clinical response. OBJECTIVE To assess the efficacy, safety and tolerability of the combination therapy of etanercept with fumarates versus etanercept monotherapy. METHODS Thirty-three patients with psoriasis were randomized 1:1 to receive etanercept combined with fumarates or etanercept monotherapy. The primary outcome measure was the difference in PASI-75 response after 24 weeks; additionally, a longitudinal analysis was performed. An important secondary outcome measure was the proportion of patients with a Physician Global Assessment (PGA) of clear or almost clear. Adverse events were collected throughout the study. RESULTS In the combination therapy group, 78% (14 out of 18 patients) reached PASI-75 at week 24 versus 57% (8 out of 14 patients) in the monotherapy group (p = 0.27). The longitudinal analysis showed a PASI reduction of 5.97% per week for the combination therapy group and of 4.76% for the monotherapy group (p = 0.11). In the combination therapy group, 94% (17 out of 18 patients) of patients had a PGA of clear/almost clear versus 64% (9 out of 14 patients) in the monotherapy group (p = 0.064). The incidence of mild gastrointestinal complaints was higher in the combination group than in the monotherapy group. CONCLUSION Using the PGA, combination therapy showed a trend towards faster improvement in the first 24 weeks. The difference in the PASI score between the two groups was not statistically significant. Addition of fumarates to etanercept for 48 weeks appeared safe with an acceptable tolerability.
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Kretzschmar B, Pellkofer H, Weber MS. The Use of Oral Disease-Modifying Therapies in Multiple Sclerosis. Curr Neurol Neurosci Rep 2016; 16:38. [PMID: 26944956 DOI: 10.1007/s11910-016-0639-4] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Three oral disease-modifying drugs-fingolimod, teriflunomide, and dimethyl fumarate (DMF)-are available for treatment of relapsing forms of multiple sclerosis (MS). All three agents were approved in the last decade, primarily on the basis of a moderate to substantial reduction in the occurrence of MS relapses and central nervous system lesion formation detected by MRI. In the trials leading to approval, the first oral disease-modifying drug, fingolimod, reduced the annualized relapse rate (ARR) from 0.40 in placebo-treated patients to 0.18 (FREEDOMS) and from 0.33 in patients treated with interferon β1a intramuscularly to 0.16 (TRANSFORMS). Teriflunomide, approved on the basis of the two placebo-controlled trials TEMSO and TOWER, demonstrated a reduction in the ARR from 0.54 to 0.37 and from 0.50 to 0.32 respectively. The latest oral MS medication, approved in 2014, is DMF, which had been used in a different formulation for treatment of psoriasis for decades. In the 2-year DEFINE study, the proportion of patients with a relapse was reduced to 27 %, compared with 46 % in placebo arm, whereas in the CONFIRM trial, the ARR was reduced from 0.40 (placebo) to 0.22 in the DMF-treated group of patients. In this review, we will elucidate the mechanisms of action of these three medications and compare their efficacy, safety, and tolerability as a practical guideline for their use. We will further discuss effects other than relapse reduction these small molecules may exert, including potential activities within the central nervous system, and briefly summarize emerging data on new oral MS drugs in clinical development.
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Affiliation(s)
- Benedikt Kretzschmar
- Department of Neurology, University Medical Center, 37075, Göttingen, Germany
- Doctor's Office Knaak/Christmann/Wüstenhagen of Neurology and Psychiatry, 34346, Hann. Münden, Germany
| | - Hannah Pellkofer
- Department of Neurology, University Medical Center, 37075, Göttingen, Germany
- Institute of Neuropathology, University Medical Center, 37075, Göttingen, Germany
| | - Martin S Weber
- Department of Neurology, University Medical Center, 37075, Göttingen, Germany.
- Institute of Neuropathology, University Medical Center, 37075, Göttingen, Germany.
- Department of Neuropathology, Department of Neurology, University Medical Center, Georg August University, Robert-Koch-Str. 40, 37099, Göttingen, Germany.
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Balak D, Fallah Arani S, Hajdarbegovic E, Hagemans C, Bramer W, Thio H, Neumann H. Efficacy, effectiveness and safety of fumaric acid esters in the treatment of psoriasis: a systematic review of randomized and observational studies. Br J Dermatol 2016; 175:250-62. [DOI: 10.1111/bjd.14500] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/15/2016] [Indexed: 12/11/2022]
Affiliation(s)
- D.M.W. Balak
- Department of Dermatology; Erasmus MC; University Medical Center; Rotterdam the Netherlands
| | - S. Fallah Arani
- Department of Dermatology; Erasmus MC; University Medical Center; Rotterdam the Netherlands
| | - E. Hajdarbegovic
- Department of Dermatology; Erasmus MC; University Medical Center; Rotterdam the Netherlands
| | - C.A.F. Hagemans
- Department of Dermatology; Erasmus MC; University Medical Center; Rotterdam the Netherlands
| | - W.M. Bramer
- Medical Library; Erasmus MC; University Medical Center; Rotterdam the Netherlands
| | - H.B. Thio
- Department of Dermatology; Erasmus MC; University Medical Center; Rotterdam the Netherlands
| | - H.A.M. Neumann
- Department of Dermatology; Erasmus MC; University Medical Center; Rotterdam the Netherlands
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Fumaric acid esters for psoriasis: a systematic review. Ir J Med Sci 2016; 186:161-177. [PMID: 27271164 DOI: 10.1007/s11845-016-1470-2] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2015] [Accepted: 05/16/2016] [Indexed: 11/27/2022]
Abstract
BACKGROUND Psoriasis is a chronic skin disease associated with increased morbidity and mortality. Effective and safe long term treatment options are required to manage the illness successfully. A number of systemic agents are available, however, each of them has potentially significant side effects. Fumaric acid esters (FAE) are used first line in Germany for the management of moderate to severe psoriasis, however, their use in Ireland is on an unlicensed basis (Clinical and Experimental Dermatology 37:786-801, 2012). OBJECTIVES The purpose of this literature review is to evaluate the efficacy and safety of FAEs in the management of moderate to severe psoriasis in adult patients. The reviewer intends to systematically review all available literature on the efficacy and/or safety of fumaric acid esters in the management of moderate to severe psoriasis in adult patients. METHODS A systematic review of the literature was performed by one reviewer. The PubMed, TRIP, Embase, and Cochrane Collaboration databases were systematically interrogated to include randomised controlled trials, cohort studies and case studies evaluating the efficacy and/or safety of FAEs in the management of moderate to severe psoriasis in adult patients. Inclusion criteria were studies which included adults over 18 years of age, with a diagnosis of moderate to severe chronic plaque psoriasis, who were treated with FAEs and no other systemic anti-psoriatic agents concurrently. Exclusion criteria were studies involving children, mild psoriasis, studies which did not include patients with chronic plaque psoriasis, the use of FAE for the management of illnesses other than psoriasis, and patients treated with more than one systemic anti-psoriatic agent concurrently. RESULTS In total 19 articles were selected for review including 2 randomised placebo controlled trials, 1 non-randomised comparative study, 7 retrospective cohort studies, 2 prospective cohort studies and 7 case studies. The findings suggest that FAEs are a safe and effective treatment option for the management of moderate to severe psoriasis in adult patients. Gastrointestinal side effects may occur on treatment initiation and may be minimised by slow dose titration. Lymphocytopenia and eosinophilia are common, however, they are rarely of significance and there is no high level of evidence available to suggest a resultant increased risk of infection or malignancy. Rarely alterations of renal and hepatic function may occur, however, these are largely reversible on treatment withdrawal. CONCLUSION In conclusion, the use of FAE in the management of moderate to severe psoriasis is a promising treatment option, especially for those patients intolerant of, or unresponsive to other agents. If blood parameters are closely monitored during treatment as per the European Medicine Agencies guidelines (European Medicines Agency, 'Updated recommendations to minimise the risk of the rare brain infection PML with Tecfidera', http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2015/10/WC500196017.pdf , 2015) they may be safely used in practice. The licensing of FAEs in Ireland for the treatment of moderate to severe psoriasis would be desirable, increasing available treatment options.
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Prosperini L, Pontecorvo S. Dimethyl fumarate in the management of multiple sclerosis: appropriate patient selection and special considerations. Ther Clin Risk Manag 2016; 12:339-50. [PMID: 27042079 PMCID: PMC4780395 DOI: 10.2147/tcrm.s85099] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Delayed-release dimethyl fumarate (DMF), also known as gastroresistant DMF, is the most recently approved oral disease-modifying treatment (DMT) for relapsing multiple sclerosis. Two randomized clinical trials (Determination of the Efficacy and Safety of Oral Fumarate in Relapsing-Remitting MS [DEFINE] and Comparator and an Oral Fumarate in Relapsing-Remitting Multiple Sclerosis [CONFIRM]) demonstrated significant efficacy in reducing relapse rate and radiological signs of disease activity, as seen on magnetic resonance imaging. The DEFINE study also indicated a significant effect of DMF on disability worsening, while the low incidence of confirmed disability worsening in the CONFIRM trial rendered an insignificant reduction among the DMF-treated groups when compared to placebo. DMF also demonstrated a good safety profile and acceptable tolerability, since the most common side effects (gastrointestinal events and flushing reactions) are usually transient and mild to moderate in severity. Here, we discuss the place in therapy of DMF for individuals with relapsing multiple sclerosis, providing a tentative therapeutic algorithm to manage newly diagnosed patients and those who do not adequately respond to self-injectable DMTs. Literature data supporting the potential role of DMF as a first-line therapy are presented. The possibility of using DMF as switching treatment or even as an add-on strategy in patients with breakthrough disease despite self-injectable DMTs will also be discussed. Lastly, we argue about the role of DMF as an exit strategy from natalizumab-treated patients who are considered at risk for developing multifocal progressive leukoencephalopathy.
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Affiliation(s)
- Luca Prosperini
- Department of Neurology and Psychiatry, Sapienza University, Rome, Italy
| | - Simona Pontecorvo
- Department of Neurology and Psychiatry, Sapienza University, Rome, Italy
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Abstract
PURPOSE OF REVIEW The purpose of this review is to summarize mechanisms of action, efficacy and safety of established disease-modifying treatments (DMTs) that have been widely approved for use in relapsing-remitting multiple sclerosis (RRMS). RECENT FINDINGS Established and widely used DMTs for the treatment of RRMS include the interferon-β agents, glatiramer acetate, natalizumab, fingolimod, teriflunomide and dimethyl fumarate. These DMTs have quite different mechanisms of action, efficacy and safety and tolerability profiles, which are summarized concisely in the article below. SUMMARY The treatment algorithm for RRMS is becoming increasingly complex with the ever-expanding armamentarium of DMTs. The choice of DMT will become an increasingly individual decision, based on a number of factors, including disease activity and severity, safety/tolerability profile and patient preference. Neurologists treating patients with multiple sclerosis (MS) will need a thorough knowledge of efficacy, safety and tolerability of the spectrum of DMTs available for treatment of RRMS to provide comprehensive clinical care.
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Mahajan VK. Psoriasis treatment: Unconventional and non-standard modalities in the era of biologics. World J Dermatol 2016; 5:17. [DOI: 10.5314/wjd.v5.i1.17] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2015] [Revised: 10/25/2015] [Accepted: 12/18/2015] [Indexed: 02/06/2023] Open
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Kastrati I, Siklos MI, Calderon-Gierszal EL, El-Shennawy L, Georgieva G, Thayer EN, Thatcher GRJ, Frasor J. Dimethyl Fumarate Inhibits the Nuclear Factor κB Pathway in Breast Cancer Cells by Covalent Modification of p65 Protein. J Biol Chem 2015; 291:3639-47. [PMID: 26683377 DOI: 10.1074/jbc.m115.679704] [Citation(s) in RCA: 103] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2015] [Indexed: 01/08/2023] Open
Abstract
In breast tumors, activation of the nuclear factor κB (NFκB) pathway promotes survival, migration, invasion, angiogenesis, stem cell-like properties, and resistance to therapy--all phenotypes of aggressive disease where therapy options remain limited. Adding an anti-inflammatory/anti-NFκB agent to breast cancer treatment would be beneficial, but no such drug is approved as either a monotherapy or adjuvant therapy. To address this need, we examined whether dimethyl fumarate (DMF), an anti-inflammatory drug already in clinical use for multiple sclerosis, can inhibit the NFκB pathway. We found that DMF effectively blocks NFκB activity in multiple breast cancer cell lines and abrogates NFκB-dependent mammosphere formation, indicating that DMF has anti-cancer stem cell properties. In addition, DMF inhibits cell proliferation and significantly impairs xenograft tumor growth. Mechanistically, DMF prevents p65 nuclear translocation and attenuates its DNA binding activity but has no effect on upstream proteins in the NFκB pathway. Dimethyl succinate, the inactive analog of DMF that lacks the electrophilic double bond of fumarate, is unable to inhibit NFκB activity. Also, the cell-permeable thiol N-acetyl l-cysteine, reverses DMF inhibition of the NFκB pathway, supporting the notion that the electrophile, DMF, acts via covalent modification. To determine whether DMF interacts directly with p65, we synthesized and used a novel chemical probe of DMF by incorporating an alkyne functionality and found that DMF covalently modifies p65, with cysteine 38 being essential for the activity of DMF. These results establish DMF as an NFκB inhibitor with anti-tumor activity that may add therapeutic value in the treatment of aggressive breast cancers.
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Affiliation(s)
| | - Marton I Siklos
- Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, Chicago, Illinois 60612
| | | | | | | | - Emily N Thayer
- Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, Chicago, Illinois 60612
| | - Gregory R J Thatcher
- Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, Chicago, Illinois 60612
| | - Jonna Frasor
- From the Departments of Physiology and Biophysics and
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Dubey D, Kieseier BC, Hartung HP, Hemmer B, Warnke C, Menge T, Miller-Little WA, Stuve O. Dimethyl fumarate in relapsing-remitting multiple sclerosis: rationale, mechanisms of action, pharmacokinetics, efficacy and safety. Expert Rev Neurother 2015; 15:339-46. [PMID: 25800129 DOI: 10.1586/14737175.2015.1025755] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
Dimethyl fumarate (DMF), a fumaric acid ester, is a new orally available disease-modifying agent that was recently approved by the US FDA and the EMA for the management of relapsing forms of multiple sclerosis (MS). Fumaric acid has been used for the management of psoriasis, for more than 50 years. Because of the known anti-inflammatory properties of fumaric acid ester, DMF was brought into clinical development in MS. More recently, neuroprotective and myelin-protective mechanism actions have been proposed, making it a possible candidate for MS treatment. Two Phase III clinical trials (DEFINE, CONFIRM) have evaluated the safety and efficacy of DMF in patients with relapsing-remitting MS. Being an orally available agent with a favorable safety profile, it has become one of the most commonly prescribed disease-modifying agents in the USA and Europe.
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Balak DMW, Bouwes Bavinck JN, de Vries APJ, Hartman J, Neumann HAM, Zietse R, Thio HB. Drug-induced Fanconi syndrome associated with fumaric acid esters treatment for psoriasis: a case series. Clin Kidney J 2015; 9:82-9. [PMID: 26798466 PMCID: PMC4720194 DOI: 10.1093/ckj/sfv114] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2015] [Accepted: 10/12/2015] [Indexed: 01/02/2023] Open
Abstract
BACKGROUND Fumaric acid esters (FAEs), an oral immunomodulating treatment for psoriasis and multiple sclerosis, have been anecdotally associated with proximal renal tubular dysfunction due to a drug-induced Fanconi syndrome. Few data are available on clinical outcomes of FAE-induced Fanconi syndrome. METHODS Descriptive case series with two cases of Fanconi syndrome associated with FAE treatment diagnosed at two Dutch university nephrology departments, three cases reported at the Dutch and German national pharmacovigilance databases and six previously reported cases. RESULTS All 11 cases involved female patients with psoriasis. The median age at the time of onset was 38 years [interquartile range (IQR) 37-46]. Patients received long-term FAEs treatment with a median treatment duration of 60 months (IQR 28-111). Laboratory tests were typically significant for low serum levels of phosphate and uric acid, while urinalysis showed glycosuria and proteinuria. Eight (73%) patients had developed a hypophosphataemic osteomalacia and three (27%) had pathological bone fractures. All patients discontinued FAEs, while four (36%) patients were treated with supplementation of phosphate and/or vitamin D. Five (45%) patients had persisting symptoms despite FAEs discontinuation. CONCLUSIONS FAEs treatment can cause drug-induced Fanconi syndrome, but the association has been reported infrequently. Female patients with psoriasis treated long term with FAEs seem to be particularly at risk. Physicians treating patients with FAEs should be vigilant and monitor for the potential occurrence of Fanconi syndrome. Measurement of the urinary albumin:total protein ratio is a suggested screening tool for tubular proteinuria in Fanconi syndrome.
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Affiliation(s)
- Deepak M W Balak
- Department of Dermatology , Erasmus Medical Center , Rotterdam , The Netherlands
| | | | - Aiko P J de Vries
- Division of Nephrology, Department of Medicine , Leiden University Medical Center , Leiden , The Netherlands
| | - Jenny Hartman
- Netherlands Pharmacovigilance Centre Lareb , 's-Hertogenbosch , The Netherlands
| | | | - Robert Zietse
- Division of Nephrology and Transplantation, Department of Internal Medicine , Erasmus Medical Center , Rotterdam , The Netherlands
| | - Hok Bing Thio
- Department of Dermatology , Erasmus Medical Center , Rotterdam , The Netherlands
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Das RK, Brar SK, Verma M. Recent advances in the biomedical applications of fumaric acid and its ester derivatives: The multifaceted alternative therapeutics. Pharmacol Rep 2015; 68:404-14. [PMID: 26922546 DOI: 10.1016/j.pharep.2015.10.007] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2015] [Revised: 10/17/2015] [Accepted: 10/19/2015] [Indexed: 12/29/2022]
Abstract
Several lines of evidence have demonstrated the potential biomedical applications of fumaric acid (FA) and its ester derivatives against many human disease conditions. Fumaric acid esters (FAEs) have been licensed for the systemic treatment of the immune-mediated disease psoriasis. Biogen Idec Inc. announced about the safety and efficacy of the formulation FAE (BG-12) for treating RRMS (relapsing-remitting multiple sclerosis). Another FAE formulation DMF (dimethyl fumarate) was found to be capable of reduction in inflammatory cardiac conditions, such as autoimmune myocarditis and ischemia and reperfusion. DMF has also been reported to be effective as a potential neuroprotectant against the HIV-associated neurocognitive disorders (HAND). Many in vivo studies carried out on rat and mice models indicated inhibitory effects of fumaric acid on carcinogenesis of different origins. Moreover, FAEs has emerged as an important matrix ingredient in the fabrication of biodegradable scaffolds for tissue engineering applications. Drug delivery vehicles composed of FAEs have shown promising results in delivering some leading drug molecules. Apart from these specific applications and findings, many more studies on FAEs have revealed new therapeutic potentials with the scope of clinical applications. However, until now, this scattered vital information has not been written into a collective account and analyzed for minute details. The aim of this paper is to review the advancement made in the biomedical application of FA and FAEs and to focus on the clinical investigation and molecular interpretation of the beneficial effects of FA and FAEs.
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