Effects of Delgocitinib Ointment 0.5% on the Normal Mouse Skin and Epidermal Tight Junction Proteins in Comparison With Topical Corticosteroids

2020 ◽  
Vol 48 (8) ◽  
pp. 1008-1016
Author(s):  
Akiko Anagawa-Nakamura ◽  
Katsunori Ryoke ◽  
Yuzo Yasui ◽  
Toshiyuki Shoda ◽  
Shoichiro Sugai
Keyword(s):  
Tight Junction ◽  
Immunohistochemical Staining ◽  
Kinase Inhibitor ◽  
Mouse Skin ◽  
Janus Kinase ◽  
Skin Atrophy ◽  
Barrier Dysfunction ◽  
Once Daily ◽  
Topical Corticosteroids

Delgocitinib ointment 0.5% is the world’s first topical Janus kinase inhibitor product and was approved for treatment of atopic dermatitis (AD) in Japan. Although topical corticosteroids (TCSs) have been the mainstay of pharmacotherapy in AD over the past decades, long-term use of TCSs causes skin atrophy and alteration of the epidermal tight junction (TJ) leading to epidermal barrier dysfunction. In this study, delgocitinib ointment 0.5% or representative TCSs of different potencies were applied dermally once daily to the ear pinna of normal ICR mice for 14 days, and ear pinna thickness, histopathology, and immunohistochemistry for epidermal TJ proteins claudin-1 and -4 were evaluated. All the TCSs caused decreases in ear pinna thickness with epidermal thinning, sebaceous gland atrophy, and atrophy/decreased number of the subcutaneous adipocytes and decreased immunohistochemical staining intensity for epidermal claudins. In contrast, delgocitinib ointment 0.5% did not cause any of those changes. In conclusion, once daily topical delgocitinib ointment 0.5% for 14 days did not cause skin atrophy or decreased immunohistochemical staining of epidermal claudins, which are common safety concerns associated with TCSs. These characteristics suggest that delgocitinib ointment 0.5% has an improved safety profile over currently available TCS therapies particular for the long-term AD treatment.

scholarly journals Long‐term safety and efficacy of delgocitinib ointment, a topical Janus kinase inhibitor, in adult patients with atopic dermatitis

2019 ◽  
Vol 47 (2) ◽  
pp. 114-120 ◽  
Author(s):  
Hidemi Nakagawa ◽  
Osamu Nemoto ◽  
Atsuyuki Igarashi ◽  
Hidehisa Saeki ◽  
Ryusei Murata ◽  
...  
Keyword(s):  
Atopic Dermatitis ◽  
Kinase Inhibitor ◽  
Janus Kinase ◽  
Adult Patients ◽  
Janus Kinase Inhibitor ◽  
Safety And Efficacy

scholarly journals Oral Janus Kinase Inhibitor for the Treatment of Rheumatoid Arthritis: Tofacitinib

2013 ◽  
Vol 2013 ◽  
pp. 1-9 ◽  
Author(s):  
Han Ni ◽  
Soe Moe ◽  
Kay Thi Myint ◽  
Aung Htet
Keyword(s):  
Rheumatoid Arthritis ◽  
Safety Profile ◽  
Kinase Inhibitor ◽  
Meta Analysis ◽  
Janus Kinase ◽  
Serious Adverse Events ◽  
Janus Kinase Inhibitor ◽  
Immune Modulators ◽  
Serious Infections

Since the introduction of immune modulators in the treatment of rheumatoid arthritis (RA), there has been hope that orally effective biologic agents would be developed. Tofacitinib, a Janus kinase inhibitor, has become the first oral biologic to receive approval for use in active RA patients. This paper reviews the efficacy and safety profile of Tofacitinib at dosages of 5 mg and 10 mg twice daily. Remarkable improvement in terms of ACR 20 response and HAQ-DI score was noted at month 3 and month 6. DAS 28-4 ESR < 2.6 achievement was noticeably obvious at month 6 for both dosages. No significant serious adverse events, serious infections, neutropenia, or anaemia were observed compared to placebo. In fact, Tofacitinib 5 mg was even found to have significant protective effect of anaemia in the meta-analysis (P=0.004). Tofacitinib has a noticeable efficacy in controlling disease activity in RA with a manageable safety profile. However, longer studies are needed for its long-term safety profile.

scholarly journals Lactobacillus casei and Epidermal Growth Factor Prevent Osmotic Stress-Induced Tight Junction Disruption in Caco-2 Cell Monolayers

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3578
Author(s):  
Geetha Samak ◽  
Rupa Rao ◽  
Radhakrishna Rao
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Osmotic Stress ◽  
Tight Junction ◽  
Lactobacillus Casei ◽  
Kinase Inhibitor ◽  
Adherens Junction ◽  
Barrier Dysfunction ◽  
Cell Monolayers ◽  
Epidermal Growth

Osmotic stress plays a crucial role in the pathogenesis of many gastrointestinal diseases. Lactobacillus casei and epidermal growth factor (EGF) effects on the osmotic stress-induced epithelial junctional disruption and barrier dysfunction were investigated. Caco-2 cell monolayers were exposed to osmotic stress in the presence or absence of L. casei or EGF, and the barrier function was evaluated by measuring inulin permeability. Tight junction (TJ) and adherens junction integrity were assessed by immunofluorescence confocal microscopy. The role of signaling molecules in the L. casei and EGF effects was determined by using selective inhibitors. Data show that pretreatment of cell monolayers with L. casei or EGF attenuates osmotic stress-induced TJ and adherens junction disruption and barrier dysfunction. EGF also blocked osmotic stress-induced actin cytoskeleton remodeling. U0126 (MEK1/2 inhibitor), the MAP kinase inhibitor, blocked EGF-mediated epithelial protection from osmotic stress. In contrast, the L. casei-mediated epithelial protection from osmotic stress was unaffected by U0126, AG1478 (EGFR tyrosine kinase inhibitor), SP600125 (JNK1/2 inhibitor), or SB202190 (P38 MAP kinase inhibitor). On the other hand, Ro-32-0432 (PKC inhibitor) blocked the L. casei-mediated prevention of osmotic stress-induced TJ disruption and barrier dysfunction. The combination of EGF and L. casei is more potent in protecting the barrier function from osmotic stress. These findings suggest that L. casei and EGF ameliorate osmotic stress-induced disruption of apical junctional complexes and barrier dysfunction in the intestinal epithelium by distinct signaling mechanisms.

Drug Interactions Between Peficitinib, an Orally Administered, Once-Daily Janus Kinase Inhibitor, and Rosuvastatin in Healthy Subjects

2016 ◽  
Vol 56 (7) ◽  
pp. 747-757 ◽  
Author(s):  
Tong Zhu ◽  
Barbara Parker ◽  
Tomasz Wojtkowski ◽  
Tetsuya Nishimura ◽  
Jay P. Garg ◽  
...  
Keyword(s):  
Drug Interactions ◽  
Healthy Subjects ◽  
Kinase Inhibitor ◽  
Janus Kinase ◽  
Once Daily ◽  
Janus Kinase Inhibitor

scholarly journals Safety of baricitinib for the treatment of rheumatoid arthritis over a median of 4.6 and up to 9.3 years of treatment: final results from long-term extension study and integrated database

2021 ◽  
pp. annrheumdis-2021-221276
Author(s):  
Peter C Taylor ◽  
Tsutomu Takeuchi ◽  
Gerd R Burmester ◽  
Patrick Durez ◽  
Josef S Smolen ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Kinase Inhibitor ◽  
Incidence Rates ◽  
Janus Kinase ◽  
Phase Iii ◽  
Major Adverse Cardiovascular Events ◽  
Integrated Analysis ◽  
Link Type ◽  
Serious Infections

ObjectiveTo report long-term safety from the completed extension trial of baricitinib, an oral selective Janus kinase inhibitor, in patients with active rheumatoid arthritis (RA).MethodsTreatment-emergent adverse events are summarised from an integrated database (9 phase III/II/Ib and 1 long-term extension) of patients who received any baricitinib dose (All-bari-RA). Standardised incidence ratio (SIR) for malignancy (excluding non-melanoma skin cancer (NMSC)) and standardised mortality ratio (SMR) were estimated. Additional analysis was done in a subset of patients who had ever taken 2 mg or 4 mg baricitinib.Results3770 patients received baricitinib (14 744 patient-years of exposure (PYE)). All-bari-RA incidence rates (IRs) per 100 patient-years at risk were 2.6, 3.0 and 0.5 for serious infections, herpes zoster and major adverse cardiovascular events (MACE), respectively. In patients aged ≥50 with ≥1 cardiovascular risk factor, the IR for MACE was 0.77 (95% CI 0.56 to 1.04). The IR for malignancy (excluding NMSC) during the first 48 weeks was 0.6 and remained stable thereafter (IR 1.0). The SIR for malignancies excluding NMSC was 1.07 (95% CI 0.90 to 1.26) and the SMR was 0.74 (95% CI 0.59 to 0.92). All-bari-RA IRs for deep vein thrombosis (DVT)/pulmonary embolism (PE), DVT and PE were 0.5 (95% CI 0.38 to 0.61), 0.4 (95% CI 0.26 to 0.45) and 0.3 (95% CI 0.18 to 0.35), respectively. No clear dose differences were noted for exposure-adjusted IRs (per 100 PYE) for deaths, serious infections, DVT/PE and MACE.ConclusionsIn this integrated analysis including long-term data of baricitinib from 3770 patients (median 4.6 years, up to 9.3 years) with active RA, baricitinib maintained a similar safety profile to earlier analyses. No new safety signals were identified.Trial registration numberNCT01185353, NCT00902486, NCT01469013, NCT01710358, NCT02265705, NCT01721044, NCT01721057, NCT01711359 and NCT01885078.

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