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Tofacitinib Treatment Safety in Moderate to Severe Ulcerative Colitis: Comparison of Observational Population Cohort Data From the IBM MarketScan® Administrative Claims Database With Tofacitinib Trial Data.
Curtis, JR, Regueiro, M, Yun, H, Su, C, DiBonaventura, M, Lawendy, N, Nduaka, CI, Koram, N, Cappelleri, JC, Chan, G, et al
Inflammatory bowel diseases. 2021;(9):1394-1408
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Abstract
BACKGROUND Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). We aimed to estimate the overall incidence of safety events in patients with UC in a real-life population cohort for comparison with the tofacitinib UC clinical trial program. METHODS Clinical trial-like criteria were applied to an IBM MarketScan® claims database population-based cohort (n = 22,967) of patients with UC (October 2010 to September 2015) to identify a UC trial-like cohort treated with tumor necrosis factor inhibitors (TNFi; n = 6366) to compare with the tofacitinib UC clinical trial cohort (n = 1157). RESULTS Incidence rates (events per 100 patient-years; [95% confidence interval]) in the UC trial-like cohort were as follows: serious infections, 3.33 (2.73-4.02); opportunistic infections (OIs; excluding herpes zoster [HZ]), 1.45 (1.06-1.93); HZ, 1.77 (1.34-2.29); malignancies (excluding nonmelanoma skin cancer [NMSC]), 0.63 (0.43-0.90); NMSC, 1.69 (1.35-2.10); major adverse cardiovascular events (MACE), 0.51 (0.31-0.79); pulmonary embolism (PE), 0.54 (0.30-0.89); deep vein thrombosis (DVT), 1.41 (1.00-1.93); and gastrointestinal perforations, 0.31 (0.16-0.54). Compared with the UC trial-like cohort, tofacitinib-treated patients had numerically lower incidence rates for serious infections (1.75 [1.27-2.36]), OIs (excluding HZ; 0.16 [0.04-0.42]), NMSC (0.78 [0.47-1.22]), PE (0.16 [0.04-0.41]), and DVT (0.04 [0.00-0.23]), and a higher rate for HZ (3.57 [2.84-4.43]); rates for malignancies (excluding NMSC), MACE, and gastrointestinal perforations were similar. CONCLUSIONS When acknowledging limitations of comparing claims data with controlled clinical trial data, incidence rates for HZ among TNFi-treated patients in the UC trial-like cohort were lower than in the tofacitinib UC clinical trial cohort; rates for serious infections, OIs, NMSC, PE, and DVT were numerically higher. CLINICALTRIALS.GOV: NCT00787202, NCT01465763, NCT01458951, NCT01458574, NCT01470612.
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Successful management with Janus kinase inhibitor tofacitinib in refractory juvenile dermatomyositis: a pilot study and literature review.
Yu, Z, Wang, L, Quan, M, Zhang, T, Song, H
Rheumatology (Oxford, England). 2021;(4):1700-1707
Abstract
OBJECTIVES JDM is a rare autoimmune inflammatory muscle disease with a pronounced IFN signature. Treatment for children with JDM has improved over the years with the use of steroids and immunosuppressive agents. However, there remains a subset of children who have refractory disease. Janus kinase and type I IFN signalling production are suspected to contribute to the pathogenesis of JDM. Our pilot study investigated the use of tofacitinib, a Janus kinase inhibitor, in refractory JDM cases to provide new therapeutic options for better treatment. METHODS Refractory JDM was defined as patients who failed two or more steroid sparing agents or high-dose steroids. Tofacitinib was given to three refractory JDM patients with a dose of 5 mg twice per day for at least 6 months. Core set measures defined by Pediatric Rheumatology International Trials Organization were evaluated at month 0, 3 and 6 along with other systemic evaluations. A literature review was conducted to identify all the cases using Janus kinase inhibitors in JDM. RESULTS All three subjects tolerated and responded well to tofacitinib with significant improvement in Child Myositis Assessment Scale, manual muscle testing-8, physician global disease activity and inflammatory indices without occurrence of severe adverse events. CONCLUSION This pilot study showed improvement of muscle strength, resolution of cutaneous lesions, increased daily quality of life and successful tapering of steroids when tofacitinib used in selected cases. Tofacitinib can be considered with caution when treating refractory JDM cases. Further randomized controlled trials are warranted to assess its efficacy in JDM.
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Insight into the Isolation, Synthesis, and Structure-Activity Relationship of Piperine Derivatives for the Development of New Compounds: Recent Updates.
Afreen, , Salahuddin, , Mazumder, A, Joshi, S, Kumar, R, Yar, MS, Ahsan, MJ
Current topics in medicinal chemistry. 2021;(30):2715-2751
Abstract
Currently, black pepper commands the leading position among all the spices as a spice of great commercial importance in all the world trade and finds its way into the dietary habits of millions of people worldwide. Black pepper is biologically known as Piper nigrum and contains piperine as the main active chemical constituent. This paper highlights various general methods for extracting piperine from the crude drug such as maceration extraction, hydrotropic extraction, accelerated solvent extraction, thin-layer chromatography, and extraction with ethanol & dichloromethane Ionic fluid-based ultrasonic-assisted extraction, etc. In this review, piperine and its analogs exhibit numerous pharmacological activities and synthetic schemes of insecticidal activity, anti-cancer activity, anti-inflammatory activity, anti-diabetic activity, anti-hyperlipidemic activity, antifungal activity, narcotic activity, etc. and its structure-activity relationship. The biochemistry of piperine has also been summarized in the presented article. This very exhaustive review details the complete information about piperine, its derivatives, and further processing. Furthermore, the current study summarises recent research that has linked piperine to its use as a treatment for a variety of ailments.
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Study of Tofacitinib in Refractory Dermatomyositis: An Open-Label Pilot Study of Ten Patients.
Paik, JJ, Casciola-Rosen, L, Shin, JY, Albayda, J, Tiniakou, E, Leung, DG, Gutierrez-Alamillo, L, Perin, J, Florea, L, Antonescu, C, et al
Arthritis & rheumatology (Hoboken, N.J.). 2021;(5):858-865
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Abstract
OBJECTIVE This open-label 12-week study was conducted to evaluate the efficacy and safety of tofacitinib, a JAK inhibitor, in treatment-refractory active dermatomyositis (DM). METHODS Tofacitinib in extended-release doses of 11 mg was administered daily to 10 subjects with DM. Prior to treatment, a complete washout of all steroid-sparing agents was performed. The primary outcome measure was assessment of disease activity improvement based on the International Myositis Assessment and Clinical Studies group definition of improvement. Response rate was measured as the total improvement score according to the 2016 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) myositis response criteria. Secondary outcome measures included Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) scores, chemokine levels, immunohistochemical analysis of STAT1 expression in the skin, RNA sequencing analysis, and safety. RESULTS At 12 weeks, the primary outcome was met in all 10 subjects. Five (50%) of 10 subjects experienced moderate improvement in disease activity, and the other 50% experienced minimal improvement according to the 2016 ACR/EULAR myositis response criteria. The secondary outcome of the mean change in the CDASI activity score over 12 weeks was statistically significant (mean ± SD 28 ± 15.4 at baseline versus 9.5 ± 8.5 at 12 weeks) (P = 0.0005). Serum chemokine levels of CXCL9/CXCL10 showed a statistically significant change from baseline. A marked decrease in STAT1 signaling in association with suppression of interferon target gene expression was demonstrated in 3 of 9 skin biopsy samples from subjects with dermatomyositis. The mean ± SD level of creatine kinase in the 10 subjects at baseline was 82 ± 34.8 IU/liter, highlighting that disease activity was predominantly located in the skin. CONCLUSION This is the first prospective, open-label clinical trial of tofacitinib in DM that demonstrates strong clinical efficacy of a pan-JAK inhibitor, as measured by validated myositis response criteria. Future randomized controlled trials using JAK inhibitors should be considered for treating DM.
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Bipolar Distribution of Minimum Inhibitory Concentration of Q203 Across Mycobacterial Species.
Wang, J, Jing, W, Shi, J, Huo, F, Shang, Y, Wang, F, Chu, N, Pang, Y
Microbial drug resistance (Larchmont, N.Y.). 2021;(8):1013-1017
Abstract
In this study, we conducted an experimental study to evaluate in vitro susceptibility of Q203 against Mycobacterium tuberculosis, as well as the major pathogenic nontuberculous mycobacterial species. A total of 344 nonduplicate mycobacterium isolates were randomly selected for in vitro susceptibility testing. Overall, Q203 exhibited excellent activity against multidrug-resistant (MDR-) and extensively drug-resistant tuberculosis (XDR-TB) isolates, whereas it showed high minimum inhibitory concentration (MIC) values for all nontuberculous mycobacteria (NTM) isolates tested. The MIC50 and MIC90 values were both 0.008 mg/L for MDR- and XDR-TB isolates, respectively. In contrast, the MIC50 and MIC90 values of four NTM species were all >16 mg/L. QcrB of M. tuberculosis, a component of the CytBC1 complex of the respiratory chain targeted by Q230, shared 89.7% amino acid sequence identity with Mycobacterium avium QcrB, 87.9% with that of Mycobacterium intracellulare, and 84.0% with that of Mycobacterium fortuitum, whereas with low sequence identity observed in QcrB sequence of Mycobacterium abscessus. Notably, the QcrBs of M. avium and M. intracellulare contained a 10-amino acid insertion in the linker between the eighth and ninth helical region. In conclusion, our data demonstrate the bipolar distribution of Q203 MICs across mycobacterial species. Compared with the high MICs in four clinically relevant mycobacterial species, MDR- and XDR-TB isolates have extremely low MICs, indicating that Q203 is a particularly promising candidate for TB treatment. In addition, the 10-amino acid insertion within QcrBs of M. avium and M. intracellulare may be a plausible explanation for the natural resistance to Q203 among these two species.
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Effectiveness of the piperine-supplemented Curcuma longa L. in metabolic control of patients with type 2 diabetes: a randomised double-blind placebo-controlled clinical trial.
Neta, JFF, Veras, VS, Sousa, DF, Cunha, MDCDSO, Queiroz, MVO, Neto, JCGL, Damasceno, MMC, Araújo, MFM, Freitas, RWJF
International journal of food sciences and nutrition. 2021;(7):968-977
Abstract
There is robust evidence of using Curcuma longa L. in reducing metabolic levels in people with diabetes. This study analysed the effectiveness of Curcuma longa L. in the metabolic control of patients with type 2 diabetes in Brazil. A randomised double-blind placebo-controlled clinical trial was conducted with 71 participants divided into a Curcuma longa L. group (500 mg/day with piperine 5 mg) and a placebo group, for 120 days. Anthropometric, clinical and biochemical variables were evaluated at baseline, 60 and 120 days after the beginning of the intervention. Paired and independent Student's t-test and chi-square test were used for statistical analysis. The curcuma group presented a significantly decreased glycaemia (p=.013), glycated haemoglobin (p=.015), HOMA index (p=.037) and triglycerides (TGs) (p=.002). The use of piperine-added Curcuma longa L. was effective in the glycaemic and TG control of patients with type 2 diabetes.
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Small Molecule Fisetin Modulates Alpha-Synuclein Aggregation.
Rosado-Ramos, R, Godinho-Pereira, J, Marques, D, Figueira, I, Fleming Outeiro, T, Menezes, R, Nunes Dos Santos, C
Molecules (Basel, Switzerland). 2021;(11)
Abstract
Phenolic compounds are thought to be important to prevent neurodegenerative diseases (ND). Parkinson's Disease (PD) is a neurodegenerative disorder known for its typical motor features, the deposition of α-synuclein (αsyn)-positive inclusions in the brain, and for concomitant cellular pathologies that include oxidative stress and neuroinflammation. Neuroprotective activity of fisetin, a dietary flavonoid, was evaluated against main hallmarks of PD in relevant cellular models. At physiologically relevant concentrations, fisetin protected SH-SY5Y cells against oxidative stress overtaken by tert-butyl hydroperoxide (t-BHP) and against methyl-4-phenylpyridinuim (MPP+)-induced toxicity in dopaminergic neurons, the differentiated Lund human Mesencephalic (LUHMES) cells. In this cellular model, fisetin promotes the increase of the levels of dopamine transporter. Remarkably, fisetin reduced the percentage of cells containing αsyn inclusions as well as their size and subcellular localization in a yeast model of αsyn aggregation. Overall, our data show that fisetin exerts modulatory activities toward common cellular pathologies present in PD; remarkably, it modulates αsyn aggregation, supporting the idea that diets rich in this compound may prove beneficial.
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Active notch protects MAPK activated melanoma cell lines from MEK inhibitor cobimetinib.
Porcelli, L, Mazzotta, A, Garofoli, M, Di Fonte, R, Guida, G, Guida, M, Tommasi, S, Azzariti, A
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 2021;:111006
Abstract
The crosstalk between Notch and MAPK pathway plays a role in MEK inhibitor resistance in BRAFV600E metastatic melanoma (MM) and promotes migration in GNAQQ209L uveal melanoma (UM) cells. We determined the cytotoxicity of combinatorial inhibition of MEK and Notch by cobimetinib and γ-secretase inhibitor (GSI) nirogacestat, in BRAFV600E and BRAF wt MM and GNAQQ209L UM cells displaying different Erk1/2 and Notch activation status, with the aim to elucidate the impact of Notch signaling in the response to MEK inhibitor. Overall the combination was synergic in BRAFV600E MM and GNAQQ209L UM cells and antagonistic in BRAF wt one. Focusing on UM cells, we found that cobimetinib resulted in G0/G1 phase arrest and apoptosis induction, whereas the combination with GSI increased treatment efficacy by inducing a senescent-like state of cells and by blocking migration towards liver cancer cells. Mechanistically, this was reflected in a strong reduction of cyclin D1, in the inactivation of retinoblastoma protein and in the increase of p27KIP1 expression levels. Of note, each drug alone prevented Notch signaling activation resulting in inhibition of c-jun(Ser63) and Hes-1 expression. The combination achieved the strongest inhibition on Notch signaling and on both c-jun(Ser63) and Erk1/2 activation level. In conclusion we unveiled a coordinate action of MAPK and Notch signaling in promoting proliferation of BRAFV600E MM and GNAQQ209L UM cells. Remarkably, the simultaneous inhibition of MEK and Notch signaling highlighted a role for the second pathway in protecting cells against senescence in GNAQQ209L UM cells treated with the MEK inhibitor.
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[Advances in treatment of narcolepsy].
Xu, Q, Lou, G, Wang, T, Zhang, L
Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences. 2020;(4):419-424
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Abstract
Narcolepsy is the most common cause of excessive daytime sleepiness (EDS) following obstructive sleep apnea. Its treatment aims to reduce EDS and cataplexy, improve nighttime sleep disturbance, sleep paralysis and sleep-related hallucinations. Pitolisant (a histamine H3 receptor antagonist) and solriamfetol (a norepinephrine reuptake inhibitor) have recently been approved effective for narcolepsy in the United States and the European Union. Pitolisant has proved to be effective for both EDS and cataplexy. Besides being effective on EDS, solriamfetol seems to have advantages in abuse potential and withdrawal syndrome. As potential treatments for EDS and cataplexy associated with narcolepsy, several new drugs are being developed and tested. These new drugs include new hydroxybutyrate preparations (controlled release sodium hydroxybutyrate FT218, low sodium hydroxybutyrate JZP-258), selective norepinephrine reuptake inhibitor (AXS-12), and modafinil combined with astroglial junction protein inhibitor (THN102). This paper reviews the recently approved drugs and potential treatments for narcolepsy.
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Antimicrobial and Wound Treatment Aspects of Micro- and Nanoformulations of Carboxymethyl, Dialdehyde, and TEMPO-Oxidized Derivatives of Cellulose: Recent Advances.
Alavi, M, Nokhodchi, A
Macromolecular bioscience. 2020;(4):e1900362
Abstract
The remedy for infected chronic wounds such as diabetic foot ulcers is more complicated particularly in the case of patients with an inefficient immune system. Also, fighting against microbial infections in the wound site by available antibiotics may not be effective because of emerging antibiotic resistance properties among pathogenic bacteria and fungi. Recently, applications of micro- and nanoformulations of biomaterials have demonstrated improved therapeutic abilities for wound dressings. In this way, carboxymethyl, dialdehyde, and 2,2,6,6-tetramethylpiperidine-1-oxyl-oxidized celluloses are common biomaterials having outstanding physicochemical and therapeutic properties compared to unmodified cellulose. Therefore, in this review, recent progress in the field of wound healing and antimicrobial activities of these derivatives are presented and discussed.