Research Spotlight

Posted January 26th 2016

Flavaglines Ameliorate Experimental Colitis and Protect Against Intestinal Epithelial Cell Apoptosis and Mitochondrial Dysfunction.

Jie Han M.S.

Jie Han, M.S.

Han, J., Q. Zhao, C. Basmadjian, L. Desaubry and A. L. Theiss (2016). “Flavaglines Ameliorate Experimental Colitis and Protect Against Intestinal Epithelial Cell Apoptosis and Mitochondrial Dysfunction.” Inflammatory Bowel Diseases 22(1): 55-67.E

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BACKGROUND: Flavaglines are a family of natural compounds shown to have anti-inflammatory and cytoprotective effects in neurons and cardiomyocytes. Flavaglines target prohibitins as ligands, which are scaffold proteins that regulate mitochondrial function, cell survival, and transcription. This study tested the therapeutic potential of flavaglines to promote intestinal epithelial cell homeostasis and to protect against a model of experimental colitis in which inflammation is driven by epithelial ulceration. METHODS: Survival and homeostasis of Caco2-BBE and IEC-6 intestinal epithelial cell lines were measured during treatment with the flavaglines FL3 or FL37 alone and in combination with the proinflammatory cytokines tumor necrosis factor (TNF) alpha and interferon gamma. Wild-type mice were intraperitoneally injected with 0.1 mg/kg FL3 or vehicle once daily for 4 days during dextran sodium sulfate-induced colitis to test the in vivo anti-inflammatory effect of FL3. RESULTS: FL3 and FL37 increased basal Caco2-BBE and IEC-6 cell viability, decreased apoptosis, and decreased epithelial monolayer permeability. FL3 and FL37 inhibited TNFalpha- and interferon gamma-induced nuclear factor kappa B and Cox2 expression, apoptosis, and increased permeability in Caco2-BBE cells. FL3 and FL37 protected against TNFalpha-induced mitochondrial superoxide generation by preserving respiratory chain complex I activity and prohibitin expression. p38-MAPK activation was essential for the protective effect of FL3 and FL37 on barrier permeability and mitochondrial-derived reactive oxygen species production during TNFalpha treatment. Mice administered FL3 during dextran sodium sulfate colitis exhibited increased colonic prohibitin expression and p38-MAPK activation, preserved barrier function, and less inflammation. CONCLUSIONS: These results suggest that flavaglines exhibit therapeutic potential against colitis and preserve intestinal epithelial cell survival, mitochondrial function, and barrier integrity.


Posted January 26th 2016

Delayed-Release Dimethyl Fumarate and Pregnancy: Preclinical Studies and Pregnancy Outcomes from Clinical Trials and Postmarketing Experience.”

J. Theodore Phillips M.D.

J. Theodore Phillips, M.D.

Gold, R., J. T. Phillips, E. Havrdova, A. Bar-Or, L. Kappos, N. Kim, T. Thullen, P. Valencia, L. Oliva, M. Novas, J. Li, M. T. Sweetser, N. Kurukulasuriya, V. Viglietta and R. J. Fox (2015). “Delayed-Release Dimethyl Fumarate and Pregnancy: Preclinical Studies and Pregnancy Outcomes from Clinical Trials and Postmarketing Experience.” Neurol Ther 4(2): 93-104.

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INTRODUCTION: Delayed-release dimethyl fumarate (DMF; also known as gastro-resistant DMF) is an oral agent for the treatment of relapsing forms of multiple sclerosis (MS). No formal studies of DMF were conducted in pregnant women, although pregnancies have occurred during clinical trials and in the postmarketing setting. METHODS: Preclinical developmental and reproductive toxicology studies were performed with DMF in rats and rabbits. As of March 26, 2014, the DMF clinical development program included a total of 4132 subjects consisting of 2898 patients with MS, 320 psoriasis patients, 101 rheumatoid arthritis patients, and 813 healthy volunteers. Subjects were required to use reliable contraception and immediately discontinue treatment in the event of pregnancy. RESULTS: Animal studies showed no evidence of impaired fertility or teratogenicity with DMF. Overall as of June 30, 2014, 63 pregnancies were reported in clinical trials. Outcomes are known for 39 of 42 subjects receiving DMF and include 26 live births (67%), three spontaneous abortions (8%), and 10 elective terminations (26%); follow-up is ongoing in 2 cases and one patient was lost to follow-up. The incidence of spontaneous abortion in subjects exposed to DMF was consistent with the expected rate of early pregnancy loss in the general population (12-22%). A total of 135 pregnancies were reported in the postmarketing setting (spontaneous and solicited reports). Outcomes are known for 30 cases and include 10 live births, 13 spontaneous abortions, and 5 elective terminations; follow-up is ongoing in 103 cases and 2 patients have been lost to follow-up. CONCLUSION: Although data are limited and all known exposures have occurred in the first trimester, no increased risk of fetal abnormalities or adverse pregnancy outcomes associated with gestational exposure to DMF has been observed. FUNDING: Biogen, Inc.


Posted January 26th 2016

Consensus Management of Gastrointestinal Events Associated with Delayed-Release Dimethyl Fumarate: A Delphi Study.

J. Theodore Phillips M.D.

J. Theodore Phillips, M.D.

Theodore Phillips, J., A. A. Erwin, S. Agrella, M. Kremenchutzky, J. F. Kramer, M. J. Darkes, J. Kendter, H. Abourjaily, J. Rana and R. J. Fox (2015). “Consensus Management of Gastrointestinal Events Associated with Delayed-Release Dimethyl Fumarate: A Delphi Study.” Neurol Ther 4(2): 137-146.

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INTRODUCTION: Delayed-release dimethyl fumarate (DMF, also known as gastro-resistant DMF) is indicated for the treatment of patients with relapsing multiple sclerosis. Gastrointestinal (GI) adverse events (AEs) occur with DMF therapy. METHODS: We used a Delphi process to reach consensus among North American clinicians on effective real-world management strategies for GI AEs associated with DMF. Clinicians were asked to complete two rounds of questionnaires developed by a steering committee; consensus in round 2 was attained if >/=70% of respondents agreed on a particular strategy. RESULTS: Consensus was reached on several strategies to manage GI AEs, including administering DMF with food, slow titration, dose reduction, and use of symptomatic therapies. CONCLUSION: These consensus strategies provide clinicians with information on real-world approaches used to address the tolerability of DMF in patients with multiple sclerosis. FUNDING: Biogen.


Posted January 26th 2016

Long stem reverse shoulder arthroplasty and cerclage for treatment of complex long segment proximal humeral fractures with diaphyseal extension in patients more than 65 years old.

Brody Flanagin M.D.E

Brody Flanagin, M.D.

Garofalo, R., B. Flanagin, A. Castagna, E. Y. Lo and S. G. Krishnan (2015). “Long stem reverse shoulder arthroplasty and cerclage for treatment of complex long segment proximal humeral fractures with diaphyseal extension in patients more than 65 years old.” Injury 46(12): 2379-2383.

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INTRODUCTION: Treatment of long segment proximal humeral fractures with extension below the surgical neck into the diaphysis remains a significant challenge for orthopaedic surgeons. The purpose of this paper was to evaluate the clinical and radiological outcomes following primary long-stem RSA with cerclage fixation for complex long segment proximal humeral fractures with diaphyseal extension in patients more than 65 years old. MATERIAL AND METHODS: Between February 2010 and March 2013, 22 patients who suffered a complex proximal humerus fracture with extended diaphyseal involvement underwent surgery with long-stem RSA and cerclages fixation. There were 17 female and 5 male patients, and the mean age was 77.2 years at time of surgery (range 65-84 years). All patients had a 3 or 4-part proximal humerus fracture or a two part fracture with a split of humeral head, with extension to the proximal diaphysis. Clinical and radiographic follow-up was performed on all 22 patients at 6 weeks, at 3, 6, and 12 months postoperatively, and then at 2 years. Clinical evaluation consisted of the shoulder rating Constant scale. X ray evaluation was done to evaluate fracture healing and eventually humeral and glenoid component loosening or other complications. RESULTS: No infections were reported, neither other serious complications. Two patients developed a seroma and one patient developed chronic pain at that was treated with referral to pain management. No patients were lost at follow-up. At final follow-up, average active elevation was 132.5 degrees (range 100 degrees -140 degrees ), external rotation 30 degrees (range 55 degrees -10 degrees ). Average abduction was 120 degrees (range 90 degrees -135 degrees ). The mean adjusted Constant score was 72/100 (range 64-82). All fractures were healed within 3 months after surgery. No loosening of the humeral or glenoid components and no episodes of dislocation/instability were observed in this series. We did not observe scapular notching in any patient on the x-ray at most recent follow-up. CONCLUSION: Long-stem RSA with cerclages wire fixation represents a viable treatment option for complex long-segment displaced proximal humerus fractures with diaphyseal extension in patients older than 65 years. Our results suggest clinical outcomes at two years of follow up are satisfactory with an acceptable complication rate.


Posted January 26th 2016

Pregnancy Outcomes in Subjects Exposed to Certolizumab Pegol.

John Cush M.D.

John Cush, M.D.

Clowse, M. E., D. C. Wolf, F. Forger, J. J. Cush, A. Golembesky, L. Shaughnessy, D. De Cuyper and U. Mahadevan (2015). “Pregnancy Outcomes in Subjects Exposed to Certolizumab Pegol.” Journal of Rheumatology 42(12): 2270-2278.

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OBJECTIVE: To provide information on pregnancy outcomes in women receiving certolizumab pegol (CZP). METHODS: The UCB Pharma safety database was searched for pregnancies through to September 1, 2014. Reports for maternal and paternal CZP exposure were included and outcomes examined, and data on CZP exposure, pregnancy, comorbidities, and infant events were extracted by 2 independent reviewers. Concomitant medications and disease activity were reviewed for clinical trial patients. RESULTS: Of 625 reported pregnancies, 372 (59.5%) had known outcomes. Paternal exposure pregnancies (n = 33) reported 27 live births, 4 miscarriages, 1 induced abortion, and 1 stillbirth. Maternal exposure pregnancies (n = 339) reported 254 live births, 52 miscarriages, 32 induced abortions, and 1 stillbirth. Almost all reported pregnancies had exposure to CZP in the first trimester, when organogenesis takes place, and a third of them continued the drug into the second and/or third trimesters. The most frequent indications for maternal CZP use were Crohn disease (192/339) and rheumatic diseases (118/339). Twelve cases of congenital malformation and a single neonatal death were reported. CONCLUSION: Analysis of pregnancy outcomes after exposure to CZP supports previous reports, suggesting a lack of harmful effect of maternal CZP exposure on pregnancy outcomes. However, additional data from a larger number of outcomes after exposure and studies including an unexposed comparison group are required to fully evaluate CZP safety and tolerability in pregnancy.