The effects of ß-D-mannuronic acid (M2000), as a novel NSAID, on COX1 and COX2 activities and gene expression in ankylosing spondylitis patients and the murine monocyte/macrophage, J774 cell line.

Ankylosing spondylitis (AS) is a debilitating chronic inflammatory disease with genetic predisposition, which is characterized by the involvement of spine and sacroiliac joints. Due to the relatively unsuccessful treatments, we designed ß-D-mannuronic (M2000) with the beneficial effects in various experimental models as a novel non-steroidal anti-inflammatory drug (NSAID). The aims of our present study were: first, to compare the therapeutic effects of M2000, as a novel designed NSAID, with naproxen and placebo in Iranian patients with AS during 12 weeks; second, to evaluate the effect of M2000 on gene expression of cyclooxygenase enzyme (COX-1/COX-2), a key enzyme in the initiation of inflammatory pathways in AS patients; and third, to assess the activity of COX-1 and COX-2 enzymes in the presence/absence of M2000 at the different doses in the murine macrophage, J774 cell line. This was a sub-study of phase II, randomized, placebo-controlled trial with three treatment arms: M2000, naproxen, and placebo. The outcome measures were the mean changes from baseline to week 12. The gene expression was assessed by real-time PCR. The COX-1 and COX-2 activities were evaluated by ELISA in J774 cell line induced by LPS and arachidonic acid (AA). Our findings demonstrated that M2000 had beneficial therapeutic effects on pain, stiffness, and inflammation, whereas no adverse effects were observed following the use of M2000 after 12 weeks. The analysis of gene expression showed that M2000 could effectively reduce the expression levels of COX-1 and COX-2 in comparison with untreated patients. In addition, the enzymatic activities in the presence of M2000 were significantly less than LPS- and AA-treated groups. Our results indicate that M2000, as a novel designed NSAID with immunosuppressive properties, can be considered as one of the therapeutic options for the treatment of inflammatory diseases without adverse events. Clinical trial identifier IRCT2013062213739N1/ http://www.IRCT.ir .

Bundle Branch Blocks and Fragmented QRS Complex in Iranian Patients with Systemic Sclerosis.

Background: Cardiac involvement, as one of the life-threatening manifestations of systemic sclerosis (SSc), is chiefly caused by collagen fiber deposition in the myocardium, which subsequently leads to conduction abnormalities. In the present study, we aimed to investigate the prevalence and clinical significance of bundle branch blocks (BBBs) and the fragmented QRS complex (fQRS) in Iranian patients with SSc. Methods: Forty-one patients with SSc were enrolled from the outpatient SSc clinic of Shariati Hospital, Tehran University of Medical Sciences, between October 2016 and February 2017. Twelve-lead ECG was obtained and interpreted for BBBs and the fQRS. To adjust for the confounding effects of non-SSc-related cardiovascular risk factors, we calculated the Framingham risk score to estimate the risk of cardiovascular diseases. The associations between the studied conduction abnormalities and SSc cutaneous subtypes; disease duration; and the Medsger SSc severity scale of cutaneous, pulmonary, and vascular involvements were also analyzed. Results: The study population consisted of 41 Iranian patients with SSc at a mean age of 47.48±11.57 years (82.9% female). The prevalence of BBBs and the fQRS was 26.8% and 36.6%, respectively. The fQRS was associated with the limited cutaneous SSc subtype (OR: 0.100, 95%CI: 0.018-0.553, and P=0.028). BBBs and the fQRS were not associated with either the Framingham risk score or the rest of the clinicodemographic variables. Conclusion: BBBs and the fQRS were more prevalent in our patients with SSc, without any association with the involvement of the other organs. These findings may suggest the independent pathophysiology of cardiac involvement in SSc.

Evaluation of the efficacy and safety of ß-d-mannuronic acid in patients with ankylosing spondylitis: A 12-week randomized, placebo-controlled, phase I/II clinical trial.

OBJECTIVE: To evaluate the efficacy, safety and tolerability of ß-d-mannuronic acid (M2000) in the treatment of ankylosing spondylitis (AS). METHODS: The study was a 12-week randomized, double-blind, placebo-controlled, phase I/II clinical trial with 3 treatment arms: placebo, ß-d-mannuronic acid and naproxen. Patients who had AS according to the modified New York criteria, with active disease at baseline were eligible for study. Primary outcome measure was the Assessment of SpondyloArthritis international Society (ASAS) 20 response rate at week 12. RESULTS: Of the 85 randomized patients, 27 were allocated to receive placebo, 28 naproxen, and 30 ß-d-mannuronic acid. There were no statistically significant differences between treatment groups at baseline. Of the patients receiving ß-d-mannuronic acid, 57.7% achieved an ASAS20 response at week 12, compared with 59% of the patients in the naproxen group (P>0.05) and 19% of the patients in the placebo group (P=0.007). In comparison with patients receiving placebo over the 12-week treatment period, those receiving ß-d-mannuronic acid and naproxen demonstrated statistically significantly greater improvement in all secondary endpoints. Interestingly, ß-d-mannuronic acid reduced some parameters associated with inflammation more effectively than naproxen and placebo. The incidence of gastrointestinal and other adverse events were higher on naproxen than on ß-d-mannuronic acid and placebo. CONCLUSION: The present study demonstrated similar efficacy, but with a more favorable safety profile for ß-d-mannuronic acid than naproxen and, therefore, suggest that ß-d-mannuronic acid is suitable for the management of AS. TRIAL REGISTRATION: Iranian registry of clinical trials; www.irct.ir; IRCT2013062213739N1.