Evaluation of the oral administration of α-l-guluronic acid on COX-1 and COX-2 gene expression profile in ankylosing spondylitis patients.

Ankylosing spondylitis (AS) is a chronic autoimmune arthritis disease with a genetic background, affecting the skeletal axis, sacroiliac, and peripheral joints. Nonsteroidal anti-inflammatory drugs (NSAIDs) are the first-line treatment for AS to alleviate the inflammation and pain. Despite the beneficial effect, their use is accompanied by a wide variety of possible side effects in the gastrointestinal and kidneys. The α-l-guluronic acid (G2013) is a new nonsteroidal anti-inflammatory patented (PCT/EP2017/067920) drug, which has shown its anti-inflammatory properties in the previous investigations. The present study revealed the oral administration effect of G2013 on COX-1 and COX-2 gene expression in AS patients. The blood samples of twelve 18-45 years old patients suffering AS and BASDAI >4, and BASFI >4, before and after 12 weeks of treatment with G2013 and 12 blood samples of healthy volunteers were collected and the effect of G2013 on the gene expression of COX-1 and COX-2 enzymes were assessed by Real-Time PCR. The results indicate that G2013 is able to reduce the gene expression level of COX-1 and COX-2 enzymes in treated AS patients compared to healthy control. Statistically significant differences were not observed between the treatment and the healthy control groups. According to the findings, G2013 might be categorized and introduced as a novel NSAID for the treatment of AS.

Effects of guluronic acid, as a new NSAID with immunomodulatory properties on IL-17, RORγt, IL-4 and GATA-3 gene expression in rheumatoid arthritis patients.

Aim: Rheumatoid arthritis (RA) is a prevalent inflammatory, autoimmune diseases characterized by inflammation and destruction of joints. Disease-modifying anti-rheumatic drugs (DMARDs) and biological drugs can have modulatory interference in disease process. In this study, the effect of Guluronic Acid (G2013) as a novel non-steroidal anti-inflammatory drug (NSAID) with immunomodulatory effects was evaluated on IL-17, RORγt, IL-4 and GATA-3 gene expression in RA patients.Methods: Fourteen patients with RA who had an inadequate response to conventional treatments were included in this clinical trial. During this trial, patients were permitted to continue the conventional therapy excluding NSAIDs. G2013 was administered orally at dose of 500 mg twice daily for 12 weeks. The peripheral blood mononuclear cells (PBMCs) were collected before and after treatment to evaluate the gene expression levels of IL-4, GATA-3, IL-17 and RORγt.Results: Primary and secondary efficacy endpoints and Disease Activity Score (DAS) 28 showed an improvement after 12 weeks of treatment. G2013 has a potent efficacy on gene expression of these molecules, so that it could decrease IL-17 and RORγt levels and increase IL-4 and GATA-3 levels after 12 weeks of treatment. Reduction of IL-17 was statistically non-significant whereas for its transcription factor (RORγt) was statistically significant. Moreover, the gene expression results were in accordance with the clinical and preclinical assessments.Conclusion: G2013 as a natural novel drug showed a significant increase on IL-4 and GATA-3 and a significant decrease on RORγt gene expression after 12 weeks oral administration of this drug in RA patients. (Clinical trial identifier: IRCT2016092813739N5).

A randomized clinical trial for the assessment of the efficacy and safety of guluronic acid (G2013) in patients with rheumatoid arthritis.

Objective: To evaluate the safety, efficacy and tolerability of guluronic acid (G2013) in order to treat the rheumatoid arthritis patients who had inadequate response to conventional drugs. Methods: A randomized, 12-week clinical trial with two treatment arms: guluronic acid (G2013) and conventional treatment was performed. The diagnosed RA patients according to the ACR/European League against Rheumatism 2010 classification criteria, with an active disease at baseline that had inadequate response to conventional therapy were considered for the study. G2013 was administered orally twice a day with capsules of 500 mg during a period of 12 weeks and the patients were followed up for the safety and efficacy. Results: Our data showed that, the mean changes in the G2013 and control groups were -7.54 and -2.5 for tender joint count; -7.59 and -3.59 for swollen joint count; -30 and -0.9 for physician global assessment; -23.18 and -1.81 for patient global assessment; -14.45 and -1.45 for erythrocyte sedimentation rate, respectively. Improvements seen with G2013 were significantly greater than those with conventional drugs. In total, in 15.3% of G2013-treated patients and 69.2% of conventional-treated patients adverse events (AEs) occurred in this study. Conclusion: These data from routine rheumatology clinical practice highlight the effectivenessof G2013 in combination with conventional therapy with more desirable safety profile compared to the conventional-treated patients. Therefore, G2013 therapy could be an appropriate choice in order to manage the RA disease. (Clinical trial identifier: IRCT2016092813739N5).

Preclinical and pharmacotoxicology evaluation of α-l-guluronic acid (G2013) as a non-steroidal anti-inflammatory drug with immunomodulatory property.

CONTEXT: Therapeutic effects of α-l-guluronic acid with the greatest tolerability and efficacy (G2013) have been shown in experimental model of multiple sclerosis and other in vitro and in vivo examinations regarding α-l-guluronic acid; there are no toxicological researches on its safety although the pharmacological impacts have been recorded. OBJECTIVE: This study was designed to determine the acute and sub chronic toxicity of α-l-guluronic acid in healthy male and female BALB/c mice. MATERIALS AND METHODS: For the acute toxicity study, the animals orally received five different single doses of α-l-guluronic acid and were kept under observation for 14 d. In the sub-chronic study, 24 male and female BALB/c mice were divided into four groups and treated daily with test substance preparation at dose levels of 0, 50, 250, and 1250 mg/kg body weight for at least 90 consecutive days. The mortality, body weight changes, clinical signs, hematological and biochemical parameters, gross findings, histopathological, and organs weight determinants were monitored during this study. RESULTS: The results of acute toxicity indicated that the LD50 of α-l-guluronic acid is 4.8 g/kg. We found no mortality or abnormality in clinical signs, body weight, relative organs weight, or necropsy in any of the animals in the subchronic study. Additionally, the results showed no significant difference in hematological, biochemical, and histopathological parameters in rats. CONCLUSIONS: Our results suggest that α-l-guluronic acid has high safety when administered orally in animals.

Assessment of immunological profile in ankylosing spondylitis patients following a clinical trial with guluronic acid (G2013), as a new NSAID with immunomodulatory properties.

The present research aims to study the effects of guluronic acid (G2013) on gene expression levels of the T-bet, GATA3, RORγt, AHR, and FOXP3 transcription factors and on gene expression of their related cytokines following oral administration of this drug in ankylosing spondylitis (AS) patients. In this trial (clinical trial identifier: IRCT2016091813739N4), 14 AS patients and 12 age- and sex-matched healthy individuals were enrolled. The level of transcription factors' gene expression and expression of their related cytokines were measured by quantitative real-time PCR, before and 3 months after G2013 therapy. Our data indicated that the gene expression levels of the T-bet and IFN-γ were not significantly reduced during 12 weeks of treatment with G2013 (p > 0.05). The findings showed that the gene expression levels of the GATA3 and IL-4 increased significantly during 12 weeks of treatment with G2013 (p < 0.05). In addition, gene expression levels of the RORγt, IL-17, AHR, and IL-22 decreased significantly during the 12-week treatment with G2013 (p < 0.05). Moreover, the gene expression level of the FOXP3 increased significantly during 12 weeks of treatment with G2013, but the gene expression level of IL-10 did not increase significantly (p < 0.05, p > 0.05, respectively). The present study showed that oral intake of G2013 was able to modify the severity of articular and inflammatory symptoms of AS through reducing the gene expression levels of the RORγt, IL-17, AHR, and IL-22 and increasing the gene expression levels of the GATA3, IL-4, and FOXP3.

The safety and efficacy of Guluronic acid (G2013) in ankylosing spondylitis: A randomized controlled parallel clinical trial.

BACKGROUND: To assess the therapeutic efficacy, safety and tolerability of Guluronic acid (G2013) in patients with ankylosing spondylitis (AS) patients. METHODS: This investigation was a 12-week randomized, placebo-controlled, phase I/II clinical trial involving 75 AS patients that were randomly divided into 3 groups: 25 as placebo, 25 Guluronic acid and 25 naproxen groups. Patients who had AS with active disease at baseline according to the modified New York criteria were considered for this trial. The primary consequence measure was the Appraisement of Spondyloarthritis International Society (ASAS) 20 response-rate at week 12. RESULTS: There were no statistically significant differences between groups at the entry. ASAS20 response at week 12 was achieved (60.8%) in patients receiving Guluronic acid compared with - (68.4% of) - patients in the naproxen group (p > 0.05) and (21.0%) of patients in the placebo group. In comparison with the placebo group from the baseline to week 12, patients who received Guluronic acid and naproxen showed significantly greater improvement in all secondary endpoints. Moreover, Guluronic acid decreased some inflammatory parameters more dramatically than naproxen and placebo group. Patients in the naproxen group had more incidence of gastrointestinal and others adverse events in comparison with Guluronic acid and placebo groups. CONCLUSION: The present research indicated that Guluronic acid and naproxen are similar in terms of efficacy. However, Guluronic acid had more notable safety characteristics identifying information than naproxen. Accordingly, it is proposed that Guluronic acid could be appropriate for management of AS. Clinical trial identifier; IRCT2016091813739N4.

Monogenic Auto-inflammatory Syndromes: A Review of the Literature.

Auto-inflammatory syndromes are a new group of distinct hereditable disorders characterized by episodes of seemingly unprovoked inflammation (most commonly in skin, joints, gut, and eye), the absence of a high titer of auto-antibodies or auto-reactive T cells, and an inborn error of innate immunity. A narrative literature review was carried out of studies related to auto-inflammatory syndromes to discuss the pathogenesis and clinical manifestation of these syndromes. This review showed that the main monogenic auto-inflammatory syndromes are familial Mediterranean fever (FMF), mevalonate kinase deficiency (MKD), Blau syndrome, TNF receptor-associated periodic syndrome (TRAPS), cryopyrin-associated periodic syndrome (CAPS), and pyogenic arthritis with pyoderma gangrenosum and acne (PAPA). The data suggest that correct diagnosis and treatment of monogenic auto-inflammatory diseases relies on the physicians' awareness. Therefore, understanding of the underlying pathogenic mechanisms of auto-inflammatory syndromes, and especially the fact that these disorders are mediated by IL-1 secretion stimulated by monocytes and macrophages, facilitated significant progress in patient management.