Efficacy and safety of interleukin-1 antagonists in rheumatoid arthritis: a systematic review and meta-analysis

Abstract

Rheumatoid arthritis patients have a high level of pro-inflammatory interleukin-1. Augmenting the blockade of interleukin-1 receptors by external interleukin-1 receptor antagonist modifies the progression of the disease. Therefore, the aim of this study was to evaluate the clinicalefficacy and safety of interleukin-1 receptor antagonist (anakinra) in the treatment of rheumatoid arthritis. Clinical trials and extension studies that compared anakinra with placebo or other medications were included. Electronic bibliographic databases: PubMed, Scopus, and Web of Sciences were searched from inception to November 2017. The American College of Rheumatology 20% (ACR20) improvement was the primary efficacy outcome measure. Total number of adverse drug events, serious adverse drug events, total treatment withdrawals, and treatment-related withdrawals were safety outcome measures. Ten studies were included in this review. One study did not fulfil quantitative criteria and was assessed qualitatively. Six clinical trials and three extension studies were included in meta-analysis. Patients treated with anakinra are 42% more likely to have ACR20 response than patients without IL-1Ra (pooled RR 1.42; 95% CI 1.01, 2.00). Patients on 30-150 mg anakinra have lower Health Assessment Questionnaire (HAQ) score than patients without IL-1Ra (SMD - 0.28; 95% CI - 0.53, - 0.03). The inflammatory marker erythrocyte sedimentation rate (ESR) was significantly lower among patients treated with 30-150 mg anakinra (SMD - 0.44; 95% CI - 0.65, - 0.23). Patients on anakinra have a 34% more risk of treatment-related withdrawal than placebo. The other parameters were not found to be statistically significant. Anakinra has a significant improvement in ACR20, HAQ, and ESR. The ACR20 response is maintained after 48 weeks of treatment. Anakinra shows higher episodes of treatment-related withdrawals than placebo

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In vivo and in vitro investigation of anti-inflammatory and mucus-regulatory activities of a fixed combination of thyme and primula extracts

Abstract

Hypersecretion of viscous mucus is one of the hallmark symptoms of acute and chronic bronchitis and typically develops secondary to an inflammation of the airway epithelium. Bronchipret® TP film-coated tablets (BRO), an herbal medicinal product containing a fixed combination of thyme herb and primula root extracts, has been successfully used clinically for the treatment of acute bronchitis for more than two decades. However, the underlying pharmacological mechanisms of action have not been fully understood so far. We investigated the anti-inflammatory and mucus-regulatory effects of orally administered BRO in an animal model of pulmonary inflammation that was experimentally induced by intratracheal LPS instillation. BRO was administered once daily for up to three days following the induction of inflammation. Treatment with BRO effectively inhibited polymorphonuclear cell influx into the lung as well as the increase in Mucin 5ac (Muc5ac) protein. Furthermore, the LPS-induced increase of goblet cell numbers was significantly attenuated by BRO treatment. Subsequent in vitro investigations with IL-13 stimulated human primary respiratory epithelium and the Calu-3 respiratory epithelial cell line in air-liquid-interface culture confirmed the effects on mucus production and goblet cell numbers observed in the in vivo studies. They further suggest that the reduction of Muc5ac protein secretion by BRO is associated with reduced Muc5ac mRNA expression as assessed by quantitative Real-Time PCR. Our studies provide evidence that BRO exerts both anti-inflammatory and mucus-regulatory activity and that BRO's effect on mucin production is partially independent from its anti-inflammatory activity. These results contribute to the understanding of the modes of action underlying the clinical efficacy of BRO in acute bronchitis patients.

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5th Annual Congress on Clinical Pharmacy & Pharmacology: Altered cytokine profile under control of the sero...

5th Annual Congress on Clinical Pharmacy & Pharmacology: Altered cytokine profile under control of the sero...: Altered cytokine profile under control of the serotonergic system determines the regulation of CYP2C11 and CYP3A isoforms Abstract ...

Altered cytokine profile under control of the serotonergic system determines the regulation of CYP2C11 and CYP3A isoforms

Abstract

The aim of this study is to assess a potential mechanism by which the serotonergic system can control the expression and activity of cytochrome (CYP) 2C11 and CYP3A isoforms during liver insufficiency. A rat model of diethylnitrosamine (DEN)-induced liver insufficiency was developed by administering 50 mg/kg of DEN twice a week for 7 weeks. Dysfunction of the serotonergic system was evoked by feeding the rats with a tryptophan-free diet for three weeks. Dysfunction of the serotonergic system during liver insufficiency decreased the level of proinflammatory cytokines (TGF-β and IL-1β) and increased the level of an anti-inflammatory cytokine (IL-4). Simultaneously, activation of the repressive mechanism IL-4/JAK1/STAT6/SOCS1 of the JAK2/STAT5b-mediated signal transduction pathway and the pERK1/2/GR/STAT6 signal transduction pathway resulted in the suppression of the CYP2C11 and CYP3A isoforms Moreover, dysfunction of the serotonergic system during liver insufficiency equalized the level of testosterone to the basal level, did not change the steady state of the corticosterone level and significantly enhanced the reduced level of growth hormone. An altered cytokine profile under control of the serotonergic system determines the regulation of CYP2C11 and CYP3A isoforms during liver insufficiency through mechanisms based on posttranscriptional and posttranslational processes.

KEYWORDS:

Cytochrome P450; Cytokines; Gene expression; Hormones; Nervous system; Serotonin receptor

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Structural elements of stromal interaction molecule function

Abstract

Stromal interaction molecule (STIM)-1 and -2 are multi-domain, single-pass transmembrane proteins involved in sensing changes in compartmentalized calcium (Ca2+) levels and transducing this cellular signal to Orai1 channel proteins. Our understanding of the molecular mechanisms underlying STIM signaling has been dramatically improved through available X-ray crystal and solution NMR structures. This high-resolution structural data has revealed that intricate intramolecular and intermolecular protein-protein interactions are involved in converting STIMs from the quiescent to activation-competent states. This review article summarizes the current high resolution structural data on specific EF-hand, sterile α motif and coiled-coil interactions which drive STIM function in the activation of Orai1 channels. Further, the work discusses the effects of post-translational modifications on the structure and function of STIMs. Future structural studies on larger STIM:Orai complexes will be critical to fully defining the molecular bases for STIM function and how post-translational modifications influence these mechanisms.

KEYWORDS:

Coiled-coil; EF-SAM; Glutathionylation; Glycosylation; Phosphorylation; STIM1; STIM2; Solution NMR; Stromal interaction molecule; X-ray crystallography

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Design, synthesis and pharmacological evaluation of ALK and Hsp90 dual inhibitors bearing resorcinol and 2,4-diaminopyrimidine motifs.

Abstract

Rather than by directly focusing on the ever-changing ALK mutants, here we report an alternative strategy to overcome the drug resistance caused by treatment of ALK inhibitors by developing ALK and Hsp90 dual targeting inhibitors. Since Hsp90 is a molecular chaperone that regulates the maturation, activation and stability of numerous "client proteins" including ALK, dual targeting ALK and Hsp90 may bring more benefits and efficacy against drug resistance of ALK inhibitors. By using our previously developed ALK inhibitor 6 and the clinical Hsp90 inhibitors AUY922 or AT13387 as the templates, we developed several series of resorcinol tethered 2,4-diaminopyrimidines as ALK/Hsp90 dual inhibitors bearing various linkers at different linking sites. Compound 10h and 10j showed high potency against ALK (17.3 vs 9.8 nM) and Hsp90α (100 vs 40 nM). They also have high potency against ALK resistant mutants, especially the gatekeeper mutation ALKL1196M. Both compounds showed strong antiproliferative activity against the ALK-addictive H3122 cells (11 vs 13 nM). The dual functioning mechanism is further confirmed by their down-regulation of the Hsp90 clients ALK and AKT, and up-regulation of the chaperone protein Hsp70 in H3122 cells.

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Clinical Efficacy of a Dual Action, Topical Anti-edematous and Anti-inflammatory Device for the Treatment of External Hemorrhoids

Abstract

Objective: External hemorrhoids are enlarged, bulging blood vessels in and around the anus and lower rectum. They associate several pathologies such as engorged, edematous and inflamed sinusoids, with numerous proinflammatory cytokines on their surface, requiring a multi-target therapeutic approach. In the absence of any effective treatment, we assessed a newly conceived osmotically active, hypertonic, filmogen solution (Pileseptine-e) directed at attracting hypotonic liquid and helping suppress inflammation. The clinical efficacy and safety of Pileseptine-e on external hemorrhoids was evaluated in this study.
Methods: A 2-week treatment + 1-week follow-up, comparative, randomized, double blind, clinical trial with Pileseptine-e (n=37, test product) versus saline spray (n=17, placebo) was performed in patients suffering from external hemorrhoids. Test and placebo products were applied as 3-4 sprays, 3-4 times per day, for 14 consecutive days. Parameters were evaluated employing a 0-4 or 0-10 scoring scale, before treatment (baseline, T0), 2h after 1st treatment, and on Days 2, 3, 8, and 14, with follow-up check on Day 21.
Results: The test product induced an instant and strong outward exudation of liquid from inside the edematous hemorrhoids, thereby cleaning their surface, keeping it hydrated, and reducing pain and itching. A strong reduction in the size of hemorrhoids and rectal bleeding was also observed, which improved the quality of life of the patients considerably. The placebo product also provided noticeable symptomatic relief, but without effect on the size of hemorrhoids. No adverse effects were observed in any patient.
Conclusion: Reducing edema to allow hemorrhoidal volume to regress, and to normalize the structural physiology of the anal area, is the primary prerequisite to treat external hemorrhoids. Pileseptine-e is an antiedematous, cleaning, hydrating, safe and non-irritant filmogen solution that represents great advancement in the treatment of external hemorrhoids.

Keywords: External hemorrhoids; Filmogen; Osmotic; Antiedematous; Anti-inflammatory solution