Prostacyclin mimetics (PMs) are effective for the treatment of pulmonary arterial hypertension (PAH). However, their clinical use may be limited by their adverse events. This study aims to quantify the different PM adverse events (AEs) with regard to their selectivity towards the prostacyclin (IP) receptor and their administrative routes. The study included randomised, placebo-controlled trials comparing iloprost, beraprost, treprostinil, and selexipag to placebo (published 2002–2016). We report the group efficacy differences between treatment and placebo by weighted and standardised mean difference. The probability of adverse events was determined by the odds ratio (OR). Of the 14 randomised clinical trials involving 3518 PAH patients, outcome and adverse event data were meta-analysed by drug type and route of administration. Prostacyclin mimetics comparison demonstrated a more significant discontinuation of the IP-selective agonist, selexipag, due to an adverse event (OR = 2.2; 95% CI: 1.5, 3.3). Compared to placebo, site pain associated with subcutaneously administered treprostinil was the most significant likely adverse event (OR = 17.5; 95% CI: 11.1, 27.1). Parenteral PMs were associated with fewer adverse effects overall. The overall efficacy of PMs to improve 6-minute walk distance by 16.3 meters was significant (95% CI: 13.0, 19.7). Decreases in pulmonary vascular resistance index (SMD = −5.5; 95% CI: −10.1, −0.9; I2 = 98%) and mean pulmonary arterial pressure (SMD = −1.0; 95% CI: −2.6, −0.7; I2 = 99%) in treatment groups were found to be significant. Adverse event profiles varied in response to administration route and PM type but were not negated by use of a selective IP agonist. Prostacyclin mimetics exposure to non-target IP receptors may underpin some AEs reported.

Histone 3 lysine 27 (H3K27) demethylation constitutes an important epigenetic mechanism of gene activation. It is mediated by the Jumonji C domain-containing lysine demethylases KDM6A and KDM6B, both of which have been implicated in a wide myriad of diseases, including blood and solid tumours, autoimmune and inflammatory disorders, and infectious diseases. Here, we review and summarise the pre-clinical evidence, both in vitro and in vivo, in support of the therapeutic potential of inhibiting H3K27-targeting demethylases, with a focus on the small-molecule inhibitor GSK-J4. In malignancies, KDM6A/B inhibition possesses the ability to inhibit proliferation, induce apoptosis, promote differentiation, and heighten sensitivity to currently employed chemotherapeutics. KDM6A/B inhibition also comprises a potent anti-inflammatory approach in inflammatory and autoimmune disorders associated with inappropriately exuberant inflammatory and autoimmune responses, restoring immunological homeostasis to inflamed tissues. With respect to infectious diseases, KDM6A/B inhibition can suppress the growth of infectious pathogens and attenuate the immunopathology precipitated by these pathogens. The pre-clinical in vitro and in vivo data, summarised in this review, suggest that inhibiting H3K27 demethylases holds immense therapeutic potential in many diseases.

BackgroundHaemorrhoidal disease (HD) is a common colorectal condition that often requires surgical treatment. Less invasive procedures are usually more acceptable to patients. The aim of this study was to report the outcome of a novel and minimally invasive technique employing a radiofrequency ablation (RFA) energy (Rafaelo®) to treat HD.MethodsA total number of 27 patients who had RFA for the treatment of HD were recruited to this study. The procedure was performed under deep sedation and local anaesthesia. Patients’ demographics; haemorrhoid severity score (HSS); quality of life; pain and satisfaction scores; and recurrence rate were recorded.ResultsThe mean age of the patients was 46 (SD 14) years, 18 (67%) males and 9 (33%) females. The mean body mass index was 25 (SD 4) kg/m2. The predominant symptom of all patients was per-rectal bleeding. HSS improved from 7.2 (SD 1.9) before the procedure to 1.6 (SD 1) after the procedure (p < 0.0001). Postoperative pain scores on a scale of 0–10 were 0, 2 (SD 2), 1 (SD 2), and 0 on immediate, day-1, day-3, and 2-month follow-up questionnaire. The mean satisfacion score was 9 (SD 1.5) out of 10 on 2-month follow-up. Mean time until patients returned to normal daily activity was 3 (SD 1) days following the procedure. Quality-of-life assessments including: visual analogue scale scores (before: mean 70, SD 23; after: mean 82, SD 16; p < 0.001) and EQ-5D-5L (before: mean 0.84, SD 0.15; after: mean 0.94, SD 0.13; p < 0.05) were significantly improved. The mean length of follow-up for recurrence of symptoms was 20 months (range 12–32 months). One patient (4%) reported the recurrence of rectal bleeding 12 months after the procedure.ConclusionsRFA for the treatment of HD is safe and effective in achieving symptomatic relief. It is associated with minimal postoperative pain and low incidence of recurrence.