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ObjectivesIn the anifrolumab systemic lupus erythematosus (SLE) trial programme, there was one trial (TULIP-1) in which BILAG-based Composite Lupus Assessment (BICLA) responses favoured anifrolumab over placebo, but the SLE Responder Index (SRI(4)) treatment difference was not significant. We investigated the degree of concordance between BICLA and SRI(4) across anifrolumab trials in order to better understand drivers of discrepant SLE trial results.MethodsTULIP-1, TULIP-2 (both phase 3) and MUSE (phase 2b) were randomised, 52-week trials of intravenous anifrolumab (300 mg every 4 weeks, 48 weeks; TULIP-1/TULIP-2: n=180; MUSE: n=99) or placebo (TULIP-1: n=184, TULIP-2: n=182; MUSE: n=102). Week 52 BICLA and SRI(4) outcomes were assessed for each patient.ResultsMost patients (78%–85%) had concordant BICLA and SRI(4) outcomes (Cohen’s Kappa 0.6–0.7, nominal p<0.001). Dual BICLA/SRI(4) response rates favoured anifrolumab over placebo in TULIP-1, TULIP-2 and MUSE (all nominal p≤0.004). A discordant TULIP-1 BICLA non-responder/SRI(4) responder subgroup was identified (40/364, 11% of TULIP-1 population), comprising more patients receiving placebo (n=28) than anifrolumab (n=12). In this subgroup, placebo-treated patients had lower baseline disease activity, joint counts and glucocorticoid tapering rates, and more placebo-treated patients had arthritis response than anifrolumab-treated patients.ConclusionsAcross trials, most patients had concordant BICLA/SRI(4) outcomes and dual BICLA/SRI(4) responses favoured anifrolumab. A BICLA non-responder/SRI(4) responder subgroup was identified where imbalances of key factors driving the BICLA/SRI(4) discordance (disease activity, glucocorticoid taper) disproportionately favoured the TULIP-1 placebo group. Careful attention to baseline disease activity and monitoring glucocorticoid taper variation will be essential in future SLE trials.Trial registration numbers NCT02446912 and NCT02446899.

This multicenter, phase 3 trial evaluated oral lubiprostone for constipation associated with non-methadone opioids in patients with chronic noncancer-related pain. Adults with opioid-induced constipation (OIC; <3 spontaneous bowel movements [SBMs] per week) were randomized 1:1 to double-blind lubiprostone 24 μg or placebo twice daily for 12 weeks. The primary end point was the overall SBM response rate. Responders had at least moderate response (≥1 SBM improvement over baseline frequency) in all treatment weeks with available observed data, as well as full response (≥3 SBMs per week) for at least 9 of the 12 treatment weeks. In total, 431 patients were randomized; 212 each received lubiprostone and placebo, and 7 were not treated. Overall, the SBM response rate was significantly higher for patients treated with lubiprostone vs. placebo (27.1 vs. 18.9%, respectively; P=0.030). Overall mean change from baseline in SBM frequency was significantly greater with lubiprostone vs. placebo (3.2 vs. 2.4, respectively; P=0.001). The median time to first SBM was significantly shorter with lubiprostone vs. placebo (23.5 vs. 37.7 h, respectively; P=0.004). Compared with placebo, the patients treated with lubiprostone exhibited significant improvements in straining (P=0.004), stool consistency (P<0.001), and constipation severity (P=0.010). No significant differences were observed in quality-of-life measures or the use of rescue medication; however, the percentage of patients who used rescue medication was consistently lower in the lubiprostone group than in the placebo group at months 1 (34.9 vs. 37.7%), 2 (23.4 vs. 26.6%), and 3 (20.5 vs. 22.0%). Adverse events (AEs) >5% were diarrhea, nausea, vomiting, and abdominal pain (lubiprostone: 11.3, 9.9, 4.2, and 7.1%, respectively; placebo, 3.8, 4.7, 5.2, and 0%, respectively). None of the serious AEs (lubiprostone, 3.3%; placebo, 2.8%) were related to lubiprostone. Lubiprostone significantly improved symptoms of OIC and was well tolerated in patients with chronic noncancer pain.

Amyotrophic lateral sclerosis (ALS) is characterized by progressive loss of motor neurons. Multilineage-differentiating stress-enduring (Muse) cells are unique endogenous stem cells that show therapeutic effects on motor function in ALS mouse models. We conducted a single-center open phase II clinical trial to evaluate the safety and clinical effects of repeated intravenous injections of an allogenic Muse cell-based product, CL2020, in patients with ALS. Five patients with ALS received CL2020 intravenously once a month for a total of six doses. The primary endpoints were safety and tolerability, and the secondary endpoint was the rate of change in the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) score. In addition, serum tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), sphingosine-1-phosphate (S1P), cerebrospinal fluid chitotriosidase-1 (CHIT-1), and neurofilament light chain (NfL) levels were evaluated. The CL2020 treatment was highly tolerated without serious side effects. The ALSFRS-R score change trended upward at 12 months post-CL2020 treatment compared with that at 3 months pre-administration, but the difference was not statistically significant. Among five patients diagnosed with ALS, three exhibited a decrease in the rate of ALSFRS-R score change, one demonstrated an increase, and another showed no change. In addition, the patients’ serum IL-6 and TNF-α levels and cerebrospinal fluid CHIT-1 and NfL levels increased for up to 6 months post-treatment; however, their serum S1P levels continuously decreased over 12 months. These findings indicate a favorable safety profile of CL2020 therapy. In the near future, a double-blind study of a larger number of ALS patients should be conducted to confirm the efficacy of ALS treatment with CL2020.

Purpose We studied the effect of a platelet-rich fibrin matrix (PRFM) combined with prostaglandin E-1 (PGE-1) injection on erectile function in patients refractory to response for phosphodiesterase type 5 inhibitors (PDE5-Is). Methods This randomized, double-blind, placebo-controlled study included 80 patients. The patients were randomly assigned to four groups and blinded together with the administrating physicians to the nature of the intracorporeal injection (ICI) therapies. Group (1) received saline, group (2) received platelet-rich fibrin matrix (PRFM), group (3) received prostaglandin E-1 (PGE-1), and group (4) received a combination of PRFM + PGE-1. The patients received ICI therapy weekly for 8 consecutive weeks. Clinical information and follow-up data were obtained at 1, 2, 3, and 6 months. Results A significant increase occurred in the validated Arabic version of the International Index of Erectile Function (ArIIEF-5) score in group (4) compared to the other three groups ( p value = 0.037). There was a significant difference in erection hardness scale (EHS) scores among all groups after receiving the different treatments ( p  = 0.004). A significant increase was seen in the ArIIEF-5 score in groups 4 and 3 compared to that in groups 1 and 2 ( p  < 0.001). There was also a significant increase in the arterial dilatation % in groups 4 and 3 compared to that in groups 1 and 2 ( p  = 0.019). Conclusion The combination of PRFM plus PGE-1 had shown significant improvement in the ArIIEF-5 score, yet the patients still had mild to moderate ED.

Aims The aim of this study is to assess the efficacy and safety of lubiprostone in adults with chronic constipation. Methods This multicenter, parallel-group trial enrolled 237 patients with chronic constipation and randomized them to 4 weeks of double-blind treatment with oral lubiprostone 24 mcg or placebo twice daily. The primary efficacy endpoint was the number of spontaneous bowel movements (SBMs) after 1 week of treatment. Secondary evaluations included SBMs at weeks 2, 3, and 4; percentage of patients with a SBM within 24 h of first study dose; stool consistency; degree of straining; constipation severity; abdominal bloating and discomfort; global treatment effectiveness; and safety assessments. Results Lubiprostone-treated patients experienced greater mean numbers of SBMs at week 1 compared with placebo (5.89 versus 3.99, P = 0.0001), with significantly greater percentages having SBMs within 24 h of the first dose (61.3% versus 31.4%, P < 0.0001). At each assessment, SBM frequency and percentages of full responders (≥4 SBM per week) were significantly greater among lubiprostone-treated patients compared with placebo (P ≤ 0.0171). Lubiprostone-treated patients reported significant improvements in stool consistency, straining, and constipation severity at all weeks, and in abdominal bloating at week 1. Patient assessments of treatment effectiveness were significantly greater with lubiprostone compared with placebo at all weeks (P < 0.0004). Gastrointestinal-related disorders were the most common adverse events in both treatment groups. Conclusions In patients with chronic constipation, lubiprostone produced a bowel movement in the majority of individuals within 24 h of initial dosing, with sustained improvement in frequency as well as other constipation symptoms over 4 weeks of treatment.

Background and Objectives: Spinal stenosis, low back pain, and radiating pain to the lower extremities are caused by inflammation of the spinal canal and impaired blood flow around the nerves. Because JOINS tablets are known to have anti-inflammatory, pain-relieving, and blood circulation-enhancing properties, this research was conducted based on the assumption that they could improve spinal stenosis. Materials and Methods: This was a prospective, randomized, single-center, open-label clinical trial with a 6-month follow-up period. A total of 100 patients with lumbar spinal stenosis were randomized into two groups: 50 patients in the test group and 50 patients in the control group. The control group was prescribed the usual spinal stenosis medications (Naproxen, Limaprost, and Pregabalin), while the test group was prescribed JOINS tablets in addition to the usual medications. Results: The severity of low back pain and radiating leg pain was assessed using a Visual Analog Scale. Spinal functional outcomes were assessed using the Oswestry Disability Index (ODI) and Roland-Morris Disability Questionnaire (RMDQ), and quality of life was assessed using the Short Form 36 (SF-36), with division into Physical Component Score (PCS) and Mental Component Score (MCS). At 6 months, the JOINS group showed a greater reduction in low back pain compared with controls (p < 0.001). At all follow-up periods, the functional outcomes did not show statistically significant differences between the test and control groups. Conclusions: The significant reduction in pain suggests that JOINS tablets may be an effective adjunct for pain relief, particularly in patients at high risk of adverse effects from long-term NSAID use.

To observe the clinical efficacy of different doses of alprostadil (lipo-prostaglandin E1, lipo-PGE1) in the treatment of painful diabetic peripheral neuropathy (DPN). Sixty patients with painful DPN were equally and randomly assigned into three groups. Two groups received different doses of lipo-PGE1 by intravenous drip injection (A group: low-dose lipo-PGE1; B group: high-dose lipo-PGE1) following intravenous bolus injection of mecobalamin (MeCbl, 0.5mg once daily (QD)); the third group received MeCbl alone (C group). All patients received optimized treatment to lower blood glucose, blood pressure, and blood lipids to target levels. The efficacy of lipo-PGE1 in the three groups of patients was observed after 3weeks of treatment. The overall response rate was 90% in the B group, significantly higher than that in the A and C groups (80% and 55%, respectively; P<0.05). During the observation period, there was no incidence of serious adverse reactions (e.g., acute heart failure, sudden drop in blood pressure, or malignant arrhythmias) in any of the three groups. High-dose lipo-PGE1 has better efficacy than low-dose lipo-PGE1 or MeCbl alone in the treatment of painful DPN.

Purpose Limaprost, a prostaglandin E 1 analog, has vasodilatory properties and increases blood flow of the nerve root. However, it has not been clarified whether limaprost affects pain sensation associated with radiculopathy due to lumbar spinal stenosis (LSS). The aim of this study was to compare the efficacy of oral limaprost with nonsteroidal anti-inflammatory drugs (NSAIDs) for radiculopathy. Methods We performed a multicenter prospective randomized trial. Patients with LSS who had radicular-type neurologic intermittent claudication assessed based on a self-reported diagnostic support tool were randomized into three treatment groups. Limaprost, NSAIDs, or limaprost plus NSAIDs were administered orally for 6 weeks. Leg pain, low back pain (LBP) and the associated symptoms were assessed by a numerical rating scale (NRS) both at rest and on movement as well as the Roland–Morris Disability Questionnaire (RDQ) and Short Form (SF)-36. Results Sixty-one patients were enrolled in the study. Each treatment finally reduced radicular pain, and the improvement was prominent in a combination treatment. There were no significant differences in radicular pain among three groups at final follow-up. LBP was not influenced by limaprost, and a significant reduction of LBP and RDQ was confirmed in a combination treatment compared with limaprost. Physical function of the SF-36 subscales after a combination treatment showed a marked alleviation compared with NSAIDs. Conclusions These obtained findings suggest that the effects of limaprost seem to be limited to radicular pain, not for LBP. Overall, a combination treatment might be more effective in the management of radiculopathy induced by LSS than monotherapy with either agent.

Purpose Type 2 diabetes mellitus (T2DM) patients treated with metformin are predisposed to develop contrast-induced nephropathy (CIN) after received emergency contrast-enhanced computed tomography (CT) examination. We evaluated the protective effects of alprostadil on CIN in T2DM patients treated with metformin after contrast media (CM) administration. Methods In this single-institution, single-blind, superiority trial, we randomly assigned 451 T2DM patients taking metformin and underwent emergency contrast-enhanced CT examination to either the alprostadil group (227 patients) receiving alprostadil or the control group (224 patients) without alprostadil. All subjects stopped taking metformin and drank 500 ml water within 12 h after CM exposure. In addition, patients in the alprostadil group were injected with alprostadil (10 μg/day, for 3 days) plus 20 ml normal saline (alprostadil hydration) and the control group patients were daily injected with 20 ml normal saline as control for 3 days following CM administration. Serum creatinine (Scr) was measured before and <72 h after contrast-enhanced CT examination. CIN was defined as an increase in Scr ≥ 44.2 µmol/l (0.5 mg/dL) or >25% over baseline within 3 days of contrast administration. Results There was a lower incidence of CIN in patients underwent alprostadil hydration than drinking water monohydration after CM administration, who with either normal renal function or chronic kidney disease (baseline eGFR < 60 ml·min −1 ·1.73 m −2 ). Conclusions Alprostadil hydration was superior to drinking water monohydration regarding preventing CIN in T2DM patients treated with metformin after contrast-enhanced CT.

Background：Several studies have demonstrated that primary percutaneous coronary intervention （PCI） can result in reperfusion injury.This study aims to investigate the effectiveness of liposomal prostaglandin E l （Lipo-PGE1,Alprostadil,Beijing Tide Pharmaceutical Co.,Ltd.） for enhancing microcirculation in reperfusion injury.In addition,this study determined the optimal administration method for acute ST elevation myocardial infarction （STEMI） patients undergoing primary PCI.Methods：Totally,68 patients with STEMI were randomly assigned to two groups：intravenous administration ofLipo-PGE 1 （Group A）,and no Lipo-PGE1 administration （Group B）.The corrected thrombolysis in myocardial infarction （TIMI） frame count （cTFC） and myocardial blush grade （MBG） were calculated.Patients were followed up for 6 months.Major adverse cardiac events （MACE） were also measured.Results：There was no significant difference in the baseline characteristics between the two groups.The cTFC parameter in Group A was significantly lower than Group B （18.06 ± 2.06 vs.25.31 ± 2.59,P ＜ 0.01）.The ratio of final MBG grade-3 was significantly higher （P ＜ 0.05） in Group A （87.9％） relative to Group B （65.7％）.There was no significant difference between the two groups in final TIMI-3 flow and no-reflow.Patients were followed up for 6 months,and the occurrence of MACE in Group A was significantly lower than that in Group B （6.1％ vs.25.9％ respectively,P ＜ 0.05）.Conclusions：Myocardial microcirculation of reperfusion injury in patients with STEMI,after primary PCI,can be improved by administering Lipo-PGE1.