The demonstration that methyl tert-butyl ether is a safe and effective gallstone solvent and the development of the microprocessor-assisted solvent transfer system have revived the procedure of chemical contact dissolution of gallbladder stones, which was first described 100 years ago. This procedure of automatic computerized solvent litholysis is further enhanced by the development of a CT-index for the selection of patients with amenable stones and percutaneous gallbladder endoscopy for evaluation after dissolution. Preliminary studies have shown that ACSL with MTBE is safe and highly effective for gallbladder stone dissolution, making this technique a viable non-surgical alternative for the treatment of gallbladder stones. The emergence of new safer and more effective solvent such as ethyl propionate along with the procedure of percutaneous gallbladder ablation for the definitive prevention of gallstone recurrence promise to render ACSL highly competitive even with laparoscopic cholecystectomy.
Patients with ulcerative colitis (UC) who achieve remission with corticosteroids often relapse after tapering or discontinuation; alternative treatments limiting steroid exposure and UC relapse would be beneficial. It remains uncertain whether patients with corticosteroid-induced remission experience benefit with mesalamine granules (MG), a locally acting aminosalicylate extended-release capsule formulation for maintenance of UC remission in adults. Efficacy and safety of MG 1.5 g once daily was evaluated in patients with UC in corticosteroid-induced remission. Data from patients with previous corticosteroid use to achieve baseline UC remission were analyzed from two 6-month randomized, double-blind, placebo-controlled trials and a 24-month open-label extension (OLE). Six-month relapse-free rates were assessed using the revised Sutherland Disease Activity Index. UC-related adverse events (AEs) were recorded during the 30 months. Included were 158 steroid-treated patients in UC remission (MG, n = 105; placebo, n = 53) and 74/105 MG-treated patients who continued MG in the OLE. A significantly larger percentage of patients remained relapse-free at 6 months with MG (77.1 %) versus placebo (54.7 %; P = 0.006), with a 55 % reduction in relapse risk (hazard ratio [HR] 0.45; 95 % CI 0.25–0.79). There was a similar (49.2 %) reduction in risk of UC-related AEs at 6 months (HR 0.51; 95 % CI 0.31–0.84; P = 0.009) that was sustained during the OLE. MG 1.5 g once daily administered for maintenance of corticosteroid-induced remission was associated with low risk of relapse and UC-related AEs. NCT00744016, NCT00767728, and NCT00326209.
Background & AimsNew oral therapeutic agents are needed for patients with ulcerative colitis (UC) who are unresponsive or intolerant to conventional therapy.MethodsWe performed a double-blind, phase 2 trial of adults with active UC for 3 months or more who were naïve to biologic therapy or had been failed by, could not tolerate, or had contraindications to conventional therapies. The study was performed at 61 sites in 14 countries (screening from January 2015 through May 2017). Patients were randomly assigned to groups given apremilast 30 mg (n = 57), apremilast 40 mg (n = 55), or placebo (n = 58) twice daily for 12 weeks; patients were then randomly assigned to groups that received apremilast, 30 or 40 mg twice daily, for an additional 40 weeks. Endoscopies were performed and biopsies were collected during the screening phase, at week 12, and at week 52. Blood and fecal samples were also collected and analyzed throughout the study. The primary endpoint was clinical remission at week 12, defined as a total Mayo score of 2 or less, with no individual subscore above 1.ResultsClinical remission was achieved at week 12 by 31.6% of patients in the 30 mg apremilast group and 12.1% of patients in the placebo group (P = .01). However, only 21.8% of patients in the 40 mg apremilast group achieved clinical remission at week 12 (P = .27 compared with placebo). Differences in clinical remission between the 30 mg and 40 mg apremilast groups were associated with differences in endoscopic improvement. Both apremilast groups had similar improvements from baseline in Mayo score components (stool frequency score, rectal bleeding score, physician's global assessment). The 30 mg and 40 mg apremilast groups had greater median percent reductions in C-reactive protein (measured by a high-sensitivity blood test) and fecal calprotectin through week 12 than the placebo group. At week 52, clinical remission was achieved by 40.4% of patients initially assigned to the apremilast 30 mg group and 32.7% of patients initially assigned to the apremilast 40 mg group. The most frequent apremilast-associated adverse events were headache and nausea.ConclusionsAlthough the primary endpoint of clinical remission was not met in this phase 2 trial, a greater proportion of patients with active UC who received apremilast (30 mg or 40 mg) had improvements in clinical and endoscopic features, and markers of inflammation, at 12 weeks. Clinical remission was maintained to week 52 in up to 40% of patients who continued apremilast until that time point. ClinicalTrials.gov no: NCT02289417 New oral therapeutic agents are needed for patients with ulcerative colitis (UC) who are unresponsive or intolerant to conventional therapy. We performed a double-blind, phase 2 trial of adults with active UC for 3 months or more who were naïve to biologic therapy or had been failed by, could not tolerate, or had contraindications to conventional therapies. The study was performed at 61 sites in 14 countries (screening from January 2015 through May 2017). Patients were randomly assigned to groups given apremilast 30 mg (n = 57), apremilast 40 mg (n = 55), or placebo (n = 58) twice daily for 12 weeks; patients were then randomly assigned to groups that received apremilast, 30 or 40 mg twice daily, for an additional 40 weeks. Endoscopies were performed and biopsies were collected during the screening phase, at week 12, and at week 52. Blood and fecal samples were also collected and analyzed throughout the study. The primary endpoint was clinical remission at week 12, defined as a total Mayo score of 2 or less, with no individual subscore above 1. Clinical remission was achieved at week 12 by 31.6% of patients in the 30 mg apremilast group and 12.1% of patients in the placebo group (P = .01). However, only 21.8% of patients in the 40 mg apremilast group achieved clinical remission at week 12 (P = .27 compared with placebo). Differences in clinical remission between the 30 mg and 40 mg apremilast groups were associated with differences in endoscopic improvement. Both apremilast groups had similar improvements from baseline in Mayo score components (stool frequency score, rectal bleeding score, physician's global assessment). The 30 mg and 40 mg apremilast groups had greater median percent reductions in C-reactive protein (measured by a high-sensitivity blood test) and fecal calprotectin through week 12 than the placebo group. At week 52, clinical remission was achieved by 40.4% of patients initially assigned to the apremilast 30 mg group and 32.7% of patients initially assigned to the apremilast 40 mg group. The most frequent apremilast-associated adverse events were headache and nausea. Although the primary endpoint of clinical remission was not met in this phase 2 trial, a greater proportion of patients with active UC who received apremilast (30 mg or 40 mg) had improvements in clinical and endoscopic features, and markers of inflammation, at 12 weeks. Clinical remission was maintained to week 52 in up to 40% of patients who continued apremilast until that time point. ClinicalTrials.gov no: NCT02289417
Summary Background Mesalazine (mesalamine) granules ( MG ) were shown to be effective for the maintenance of remission of ulcerative colitis ( UC ) in two double‐blind placebo‐controlled trials. Aim To evaluate the efficacy of once‐daily MG for maintenance of remission in patients with UC who switched from other 5‐aminosalicylic acid (5‐ ASA ) formulations. Methods Data from two independent multicenter, randomised, double‐blind, placebo‐controlled, 6‐month trials evaluating patients with UC in remission were combined for analysis of a subpopulation of patients who switched from other 5‐ ASA formulations to MG 1.5 g or placebo upon randomisation. The primary endpoint was the percentage of patients who remained relapse‐free at Month 6 or end of treatment. Relapse was defined as a Sutherland Disease Activity Index ( SDAI ) rectal bleeding score ≥1 and mucosal appearance score ≥2, a UC flare or medication used to treat a UC flare. Results Of the 487 patients who received 5‐ ASA maintenance therapy at enrolment, 322 were in the MG group and 165 were in the placebo group. The percentage of patients who remained relapse‐free (based on Sutherland Disease Activity Index scores) after 6 months was significantly higher with MG than placebo (78.3% vs. 58.8%, P < 0.001). Rectal bleeding, stool frequency and the physician's rating of disease activity remained unchanged after 6 months in a higher percentage of patients using MG compared with those on placebo ( P < 0.004 for each endpoint). Conclusion Mesalazine granules 1.5 g once‐daily is effective for maintenance of remission in UC patients who switch from other 5‐ ASA formulations. ClinicalTrials.gov identifiers NCT 00744016, NCT 00767728.
Purpose: Maintenance of ulcerative colitis (UC) remission is an important goal of therapy. Easy-to-administer therapeutic agents with a favorable safety profile can have a substantial impact on patient quality of life and compliance. A unique formulation, granulated mesalamine capsules, provides both delayed and extended release of 5-aminosaliyclic acid directly to the terminal ileum and colon for once-daily dosing. Granulated mesalamine is currently in late-stage development for maintenance of UC remission. Methods: Data from 2 identically designed, randomized, multicenter trials of granulated mesalamine 1.5 g (4 capsules) once daily (N = 367) for 6 months versus placebo (N = 185) in patients who were in UC remission (assessed by revised Sutherland Disease Activity Index: rectal bleeding subscore = 0; mucosal appearance subscore < 2) were pooled to evaluate the safety profile of granulated mesalamine. Assessment of adverse events (AEs), including UC relapse, clinical hematology, blood chemistry, and urinalysis, was conducted at baseline; months 1, 3, and 6/last study visit while on study medication; and 2 weeks posttreatment and by telephone (AEs only) at week 2 and months 2, 4, and 5. Results: Demographics and baseline characteristics were similar between the 2 groups. Mean exposure to study medication was higher with granulated mesalamine (145 d) than placebo (126 d). Fewer patients who received granulated mesalamine (28%) withdrew versus patients who received placebo (43%) due to disease relapse (12% vs 21%, respectively) or AEs (11% vs 16%, respectively). For granulated mesalamine versus placebo, the most common AEs were UC flare (11% vs 24%, respectively), headache (11% vs 8%, respectively), and diarrhea (8% vs 7%, respectively). There was a low and similar incidence of renal, hepatic, or pancreatic AEs in patients in the granulated mesalamine (6%) and placebo (5%) groups. The percentage of patients who experienced serious AEs was small in both the granulated mesalamine (1%) and placebo (2%) groups, and no event reported in the granulated mesalamine group was considered drug-related. No deaths occurred during the study. Conclusion: Granulated mesalamine appears to have a favorable safety profile which, when combined with its low tablet load and convenient once-daily dosing, may support its administration as first-line therapy for maintenance of UC remission.
Neurokinin receptors may play an important role in the visceral hypersensitivity and exaggerated motor/secretory activity associated with diarrhoea-predominant irritable bowel syndrome (IBS-D).To evaluate the effects of DNK333, a novel neurokinin antagonist, in women with IBS-D.In two consecutive phase II studies, women with IBS-D were randomised to twice-daily (b.d.) DNK333 25 mg, DNK333 100 mg or placebo for 2 weeks (Trial 1), or DNK333 25 mg b.d. or placebo for 4 weeks (Trial 2). Primary efficacy variables studied were change from baseline of stool form at week 2, and satisfactory relief of IBS-related abdominal pain/discomfort and global IBS-D symptoms. Secondary efficacy variables, pharmacokinetics and safety were also evaluated.In total, 315 subjects were randomised. There were no statistically significant differences between treatment groups for the primary efficacy variables. However, analysis of combined data from both trials revealed significant differences favouring DNK333 25 mg over placebo for satisfactory relief of IBS-related abdominal pain/discomfort and global IBS-D symptoms. Trends favouring improvement with DNK333 25 mg vs. placebo were seen for all secondary efficacy variables. DNK333 had a safety profile similar to placebo.DNK333 25 mg b.d. appears to be effective and well tolerated in women with IBS-D. Further studies with neurokinin antagonists are warranted.
