Mean Disease Activity Index Score Research Articles

LOCAL BIOACTIVATION AND EFFICACY OF PALI-2108: A PROMISING PDE4 INHIBITOR PRODRUG FOR ULCERATIVE COLITIS TREATMENT

Abstract Phosphodiesterase-4 (PDE4) is a key enzyme in cAMP hydrolysis and is involved in various inflammatory and fibrotic diseases, such as ulcerative colitis (UC). PDE4 inhibition elevates intracellular cAMP, downregulates inflammatory cytokines (e.g., TNFα), and reduces cell adhesion molecules, thereby preventing local infiltration of inflammatory cells. Several PDE4 inhibitors (e.g., roflumilast and apremilast) are approved for COPD and psoriasis, with others under development for diseases such as idiopathic pulmonary fibrosis (IPF). Phase 2 clinical trials have shown that oral PDE4 inhibitors enhance clinical remission in UC patients, with a 20% placebo-adjusted improvement with low-dose apremilast. However, oral administration and systemic distribution cause central nervous system (CNS) toxicity (e.g., headaches, nausea, vomiting), leading to therapy discontinuation and limiting efficacy. Targeted and better-tolerated oral treatments are needed to fully exploit PDE4 inhibitors in UC. We assessed the efficacy of PALI-2108, an oral and locally bioactivated PDE4 inhibitor prodrug for UC treatment. PALI-2108 incorporates a galactose-derived sugar moiety, making it minimally absorbed until cleaved by the colonic bacterium enzyme β-glucuronidase. In a DSS-induced UC mouse model, PALI-2108 demonstrated that at doses of 21, 4, 0.75 mg/kg BID, and 1.5 mg/kg daily, it reduced the mean disease activity index (DAI) score over time compared to the DSS control group (Fig 1). Additionally, body weight loss over time was attenuated in the 21 and 4 mg/kg BID groups (Fig 2). A tissue distribution study showed colon preference of PALI-2108 with limited plasma levels and a colon/plasma AUC ratio exceeding 200. Additionally, oxazolone colitis induced mice treated with PALI-2108 showed colon-selective bioactivation, with negligible plasma levels compared to duodenal and ileal tissue. In a target engagement study, we used a CETSA Navigate® assay to measure PALI-2108 binding to cAMP-specific 3’, 5’-cyclic PDE4D in OXZ-treated mice. Melt and shift curves showed similar changes, indicating comparable target engagement in colon tissues between PALI-2108 and apremilast. Finally, in a tolerated dose study, we showed no CNS toxicity and emesis over effective doses in dogs. In conclusion, our results demonstrate local bioactivation of a PDE4 inhibitor pro-drug, PALI-2108, and its colon-specific distribution with limited systemic exposure. PALI-2108 has similar target engagement to other PDE4 inhibitors, dose-dependent efficacy in a UC model, and no systemic toxicity. We believe PALI-2108 is a promising novel therapy for UC, with localized bioactivation, expanded therapeutic window, and potent PDE4 inhibitory activity. PALI-2108 is in development for moderate-to-severe UC and is advancing toward regulatory filing for first-in-human studies. PALI-2108 reduced DSS induced mean disease activity index score (DAI) over time compared to control. PALI-2108 attenuated DSS induced body weight loss over time compared to control.

Effect of Abdominal Lymphatic Pump Treatment on Disease Activity in a Rat Model of Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD), such as ulcerative colitis and Crohn disease, are chronic relapsing inflammatory diseases that affect 1.5 million people in the United States. Lymphatic pump treatment (LPT) techniques were designed to enhance the movement of lymph and can be used to relieve symptoms in patients with IBD and other gastrointestinal disorders. To determine whether LPT would decrease gastrointestinal inflammation and reduce disease severity in rats with acute IBD. On day 0, rats were randomized into control or experimental groups. Control rats received normal drinking water for days 0 to 9. On days 0 to 9, rats in the experimental groups received drinking water containing 3.5% dextran sodium sulfate (DSS). On day 3, experimental rats were randomized into 3 groups. On days 3 to 8, experimental rats received either (1) no treatment or anesthesia (DSS alone); (2) 4 minutes of LPT with anesthesia administration (DSS+LPT); or (3) 4 minutes of sham treatment (ie, light touch) and anesthesia (DSS+sham). On day 9, colons and gastrointestinal lymphoid tissue were collected. Colon weight, histologic changes, disease activity index (DAI) score, and the concentration of leukocytes were measured. At day 9, the mean (SD) DAI score in the DSS+LPT group (1.0 [0.1]) was significantly decreased (P<.01) compared with the DAI score of DSS-alone rats (1.5 [0.1]). While the DAI in DSS+LPT rats was reduced on days 8 to 9, this difference was not statistically different (P>.05) compared with DSS+sham (1.3 [0.1]). No significant differences were found in colon weight, histopathologic findings, or the concentration of gastrointestinal leukocytes between DSS alone, DSS+sham, or DSS+LPT (P>.05). While DSS+LPT reduced IBD compared with DSS+sham, the decrease was not statistically significant. Considering the growing use of adjunctive treatment for the management of IBD, it is important to identify the effect of osteopathic manipulative medicine on IBD progression.

Correlation of fatigue with other disease related and psychosocial factors in patients with rheumatoid arthritis treated with tocilizumab: ACT-AXIS study.

To assess the hypothesis if tocilizumab (TCZ) is effective on disease activity, and also its effect in fatigue and other clinical and psychological disease-related factors in patients with rheumatoid arthritis (RA) treated with TCZ.A 24-week, multicenter, prospective, observational study in patients with moderate to severe RA receiving TCZ after failure or intolerance to disease-modifying antirheumatic drugs or tumor necrosis factor-alpha was conducted.Of the 122 patients included, 85 were evaluable for effectiveness (85% female, 51.9 ± 12.5 years, disease duration 8.7 ± 7.4 years). Mean change in C-reactive protein level from baseline to week 12 was −11.2 ± 4.0 (P < .001). Mean Disease Activity Index score (DAS28) decreased from 5.5 ± 1.0 at baseline to 2.7 ± 1.3 (P < .001) at week 24. Mean change in Functional Assessment of Chronic Illness Therapy score was −5.4 ± 11.2 points at week 24. Multiple regression analysis showed that the improvement in DAS28, sleep, and depression explained 56% and 47% of fatigue variance at week 12 and 24, respectively.Tocilizumab is effective in reducing disease activity and results in a clinically significant improvement in fatigue, pain, swollen joint count, morning stiffness, sleepiness, depression, and DAS28; the last 3 were specifically identified as factors explaining fatigue variance with the use of TCZ in RA patients.

Cannabis for the treatment of ulcerative colitis.

Cannabis for the treatment of ulcerative colitis.

Oral high dose Beclomethasone dipropionate for treatment of active ulcerative colitis

Oral corticosteroids (CS) have been widely used for treatment of ulcerative colitis (UC) at the price of systemic side effects. Role of topically active oral beclomethasone dipropionate (BDP) in clinical practice is still unclear. The aim of this paper is to investigate efficacy and tolerability of a high dose BDP regimen in mild to moderately active UC. Twenty-five patients (9 males, aged 25-40 years) with mild to moderately active UC, unresponsive to oral and topical 5-ASA (4.8 gr daily) and BDP (5 mg daily), were enrolled. All patients continued 5-ASA plus high dose oral BDP (15 mg od for 4 weeks and than tapered). Clinical, endoscopic, histological and laboratory parameters were monitored. Mean disease activity index (DAI) score at study entry was 8.82±4. Response to treatment was observed in all patients after 2 weeks. Remission was observed in all patients within 4-6 weeks from entering the study (mean DAI score: 2.34±0.5) and maintained throughout 6-month follow-up. No major adverse events were documented. Quality of life global evaluation score improved. This study provides the first evidence of efficacy and safety of high dose oral BDP-scheme in UC demonstrating excellent tolerability and favourable acceptability profile. This new BDPscheme might be a valid alternative to conventional oral CS when standard dose BDP is not effective. Future studies are needed to explore further clinical indications.

Effectiveness ofSaccharomyces boulardiiin a rat model of colitis

To investigate the effects of Saccharomyces boulardii (S. boulardii) in an experimental rat model of trinitrobenzene sulfonic acid (TNBS)-induced colitis. Thirty-two Wistar albino female rats were categorized into five groups. On the first day of the study, 50 mg TNBS was administered via a rectal catheter in order to induce colitis in all rats, except those in the control group. For 14 d, the rats were fed a standard diet, without the administration of any additional supplements to either the control or TNBS groups, in addition to 1 mg/kg per day S. boulardii to the S. boulardii group, 1 mg/kg per day methyl prednisolone (MP) to the MP group. The animals in the S. boulardii + MP group were coadministered these doses of S. boulardii and MP. During the study, weight loss, stool consistency, and the presence of obvious blood in the stool were evaluated, and the disease activity index (DAI) for colitis was recorded. The intestines were examined and colitis was macro- and microscopically scored. The serum and tissue levels of tumor necrosis factor-α (TNF-α) and nitric oxide (NO) were determined, and fungemia was evaluated in the blood samples. The mean DAI scores for the MP and S. boulardii + MP groups was significantly lower than the TNBS group (3.69 ± 0.61 vs 4.46 ± 0.34, P = 0.018 and 3.77 ± 0.73 vs 4.46 ± 0.34, P = 0.025, respectively). While no significant differences between the TNBS and the S. boulardii or MP groups could be determined in terms of serum NO levels, the level of serum NO in the S. boulardii + MP group was significantly higher than in the TNBS and S. boulardii groups (8.12 ± 4.25 μmol/L vs 3.18 ± 1.19 μmol/L, P = 0.013; 8.12 ± 4.25 μmol/L vs 3.47 ± 1.66 μmol/L, P = 0.012, respectively). The tissue NO levels in the S. boulardii, MP and S. boulardii + MP groups were significantly lower than the TNBS group (16.62 ± 2.27 μmol/L vs 29.72 ± 6.10 μmol/L, P = 0.002; 14.66 ± 5.18 μmol/L vs 29.72 ± 6.10 μmol/L, P = 0.003; 11.95 ± 2.34 μmol/L vs 29.72 ± 6.10 μmol/L, P = 0.002, respectively). The tissue NO levels in the S. boulardii, MP and S. boulardii + MP groups were similar. The mean serum and tissue TNF-α levels were determined to be 12.97 ± 18.90 pg/mL and 21.75 ± 15.04 pg/mL in the control group, 18.25 ± 15.44 pg/mL and 25.27 ± 11.95 pg/mL in the TNBS group, 20.59 ± 16.15 pg/mL and 24.39 ± 13.06 pg/mL in the S. boulardii group, 9.05 ± 5.13 pg/mL and 24.46 ± 10.85 pg/mL in the MP group, and 13.95 ± 10.17 pg/mL and 24.26 ± 10.37 pg/mL in the S. boulardii + MP group. Significant differences in terms of the levels of serum and tissue TNF-α and the macroscopic and microscopic scores were not found between the groups. S. boulardii fungemia was not observed in any of the rats. However, Candida fungemia was detected in one rat (14%) in the TNBS group, two rats (28%) in the S. boulardii group, three rats (50%) in the MP group, and three rats (42%) in S. boulardii + MP group. S. boulardii does not demonstrate considerable effects on the DAI, pathological scores, or cytokine levels but does decrease the tissue NO levels.

Oral, colonic‐release low‐molecular‐weight heparin: an initial open study of Parnaparin‐MMX for the treatment of mild‐to‐moderate left‐sided ulcerative colitis

Efficacy of heparin and low-molecular-weight heparins (LMWHs) in inflammatory bowel disease (IBD) treatment has been suggested. The multimatrix oral formulation MMX releases active drugs in the colon, avoiding systemic absorption. Parnaparin sodium is the LMWH chosen to be carried in the MMX formulation. To assess the safety of three different oral dosages (70, 140 and 210 mg once daily) of Parnaparin-MMX (CB-01-05) in left-sided ulcerative colitis (UC). Left-sided UC patients, with a mild-to-moderate relapse were enrolled. All patients received Parnaparin-MMX for 8 weeks. Clinical Activity Index (CAI), Disease Activity Index (DAI), Endoscopic Activity Index and IBD-QoL were assessed throughout the study. A strict clinical and laboratory follow-up, including assessment of anti-factor Xa activity, was performed. Clinical remission was defined as CAI <4. Ten UC patients were enrolled. One patient retired for clinical deterioration. No relevant side effects, including either interference with haemostasis parameters or increased bleeding, were observed. At the end of the treatment, seven patients (70%) were in clinical remission, only one achieving endoscopic healing. Mean final CAI, DAI and IBD-QoL scores were significantly improved from baseline. Parnaparin-MMX appears to be a safe treatment option in mild-to-moderate UC. Controlled studies are warranted.

Pilot Feasibility Studies of Leukocytapheresis With the Adacolumn Apheresis System in Patients With Active Ulcerative Colitis or Crohn Disease

Two uncontrolled, multicenter feasibility studies evaluated safety and pilot efficacy of selective granulocyte and monocyte adsorption apheresis (GMA) with the Adacolumn Apheresis System for treatment of moderate-to-severe ulcerative colitis (UC) and Crohn disease (CD) patients refractory/intolerant to conventional pharmacologic therapy. Patients with UC and CD, characterized by elevations in peripheral blood granulocytes, monocytes/macrophages, and proinflammatory mediators, may benefit from reductions in activated granulocytes and monocytes by selective apheresis. Patients underwent weekly Adacolumn sessions for 5 weeks. Pilot efficacy assessments used disease activity index (DAI) for UC (0-12) or CD activity index (CDAI; 0-600) for CD. Eleven of 15 UC patients completed all 5 treatments. Mean DAI scores fell from 8.4+/-1.3 (baseline) to 5.2+/-2.9 (week 7). Five patients had DAI reductions of > or = 3 points at week 7. Fourteen of 15 CD patients completed all 5 treatments. Mean CDAI scores fell from 308.0+/-76.5 (baseline) to 200.6+/-117.4 (week 7). Nine CD patients responded (CDAI reductions > or = 70 points) at week 7. Remission (CDAI score < or = 150 at week 7) was observed in 6 patients. There were no device-related serious adverse effects. Treatment with Adacolumn may be feasible and effective in patients with moderate-to-severe refractory inflammatory bowel disease. Larger sham-controlled studies are ongoing.

Rectal irrigation with short-chain fatty acids for distal ulcerative colitis

Colon cells from patients with ulcerative colitis utilize short-chain fatty acids inefficiently and may be exposed to decreased concentrations of these compounds. To test whether irrigation of the inflamed mucosa with short-chain fatty acids is useful, we conducted a six-week preliminary trial in 12 patients with distal colitis. Each patient used twice daily rectal irrigations with 100 ml of a solution containing acetate (80 mM), propionate (30 mM), and butyrate (40 mM). Two patients stopped at three weeks, one because of no improvement and the other because of complete resolution of symptoms. Of the 10 who completed the trial, nine were judged to be at least much improved and showed a change in a mean disease activity index score from 7.9 +/- 0.3 (SE) to 1.8 +/- 0.6 (SE) (P less than or equal to 0.002) and in a mucosal histology score from 7.7 +/- 0.7 (SE) to 2.6 +/- 0.7 (SE) (P less than or equal to 0.002). Thus, ulcerative colitis patients appear to benefit from increased contact with or higher than usual levels of these critical energy substrates.