In this preliminary study, 4% icodextrin lavage plus instillation was well tolerated and reduced adhesion formation and reformation following laparoscopic gynaecological surgery. A Phase III pivotal study is currently in progress.
Intra-abdominal adhesion formation causes significant post-operative morbidity. Controlled studies using animal models have been carried out to assess the tolerability and preventive efficacy of icodextrin solution (a biodegradable, biocompatible, glucose polymer). Reduction of adhesion formation was first evaluated in a rabbit double uterine horn model, applying 10-75 ml of 7.5 and 20%, or 50 ml of 2.5-20% icodextrin solution post-operatively. Significant increases in adhesion free sites (P < 0.005) were observed with volumes > or =25 ml, and at concentrations > or =4%. Efficacy of 50 ml 4 and 20% icodextrin was then evaluated both during and after surgery, demonstrating significant reductions in adhesion formation (P < 0. 002). In one study, intra- plus post-operative use of 4% icodextrin produced the greatest reduction of non-surgical site adhesions; in others, the post-operative effect was predominant. Post-surgical administration of 50 ml 4% icodextrin in a rabbit sidewall model also resulted in more adhesion-free animals, and a significant reduction (P < 0.001) in areas of adhesion formation and reformation. In a rat infection potentiation model, 4% icodextrin produced no difference in mortality, abscess formation or overall abscess score. These data suggest that 4% icodextrin offers a well-tolerated and effective means of reducing post-surgical adhesion formation.
The use of a 4% icodextrin solution for peri-operative lavage and postoperative instillation in a rabbit model of bowel anastomotic healing did not result in any difference from either LRS treated or untreated surgical controls.
This report describes local administration of submicron particle paclitaxel (SPP) (NanoPac®: ~ 800-nm-sized particles with high relative surface area with each particle containing ~ 2 billion molecules of paclitaxel) in preclinical models and clinical trials evaluating treatment of carcinomas. Paclitaxel is active in the treatment of epithelial solid tumors including ovarian, peritoneal, pancreatic, breast, esophageal, prostate, and non-small cell lung cancer. SPP has been delivered directly to solid tumors, where the particles are retained and continuously release the drug, exposing primary tumors to high, therapeutic levels of paclitaxel for several weeks. As a result, tumor cell death shifts from primarily apoptosis to both apoptosis and necroptosis. Direct local tumoricidal effects of paclitaxel, as well as stimulation of innate and adaptive immune responses, contribute to antineoplastic effects. Local administration of SPP may facilitate tumor response to systemically administered chemotherapy, targeted therapy, or immunotherapy without contributing to systemic toxicity. Results of preclinical and clinical investigations described here suggest that local administration of SPP achieves clinical benefit with negligible toxicity and may complement standard treatments for metastatic disease.
Graphical abstract
This randomized, double-blind, placebo-controlled Phase 2 clinical trial explored NorLeu(3)-A(1-7) (DSC127) safety and healing efficacy in diabetic foot ulcers. Patients with chronic, noninfected, neuropathic, or neuroischemic plantar Wagner Grade 1 or 2 foot ulcers (n = 172) were screened for nonhealing. Subjects were randomized to receive 4 weeks' once-daily topical treatment with 0.03% DSC127 (n = 26), 0.01% DSC127 (n = 27), or Placebo (n = 24), followed by 20 weeks' standard of care. DSC127 was assessed for safety (including laboratory values and adverse events), primary efficacy (% ulcers completely epithelialized at Week 12), and durability of effect. Baseline, demography, and safety parameters were compared between intent-to-treat groups and were comparable. Dose-response curves for DSC127 effect on % area reduction from baseline at Week 12 (40% placebo; 67% 0.01% DSC127; 80% 0.03% DSC127) and 24 (23% placebo; 53% 0.01% DSC127; 95% 0.03% DSC127) followed a log-linear pattern for both intent-to-treat and per-protocol populations. Covariate analysis compared reduction in ulcer area, depth, and volume from baseline; reductions in the 0.03% DSC127 group were greater at Weeks 12 and 24. Placebo-treated ulcers healed in a median 22 weeks vs. 8.5 weeks for 0.03%DSC127 (p = 0.04). This study provides preliminary evidence that DSC127 is safe and effective in accelerating the healing of diabetic foot ulcers.
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