Pain after surgery remains a significant healthcare challenge. Here, abobotulinumtoxinA (aboBoNT-A, DYSPORT) was assessed in a post-surgical pain model in pigs. Full-skin-muscle incision and retraction surgery on the lower back was followed by intradermal injections of either aboBoNT-A (100, 200, or 400 U/pig), vehicle (saline), or wound infiltration of extended-release bupivacaine. We assessed mechanical sensitivity, distress behaviors, latency to approach the investigator, and wound inflammation/healing for 5–6 days post-surgery. We followed with immunohistochemical analyses of total and cleaved synaptosomal-associated protein 25 kD (SNAP25), glial fibrillary acidic protein (GFAP), ionized calcium-binding adaptor protein-1(Iba1), calcitonin gene-related peptide (CGRP) and substance P (SP) in the skin, dorsal root ganglia (DRG) and the spinal cord of 400 U aboBoNT-A- and saline-treated animals. At Day 1, partial reversal of mechanical allodynia in aboBoNT-A groups was followed by a full reversal from Day 3. Reduced distress and normalized approaching responses were observed with aboBoNT-A from 6 h post-surgery. Bupivacaine reversed mechanical allodynia for 24 h after surgery but did not affect distress or approaching responses. In aboBoNT-A-treated animals cleaved SNAP25 was absent in the skin and DRG, but present in the ipsilateral dorsal horn of the spinal cord. In aboBoNT-A- versus saline-treated animals there were significant reductions in GFAP and Iba1 in the spinal cord, but no changes in CGRP and SP. Analgesic efficacy of aboBoNT-A appears to be mediated by its activity on spinal neurons, microglia and astrocytes. Clinical investigation to support the use of aboBoNT-A as an analgesic drug for post-surgical pain, is warranted.
Limited experiments have compared the treatment effects of repetitive cycles of radiolabelled somatostatin (SST) analogues. In vitro and in vivo experiments were conducted in an AR42J cancer cell model, comparing the antagonist [177Lu]Lu-satoreotide tetraxetan with the agonist [177Lu]Lu-DOTA-TATE in terms of their binding properties, biodistribution, anti-tumour activity and toxicity. Histopathological and immunohistochemical examinations were performed at different timepoints. In the in vitro assays, [177Lu]Lu-satoreotide tetraxetan recognised twice as many SST2 binding sites as [177Lu]Lu-DOTA-TATE. In mice treated once a week for four consecutive weeks, [177Lu]Lu-satoreotide tetraxetan (15 MBq) revealed a significantly greater median time taken to reach a tumour volume of 850 mm3 (68 days) compared to [177Lu]Lu-DOTA-TATE at 15 MBq (43 days) or 30 MBq (48 days). This was associated with a higher tumour uptake, enhanced DNA damage and no or mild effects on body weight, haematological toxicity, or renal toxicity with [177Lu]Lu-satoreotide tetraxetan (15 MBq). At the end of the study, complete tumour senescence was noted in 20% of animals treated with [177Lu]Lu-satoreotide tetraxetan, in 13% of those treated with [177Lu]Lu-DOTA-TATE at 30 MBq, and in none of those treated with [177Lu]Lu-DOTA-TATE at 15 MBq. In conclusion, repeated administrations of [177Lu]Lu-satoreotide tetraxetan were able to potentiate peptide receptor radionuclide therapy with a higher tumour uptake, longer median survival, and enhanced DNA damage, with a favourable efficacy/safety profile compared to [177Lu]Lu-DOTA-TATE.
Pain after surgery remains a significant healthcare challenge. Here, activity of abobotulinumtoxinA (aboBoNT-A, Dysport®) was assessed in a post-surgical pain model in pigs. Full-skin-muscle incision and retraction surgery on the lower flank was followed by intradermal injections of either aboBoNT-A (100, 200, or 400 U/pig), vehicle (saline), or wound infiltration of liposomal extended-release bupivacaine. Animals were assessed for mechanical sensitivity, distress behaviors, latency to approach the investigator for 5 days following surgery. Immunohistochemical analyses of total and cleaved synaptosomal-associated protein-25 kD (SNAP-25) and pain-related biomarkers were performed in the aboBoNT-A-400 U and saline groups. At Day 1, partial reversion of mechanical allodynia was achieved in aboBoNT-A groups with full reversion from Day 3. Reduced distress and normalized approaching responses were observed with aboBoNT-A from 6 h post-surgery. Bupivacaine reversed mechanical allodynia for 24 h after surgery but did not affect distress or approaching responses. Cleaved SNAP-25 was absent in the skin and dorsal root ganglia but present in the ipsilateral dorsal horn of aboBoNT-A-injected animals. A decrease in some pain-related biomarkers was seen with aboBoNT-A versus saline. Clinical investigation to support the use of aboBoNT-A as a tolerable and efficacious analgesic drug for post-surgical pain, is warranted.
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