Pharmacology/Drug Development

Neuropathic pain in osteoarthritis is one of the reasons why the pain is difficult to treat, and P2X4R plays an important role in neuropathic pain. In addition, BoNT/A has been proven to have analgesic effects on both neuropathic pain and osteoarthritis, but its exact mechanism is still unknown. This study aims to investigate the relationship between the analgesic effect of BoNT/A on osteoarthritis and the expression of P2X4R in spinal cord microglia. The analgesic effect was compared between BoNT/A and compound betamethasone. Western blot analysis was used to examine the expression of P2X4R and BDNF proteins in the spinal cord. Immunohistochemistry was used to determine the cellular location of P2X4R. Mechanical allodynia and weight asymmetry were identified using the hind paw withdrawal threshold and weight bearing test. The results showed that intra-articular injection of MIA induced persistent mechanical allodynia and weight asymmetry in rats. Both BoNT/A and betamethasone could relieve pain behavior in rats, but BoNT/A had a more obvious effect and lasted longer. Furthermore, BoNT/A could reverse the MIA-induced overexpression of BDNF and P2X4R in the spinal dorsal horn. To sum up, BoNT/A is more effective than betamethasone in relieving MIA-induced osteoarthritis pain in rats, and its analgesic effect may be related to the regulation of P2X4R-mediated BDNF release in spinal microglia and the relief of neuropathic pain in osteoarthritis.

The Ad5-nCoV vaccine is a single-dose adenovirus type 5 (Ad5) vectored vaccine expressing the SARS-CoV-2 spike protein that was well-tolerated and immunogenic in phase 1 and 2 studies. In this study, we report results on the final efficacy and interim safety analyses of the phase 3 trial.

Burn injury pain manifests as a combination of inflammatory, nociceptive, and neuropathic features. While opioids are the mainstay of burn pain management, non-opioid medications, such as gabapentinoids, have also been considered as they target the central nervous system. Increased opioid adverse events and overdose deaths in the United States led to the 2014 and 2016 guidelines to reduce opioid prescribing and consider alternatives, such as gabapentinoids. In the context of burn, the rate of gabapentinoid prescribing at the national level is unknown and it is unclear whether any shift has occurred in prescribing practices over time. We conducted a population level cohort study of adult burn patients from 2012 to 2018 to evaluate the rates and determinants of gabapentinoid prescribing, with and without opioids. Of 98,001 patients with burn, 22,521 (22.98%) received opioids and/or gabapentinoids (GABA). GABA represented 2.4% of prescriptions in 2012, but increased to 7.2% by 2018, while GABA-opioid co-prescriptions increased from 2.3% to 5.1%. The rate of increase in GABA prescriptions was higher for those aged 50-65 years or residing in the South. After adjustment, GABA was 44% more likely to be prescribed in 2017 and 2018 compared to 2012 and 2013, opioids were 38% less likely, while co-prescribing did not show a statistically significant change. Our study showed a modest increase in gabapentinoids' outpatient prescribing for burn patients after the 2014 and 2016 guidelines, indicating more opportunities for prescribers to expand non-opioid pain management in this population.

Oxaliplatin, the first-line chemotherapeutic agent against colorectal cancer (CRC), induces peripheral neuropathies, which can lead to dose limitation and treatment discontinuation. Downregulation of potassium channels, which involves histone deacetylase (HDAC) activity, has been identified as an important tuner of acute oxaliplatin-induced hypersensitivity. MS-275, a class I histone deacetylase inhibitor (HDACi), prevents acute oxaliplatin-induced peripheral neuropathy (OIPN). Moreover, MS-275 exerts anti-tumor activity in several types of cancers, including CRC. We thus hypothesized that MS-275 could exert both a preventive effect against OIPN and potentially a synergistic effect combined with oxaliplatin against CRC development. We first used RNAseq to assess transcriptional changes occurring in DRG neurons from mice treated by repeated injection of oxaliplatin. Moreover, we assessed the effects of MS-275 on chronic oxaliplatin-induced peripheral neuropathy development in vivo on mice and on cancer progression when combined with oxaliplatin, both in vivo on mice and in a mouse model of an orthotopic allograft of the CT26 cell line as well as in vitro in T84 and HT29 human CRC cell lines. We found 741 differentially expressed genes (DEGs) between oxaliplatin- and vehicle-treated animals. While acute OIPN is known as a channelopathy involving HDAC activity, chronic OIPN exerts weak ion channel transcriptional changes and no HDAC expression changes in peripheral neurons from OIPN mice. However, MS-275 prevents the development of sensory neuropathic symptoms induced by repeated oxaliplatin administration in mice. Moreover, combined with oxaliplatin, MS-275 also exerts synergistic antiproliferative and increased survival effects in CT26-bearing mice. Consistently, combined drug associations exert synergic apoptotic and cell death effects in both T84 and HT29 human CRC cell lines. Our results strongly suggest combining oxaliplatin and MS-275 administration in CRC patients in order to potentiate the antiproliferative action of chemotherapy, while preventing its neurotoxic effect.

Pyridoxine (vitamin B6) toxicity is known to cause a length-dependent, sensory predominant axonal polyneuropathy. There is debate regarding the threshold at which intake levels can cause neurological symptoms through pyridoxine toxicity. We asked if elevated plasma vitamin B6 levels were related to outcome measures in a well-characterized cohort of patients with chronic idiopathic axonal polyneuropathy (CIAP).

This review highlights a selection of potential translational directions for the treatment of diabetic polyneuropathy (DPN) currently irreversible and without approved interventions beyond pain management. The list does not include all diabetic targets that have been generated over several decades of research but focuses on newer work. The emphasis is firstly on approaches that support the viability and growth of peripheral neurons and their ability to withstand a barrage of diabetic alterations. We include a section describing Schwann cell targets and finally how mitochondrial damage has been a common element in discussing neuropathic damage. Most of the molecules and pathways described here have not yet reached clinical trials, but many trials have been negative to date. Nonetheless, these failures clear the pathway for new thoughts over reversing DPN.