Background: COVID-19 convalescent plasma (CCP) has been considered a treatment option in COVID-19. This trial assessed the efficacy of neutralizing antibody containing high-dose CCP in hospitalized adults with COVID-19 requiring respiratory support or intensive care treatment.Methods: Patients (n=105) were randomized 1:1 to either receive standard treatment and 3 units of CCP or standard treatment alone. Control group patients with progress on day 14 could cross over to the CCP group. Primary outcome was a dichotomous composite outcome of survival and no longer fulfilling criteria for severe COVID-19 on day 21. Results:The primary outcome occurred in 43.4% of patients in the CCP and 32.7% in the control group (p=0.32). The median time to clinical improvement was 26 days in the CCP group and 66 days in the control group (p=0.27). Median time to discharge from hospital was 31 days in the CCP and 51 days in the control group (p=0.24). In the subgroup that received a higher cumulative amount of neutralizing antibodies the primary outcome occurred in 56.0% (versus 32.1%), with significantly shorter intervals to clinical improvement (20 versus 66 days)(p<0.05), and to hospital discharge (21 versus 51 days, p=0.03) and better survival (day-60 probability of survival 91.6% versus 68.1%; p=0.02) compared to the control group. Conclusion:CCP added to standard treatment was not associated with significant improvement in the primary and secondary outcomes. A pre-defined subgroup analysis showed a significant benefit for CCP among those who received a larger amount of neutralizing antibodies.

Chemotherapy-induced peripheral neuropathic pain (CIPNP) is a severe dose-and therapy-limiting side effect of widely used cytostatics that is particularly difficult to treat. Here, we report increased expression of the cytochrome-P 450 -epoxygenase CYP2J6 and increased concentrations of its linoleic acid metabolite 9,10-EpOME (9,10-epoxy-12Z-octadecenoic acid) in dorsal root ganglia (DRGs) of paclitaxeltreated mice as a model of CIPNP. The lipid sensitizes TRPV1 ion channels in primary sensory neurons and causes increased frequency of spontaneous excitatory postsynaptic currents in spinal cord nociceptive neurons, increased CGRP release from sciatic nerves and DRGs, and a reduction in mechanical and thermal pain hypersensitivity. In a drug repurposing screen targeting CYP2J2, the human ortholog of murine CYP2J6, we identified telmisartan, a widely used angiotensin II receptor antagonist, as a potent inhibitor. In a translational approach, administration of telmisartan reduces EpOME concentrations in DRGs and in plasma and reverses mechanical hypersensitivity in paclitaxeltreated mice. We therefore suggest inhibition of CYP2J isoforms with telmisartan as a treatment option for paclitaxel-induced neuropathic pain.chemotherapy-induced neuropathy | neuropathic pain | TRPV1 | telmisartan | oxidized lipids R ecent studies identified members of the transient receptor potential-family of ion channels (TRPV1, TRPA1, and TRPV4) as contributors to both mechanical and cold allodynia during oxaliplatin and paclitaxel-induced neuropathy (1-5). Activation or sensitization of TRPV1 and TRPA1 can lead to enhanced release of CGRP and substance P, both of which can cause neurogenic inflammation and recruitment of T cells (6, 7).However, it remains unclear which endogenous mediators are involved in paclitaxel-dependent activation or sensitization of TRP channels, as paclitaxel cannot directly activate TRP channels (4,5,8). Interestingly, paclitaxel is an inducer of some Cytochrome-P 450 epoxygenases (e.g., CYP2C8, CYP2C9) (9). CYP epoxygenases can metabolize ω-6 fatty acids, such as arachidonic acid (AA) and linoleic acid (LA), generating either lipid epoxides such as EETs (epoxyeicosatrienoid acids) or ω-hydroxides such as 20-hydroxyeicosatetraenoic acid (20-HETE) (10, 11).Although therapeutic alternatives exist, paclitaxel is still the preferred first line of therapy for metastatic breast cancer (12), causing severe CIPNP in many treated patients. Here, we performed liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based lipid profiling of sciatic nerve, dorsal root ganglion (DRG), and dorsal horn tissue from paclitaxel-treated mice.We identified 9,10-EpOME (9,10-epoxy-12Z-octadecenoic acid), a CYP metabolite of LA, to be strongly synthesized in DRGs 24 h and 8 d after paclitaxel injection in mice. 9,10-EpOME is capable of sensitizing TRPV1 at submicromolar concentrations via a cAMP-PKA-dependent mechanism, causing enhanced frequency of spontaneous excitatory postsynaptic currents (sEPSCs) in lamina II neurons of the spin...

Sensitization of the heat-activated ion channel transient receptor potential vanilloid 1 (TRPV1) through lipids is a fundamental mechanism during inflammation-induced peripheral sensitization. Leukotriene B4 is a proinflammatory lipid mediator whose role in peripheral nociceptive sensitization is not well understood to date. Two major G-protein-coupled receptors for leukotriene B4 have been identified: the high-affinity receptor BLT1 and the low-affinity receptor BLT2. Transcriptional screening for the expression G-protein-coupled receptors in murine dorsal root ganglia showed that both receptors were among the highest expressed in dorsal root ganglia. Calcium imaging revealed a sensitization of TRPV1-mediated calcium increases in a relative narrow concentration range for leukotriene B4 (100-200 nm). Selective antagonists and neurons from knock-out mice demonstrated a BLT1-dependent sensitization of TRPV1-mediated calcium increases. Accordingly, leukotriene B4-induced thermal hyperalgesia was mediated through BLT1 and TRPV1 as shown using the respective knock-out mice. Importantly, higher leukotriene B4 concentrations (>0.5 μm) and BLT2 agonists abolished sensitization of the TRPV1-mediated calcium increases. Also, BLT2 activation inhibited protein kinase C- and protein kinase A-mediated sensitization processes through the phosphatase calcineurin. Consequently, a selective BLT2-receptor agonist increased thermal and mechanical withdrawal thresholds during zymosan-induced inflammation. In accordance with these data, immunohistochemical analysis showed that both leukotriene B4 receptors were expressed in peripheral sensory neurons. Thus, the data show that the two leukotriene B4 receptors have opposing roles in the sensitization of peripheral sensory neurons forming a self-restricting system.

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Increased exercise loads, as observed in elite athletes, seem to modulate the subjective pain perception in healthy subjects. The combination of electroencephalography (EEG) and standardized noxious stimulation can contribute to an objective assessment of the somatosensory stimulus processing. We assessed the subjective pain ratings and the electroencephalogram (EEG)-based response after standardized noxious mechanical and thermal stimuli as well as during conditioned pain modulation (CPM) in 26 elite endurance athletes and compared them to 26 recreationally active controls. Elite endurance athletes had consistently stronger somatosensory responses in the EEG to both mechanical and thermal noxious stimuli than the control group. We observed no significant group differences in the subjective pain ratings, which may have been influenced by our statistics and choice of stimuli. The CPM testing revealed that our conditioning stimulus modulated the subjective pain perception only in the control group, whereas the EEG indicated a modulatory effect of the conditioning stimulus on the spectral response only in the athletes group. We conclude that a higher activation in the cortical regions that process nociceptive information may either be an indicator for central sensitization or an altered stimulus salience in the elite endurance athletes’ group. Our findings from our CPM testing were limited by our methodology. Further longitudinal studies are needed to examine if exercise-induced changes in the somatosensory system might have a critical impact on the long-term health of athletes.