NK1 antagonists attenuate tau phosphorylation after blast and repeated concussive injury

Exposure to repeated concussive traumatic brain injury (TBI) and to blast-induced TBI has been associated with the potential development of the neurodegenerative condition known as chronic traumatic encephalopathy (CTE). CTE is characterized by the accumulation of hyperphosphorylated tau protein, with the resultant tau tangles thought to initiate the cognitive and behavioral manifestations that appear as the condition progresses. However, the mechanisms linking concussive and blast TBI with tau hyperphosphorylation are unknown. Here we show that single moderate TBI, repeated concussive TBI and blast-induced mild TBI all result in hyperphosphorylation of tau via a substance P mediated mechanism. Post-injury administration of a substance P, NK1 receptor antagonist attenuated the injury-induced phosphorylation of tau by modulating the activity of several key kinases including Akt, ERK1/2 and JNK, and was associated with improvement in neurological outcome. We also demonstrate that inhibition of the TRPV1 mechanoreceptor, which is linked to substance P release, attenuated injury-associated tau hyperphosphorylation, but only when it was administered prior to injury. Our results demonstrate that TBI-mediated stimulation of brain mechanoreceptors is associated with substance P release and consequent tau hyperphosphorylation, with administration of an NK1 receptor antagonist attenuating tau phosphorylation and associated neurological deficits. NK1 antagonists may thus represent a pharmacological approach to attenuate the potential development of CTE following concussive and blast TBI.

Medial septum neurokinin- and somatostatin-sensitive mechanisms mediate sensorimotor and nociceptive behaviours

The forebrain medial septum (MS), implicated in affective-motivational behaviours, is enriched in substance P (SP) sensitive neurokinin-1 receptors (NK1R) and somatostatin (SST) receptors (SSTR) that are located almost exclusively on cholinergic and GABAergic neurons, respectively. However, the physiological function of these receptors is poorly understood. This study characterized the actions of intraseptal SP on electrophysiological indices of septo-hippocampal activation, then utilised NK1 receptor antagonist, L-733,060, and SST to investigate the physiological role of endogenous neurotransmission at NK1R, and SST-sensitive mechanisms, in novel open field and formalin test of inflammatory pain. The findings showed that neurotransmission at NK1R mediates formalin-induced electrophysiological responses in the septo-hippocampus in anaesthetized and behaving animals. Furthermore, parallel NK1R- and SST-sensitive mechanisms affect different aspects of animal behaviours in both tests, collectively modulating attention and habituation in open field and driving formalin-induced nociception. This brings out a newer peptidergic dimension of septal physiology in nociception.

Physician concordance with update to ASCO guidelines for antiemetic use with carboplatin AUC ≥ 4.

11595 Background: In 2017, NCCN (2/2017) and ASCO (8/2017) each amended antiemetic guidelines to classify carboplatin AUC ≥4 as highly emetogenic chemotherapy (HEC), recommending upfront triple prophylaxis with an NK1 receptor antagonist (RA) + 5HT3 RA + dexamethasone. Physician concordance with the new recommendations, and the consequences for avoidable post-chemotherapy acute care, merit study. Methods: In a large electronic health record database (IBM Explorys), we identified carboplatin courses of therapy (≥14-day cycles as a proxy for AUC ≥4) and courses with ≥7-day cycles of other HEC and non-HEC therapy from 4Q 2012 through August 2018. Guideline concordance, defined as triple prophylaxis at HEC initiation, was evaluated. We also assessed 30-day post-chemotherapy acute care (inpatient or emergency department) associated with nausea or vomiting (NV) or eight other toxicities deemed avoidable in the US Centers for Medicare & Medicaid’s new oncology outcome measure OP-35. Results: 11,554 carboplatin courses were identified. Before the guideline change, rates of upfront triple prophylaxis grew from 14% in 2013 to 16% in mid-2017. Rates then rose to 26% by 1Q 2018 before dropping to 21% by 3Q 2018; quarterly rates averaged 20% (range 15%-26%) following the guideline change. In 31% of carboplatin courses we noted 30-day acute care use, of which 75% involved ≥1 of the ten OP-35 toxicities. NV (with or without acute care use) was reported in 24% of courses, and 27% of total OP-35 acute care events involved NV. Rates for NV, and for OP-35-related and NV-related acute care after carboplatin, were similar to rates after other HEC chemotherapy, and higher than rates after other non-HEC IV chemotherapy or oral HEC/MEC agents. Conclusions: Use of upfront triple antiemetic prophylaxis has increased only marginally for carboplatin AUC ≥ 4 since its 2017 re-classification as HEC in national guidelines, perhaps due to low awareness of the change. Patients receiving carboplatin had similar rates of NV and related 30-day acute care events as seen for other HEC, confirming that the new HEC definition fits clinical experience. More triple prophylaxis use is needed to reduce NV and NV-related avoidable acute care seen with carboplatin AUC ≥ 4.

What the HEC? Physician variation and attainable compliance targets in antiemetic prophylaxis.

74 Background: U.S. National Antiemetic Guidelines recommend upfront triple prophylaxis (NK1 receptor antagonist (RA) + 5HT3 RA + dexamethasone) for patients receiving highly emetogenic chemotherapy (HEC), including carboplatin AUC ≥ 4 per 2017 guidelines. While existing data show gaps in guideline compliance, variation between individual physicians is less studied, and a realistic target compliance rate remains unknown. Methods: In a large electronic health record database (IBM Explorys), we identified HEC courses of therapy initiated from 2012 to 2017. Guideline compliance was defined as triple prophylaxis at chemotherapy initiation. Patient courses for ≥ 7 day cycles of cisplatin or anthracycline + cyclophosphamide (AC), or carboplatin (≥ 14 day cycles as a proxy for AUC ≥ 4) were ascribed to oncologists based on encounter frequency. We then ranked physicians treating ≥ 5 HEC courses and evaluated guideline compliance and individual physician variation. Results: In total, 10,074 HEC courses were identified and attributed to 451 unique physicians. Overall antiemetic guideline compliance with cisplatin and AC averaged 68% and 81% respectively. When ranked by compliance, the top 20% of physicians were 2.5 - 1.5 times as compliant as the bottom 20% (cisplatin 100% vs 40%; AC 100% vs 67%). For cisplatin, 32% of physicians had > 90% compliance; the remaining 68% were evenly distributed from 0 - 90%. For AC, 56% of physicians had > 90% compliance, and another 14% had 80 - 90%; the remaining 30% were evenly distributed. For carboplatin, 62% of physicians had ≤ 10% compliance, and another 17% had 11 - 20%; however, the majority of these data preceded guideline inclusion of carboplatin AUC ≥ 4 as HEC. Rates were independent of course volume per physician. Conclusions: Considerable physician-level variation exists in triple antiemetic prophylaxis guideline adherence for HEC. Hundreds of physicians had > 90% compliance with guidelines, suggesting 90% is a realistic target. However, the majority exhibited substantial gaps in NK1 RA use in HEC, placing patients unnecessarily at risk for CINV. Interventions are needed to bolster triple antiemetic prophylaxis in HEC, perhaps especially for carboplatin.

AN EXTENSIVE REVIEW ON CHEMOTHERAPY INDUCED NAUSEA AND VOMITING

Chemotherapy induced nausea and vomiting is the among most feared and debilitating adverse events experienced by the cancer patients. Left unaddressed, CINV symptoms not only decrease quality of life, but may also affect patients’ willingness to continue chemotherapy treatment. However, adherence to guideline recommendations continues to be suboptimal therapy, and many patients still suffer unnecessarily from CINV. In addition, breakthrough/refractory CINV continues to present particular challenges. The development of effective CINV treatments with diverse mechanisms of action has expanded the options available for preventing symptoms. The US Food and Drug Administration have recently approved several new therapies for the management of CINV. NEPA is a fixed-dose combination of Netupitant (300 mg) plus Palonosetron (0.5 mg). In combination with Dexamethasone, NEPA has demonstrated superior efficacy to Palonosetron alone in patients receiving highly or moderately emetogenic chemotherapy. Rolapitant is a nextgeneration neurokinin-1receptor antagonist. Both palonosetron and rolapitant have proven particularly effective in controlling delayed CINV. Regimens that combine a serotonin 5-hydroxytryptamine–3 receptor antagonist, an NK1 receptor antagonist, and a corticosteroid now represent the standard of care for managing both acute and delayed CINV in patients receiving highly emetogenic chemotherapy. Keywords: CINV, Seratonin, Dopamine, Neurokinin, Antiemetics.