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Long-Term Safety Evaluation Of Treatment Of Constipation Due To Opioids Being Taken For Persistent Non-Cancer Pain

ABSTRACT: Adults who are taking opioid therapy for persistent non-cancer pain and have resulting opioid-induced bowel dysfunction (OBD) will be randomized (1:1) to alvimopan or placebo. The primary objective of this Phase 3 long-term safety study is to compare alvimopan with placebo for safety and tolerability in the treatment of OBD. Participants will be required to attend 8 clinic visits over approximately 1 year.

DISEASE(S): Gastrointestinal Diseases,Pain,Intestinal Diseases,Constipation,Bowel Dysfunction

PROVIDER: 2022618 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Project description:Background: Albeit with well-recorded cytoprotective function, the study of stress protein CIRBP coping with cardiotoxicity during chemotherapy remains obscured. Here we report that CIRBP plays a critical role in safeguarding against chemo-induced cardiac apoptosis and dysfunction. Methods: Treating the immortalized human ventricular myocytes (T0519) and neonatal rat ventricular myocytes (NRVMs) with three regular chemotherapeutics (DOX/Cisplatin/5-FU), and DOX-induced cardiotoxic mouse model were leveraged to explore the cardioprotection of CIRBP during chemotherapy. We took advantage of AAV9 carrying CIRBP or shCIRBP expressive cassette under cTNT promoter to interfere with cardiac CIRBP expression. A conjoint analysis of transcriptomics and proteomics was performed within T0519 to identify the latent effector of CIRBP in regulating cardiomyocyte apoptosis. By contrast with the pan-opioid receptor Alvimopan (ALV), OGFR blocker Naltrexone (NTX) was introduced to disrupt CIRBP-OGFR signaling in an attempt to provide new insight in formulating efficacious cardioprotective scheme for tumor patients. Results: We discovered that CIRBP deficiency is involved in in-vivo and in-vitro cardiomyocyte apoptosis triggered by chemotherapeutic agents. Ectopic delivery of CIRBP in mouse myocardium significantly mitigates doxorubicin-induced cardiac apoptosis and malfunction. Opioid growth factor receptor (OGFR) was further highlighted as CIRBP downstream effector responsible for cardiomyocyte chemotherapeutical apoptosis. Mechanistically, CIRBP interacts with OGFR mRNA and represses OGFR expression by reducing mRNA stability. CIRBP-mediated cytoprotection against doxorubicin-induced apoptosis relies largely on the regulation of CIRBP on OGFR. Naltrexone, an antagonist targeting OGFR of potency as well as certain opioid receptors, successfully rescues CIRBP ablation-rendered susceptibility to cardiac apoptosis and dyshomeostasis when exposed to DOX; while another antagonist Alvimopan, merely acting on opioid receptors, does not. Conclusions: Taken together, our results demonstrate that CIRBP confers myocardium resistance to chemotherapy-induced cardiac apoptosis and dysfunction via dampening OGF/OGFR axis, shedding new light on the cardioprotection of tumor patients subjected to chemotherapy.

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Long-Term Safety Evaluation Of Treatment Of Constipation Due To Opioids Being Taken For Persistent Non-Cancer Pain

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