Auxora for the Treatment of Patients With Acute Pancreatitis and Accompanying Systemic Inflammatory Response Syndrome

Bruen, Charles; Miller, Joseph; Wilburn, John; Mackey, Caleb; Bollen, Thomas L.; Stauderman, Kenneth A.; Hebbar, Sudarshan

doi:10.1097/mpa.0000000000001793

Cited by 44 publications

(43 citation statements)

References 30 publications

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“…The compound CM2489 had some chemical improvements and design to treat acute pancreatitis. The preclinical trials were successful in mice, and the phase I clinical trials were successful, allowing entry into phase II with a good safety profile and improvement in patient outcomes [ 245 , 246 ]. In addition, a clinical study, although limited by its design, has been conducted for the treatment of severe or critical COVID-19 pneumonia with this compound [ 247 ].…”

Section: Targeted Soce In Pah: a Novel Therapeutic Option?mentioning

confidence: 99%

Role of Store-Operated Ca2+ Entry in the Pulmonary Vascular Remodeling Occurring in Pulmonary Arterial Hypertension

et al. 2021

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Pulmonary arterial hypertension (PAH) is a severe and multifactorial disease. PAH pathogenesis mostly involves pulmonary arterial endothelial and pulmonary arterial smooth muscle cell (PASMC) dysfunction, leading to alterations in pulmonary arterial tone and distal pulmonary vessel obstruction and remodeling. Unfortunately, current PAH therapies are not curative, and therapeutic approaches mostly target endothelial dysfunction, while PASMC dysfunction is under investigation. In PAH, modifications in intracellular Ca2+ homoeostasis could partly explain PASMC dysfunction. One of the most crucial actors regulating Ca2+ homeostasis is store-operated Ca2+ channels, which mediate store-operated Ca2+ entry (SOCE). This review focuses on the main actors of SOCE in human and experimental PASMC, their contribution to PAH pathogenesis, and their therapeutic potential in PAH.

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Section: Targeted Soce In Pah: a Novel Therapeutic Option?mentioning

confidence: 99%

Role of Store-Operated Ca2+ Entry in the Pulmonary Vascular Remodeling Occurring in Pulmonary Arterial Hypertension

et al. 2021

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“…Based on these preclinical observations, CalciMedica successfully completed two phase I clinical trials and then tested seven patients with AP to assess the pharmacokinetic and pharmacodynamics profile of Auxora when administered by intravenous infusion. Based on these, a phase 2 open-label, dose-response clinical study evaluated the safety of Auxora in patients with AP, systemic inflammatory response syndrome (SIRS) and hypoxaemia (Bruen et al 2021). While low-dose Auxora treatment improved moderate to mild AP in 36.5% of the patients, very interestingly Auxora also improved the tolerance of solid foods, which might be explained by improved exocrine pancreatic secretion.…”

Section: Introductionmentioning

confidence: 99%

“…Based on these, a phase 2 open‐label, dose–response clinical study evaluated the safety of Auxora in patients with AP, systemic inflammatory response syndrome (SIRS) and hypoxaemia (Bruen et al . 2021). While low‐dose Auxora treatment improved moderate to mild AP in 36.5% of the patients, very interestingly Auxora also improved the tolerance of solid foods, which might be explained by improved exocrine pancreatic secretion.…”

Section: Introductionmentioning

confidence: 99%

Bile acid‐ and ethanol‐mediated activation of Orai1 damages pancreatic ductal secretion in acute pancreatitis

Pallagi

Görög

Papp

et al. 2022

The Journal of Physiology

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 Sustained intracellular Ca 2+ overload in pancreatic acinar and ductal cells is a hallmark of biliary and alcohol-induced acute pancreatitis, which leads to impaired ductal ion and fluid secretion. Orai1 is a plasma membrane Ca 2+ channel that mediates extracellular Ca 2+ influx upon endoplasmic reticulum Ca 2+ depletion. Our results showed that Orai1 is expressed on the luminal plasma membrane of the ductal cells and selective Orai1 inhibition impaired Stim1-dependent extracellular Ca 2+ influx evoked by bile acids or ethanol combined with non-oxidative ethanol metabolites. The prevention of sustained extracellular Ca 2+ influx protected ductal cell secretory functions in in vitro models and maintained exocrine pancreatic secretion in in vivo AP models. Orai1 inhibition prevents the bile acid-, and alcohol-induced damage of the pancreatic ductal secretion and holds the potential of improving the outcome of acute pancreatitis.

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“…The S1 and RBD-elicited Ca 2+ signals in macrophages and stellate cells, demonstrated in this study, would be likely to exacerbate an otherwise mild case of AP initiated, for example, by the primary action of bile acids or a combination of ethanol and fatty acids on the acinar cells, and could help to explain the known cases of severe AP associated with SARS-CoV-2 infection 4 , 24 . Our finding that the S1- and RBD-elicited Ca 2+ signals can be inhibited by an Orai1 CRAC channel blocker, is a further argument in favour of this pharmacological treatment against AP 5 , 25 .…”

Section: Discussionmentioning

confidence: 63%

SARS-CoV-2 S Protein Subunit 1 Elicits Ca2+ Influx – Dependent Ca2+ Signals in Pancreatic Stellate Cells and Macrophages In Situ

2022

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The S protein subunit 1 (S1) of SARS-CoV-2 is known to be responsible for the binding of the virus to host cell receptors, but the initial intracellular signalling step following receptor activation of cells in the exocrine pancreas are unknown. Using an intact live mouse pancreatic lobule preparation, we observed that S1 elicited Ca2+ signals in stellate cells and macrophages, but not in the dominant acinar cells. The Ca2+ signals occurred mostly in the form of repetitive Ca2+ spikes. The probability of observing Ca2+ signals depended on the S1 concentration. The threshold was close to 70 nM, whereas at 600 nM, all cells responded. The SARS-Cov-2 nucleocapsid protein did not elicit any Ca2+ signals in any of the three cell types tested. The S1-induced Ca2+ signals in stellate cells started much faster (122 ± 37s) than those in macrophages (468 ± 68s). Furthermore, the interleukin-18 binding protein (IL-18BP) abolished the responses in macrophages without affecting the Ca2+ signals in stellate cells. The S1-elicited Ca2+ signals were completely dependent on the presence of external Ca2+ and were abolished by a selective inhibitor (CM4620) of Orai1 Ca2+ Release Activated Ca2+ channels. SARS-CoV-2 may contribute to acute pancreatitis, an often fatal inflammatory human disease. The S1-elicited Ca2+ signals we have observed in the pancreatic stellate cells and endogenous macrophages may play an important part in the development of the inflammatory process.

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Auxora for the Treatment of Patients With Acute Pancreatitis and Accompanying Systemic Inflammatory Response Syndrome

Abstract: Supplemental digital content is available in the text.

Cited by 44 publications

References 30 publications

Role of Store-Operated Ca2+ Entry in the Pulmonary Vascular Remodeling Occurring in Pulmonary Arterial Hypertension

Role of Store-Operated Ca2+ Entry in the Pulmonary Vascular Remodeling Occurring in Pulmonary Arterial Hypertension

Bile acid‐ and ethanol‐mediated activation of Orai1 damages pancreatic ductal secretion in acute pancreatitis

SARS-CoV-2 S Protein Subunit 1 Elicits Ca2+ Influx – Dependent Ca2+ Signals in Pancreatic Stellate Cells and Macrophages In Situ

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