Clinical trial NCT05083520: Incidence of Cereblon in Intensive Care Patients
Official title: Incidence of Cereblon in Intensive Care Patients
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Critical Illness
Sepsis
Keywords: Critical care
Cereblon
Lead sponsor: Buca Seyfi Demirsoy State Hospital
Sponsor class: OTHER
First posted: 2021-10-19
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: OTHER
Time perspective: CROSS_SECTIONAL
Sampling method: PROBABILITY_SAMPLE
Study population: critical care patient

Brief summary: Classical immunomodulatory drugs (IMiDs) like thalidomide and its second- and third-generation analogues lenalidomide, pomalidomide, avadomide (CC-122), and iberdomide (CC-220) have constantly emerged to new therapeutic areas. Originally developed as a sedative and banned in 1961 for its teratogenic effects when used during pregnancy, thalidomide and a number of newly developed analogues are approved for the treatment of multiple myeloma (MM),4 erythema nodosum5 and myelodysplastic syndrome (MDS) Thalidomide was used as a treatment for morning sickness from 1957 until 1961 but was withdrawn from the market after it was discovered that it caused birth defects. Because of their pleiotropic and especially anti-angiogenic properties, IMiDs have further been reported effective in many off-label indications as for Hodgkin's lymphoma, light chain-associated (AL) amyloidosis, and acute myeloid leukemia (AML).

The drug thalidomide binds to cereblon and changes which substrates can be degraded by it, which leads to an antiproliferative effect on myeloma cells and possibly the teratogenic effect on fetal development. The idea that cereblon modulation is responsible for the teratogenic activity of thalidomide in the chick and zebrafish was cast into doubt due to a 2013 report that pomalidomide (a more potent thalidomide analog) does not cause teratogenic effects in these same model systems even though it binds with cereblon more strongly than thalidomide.

Cereblon (CRBN) is a substrate receptor of the E3 ubiquitin ligase complex. Several key findings suggest diverse roles of CRBN, including its regulation of the large-conductance calcium- and voltage-activated potassium (BKCa) channels, regulation of thalidomide-binding proteins, and mediation of lenalidomide treatment in multiple myeloma. Recent studies also indicate that CRBN is involved in energy metabolism and negatively regulates AMP-activated protein kinase signaling. Recent studies also indicate that CRBN is involved in energy metabolism and negatively regulates AMP-activated protein kinase signaling. Mice with genetic depletion of CRBN are resistant to various stress conditions including a high-fat diet, endoplasmic reticulum stress, ischemia/reperfusion injury, and alcohol-related liver damage.

There are different drugs that have an immunomodulating effect, such as thalidomide analogs, and are used in various situations. Some of the diseases in which the immune system plays a role in its etiology are Acute Respiratory Distress Syndrome (ARDS), Acute Lung Injury (ALI), septic shock, and sepsis. In cases of lung injury such as sepsis, septic shock, ARDS, ALI, the immune system is over-activated and as a result, the immune system cells damage the own tissue of the lung. To break this mechanism, immunomodulatory drugs are used in intensive care in the treatment of these diseases.

There is no publication regarding the role of Cereblon in the mechanism of action of these immunomodulatory drugs used in intensive care. In these intensive care diagnoses (sepsis, ARDS, ALI), there is no publication showing the correlation between the severity of the disease and Cereblon protein. Other laboratory parameters are used to estimate the effects (mortality and morbidity) of these diseases on the patient. At the end of the investigators study, the investigators think that the Cereblon gene can be used in this estimation of mortality or morbidity.


Eligibility criteria: Inclusion Criteria:

* Being over 18 years old,
* Having (-) Covid PCR test,
* Being intubated,
* Getting permission from the patient's relatives to be included in the study

Exclusion Criteria:

* Being under the age of 18,
* Having (+) Covid PCR test,
* Not be able to get consent from the relatives of the patient

Primary outcomes:
measure: The presence of Cereblon protein
timeFrame: until 31 December 2021
Secondary outcomes:
measure: The relationship between Cereblon and intensive care length of stay
timeFrame: until 31 December 2021
Other outcomes:
Locations:
Study officials:
affiliation: Izmir Democracy University
name: Pınar Ayvat, ass. prof.
role: STUDY_CHAIR
References:
citation: Yang H, Song Z, Hong D. CRBN knockdown mitigates lipopolysaccharide-induced acute lung injury by suppression of oxidative stress and endoplasmic reticulum (ER) stress associated NF-kappaB signaling. Biomed Pharmacother. 2020 Mar;123:109761. doi: 10.1016/j.biopha.2019.109761. Epub 2019 Dec 19.
citation: Gil M, Kim YK, Kim HY, Pak HK, Park CS, Lee KJ. Cereblon deficiency confers resistance against polymicrobial sepsis by the activation of AMP activated protein kinase and heme-oxygenase-1. Biochem Biophys Res Commun. 2018 Jan 1;495(1):976-981. doi: 10.1016/j.bbrc.2017.11.098. Epub 2017 Nov 21.