Xanthohumol as an Adjuvant in the Treatment of Septic Shock

Official title

Analysis of Anti-inflammatory Effect of Hop Extract Rich in Xanthohumol in Patients Treated for Septic Shock

Overview

Septic shock (SS) is a life-threatening condition resulting from excessive inflammatory response to bacterial, viral or/and fungal infections. It is associated with dysregulation of the immune system, activation of immune cells, and massive release of cytokines, commonly known as the cytokine storm (CS). The clinical manifestations of SS depend on the initial site of infection. However, the classic symptoms are associated with severe dysfunction of the respiratory and cardiovascular systems, which are observed from the early phase. Respiratory insufficiency frequently requires different forms of oxygen supplementation, including mechanical ventilation and even extracorporeal oxygenation. The severity of respiratory and other organ dysfunction depends on the inflammatory response to the infection and circulating toxins, which correspond to excessive cytokine release. In the past years, several studies documented that reduction of SS-related inflammatory response and CS improved organ function and alleviated the clinical course of SS. Unfortunately, an effective strong anti-inflammatory without side effects medications has not yet been found. Therefore, the use of natural anti-inflammatory and antioxidant substances seems very promising. Xanthohumol (Xn) is a natural prenylated chalcone extracted from the female inflorescences of hop cones (Humulus lupus) and possesses strong anti-inflammatory and antioxidant properties. It is widely used as a supplement to diet. Xanthohumol inhibits CS and has been showed to be an effective medication for reducing the severity of lung injury. It has been documented that Xn inhibits proinflammatory pathways in a different manner. A decrease in cytokine production and release can affect endothelial function and correct inflammatory-related vascular hyperpermeability, reducing uncontrolled water shift to extravascular space and then tissue edema. Clinical observation showed that administration of Xn alleviated clinical course, improved respiratory function, and reduced mortality in critically ill COVID-19 patients. Xanthohumol is safe and well tolerated by humans, and no adverse effects have been reported yet. Based on its strong anti-inflammatory and antioxidative properties, it can be speculated that the use of Xn can effectively reduce the inflammatory response and improve the clinical course in SS patients.

Interventions

• Dietary supplement Xanthohumol
  Patients, who received Xanthohumol (Chmiel-Xn-Active, SALUTIS Pharmacy, Poland) as adjunctive therapy to treatment recommended by Surviving Sepsis Campaign. Xanthohumol is administrated by the nosogastric tube three times a day \*every 8 hours) at the dose of 2 mg.\\/kg body weight for 10 days. The first dose of Xanthohumol is administrated within 4 hours after the admission to the ICU.

Primary outcome measures

• Xanthohumol as an adjunctive treatment improves clinical course in ill septic shock patents [Time frame: 7 and 28 days mortality]
• Xanthohumol as an adjunctive treatmenty affects a severity of inflammation [Time frame: 7 time points: just after ICU admission and on the days 1,2,3,4,5 and 6 after ICU admission.]
• Xanthohumol as an adjunctive treatment affects sepsis-related glycocalyx injury [Time frame: 7 time points: just after ICU admission and on the days 1,2,3,4,5 and 6 after ICU admission.]

Secondary outcome measures (11)

• Xanthohumol as an adjunctive treatment affects plasma interleukin 1beta concentration. [Time frame: 7 time points: just after ICU admission and on the days 1,2,3,4,5 and 6 after ICU admission.]
• Xanthohumol as an adjunctive treatment changes plasma tumor necrosis factor-alpha concentration. [Time frame: 7 time points: just after ICU admission and on the days 1,2,3,4,5 and 6 after ICU admission.]
• Xanthohumol as an adjunctive treatment affects plasma interleukin 6 concentration. [Time frame: 7 time points: just after ICU admission and on the days 1,2,3,4,5 and 6 after ICU admission.]
• Xanthohumol as an adjunctive treatment affects plasma interleukin 8 concentration. [Time frame: 7 time points: just after ICU admission and on the days 1,2,3,4,5 and 6 after ICU admission.]
• Xanthohumol as an adjunctive treatment affects plasma interleukin 17 concentration [Time frame: 7 time points: just after ICU admission and on the days 1,2,3,4,5 and 6 after ICU admission.]
• Xanthohumol as an adjunctive treatment affects plasma interleukin 23 concentration. [Time frame: 7 time points: just after ICU admission and on the days 1,2,3,4,5 and 6 after ICU admission.]
• Xanthohumol as an adjunctive treatment affects plasma interleukin 40 concentration [Time frame: 7 time points: just after ICU admission and on the days 1,2,3,4,5 and 6 after ICU admission.]
• Xanthohumol as an adjunctive treatment affects plasma syndecan 1 concentration. [Time frame: 7 time points: just after ICU admission and on the days 1,2,3,4,5 and 6 after ICU admission.]
• Xanthohumol as an adjunctive treatment affects plasma vascular endothelial adhesion molecule 1 concentration. [Time frame: 7 time points: just after ICU admission and on the days 1,2,3,4,5 and 6 after ICU admission.]
• Xanthohumol as an adjunctive treatment affects plasma E-selectin concentration. [Time frame: 7 time points: just after ICU admission and on the days 1,2,3,4,5 and 6 after ICU admission.]
• Xanthohumol as an adjunctive treatment affects plasma vascular endothelial growth factor concentration. [Time frame: 7 time points: just after ICU admission and on the days 1,2,3,4,5 and 6 after ICU admission.]

Eligibility criteria

Inclusion criteria

• a septic shock in the early, acute phase,
• respiratory insufficiency required mechanical ventilation with PaO2/FiO2 < 150,
• bacterial infection,
• procalcitonin higher than 5 ng/mL and interleukin 6 higher than 100 pg/mL,
• no allergy to hops or their derivatives,
• hemodynamic instability requiring vasopressor infusions

Exclusion criteria

• lack of agreement
• septic shock treated for more than 1 day,
• history of severe chronic cardiac, pulmonary and/or liver diseases

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Single blind

Primary purpose

Treatment

Study locations

Poland · 1 center

• Intensive Care Unit, University Hospital No 4, — Lublin

Publications

• Bartmanska A, Tronina T, Poplonski J, Huszcza E. Biotransformations of prenylated hop flavonoids for drug discovery and production. Curr Drug Metab. 2013 Dec;14(10):1083-97. doi: 10.2174/1389200214666131211151855. PMID 24329115
• Bosmann M, Ward PA. The inflammatory response in sepsis. Trends Immunol. 2013 Mar;34(3):129-36. doi: 10.1016/j.it.2012.09.004. Epub 2012 Oct 2. PMID 23036432
• Chen X, Li Z, Hong H, Wang N, Chen J, Lu S, Zhang H, Zhang X, Bei C. Xanthohumol suppresses inflammation in chondrocytes and ameliorates osteoarthritis in mice. Biomed Pharmacother. 2021 May;137:111238. doi: 10.1016/j.biopha.2021.111238. Epub 2021 Jan 28. PMID 33517187
• Corrado C, Barreca MM, Raimondo S, Diana P, Pepe G, Basilicata MG, Conigliaro A, Alessandro R. Nobiletin and xanthohumol counteract the TNFalpha-mediated activation of endothelial cells through the inhibition of the NF-kappaB signaling pathway. Cell Biol Int. 2023 Mar;47(3):634-647. doi: 10.1002/cbin.11963. Epub 2022 Nov 15. PMID 36378586
• Costa R, Negrao R, Valente I, Castela A, Duarte D, Guardao L, Magalhaes PJ, Rodrigues JA, Guimaraes JT, Gomes P, Soares R. Xanthohumol modulates inflammation, oxidative stress, and angiogenesis in type 1 diabetic rat skin wound healing. J Nat Prod. 2013 Nov 22;76(11):2047-53. doi: 10.1021/np4002898. Epub 2013 Nov 7. PMID 24200239
• Dabrowski W, Gagos M, Siwicka-Gieroba D, Piechota M, Siwiec J, Bielacz M, Kotfis K, Stepulak A, Grzycka-Kowalczyk L, Jaroszynski A, Malbrain ML. Humulus lupus extract rich in xanthohumol improves the clinical course in critically ill COVID-19 patients. Biomed Pharmacother. 2023 Feb;158:114082. doi: 10.1016/j.biopha.2022.114082. Epub 2022 Dec 9. PMID 36508996
• Dartiguelongue JB. Systemic inflammation and sepsis. Part I: Storm formation. Arch Argent Pediatr. 2020 Dec;118(6):e527-e535. doi: 10.5546/aap.2020.eng.e527. English, Spanish. PMID 33231055
• Chong DLW, Sriskandan S. Pro-inflammatory mechanisms in sepsis. Contrib Microbiol. 2011;17:86-107. doi: 10.1159/000324022. Epub 2011 Jun 9. PMID 21659748

Identifiers

NCT: NCT06225258 · SEPXN

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗