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The Effects of Atazanavir-induced Hyperbilirubinemia During Human Endotoxemia

Information source: Radboud University
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Endotoxemia; Inflammation; Multi Organ Dysfunction Syndrome; Sepsis

Intervention: Atazanavir (Drug); E. coli endotoxin (Drug)

Phase: N/A

Status: Completed

Sponsored by: Radboud University

Official(s) and/or principal investigator(s):
Peter Pickkers, MD, PhD, Principal Investigator, Affiliation: Radboud University Nijmegen Medical Centre, The Netherlands

Summary

Excessive inflammation, production of free radicals and vascular injury are considered the main contributors to the development of organ dysfunction in patients with severe infections and sepsis. The endogenously produced unconjugated bilirubin is one of the most powerful anti-oxidants of the human body and the administration of bilirubin in animal experiments has been shown to protect from inflammation-induced death. However, bilirubin for human administration is not yet available. Therefore, we wish to exploit one of the side effects of atazanavir, a registered drug currently used as a protease inhibitor in HIV infected patients. Atazanavir inhibits the enzyme UPD glucuronosyl transferase enzyme (UGT1A1) and therefore increases endogenously produced bilirubin levels moderately. To study the effect of hyperbilirubinemia during inflammation we will apply the human endotoxemia model. The human endotoxemia model permits elucidation of key players in the immune response to a gram negative stimulus in vivo, therefore serving as a useful tool to investigate potential novel therapeutic strategies in a standardized setting. We hypothesize that atazanavir-induced hyperbilirubinemia has beneficial anti-inflammatory and vascular effects during human endotoxemia.

Clinical Details

Official title: The Effects of Atazanavir-induced Hyperbilirubinemia on the Innate Immune Response During Human Endotoxemia. A Parallel Double Blind Placebo Controlled Pilot Study.

Study design: Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Primary outcome: The effect of atazanavir-induced hyperbilirubinemia on systemic activation of the innate immune response by measurement of various cytokines induced by a lipopolysaccharide (LPS) challenge.

Secondary outcome:

To determine if the attenuated vascular response to endothelium dependent vasodilators and vasoconstrictors during endotoxemia can be prevented by atazanavir-induced hyperbilirubinemia.

To detect the effects of human endotoxemia on gastric perfusion measured by tonometry in the presence or absence of atazanavir-induced hyperbilirubinemia.

To determine if atazanavir induced hyperbilirubinemia can attenuate subclinical renal damage (determined by several markers of acute kidney injury) known to occur during human endotoxemia.

To determine the effect of atazanavir induced hyperbilirubinemia on heme oxygenase induction and activity during human endotoxemia.

Eligibility

Minimum age: 18 Years. Maximum age: 35 Years. Gender(s): Male.

Criteria:

Inclusion Criteria:

- Healthy male volunteers

Exclusion Criteria:

- Use of any medication or anti-oxidant vitamin supplements.

- History of allergic reaction to atazanavir.

- Smoking.

- Previous spontaneous vagal collapse.

- History, signs or symptoms of cardiovascular disease.

- (Family) history of myocardial infarction or stroke under the age of 65 years.

- Cardiac conduction abnormalities on the ECG consisting of a 2nd degree

atrioventricular block or a complex bundle branch block.

- Hypertension (defined as RR systolic > 160 or RR diastolic > 90).

- Hypotension (defined as RR systolic < 100 or RR diastolic < 50).

- Renal impairment (defined as plasma creatinin >120 μmol/l).

- Liver enzyme abnormalities or positive hepatitis serology.

- Subjects with a total bilirubin level above 15 μmol/L and a normal direct bilirubin

level suggesting Gilbert Syndrome.

- Positive HIV serology or any other obvious disease associated with immune deficiency.

- Febrile illness in the week before the LPS challenge.

- Participation in a drug trial or donation of blood 3 months prior to the LPS

challenge.

Locations and Contacts

Radboud University Nijmegen Medical Centre, Nijmegen, Gelderland 6500 HB, Netherlands
Additional Information

Starting date: May 2009
Last updated: August 13, 2015

Page last updated: August 23, 2015

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