Rationale: The vagus nerve exerts an anti-inflammatory effect in in vitro and animal
experiments. This 'vagal anti-inflammatory pathway' is mediated by the nicotinergic α7nACh
receptor that can be selectively stimulated by GTS-21. Activation of the cholinergic
anti-inflammatory pathway via vagus nerve stimulation or α7nAChR agonists improves outcome in
animal models of endotoxemia, sepsis and experimental arthritis. Up to now, the
anti-inflammatory effects of oral administration of GTS-21 in humans in vivo has not been
investigated.
Objective: Primary aim: to investigate the anti-inflammatory effects of oral administration
of GTS-21 on the inflammatory response in the human endotoxemia model and the subsequent
inflammation-induced subclinical organ dysfunction. Secondary aim: to measure the effect of
LPS administration in the absence or presence of GTS-21 in human volunteers on vagal nerve
activity measured by heart rate variability analysis.
Study design: Double-blind placebo-controlled randomized cross-over intervention study in
healthy human volunteers during experimental endotoxemia.
Study population: Non-smoking healthy male volunteers, age 18-35 yrs Intervention: Subjects
will be tested in a cross-over design in 2 separate sequential sessions, 2-4 weeks apart. A
total of 12 subjects will be randomly assigned to one of two dosing groups in a 1:1 ratio:
GTS-21 followed by Placebo n=6, Placebo followed by GTS-21 n=6. Subjects will receive 150mg
GTS-21 or placebo orally tid 3 days before LPS injection and an oral dose of 150 mg GTS-21 or
placebo the morning of the day of LPS administration (07:00 AM). Subjects will then receive
an oral dose of 150 mg GTS-21 or placebo at 08:00 AM and another oral dose of 150 mg GTS-21
or placebo at 1 hour before LPS administration (t=0). Before LPS injection, prehydration will
be performed by infusion of 1.5 L 2.5% glucose/0.45% saline solution in 1 hour. One hour
after the last dose of GTS-21 or placebo, LPS derived from E coli O:113 will be injected (2
ng/kg iv in 1 minute). There will be a 14 day washout period for patients in all groups. The
last group of subjects will be subjected to an identical dose of LPS and placebo at two
different moments 2-4 weeks apart to obtain time controls.
Main study parameters/endpoints: Main study endpoint is the concentration of circulating
cytokines after LPS in the absence and presence of GTS-21.
Nature and extent of the burden and risks associated with participation, benefit and group
relatedness: A medical interview and physical examination is part of this study.
Approximately 350 ml blood will be withdrawn and urine will be collected. There will be mild
discomfort associated with participation in this study, as LPS induces flu-like symptoms for
approximately 4 hrs. GTS-21 was found to be well tolerated at a dose of 150 mg three times
daily (450 mg/day).