Effects of the AMPA antagonist ZK 200775 on visual function: a randomized controlled trial.
BACKGROUND
ZK 200775 is an antagonist at the alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor and had earned attention as a possible neuroprotective agent in cerebral ischemia. Probands receiving the agent within phase I trials reported on an alteration of visual perception. In this trial, the effects of ZK 200775 on the visual system were analyzed in detail.


METHODS
In a randomised controlled trial we examined eyes and vision before and after the intravenous administration of two different doses of ZK 200775 and placebo. There were 3 groups of 6 probands each: Group 1 recieved 0.03 mg/kg/h, group 2 0.75 mg/kg/h of ZK 200775, the control group received 0.9% sodium chloride solution. Probands were healthy males aged between 57 and 69 years. The following methods were applied: clinical examination, visual acuity, ophthalmoscopy, colour vision, rod absolute threshold, central visual field, pattern-reversal visual evoked potentials (pVEP), ON-OFF and full-field electroretinogram (ERG).


RESULTS
No effect of ZK 200775 was seen on eye position or motility, stereopsis, pupillary function or central visual field testing. Visual acuity and dark vision deteriorated significantly in both treated groups. Color vision was most remarkably impaired. The dark-adapted ERG revealed a reduction of oscillatory potentials (OP) and partly of the a- and b-wave, furthermore an alteration of b-wave morphology and an insignificantly elevated b/a-ratio. Cone-ERG modalities showed decreased amplitudes and delayed implicit times. In the ON-OFF ERG the ON-answer amplitudes increased whereas the peak times of the OFF-answer were reduced. The pattern VEP exhibited lower amplitudes and prolonged peak times.


CONCLUSIONS
The AMPA receptor blockade led to a strong impairment of typical OFF-pathway functions like color vision and the cone ERG. On the other hand the ON-pathway as measured by dark vision and the scotopic ERG was affected as well. This further elucidates the interdependence of both pathways.


BACKGROUND
ClinicalTrials.gov NCT00999284.
Bergholz
Richard
R
Department of Ophthalmology, Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany. richard.bergholz@charite.de
Staks
Thomas
T
Rüther
Klaus
K
D000368:Aged; D055253:Color Vision / Q000187:drug effects / Q000502:physiology; D003624:Darkness; D004596:Electroretinography; D005074:Evoked Potentials, Visual / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D063065:Organophosphonates / Q000494:pharmacology*; D011810:Quinoxalines / Q000494:pharmacology*; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors*; D014785:Vision, Ocular / Q000187:drug effects* / Q000502:physiology*; D014792:Visual Acuity / Q000187:drug effects / Q000502:physiology
D063065:Organophosphonates; D011810:Quinoxalines; D018091:Receptors, AMPA; C114423:ZK 200775