Effects of the AMPA antagonist ZK 200775 on visual function: a randomized controlled trial

Richard Bergholz, Thomas Staks, Klaus Rüther, Richard Bergholz, Thomas Staks, Klaus Rüther

Abstract

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.

Methodology: 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).

Principal findings: 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.

Trial registration: ClinicalTrials.gov NCT00999284.

Conflict of interest statement

Competing Interests: Thomas Staks is employed at Bayer Schering AG, which funded this trial. Thomas Staks took part only in the study design. None of the authors have any financial, personal, or professional interests that could be construed to have influenced their paper. Bayer Schering AG has ceased any further research on ZK200775 and there are no further products in development that are related to ZK200775. As far as the authors know, Bayer Schering AG has no patent on ZK200775 any more and there are no products marketed that are related to ZK200775. The trial was funded by Bayer Schering AG and was accomplished in 1997. At that time, the development of ZK200775 and other AMPA-antagonists for the treatment of cerebral ischemia was very promising. Finally, research on ZK200775 as a therapeutic agent was ceased since there were life-threatening side-effects that could not be eliminated. Bayer Schering AG currently has no interests in any further development of the AMPA-antagonist ZK200775. Thomas Staks, as an employee of Bayer Schering AG, only took part in the design of the study. The data presented here was collected, analysed and prepared exclusively by Klaus Rüther and Richard Bergholz. Both are independent researchers and are not affiliated to Bayer Schering AG. Any bias due to competing interests is impossible. The authors assure that the role of Bayer Schering AG does not compromise their adherence to all the PLoS ONE policies on sharing data and materials. The reason for presenting this manuscript is the uniqueness of an in vivo blockade of AMPA receptors in humans.

Figures

Figure 1. Visual acuity.
Figure 1. Visual acuity.
Time course of mean values +/− 2 * standard deviation for 6 subjects of each group. A significant deterioration compared to baseline was observed in both verum groups 4 hours after treatment (asterisked bars). As the pupil of the right eye was dilated acuity testing was only performed in the left eye.
Figure 2. Lanthony Panel D-15 test of…
Figure 2. Lanthony Panel D-15 test of color vision.
Time course of error score +/− 2 * standard deviation. Mean values for 6 subjects of each group. A significant deterioration compared to baseline was observed in both treated groups immediately after treatment (asterisked bars).
Figure 3. Rod threshold.
Figure 3. Rod threshold.
Time course of mean rod threshold +/− 2 * standard deviation for both eyes of all probands. Significant changes (marked with an asterisk) compared to baseline occured in both treated groups after 4 hours and also after 22 hours in group 2.
Figure 4. Mean dark adapted full-field ERG.
Figure 4. Mean dark adapted full-field ERG.
Recordings for each group and flash strength at baseline (black line) and 4 hours after treatment (gray line). The effect of ZK200775 was subtle but recognizable. Statistically significant amplitude reduction of the a- and b-wave occured in the low dose group after 4 hours.
Figure 5. Mean cone-ERG.
Figure 5. Mean cone-ERG.
Recordings of each group for baseline (thin line) and 4 hours after treatment (thick line). An almost dose-dependent amplitude decrease can be seen in all cone-ERG modalities. Significant increments (+) and decrements (−) of the deflections as compared to baseline are marked in the according graphs (PT = peak time, amp = amplitude).
Figure 6. Mean ON-OFF-ERG.
Figure 6. Mean ON-OFF-ERG.
Recordings of each group for baseline (thin line) and 4 hours after treatment (thick line). In group 1 the recordings of only 4 of 6 probands were considered due to unrecognizable OFF-answers in 2 probands. An increase of on-answer amplitude in both treated groups seems obvious but was statistically not significant. However, there was a significant reduction of OFF-answer peak time (PT) in both treated groups 4 hours after treatment.
Figure 7. Mean pattern visual evoked potential.
Figure 7. Mean pattern visual evoked potential.
Recordings for each group and check size. Stimulation of the left eye with natural pupil. Thin lines: baseline recordings, thick lines: recordings 4 hours after treatment. This figure shows a virtually dose-dependent amplitude decrease and peak time prolongation. Significant increments (+) and decrements (−) of the deflections as compared to baseline are marked in the according graphs (PT = peak time, amp = amplitude).
Figure 8. Consort flow chart.
Figure 8. Consort flow chart.

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