CGS 19755

Failure of the competitive N-methyl-D-aspartate antagonist Selfotel (CGS 19755) in the treatment of severe head injury: results of two phase III clinical trials. The Selfotel Investigators.[Pubmed:10541229]

J Neurosurg. 1999 Nov;91(5):737-43.

OBJECT: Excessive activity of excitatory amino acids released after head trauma has been demonstrated to contribute to progressive injury in animal models and human studies. Several pharmacological agents that act as antagonists to the glutamate receptor have shown promise in limiting this progression. The efficacy of the N-methyl-D-aspartate receptor antagonist Selfotel (CGS 19755) was evaluated in two parallel studies of severely head injured patients, defined as patients with post resuscitation Glasgow Coma Scale scores of 4 to 8. METHODS: A total of 693 patients were prospectively enrolled in two multicenter double-blind studies. Comparison between the treatment groups showed no significant difference with regard to demographic data, previous incidence of hypotension, and severity of injury. As the study progressed, the Safety and Monitoring Committee became concerned about possible increased deaths and serious brain-related adverse events in the treatment arm of the two head injury trials, as well as deaths in the two stroke trials being monitored concurrently. The Selfotel trials were stopped prematurely because of this concern and because an interim efficacy analysis indicated that the likelihood of demonstrating success with the agent if the studies had been completed was almost nil. CONCLUSIONS: Subsequently, more complete data analysis revealed no statistically significant difference in mortality rates in all cases between the two treatment groups in the head injury trials. In this report the authors examine the studies in detail and discuss the potential application of the data to future trial designs.

First observations of the safety and tolerability of a competitive antagonist to the glutamate NMDA receptor (CGS 19755) in patients with severe head injury.[Pubmed:10521143]

J Neurotrauma. 1999 Sep;16(9):843-50.

A dose escalation, safety, and tolerability study of a competitive antagonist to the N-methyl-D-aspartate (NMDA) glutamate receptor (CGS 19755, Selfotel) in patients with severe head injury is reported. The drug was administered i.v. on two separate occasions, 24 h apart, to 31 patients. The dosage was escalated during the study from 1 mg/kg to 6 mg/kg. Continuous monitoring of mean arterial pressure (MABP), intracranial pressure (ICP), cerebral pressure (CPP), arterial oxygen saturation (SaO2), jugular bulb oxygen saturation (SjO2), and temperature was performed. Intermittent measurements of middle cerebral artery (MCA) velocity via transcranial Doppler ultrasound were also made 2 h before drug administration and continued for 24 h after dosing. The patients were ventilated and sedated with morphine and either midazolam or propofol. There were no behavioral changes during or after administration of the drug, and disorders of perception were reported by only three subjects, several days after relatively low doses; these were transient and were not recalled at later follow-up. We did not detect consistent changes in any of the hemodynamic parameters monitored, up to dosages of 3 mg/kg. After higher doses, some patients showed changes in MABP, ICP, and temperature during the 4 to 8-h period following the first bolus of the drug, with a return toward baseline afterwards. No consistent, serious, adverse events were considered to be due to drug effects, and death, in the one patient who died, was due to the effects of the injury. Our results indicate that CGS 19755 may be given at dosages < or = 3-5 mg/kg with acceptable safety and tolerability in stable, ventilated, and carefully monitored severe head-injured patients.

Effects of (+)-HA-966, CGS-19755, phencyclidine, and dizocilpine on repeated acquisition of response chains in pigeons: systemic manipulation of central glycine sites.[Pubmed:10087045]

J Pharmacol Exp Ther. 1999 Apr;289(1):521-7.

The effects of i.m. injections of (+)-HA-966, a glycine-site antagonist at the N-methyl-D-aspartate (NMDA) subtype of the glutamate receptor, its enantiomer (-)-HA-966, the competitive glutamate antagonist CGS-19755, the uncompetitive glutamate antagonists phencyclidine and dizocilpine, and the micro opioid agonist morphine were evaluated in a repeated acquisition task in pigeons. All of the drugs produced dose-dependent decreases in rates of responding. The NMDA receptor and channel blockers and (+)-HA-966 appeared to have a greater effect on acquisition than did morphine at doses that did not fully suppress responding. The rate suppression and learning impairment produced by a large dose of (+)-HA-966 (100 mg/kg) were completely prevented by coadministration of the glycine-site agonist D-serine (560 mg/kg) but not by its enantiomer, L-serine (1000 mg/kg). D-Serine, however, produced incomplete antagonism of the effects of dizocilpine and phencyclidine and failed to alter those of CGS-19755. These findings provide evidence that reducing the activity of the NMDA subtype of the glutamate receptor through pharmacological action at any of three sites produces similar decrements in acquisition, and those produced through antagonism of the glycine site are differentially sensitive to the glycine-site agonist D-serine.

The NMDA receptor antagonist CGS 19755 disrupts recovery following cerebellar lesions.[Pubmed:16518022]

Restor Neurol Neurosci. 2006;24(1):1-7.

PURPOSE: To test whether activation of NMDA receptors is required for the maintenance of the posture and motor behavior recovered from cerebellar lesions, an NMDA antagonist (CGS 19755) was systemically administered to totally or partially cerebellectomized rats. METHODS: Three groups of animals were tested: rats that had undergone a total cerebellectomy four months before drug administration; rats that had undergone a right hemicerebellectomy four months before drug administration; intact control animals. RESULTS: Under drug action in the control animals the postural pattern was slightly influenced, showing a light worsening, and motor skills requiring coordinated motor performance and subtle balance control were markedly worsened. Conversely, in the lesioned groups the cerebellar symptomatology dramatically worsened, and both groups of animals looked like they had just been operated, exhibiting the whole repertoire of postural and motor behaviors of cerebellar origin. In particular, limb hyperflexion, wide-based locomotion and the tendency to side falls were prevalent in the cerebellectomized animals, while tremor and body tilt were prevalent in the hemicerebellectomized group. CONCLUSION: The reappearance of severe postural and motor symptomatology has to be interpreted as a "decompensation" evoked by the NMDA-receptor antagonist, suggesting the involvement of NMDA receptors in the maintenance of compensation of disturbances of cerebellar origin.

Correlation of CGS 19755 neuroprotection against in vitro excitotoxicity and focal cerebral ischemia.[Pubmed:7673380]

J Cereb Blood Flow Metab. 1995 Sep;15(5):865-76.

The in vivo neuroprotective effect and brain levels of cis-4-phosphonomethyl-2-piperidine carboxylic acid (CGS 19755), a competitive N-methyl-D-aspartate (NMDA) antagonist, were compared with its in vitro neuroprotective effects. The dose-response for in vitro neuroprotection against both NMDA toxicity and combined oxygen-glucose deprivation (OGD) was determined in murine neocortical cultures. Primary cultures of neocortical cells from feta mice were injured by exposure to 500 microM NMDA for 10 min or to OGD for 45 min. The effect of CGS 19755 in both injury paradigms was assessed morphologically and quantitated by determination of lactate dehydrogenase release. Near complete neuroprotection was found at high doses of CGS 19755. The ED50 for protection against NMDA toxicity was 25.4 micro M, and against OGD the ED50 was 15.2 microM. For the in vivo paradigm rabbits underwent 2 h of left internal carotid, anterior cerebral, and middle cerebral artery occlusion followed by 4 h reperfusion; ischemic injury was assessed by magnetic resonance imaging and histopathology. The rabbits were treated with 40 mg/kg i.v. CGS 19755 or saline 10 min after arterial occlusion. CSF and brain levels of CGS 19755 were 12 microM and 5 microM, respectively, at 1 h, 6 microM and 5 microM at 2 h, and 13 microM and 7 microM at 4 h. These levels were neuroprotective in this model, reducing cortical ischemic edema by 48% and ischemic neuronal damage by 76%. These results suggest that a single i.v. dose penetrates the blood-brain barrier, attaining sustained neuroprotective levels that are in the range for in vitro neuroprotection.

Behavioral pharmacological profile of CGS 19755, a competitive antagonist at N-methyl-D-aspartate receptors.[Pubmed:2547931]

J Pharmacol Exp Ther. 1989 Aug;250(2):454-60.

CGS 19755 (cis-4-phosphonomethyl-2-piperidine-carboxylic acid), a competitive antagonist at N-methyl-D-aspartate (NMDA)-preferring receptors, blocked both NMDA-induced convulsions in normal CF1 mice and sound-induced wild running in seizure-prone DBA/2 mice. The ED50 values for CGS 19755 to produce these effects (in the range of 2 mg/kg i.p.) were at least 3-fold lower than those which impaired the traction reflex, an index of motor coordination. When administered p.o. by gavage, CGS 19755 had little or no effect in these test procedures. In an experimental model of anxiety in rats, CGS 19755 significantly increased conflict responding within a relatively narrow dose range (minimum effective dose, 1.73 mg/kg i.p.). At higher doses of CGS 19755, this effect appeared to be obscured by drug-induced reductions in overall responding. Potential muscle relaxant effects were also suggested by the generalization of CGS 19755 to diazepam discriminative stimuli (ED50 = 9.0 mg/kg i.p.) and by impaired rotorod performance (ED50 = 6.2 mg/kg i.p.) in rats. Although some resemblances were apparent between the behavioral effects of CGS 19755 and those of phencyclidine-type drugs, the phencyclidine-like behaviors appeared only at considerably higher doses of CGS 19755 than those associated with anticonflict activity, and only partial generalization of CGS 19755 to dexoxadrol was observed at high doses. CGS 19755 promises to be an important new research tool for investigating the function of brain NMDA receptors.

CGS 19755, a selective and competitive N-methyl-D-aspartate-type excitatory amino acid receptor antagonist.[Pubmed:2899170]

J Pharmacol Exp Ther. 1988 Jul;246(1):65-75.

CGS 19755 (cis-4-phosphonomethyl-2-piperidine carboxylic acid) was found to be a potent, stereospecific inhibitor of N-methyl-D-aspartate (NMDA)-evoked, but not KCl-evoked, [3H] acetylcholine release from slices of the rat striatum. The concentration-response curve to NMDA was shifted to the right by CGS 19755 (pA2 = 5.94), suggesting a competitive interaction with NMDA-type receptors. CGS 19755 inhibited the binding of [3H]-3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid to NMDA-type receptors with an IC50 of 50 nM, making it the most potent NMDA-type receptor antagonist reported to date. CGS 19755 failed to interact with 23 other receptor types as assessed by receptor binding, including the quisqualate- and kainate-type excitatory amino acid receptors. In crude P2 fractions, no evidence was obtained to suggest that CGS 19755 is taken up by an active transport system. Furthermore, CGS 19755 failed to affect the uptake of L-[3H]glutamate, or to interact with aconitine-induced inhibition of L-[3H]glutamate uptake, the latter finding suggesting a lack of membrane-stabilizing or local anesthetic properties. CGS 19755 selectively antagonized the excitatory effect of iontophoretically applied NMDA in the red nucleus of the rat without affecting the excitatory effects of quisqualate. CGS 19755 blocked the harmaline-induced increase in cerebellar cyclic GMP levels at a dose of 4 mg/kg i.p. with a duration of action exceeding 2 hr. CGS 19755 inhibited convulsions elicited by maximal electroshock in rat (ED50 = 3.8 mg/kg i.p. 1 hr after administration) and in mouse (ED50 = 2.0 mg/kg i.p. 0.5 hr after administration). Likewise, convulsions elicited by picrotoxin were inhibited by CGS 19755, whereas the compound was relatively weak in protecting against convulsions elicited by pentylenetetrazole or strychnine. CGS 19755 produced retention performance deficits in a dark avoidance task. However, CGS 19755 did not show a unique propensity for learning and memory disruption compared to other anticonvulsants.