Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0917798 (cerebral ischemia)
 17,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Blockade of the N-methyl D-aspartate (NMDA) receptor by the ion-channel-blocking drug aptiganel hydrochloride (CNS 1102, Cerestat) is neuroprotective in focal cerebral ischemia. Short intravenous infusions of up to 30 microg/kg have been well tolerated by healthy male volunteers. We undertook a randomized, double-blind, placebo-controlled study in 20 male volunteers to examine the safety, tolerability, and cardiovascular and psychomotor effects of a dosing paradigm similar to that envisaged for therapeutic use. Aptiganel HCl was infused over 4 h in total doses of 15, 32, 50, or 73 microg kg. Mean arterial pressure increased significantly with dose group (p < 0.01, analysis of covariance). Motor reaction time was related to maximal plasma concentration (r2 = 0.21, p < 0.001). Transient symptoms and signs of peripheral paresthesiae, light-headedness, and euphoria were seen at total doses of 32 microg/ kg. Higher doses were associated with motor retardation, perceptual disturbances, and hallucinations (one case). Clearance was 125 +/- 55 L/h, and volume of distribution was 537 +/- 1,261. Total doses of up to 32 microg/kg of aptiganel HCl infused over 4 h are well tolerated by healthy males. Aptiganel HCl causes elevation of blood pressure and is associated with central nervous system symptoms and signs similar to other noncompetitive NMDA antagonists.
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PMID:Effects of prolonged infusions of the NMDA antagonist aptiganel hydrochloride (CNS 1102) in normal volunteers. 926 Jul 29

A wealth of experimental evidence demonstrates that cerebral ischemia causes excessive release of glutamate and that glutamate contributes to ischemic injury. Glutamate antagonism by any of several mechanisms can ameliorate the extent of infarction. These antagonists comprise noncompetitive blockers of the ion channel associated with the N-methyl-D-aspartate (NMDA) receptor [e.g., aptiganel (Cerestat)], competitive antagonists of the glutamate recognition site of the NMDA receptor (e.g., selfotel) or of the glycine recognition site (e.g., ACEA 1021, GV150526), antagonists at the polyamine site (e.g., eliprodil), and drugs that may interfere with glutamate release by sodium channel blockade as well as having other actions (e.g., lubeluzole, 619C89). Clinical experience suggests that although some NMDA antagonists are poorly tolerated at putative neuroprotective doses (e.g., selfotel), potentially neuroprotective plasma concentrations can be achieved in humans with others (e.g., aptiganel), though tolerable adverse effects are frequently observed. These clinical effects include hypertension (which is probably preferable to the hypotension seen with nimodipine and lifarizine), sedation, confusion or hallucinations and, at high doses, catatonia. Glycine antagonists may be associated with fewer adverse effects, but preclinical studies suggest that brain penetration may be low. Although recent studies with selfotel and eliprodil have been discontinued because of insufficient evidence for a satisfactory risk/benefit ratio, encouraging experience with aptiganel, magnesium, and glycine antagonists has prompted continued clinical trials with these agents. To be of sufficient size to detect a clinically useful improvement in outcome, these trials need to be large (600-1,000 patients). Present trials with aptiganel (Cerestat) are comparing the efficacy and tolerability of two doses vs. placebo in patients treated within 6 hours of ischemic stroke. Outcome is assessed by the modified Rankin Scale at 3 months.
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PMID:Cerestat and other NMDA antagonists in ischemic stroke. 937 Nov 55

Recent studies have demonstrated a neuroprotective effect of the noncompetitive N-methyl-D-aspartate receptor antagonist aptiganel HCl (Cerestat) in focal cerebral ischemia. In the present study, we investigated the protective ability of aptiganel HCl after controlled cortical impact injury (impact depth = 2 mm; impactor velocity = 7 mm/sec) of the left temporoparietal cortex in rats. Intravenous aptiganel HCl (2 mg/kg) or a respective volume of vehicle was injected 15 min after trauma. Animals were sacrificed 24 h after trauma. Contusion volume was measured planimetrically from hematoxylin-eosin-stained coronal slices. Hemispheric swelling and water content were determined gravimetrically. Thirty minutes before sacrifice, a Codman intracranial pressure (ICP) probe was placed in the right hemisphere, and ICP as well as mean arterial blood pressure (MABP) and cerebral perfusion pressure (CPP) were monitored. Aptiganel HCl reduced contusion volume by 13.6% in treated rats (p < 0.05). Hemispheric swelling was also significantly diminished by 31.5% in accordance to a decrease in hemispheric water content (controls, 82.78 +/- 0.12%, vs. aptiganel HCl, 82.30 +/- 0.18%, p < 0.05). Posttraumatic ICP was not significantly lower in the aptiganel HCl treated animals (25.5 +/- 2.4 mm Hg vs. 32.0 +/- 2.7 mm Hg, p = 0.096). MABP was found to be higher in the treatment group 24 h after injury (107.8 +/- 3.6 mm Hg vs. 89.9 +/- 2.4 mm Hg, p < 0.001), resulting in a higher CPP (82.6 +/- 4.2 mm Hg vs. 57.2 +/- 4.6 mm Hg, p < 0.05). Taken together, aptiganel HCl exerts various beneficial effects following experimental traumatic brain injury. It decreases contusion volume and hemispheric swelling as well as water content. Thus, this drug appears promising for further clinical trials in brain trauma.
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PMID:Protective effects of aptiganel HCl (Cerestat) following controlled cortical impact injury in the rat. 952 19

Recent studies revealed a neuroprotective effect of the non-competitive NMDA receptor antagonist Aptiganel HCL (Cerestat CNS 1102) in focal cerebral ischemia. This study investigates the influence of Cerestat on contusion volume, post-traumatic brain edema and intracranial pressure (ICP) following Controlled Cortical Impact Injury (CCII). In rats (n = 54) CCII was applied to the left hemisphere using a pneumatic impactor. Cerestat (2 mg/kg i.v.) or vehicle was injected 15 min after injury animals were sacrificed 24 hours later. Contusion volume was measured planimetrically (n = 18). Hemispheric swelling and water content were determined gravimetrically (n = 20). ICP, mean arterial blood pressure (MABP) and cerebral perfusion pressure (CPP) were monitored for 30 min before sacrifice (n = 16). Cerestat reduced contusion volume from 77.3 +/- 5.8 mm3 to 66.8 +/- 3.9 mm3 (p < 0.05). Hemispheric swelling was also diminished from 11.1 +/- 0.8% to 8.2 +/- 1.4% as soon was water content (Cerestat 82.30 +/- 0.18% vs. control: 82.78 +/- 0.12%, p < 0.05). ICP was decreased by treatment from 31.7 +/- 3.5 mm Hg to 26.3 +/- 2.2 mm Hg and CPP was significantly improved (82.1 +/- 4.4 mm Hg vs 57.7 +/- 4.8 mm Hg; p < 0.05) 24 hours after injury. Cerestat administration was associated with decrease contusion volume, less hemispheric swelling, a lower ICP and increased CPP.
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PMID:Neuroprotective properties of aptiganel HCL (Cerestat) following controlled cortical impact injury. 977 60