Tirilazad mesylate does not improve early cerebral metabolic recovery following compression ischemia in dogs.

Abstract

Background and Purpose: Tirilazad mesylate (U74006F) has been reported to improve recovery following cerebral ischemia. We conducted a randomized blinded study to determine if the drug would improve immediate metabolic recovery after complete cerebral compression ischemia.Methods: Mongrel dogs were anesthetized with pentobarbital and fentanyl and treated with either vehicle (citrate buffer, n=8) or tirilazad (1.5 mg/kg i.v. plus 0.18 mg/kg/hr, n=8). Normothermic complete cerebral compression ischemia was produced for 12 minutes by lateral ventricular fluid infusion to raise intracranial pressure above systolic arterial pressure. Cerebral high-energy phosphate concentrations and intracellular pH were measured by phosphorus magnetic resonance spectroscopy. Cerebral blood flow was measured with radiolabeled microspheres, and oxygen consumption was calculated from sagittal sinus blood samples. Somatosensory evoked potentials were measured throughout the experiment.Results: During ischemia, both groups demonstrated complete loss of high-energy phosphates and a fall in intracellular pH (vehicle, 5.76±0.23; tirilazad, 5.79±0.26; mean±SEM). At 180 minutes of reperfusion, there were no differences between groups in recovery of intracellular pH (vehicle, 6.89±0.07; tirilazad, 6.88±0.18), phosphocreatine concentration (vehicle, 89±16%; tirilazad, 94±24% of baseline value), oxygen consumption (vehicle, 2.6±0.2 ml/min/100 g; tirilazad, 1.8+0.5 ml/min/100 g), or somatosensory evoked potential amplitude (vehicle, 11±6%; tirilazad, 7±4% of baseline value). Forebrain blood flow fell below baseline levels at 180 minutes of reperfusion in the tirilazad-treated animals but not in the vehicle-treated dogs (vehicle, 28±4 ml/min/100 g; tirilazad, 18±5 ml/min/100 g).Conclusions: We conclude that tirilazad pretreatment does not improve immediate metabolic recovery 3 hours following 12 minutes of normothermic complete ischemia produced by cerebral compression.

Tirilazad Pretreatment Improves Early Cerebral Metabolic and Blood Flow Recovery from Hyperglycemic Ischemia

“…Extracranial contamination of sagittal sinus blood from diploic veins was assumed to be small and of similar mag nitude in each treatment group. Phosphorus MRS was performed with a 5-cm surface coil tuned to 32.5 MHz in a 1.89-T superconducting mag net with a 25-cm bore diameter (Oxford Instruments, Ox ford, England) as previously described (Nishijima et aI., 1989;Hum et aI., 1991a;Helfaer et al, 1992;Maruki et aI., 1993a). Areas under the peaks corresponding to phos phocreatine and the j3-phosphorus of ATP were measured by planimetry and normalized by the corresponding areas of the baseline spectra.…”

Lazaroids: efficacy and mechanism of action of the 21-aminosteroids in neuroprotection

“…63 However, tirilazad had no effect on the recovery of intracellular pH, oxygen consumption, somatosensory-evoked potentials and cerebral blood¯ow during a 3-h reperfusion phase. 23…”