Antioxidant 21-aminosteroid "U-74389G" ameliorates the short-time effect of hypoxia-reoxygenation on the platelet count in rats.

AIM: The aim of this experimental study was to examine the effect of the antioxidant drug "U-74389G", on rat model and particularly in a hypoxia-reoxygenation protocol. The beneficial effect or non-effectiveness of that molecule were studied hematologically using blood mean platelet count. Results were that U-74389G administration interacted or not with reoxygenation time decreased the platelet count by 6.12% ± 3.58% (p = 0.0857) and 12.83% ± 5.79% (p = 0.0303) respectively. CONCLUSIONS: U-74389G administration interacted or not with reoxygenation time decreases the platelet count within short-term time of 2 hours by different significance levels.

Symptomatic lumbar facet joint cysts treated by CT-guided intracystic and intra-articular steroid injections.

OBJECTIVE: To evaluate percutaneous computed tomography (CT)-guided intracystic and intra-articular steroid injections for the treatment of lumbar facet joint cyst causing radicular pain. METHODS: A single-centre prospective study involving 120 consecutive patients with symptomatic lumbar facet joint cyst-induced radicular pain was done (72 women, 48 men). The average age was 68.2 years (52-84). Patients were treated by percutaneous CT-guided intracystic and intra-articular steroid injections. The clinical course of nerve root pain was evaluated after 1 day, and 1, 3 and 6 months, with long-term follow-up after 12 months. RESULTS: Patient follow-ups in our series show supportive results: within 120 patients, 54% of patients were satisfied with a long-lasting result from the first intra-cystic and intra-articular steroid injections (n = 65), while 20.8% were satisfied with a long-lasting result from a second intervention. Combining these two results shows that 75% of patients were satisfied with a long-lasting result. CONCLUSIONS: Our results showed that percutaneous treatment of vertebral lumbar facet joint cysts by double injections is an effective and economic therapeutic technical management among 75% of our patients. Thus we recommend that it should be considered as a first choice of treatment. KEY POINTS: Lumbar facet joint cysts are a common feature of back and radicular pain. They may be treated effectively by interventional radiologists using CT guidance. Percutaneous treatment using double injections can save surgery in 75% of patients.

[Evaluation of the efficacy of CT-guided epidural and transforaminal steroid injections in patients with diskogenic radiculopathy]. / Evaluation de l'efficacité des infiltrations canalaires et foraminales de corticoïdes guidées par TDM dans le traitement des radiculalgies par conflit disco radiculaire.

PURPOSE: To evaluate the efficacy of CT-guided epidural and transforaminal steroid injections in patients with diskogenic radiculopathy. MATERIALS AND METHODS: Seventy patients underwent CT guided injections after failure of medical management. Only patients with minimal degenerative changes and diskogenic monoradicular symptoms were treated. Only two patients with fibrosis were included. RESULTS: 78.6% of patients experienced persistent symptomatic improvement. No difference was noted between lumbar segments and there was no more failures with epidural injections compared to transforaminal injections. Cervical disk herniations responded better than lumbar disk herniations. Good results were obtained in younger patients (M=46.25 years), symptomatic for 3-4 months or less, and with clear radicular symptoms and clinical neurological deficits (hypoesthesia, absent DTR) without motor deficit. No patient with severe spinal stenosis (S-) was included and the disk herniations were small (b1, b2, c1, c2 or d1, d2). Only a single injection was needed. Cortivazol provided superior results compared to dexamethasone. CONCLUSION: CT-guided injections should be included in the therapeutic armamentarium after standard medical management, with cure as the goal.

Enhanced brain delivery with lower hepatic exposure of lazaroid loaded nanostructured lipid carriers developed using a design of experiment approach.

The current study was designed to develop and optimize lazaroid loaded nano-structured lipid carriers (LAZ-NLCs) using design of experiment approach for enhancing lazaroid brain exposure. Response surface plots were used to determine the effects of independent variables (amount of PEGylating agent and liquid lipid) on dependent variables (particle size, zeta potential and encapsulation efficiency), while numerical optimization was used for optimizing LAZ-NLCs composition. The optimal LAZ-NLCs were spherical in shape with measured size of 172.3 ±â€¯3.54 nm, surface charge of -4.54 ±â€¯0.87 mV and encapsulation efficiency of 85.01 ±â€¯2.60%. The optimal LAZ-NLCs were also evaluated for hemolytic potential, storage stability and solid-state properties. The plasma pharmacokinetics along with brain and hepatic distributions of control lazaroid citrate solution and optimal LAZ-NLCs formulation were evaluated in Sprague-Dawley rats after the single bolus intravenous administration. The optimized LAZ-NLCs and the control lazaroid citrate solution had similar plasma pharmacokinetic profiles; however, differential organ bio-distributions were observed. The lazaroid exposure in brain was enhanced by two times with a decreased liver exposure by half for the NLCs group compared to the solution group.

Neuronal tumour necrosis factor-α and interleukin-1ß expression in a porcine model of intracerebral haemorrhage: Modulation by U-74389G.

Tumour necrosis factor α (TNF-α) and interleukin 1ß (IL-1ß) are important mediators of intracerebral haemorrhage (ICH) inflammatory response. Lazaroids, established antioxidants and neuroprotectants, have been studied in several brain pathologies. The present study was designed to investigate: a) TNF-α and IL-1ß changes, in neurons and b) U-74389G effects, 4 and 24h after haematoma induction in a porcine model of intracerebral haemorrhage. In twenty male landrace pigs (swines) aged 135-150 days old, autologous whole blood was injected around the right basal ganglia territory; in ten of the pigs the lazaroid compound U-74389G was administered. Brain TNF-α and IL-1ß immunopositive neurons were determined by immunoarray techniques at 4 and 24h timepoints. After the haematoma induction the number of TNF-α immunopositive neurons ipsilateral to the haematoma was significantly higher compared to the contralateral site at 4h (p<0.0005), while U-74389G significantly reduced the number of TNF-α immunopositive neurons, ipsilateral to the haematoma, at 4h (p=0.002); at 24h, TNF-α immunopositive neurons were found significantly lower in the control group ipsilateral to the haematoma in comparison to 4h timepoint(p<0.0005). The number of IL-1ß immunopositive neurons at 4h after the hematoma induction was significantly higher ipsilateral to the haematoma site (p<0.0005). U-74389G had no statistical significant effect. TNF-α and IL-1ß, increase in neurons, 4h after the haematoma induction, ipsilateral to the haematoma site. The administration of the antioxidant compound U-74389G, results in early (at 4h) decrease of TNF-α immunopositive neurons but shows no statistical significant effect to IL-1ß immunopossitive neurons.

Pharmacologic Management of Subarachnoid Hemorrhage.

Subarachnoid hemorrhage (SAH) remains a condition with suboptimal functional outcomes, especially in the young population. Pharmacotherapy has an accepted role in several aspects of the disease and an emerging role in several others. No preventive pharmacologic interventions for SAH currently exist. Antiplatelet medications as well as anticoagulation have been used to prevent thromboembolic events after endovascular coiling. However, the main focus of pharmacologic treatment of SAH is the prevention of delayed cerebral ischemia (DCI). Currently the only evidence-based medical intervention is nimodipine. Other calcium channel blockers have been evaluated without convincing efficacy. Anti-inflammatory drugs such as statins have demonstrated early potential; however, they failed to provide significant evidence for the use in preventing DCI. Similar findings have been reported for magnesium, which showed potential in experimental studies and a phase 2 trial. Clazosentane, a potent endothelin receptor antagonist, did not translate to improve functional outcomes. Various other neuroprotective agents have been used to prevent DCI; however, the results have been, at best inconclusive. The prevention of DCI and improvement in functional outcome remain the goals of pharmacotherapy after the culprit lesion has been treated in aneurysmal SAH. Therefore, further research to elucidate the exact mechanisms by which DCI is propagated is clearly needed. In this article, we review the current pharmacologic approaches that have been evaluated in SAH and highlight the areas in which further research is needed.

Effects of U-74389G (21-Lazaroid) and Ascorbic Acid on Liver Recovery After Acute Ischemia and Reperfusion in Rats.

BACKGROUND/AIM: The free radical-scavenging effects of the lazaroid U-74389G have been shown in several experimental models to protect the liver from ischemia/reperfusion (I/R), however, the mechanism of cytoprotection is not fully understood. Similar findings were observed when ascorbic acid was administered. This study investigates the effects of infusion of lazaroid U-74389G and ascorbic acid on cytokines and liver structure in a liver I/R rat model. MATERIALS AND METHODS: Sixty male Wistars rats, weighting 220-290 g, were used in the study. Six experimental groups were formed: Group 1 (control group): ischemia for 30 min and reperfusion for 60 min; group 2 (control group): ischemia for 30 min and reperfusion for 120 min; group 3: ischemia for 30 min, intraportal injection of ascorbic acid, and reperfusion for 60 min; group 4: ischemia for 30 min, ascorbic acid administration, and reperfusion for 120 min; group 5: ischemia for 30 min, U-74389G administration, and reperfusion for 60 min; and group 6: ischemia for 30 min, U-74389G administration, and reperfusion for 120 min. Tissue and blood sampling took place upon completion of each model's reperfusion. U-74389G was administered at 10 mg/kg animal body weight and ascorbic acid at 100 mg/kg. Anesthesia was induced with ketamine and xylazine. Surgery was performed through a midline laparotomy. The portal vein and the common hepatic artery were isolated and prepared for occlusion. Blood samples and wedge liver biopsies were taken to measure levels of liver enzymes, cytokines and for microscopic analysis upon completion of reperfusion once for each model. RESULTS: Histopathological evaluation revealed a statistically significant reduction in the degree of necrosis of liver tissue in the treated groups compared to the control groups 1 and 2 [groups 3, 5 (p=0.010) and 4, 6 (p<0.0005)]. On the other hand, tissue malondialdehyde levels (MDA) were statistically significantly increased only between control group 2 and groups 4, 6 (p<0.0005). There was no statistically significant difference in tumor necrosis factor-α between groups. As for liver enzymes, only alkaline phosphatase (ALP) and gamma-glutamyl transferase (gGT) were statistically significantly reduced in treated groups 3 and 5 (ALP: p=0.027, and gGT: p=0.002) and 4 and 6 (ALP: p=0.004, and gGT: p=0.015) compared to control groups 1 and 2. CONCLUSION: Based on histological data and the reduction of some of the liver enzymes, in spite of a rise of malondialdehyde, in this rat model, administration of U-74389G in liver ischemia/reperfusion (I/R) injury has potential in attenuating liver damage.

Reproducibility of measurements of cerebral infarct volume on CT scans.

BACKGROUND AND PURPOSE: Infarct volume is increasingly used as an outcome measure in clinical trials of therapies for acute ischemic stroke. We tested which of 5 different methods to measure infarct size or volume on CT scans has the highest reproducibility. METHODS: Infarct volume and total intracranial volume were measured with Leica Q500 MCP image analysis software, or with a caliper, on 38 CT scans of patients who participated in the Tirilazad Efficacy Stroke Study II (TESS II). The scans were performed 8 days (+/-2 days) after the onset of symptoms. The 5 methods tested were based on (1) semiautomated pixel thresholding, (2) manual tracing of the perimeter, (3) a stereological counting grid, (4) measurement of the 3 largest diameters, and (5) the single largest diameter. The measurements were performed independently by 2 observers; the first observer performed all measurements twice. RESULTS: The single largest diameter did not correlate well with infarct volume. Of the other methods, manual tracing of the perimeter of the infarct had the lowest intraobserver and interobserver variability: coefficients of variation were 8.6% and 14.1%, respectively. For total intracranial volume, manual tracing also provided the highest reproducibility: intraobserver and interobserver coefficients of variation were 3.3% and 4.9%, respectively. CONCLUSIONS: Manual tracing of the perimeter is the most reproducible method for measuring the volumes of the infarct and the total intracranial space in multicenter trials of therapies for acute ischemic stroke.

Neuroprotection in transient focal cerebral ischemia by combination drug therapy and mild hypothermia: comparison with customary therapeutic regimen.

BACKGROUND AND PURPOSE: A combined therapeutic approach has been advocated repeatedly for treatment of focal cerebral ischemia. A clinical example of combined therapy is administration of nimodipine, mannitol, dexamethasone, and barbiturates during temporary occlusion of a cerebral artery in neurovascular surgery. We have recently demonstrated outstanding neuroprotective properties of a combination therapy with magnesium (calcium antagonist and glutamate antagonist), tirilazad (antioxidant), and mild hypothermia (MTH). In this study we compared this treatment strategy with the customary treatment options in a rat model of transient focal cerebral ischemia. METHODS: Sprague-Dawley rats (n=120) were subjected to 90 minutes of middle cerebral artery occlusion by an intraluminal filament (n=10 per group). In experiment 1, the customary treatment options (nimodipine, mannitol, dexamethasone, methohexital) were evaluated as monotherapy and in combination. In experiment 2, the customary and the new combination therapy (MTH) were compared. Mild hypothermia (33 degrees C) was maintained for 2 hours. Neurological examinations were performed daily. Infarct size was assessed histologically after 7 days. RESULTS: In experiment 1, infarct volume was attenuated by 34% at maximum, with mannitol and methohexital being the most effective drugs given as monotherapy. In experiment 2, combined administration of the customary treatment options had no additive effect (infarct volume -36%). Combination therapy with MTH reduced total infarction by 73% and almost completely abolished cortical infarction (-91%). None of the animals of this group had any residual neurological deficit at the end of the observation period (P<0.05 versus all other groups). CONCLUSIONS: The efficacy of drugs (monotherapy or in combination) most commonly used for neuroprotection during neurovascular surgery is limited. The newly proposed combination therapy (magnesium, tirilazad, and mild hypothermia), which is based on pathophysiological considerations, seems to be a promising alternative for neuroprotection in cerebrovascular surgery.

Effect of age and gender on tirilazad pharmacokinetics in humans.

Tirilazad mesylate pharmacokinetics were assessed in 12 young and 12 elderly volunteers (six men and six women per age group). Subjects received single 10-minute intravenous infusions of 1.5 mg/kg and 3.0 mg/kg tirilazad mesylate. Plasma tirilazad mesylate concentrations were determined by HPLC. There were no significant dose effects on clearance, but half-life increased with dose because of assay insensitivity at the lower dose. Mean half-lives were 16.3 +/- 15.5 and 21.4 +/- 12.6 hours for young and elderly subjects, respectively, at the 3.0 mg/kg dose. At the same dose, mean tirilazad mesylate systemic clearance was 0.630 +/- 0.254 and 0.428 +/- 0.090 L/hr/kg, respectively. The decreased clearance in elderly volunteers was primarily attributable to a lower clearance in elderly women relative to young women. The small effect of age on tirilazad clearance is likely to have minimum clinical impact. Tirilazad clearance was approximately 40% higher in young women than in young men. The clinical importance of this observation is unknown.

Lazaroid U-74389G for 48-hour canine liver preservation.

Lazaroids have been reported to attenuate preservation and reperfusion injury. In this study, we examined whether lazaroids can improve the outcome after 48-hr canine liver preservation and transplantation. Adult female beagle dogs were randomized into 4 dosage groups (5 animals each). Lazaroid U-74389G was intravenously administered at a dose of 0 mg/kg, 6 mg/kg, 10 mg/kg, or 15 mg/kg to donors 30 min before harvesting and also to recipients 30 min before revascularization. Control animals (0 mg/kg) were given the lazaroid vehicle. The liver grafts were orthotopically transplanted after 48 hr of hypothermic preservation in UW solution. Lazaroid treatment significantly improved outcome after transplantation. Five-day animal survival increased from 0% in the control to 60% in the 6 mg/kg group, 100% in the 10 mg/kg group, and 80% in the 15 mg/kg group. Lazaroid protected the hepatocytes from damage during preservation, and enhanced energy charge and hepatic blood flow after reperfusion. Histological alterations were significantly less severe in the lazaroid-treated groups. The area of necrotic hepatocytes decreased from 43.7 +/- 17.7 in the control to 13.5 +/- 3.0 in the lazaroid 10 mg/kg group. These results indicate that lazaroid U-74389G has potential for improvement of clinical liver preservation.

The effect of lazaroid (U74500A), a novel inhibitor of lipid peroxidation, on 24-hour heart preservation. A study based on a working model using cross-circulated blood-perfused rabbit hearts.

Lazaroid, an inhibitor of iron-mediated lipid peroxidation, has been shown to reduce free radical-mediated injury after ischemia and reperfusion. We thus examined the efficacy of pretreatment with lazaroid (U74500A) in enhancing functional recovery after 24-hr heart preservation. An isolated rabbit heart model perfused with the blood from a support rabbit was used. Before preservation, either U74500A (4 mg/kg, group L; n = 6) or solvent (group S; n = 7) was given to the donor rabbit. After 24-hr preservation with UW solution at 0 degrees C, all hearts were perfused with cross-circulated blood for 60 min with the Langendorff mode followed by 40 min of the working mode. In group S, ventricular fibrillation (Vf) after reperfusion was observed in all hearts, whereas no Vf was observed in the U74500A-pretreated group. In group L, the serum creatine phosphokinase; its isozyme, troponin-T; and serum lipid peroxide levels after 10 min of reperfusion were all significantly (P < 0.05) lower than those in group S. The Frank-Starling curve (indicating the left atrial pressure-aortic flow relationship) showed a significant left and upward shift in group L compared with that in group S (P < 0.0001). The heart pretreated with U74500A showed less ischemia-reperfusion injury, better ventricular function, and a lower lipid peroxide level. We thus conclude that the inhibition of lipid peroxidation with lazaroid appears to offer some potential benefits for long-term heart preservation.

Effect of delayed administration of U74006F (tirilazad mesylate) on recovery of locomotor function after experimental spinal cord injury.

Beginning at either 30 minutes, 2 hours, 4 hours, or 8 hours after 180 g compression of the cat L2 spinal cord for 5 minutes, infusion of U74006F was initiated. In this series, the cats received a total U74006F dose of 5 mg/kg/48 hours. An additional group of injured cats was treated at 8 hours postinjury with a three-fold higher dose of U74006F (i.e., a total 48-hour dose of 15 mg/kg). Controls received an equal volume of vehicle (citrate-buffered saline) delivered over 48 hours. The cats were evaluated weekly for 4 weeks for recovery of overground locomotion based on an 11-point scale by an investigator blinded to the time and type (i.e., vehicle or drug) of material administered. By 4 weeks postinjury, there was no significant difference in the locomotor recovery of cats that received U74006F at either 30 minutes, 2 hours, 4 hours, or 8 hours after injury. However, only recovery in the groups treated at 30 minutes, 2 hours, or 4 hours after injury was significantly greater than vehicle-treated controls. Locomotor function in cats receiving either 5 mg/kg/48 hours or 15 mg/kg/48 hours of U74006F at 8 hours postinjury was not significantly different from that of the vehicle-treated animals. Mean (+/- SEM) 4-week recovery scores were 6.8 +/- 0.9, 5.9 +/- 1.0, 7.2 +/- 1.1, and 4.7 +/- 2.9 out of 11 for cats treated at 30 minutes, 2 hours, 4 hours, or 8 hours postinjury, respectively, with the 5 mg/kg/48 hour dose. The mean recovery score for cats treated at 8 hours after injury with the 15 mg/kg/48 hour dose was 3.4 +/- 1.8. The average score for the vehicle-treated controls was 1.8 +/- 0.8. These findings demonstrate that U74006F can significantly protect locomotor function in our model of compression spinal cord injury if administered as late as 4 hours postinjury. Delaying administration of the compound to 8 hours after injury results in considerable loss of its protective capabilities even if the dose is increased threefold.

Correlation between attenuation of posttraumatic spinal cord ischemia and preservation of tissue vitamin E by the 21-aminosteroid U74006F: evidence for an in vivo antioxidant mechanism.

In the present study, the ability of U74006F, the 21-aminosteroid inhibitor of lipid peroxidation, to attenuate posttraumatic spinal cord ischemia has been examined in cats following a moderately severe compression injury. Moreover, in an attempt to assess whether U74006F is affecting in vivo posttraumatic lipid peroxidation, the effect of the compound on injury-induced spinal tissue vitamin E depletion was also studied. Following an initial 10 min postinjury hyperperfusion (+45%), spinal cord blood flow (SCBF) returned to the preinjury level at 30 min before entering a phase of progressive hypoperfusion, which reached -42.0 +/- 4.5% by 4 h postinjury in the vehicle-treated animals. In animals that received 30 min postinjury U74006F i.v. doses of 1.0, 3.0, or 10 mg/kg (plus 0.5, 1.5, and 5.0 mg/kg maintenance doses at 2.5 h.), the SCBF decline was reduced to -23.1%, -22.9%, and -26.1%, respectively (p less than 0.05 vs. vehicle at all three doses). A 0.3 mg/kg dose did not reduce the posttraumatic fall in SCBF. In vehicle-treated cats, the vitamin E content of the injured cord segment was reduced by 78.9% at 4 h postinjury in comparison to cord samples from uninjured vehicle-treated cats. In contrast, the same doses of U74006F (1.0, 3.0, and 10 mg/kg) that attenuated posttraumatic ischemia also significantly reduced the depletion of cord vitamin E. The lowest U74006F dosage (0.3 mg/kg), which failed to affect posttraumatic ischemia development, also had no effect on spinal cord vitamin E content.(ABSTRACT TRUNCATED AT 250 WORDS)

Pitfalls and advances from the international tirilazad trial in moderate and severe head injury.

This manuscript reviews current experience with a large-scale clinical trial of the nonglucocorticoid 21-aminosteroid compound, tirilazad mesylate (U-74,006F). The trial itself now encompasses 15 countries with all central coordination conducted in the Data Coordinating Center at the University of California, San Diego. To date, the conduct of this trial has shown that diverse groups of clinicians in multiple countries have been able to work together to adhere to a tightly defined research protocol. Despite the success in initiating and conducting this trial, however, there have been several unanticipated problems that have complicated its progress. In this regard, difficulties have been associated with the use of mean Glasgow coma scores for data analysis. Similarly, a prospective identification of the risk variables was found necessary to preclude the potential for serious errors in data analysis. Lastly, a differential effect of the drug was noted in women compared to men in the European subarachnoid hemorrhage trial where a significant improvement in outcome was observed in males. This differential response appears to be linked to drug metabolism, but the problem may be further compounded by improper dosing because of failure to weigh many patients. Women appear to be routinely underdosed because their weights are routinely underestimated. Overall, this paper shows the feasibility of conducting such a large scale international trial, while also highlighting some of the potential pitfalls and problems that should be avoided in future trials of this nature.

Cardioprotective effects of Lazaroid U-74389G on ischemia-reperfusion injury in canine hearts.

BACKGROUND: Lazaroid, an inhibitor of iron-mediated lipid peroxidation, has been shown to reduce free radical-mediated injury after ischemia and reperfusion. The effect of Lazaroid U-74389G was investigated on ischemia-reperfusion injury of the heart through preservation and transplantation (Tx) in dogs. METHODS: Eleven pairs of adult mongrel dogs weighing 8.5 to 12 kg formed the recipient-donor combinations. Following electromechanical arrest of the heart using cardioplegia, the coronary vascular beds were washed out with a cold University of Wisconsin solution followed by 12-hour preservation and orthotopic Tx. Experimental animals were divided into 2 groups; 6 pairs formed the control group, and 5 formed the Lazaroid-treated group in which Lazaroid U-74389G at 10 mg/kg was administered intravenously 30 minutes before reperfusion of the heart. The cardiac function including cardiac output, left ventricular (LV) pressure, and LV dp/dt was assessed 2 hours after Tx by comparing it with the recovery rates (%) from cardiac function of donor dogs. Each transplanted heart was harvested for histological study. RESULTS: The recovery of cardiac function after Tx was significantly better in the Lazaroid-treated group than in the control group. Histologically, myocardial damage, evaluated by both light and transmission electron microscopy, was less evident in the Lazaroid-treated group than in the control group. CONCLUSION: Early cardiac function following Tx was significantly better and histological damage was less in the Lazaroid-treated group than in the control group, suggesting that Lazaroid U-74389G is effective in preventing ischemia-reperfusion injury after preservation and Tx.

Evaluation of the pharmacokinetics and tolerability of tirilazad mesylate, a 21-aminosteroid free radical scavenger: II. Multiple-dose administration.

The multiple dose tolerability and pharmacokinetics of tirilazad mesylate, a 21-aminosteroid free radical scavenger, were assessed in 50 healthy male volunteers. Volunteers were randomized to receive intravenous normal saline placebo (n = 10), citrate vehicle placebo (n = 10), or 0.5 mg/kg/day (n = 6), 1.0 mg/kg/day (n = 6), 2.0 mg/kg/day (n = 6), 4.0 mg/kg/day (n = 6), or 6.0 mg/kg/day (n = 6) tirilazad mesylate in divided doses every 6 hours for 5 days, for a total of 21 doses. Drug was infused over 10 or 30 minutes. All tirilazad mesylate treatment groups and the citrate vehicle group had significantly more frequent and more intense pain at the injection site than did the saline group, but the pain intensity did not require interruption of dosing. Three episodes of clinical thrombophlebitis were observed. No statistically significant effects of tirilazad mesylate on blood pressure, heart rate, electrocardiograms, or renal function were apparent. Moderate and transient increases in serum alanine transaminase were observed in several subjects. In the 6.0 mg/kg/day group, 50% of the subjects exhibited increased alanine transaminase. Tirilazad mesylate did not significantly affect measures of glucocorticoid activity (blood glucose, adrenocorticotropic hormone, cortisol, eosinophil, or lymphocyte levels). Tirilazad mesylate pharmacokinetics were linear over the dosage range studied. Steady state appeared to be achieved by the fifth day of dosing. After the last dose, a mean terminal half-life of 35 hours was observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Evaluation of the pharmacokinetics and tolerability of tirilazad mesylate, a 21-aminosteroid free radical scavenger: I. Single-dose administration.

The single-dose tolerability and pharmacokinetics of tirilazad mesylate, a 21-aminosteroid free radical scavenger, were assessed in 47 healthy male subjects. Subjects were randomized to receive citrate vehicle (n = 12) or 0.25 mg/kg (n = 9), 0.5 mg/kg (n = 9), 1.0 mg/kg (n = 8), or 2.0 mg/kg (n = 9) tirilazad mesylate by 0.5-hour intravenous infusion. Injection site pain was observed with approximately equal frequency in both vehicle and tirilazad mesylate treatment groups. No statistically significant effects of tirilazad mesylate on blood pressure, heart rate, electrocardiograms, liver enzymes, or renal function were apparent. Tirilazad mesylate did not significantly affect measures of glucocorticoid activity (blood glucose, adrenocorticotropic hormone, cortisol, eosinophil, or lymphocyte levels). Maximal plasma concentrations of tirilazad mesylate increased linearly with dose. Limited assay sensitivity at the lower two doses prevented determination of the dose proportionality of tirilazad area under the curve. The apparent elimination half-life at the higher doses was 3.7 hours. Clearance of tirilazad mesylate approached liver blood flow. Results indicate that intravenous infusions at these doses are well tolerated and devoid of glucocorticoid effects. Tirilazad mesylate appears to be efficiently cleared by the liver, and its pharmacokinetics are apparently linear over the dosage range studied.

Pharmacokinetics of tirilazad and U-89678 in ischemic stroke patients receiving a loading regimen and maintenance regimen of 10 mg/kg/day of tirilazad.

The pharmacokinetics of tirilazad mesylate and its active reduced metabolite, U-89678, were evaluated in ischemic stroke patients receiving 2.5 mg/kg tirilazad every 3 hours for the first 12 hours of dosing followed by 2.5 mg/kg every 6 hours for a total of 22 doses (5 days). Trough and serial samples drawn during the 6 hours after administration of the last dose were analyzed for plasma levels of tirilazad and U-89678 by means of high-performance liquid chromatography. Complete concentration-time profiles were available for 20 patients, including 12 men (mean age, 68.0 years) and 8 women (mean age, 75.0 years). Trough concentrations of tirilazad and U-89678 were consistent with the loading regimen used. The mean area under the concentration-time curve from time 0 to 6 hours (AUC0-6) of tirilazad was 8181 +/- 2398 ng.hr/mL in men and 8135 +/- 3671 ng.hr/mL in women. The mean AUC0-6 of U-89678 was 2761 +/- 1834 ng.hr/mL in men and 1477 +/- 903 ng.hr/mL in women. These results show that gender has a modest effect on the pharmacokinetics of U-89678 but little effect on the pharmacokinetics of tirilazad in elderly ischemic stroke patients. These observations are consistent with previous findings in healthy young and elderly subjects.