Doses Of Methylprednisolone Sodium Succinate Research Articles

ЛІКУВАННЯ СОБАК З УРАХУВАННЯМ ОСОБЛИВОСТЕЙ ПАТОГЕНЕЗУ ХРЕБЕТНО-СПИННОМОЗКОВИХ ТРАВМ

ЛІКУВАННЯ СОБАК З УРАХУВАННЯМ ОСОБЛИВОСТЕЙ ПАТОГЕНЕЗУ ХРЕБЕТНО-СПИННОМОЗКОВИХ ТРАВМ

Localized delivery of methylprednisolone sodium succinate with polymeric nanoparticles in experimental injured spinal cord model

With important social and economic consequences, spinal cord injuries (SCIs) still exist among major health problems. Although many therapeutic agents and methods investigated for the treatment of acute SCI, only high dose methylprednisolone (MP) is being used currently in practice. Due to the serious side effects, high dose systemic MP administration after SCI is a critical issue that is mostly considered controversial. In our study, it is aimed to develop a nanoparticle-gel combined drug delivery system for localization of MP on trauma site and eliminating dose-dependent side effects by lowering the administered dose. For this purpose, methyl prednisolone sodium succinate (MPSS) loaded polycaprolactone based nanoparticles were developed and embedded in an implantable fibrin gel. The effects of MPSS delivery system are evaluated on an acute SCI rat model, by quantification the levels of three inflammatory cytokines (interleukin-1β, interleukin-6 and caspase-3) and assessment of the damage on ultrastructural level by transmission electron microscopy. Developed NP-gel system showed very similar results with systemic high dose of MPSS. It is believed that developed system may be used as a tool for the safe and effective localized delivery of several other therapeutic molecules on injured spinal cord cases.

Cryptogenic Organizing Pneumonia During Adjuvant Chemotherapy With Oxaliplatin, 5-Fluorouracil, and Leucovorin (FOLFOX) for Colon Cancer

Lung disease associated with FOLFOX (oxaliplatin/5-fluorouracil/leucovorin) chemotherapy is uncommon. We describe a case of cryptogenic organizing pneumonia (COP) occurring in a 78-year-old woman after receiving 2 cycles of modified FOLFOX6 as adjuvant chemotherapy for treatment of resected nonmetastatic colon cancer. This patient presented with respiratory symptoms including cough with scant clear sputum and wheezing on day 10 of the second cycle of mFOLFOX6. Despite therapy with systemic antibiotics and supplemental oxygen, she had a steady and relentless progression of her respiratory symptoms and status, with chest radiographs revealing progressive bilateral pulmonary infiltrates. Further chest radiograph evaluation demonstrated findings consistent with COP. Antibiotics were discontinued and methylprednisolone sodium succinate initiated as the mainstay of management for COP. The patient required a higher dose of methylprednisolone sodium succinate than typical for initial response with doses up to 3 mg/kg per d leading to prompt improvement in her respiratory symptoms and function and declining need for supplemental oxygen therapy. Chest radiographs also showed improvement. The Naranjo adverse drug reaction probability scale indicated a probable relationship (score of 5) between the patient’s COP and the FOLFOX chemotherapy. Clinicians should be aware of the potential for this uncommon, yet severe adverse reaction associated with the FOLFOX chemotherapy.

Evaluation of the function of polymorphonuclear neutrophilic leukocytes in healthy dogs given a high dose of methylprednisolone sodium succinate

To evaluate effects of a high dose of methylprednisolone sodium succinate (MPSS) on function of polymorphonuclear neutrophilic leukocytes (PMNs) in dogs. 7 healthy male Beagles (body weight, 10.5 to 15 kg; age, 2 to 4 years). All dogs were treated by IV administration of a high dose of MPSS (30 mg/kg). Additional doses of MPSS (15 mg/kg) were administered IV at 2 and 6 hours and then at 6-hour intervals until 48 hours after the initial dose. Blood samples were collected before and 1, 2, 4, 7, and 14 days after completion of the MPSS administrations and used for evaluation of PMN functions. Isolated PMNs were used for assessment of functions, such as adhesion, migration, phagocytosis, and oxidative burst. On days 1, 2, and 4 after completion of MPSS administration, there was a decrease in PMN expression of adhesion markers such as CD11b and CD18. There was a decrease in the phagocytotic ability of PMNs on days 1, 2, and 7 after completion of MPSS administration, with a reduction in the oxidative burst of PMNs detected on day 7. No significant changes were identified for migration. All functional changes returned to their pretreatment values by 14 days after completion of MPSS treatment. Treatment with a high dose of MPSS suppressed PMN functions in dogs. Analysis of these results suggested that treatment with a high dose of MPSS can suppress some of the major functions of PMNs for at least 7 days.

The evaluation of the concentrations of methylprednisolone applied intravenously and by iontophoresis in the pig

The current clinical research on pharmacokinetics of methylprednisolone was performed on male pigs to whom was administered either intravenously or locally, via iontophoresis. Equal doses of methylprednisolone sodium succinate (MPSS) were applied, i.e. 40 mg it total per animal. In all pigs artificial inflammation of knee and elbow joints was provoked four days prior to the treatment. Four hours after the application of methylprednisolone tissue samples (both synovial fluid and hyaline cartilage) were obtained from the inflamed joints and subjected to analysis. The quantification of the drug was performed by HPLC technique. The results indicated high quantities of methylprednisolone both in the synovial fluid and hyaline cartilage, the concentrations being significantly higher in animals after iontophoretic application (17.15±3.11 and 12.70±2.19 μg/g, respectively) in comparison with the animals treated intravenously (0.33±0.11 and 0.21±0.06 μg/g, respectively). Thus, iontophoresis was proved a highly advisable clinical means of application of methylprednisolone, especially having in mind the possibility of avoiding systemic adverse effects which are present after parenteral drug administration. In addition, it enables higher therapeutic concentrations of MPSS to be obtained both in the synovial fluid and in the hyaline cartilage of the treated inflamed joints.

In vitro evaluation of the effect of trans-10, cis-12 conjugated linoleic acid on phagocytosis by canine peripheral blood polymorphonuclear neutrophilic leukocytes exposed to methylprednisolone sodium succinate

To examine whether in vitro treatment with trans-10, cis-12 conjugated linoleic acid (t10c12-CLA) restores the phagocytic capacity and oxidative burst activity (OBA) of canine polymorphonuclear neutrophilic leukocytes (PMNs) exposed to methylprednisolone sodium succinate (MPSS). Peripheral blood PMNs obtained from 12 healthy Beagles. The experimental design involved administration of a high dose of MPSS, which is the recommended protocol for dogs with acute spinal cord injury. To evaluate PMN function, blood samples were collected from dogs before IV injections of doses of MPSS or saline (0.9% NaCl) solution (time 0) and 2, 12, and 24 hours after injections ceased. Polymorphonuclear neutrophilic leukocytes were isolated from blood samples and incubated with t10c12-CLA alone or t10c12-CLA in combination with N-acetylcysteine (an antioxidant agent). Phagocytic capacity and OBA were measured simultaneously by use of flow cytometry. The phagocytic capacity and OBA of PMNs were suppressed by IV injection of MPSS and restored 12 hours after injection ceased. In vitro treatment with t10c12-CLA enhanced the phagocytic capacity and OBA of PMNs, regardless of whether dogs had been treated with MPSS. Effects of t10c12-CLA on OBA were detected only when phagocytosis was stimulated by microspheres. Use of N-acetylcysteine attenuated the stimulatory effects of t10c12-CLA. Exposure to t10c12-CLA enhanced the phagocytic capacity and OBA of canine PMNs, and this effect may have involved t10c12-CLA-induced generation of reactive oxygen species.

Effects of methylprednisolone on nitric oxide formation and survival of facial motor neurons after axotomy

The aims of this study were to evaluate the effect of a high dose (160 mg/kg) of methylprednisolone sodium succinate (MPSS) on the formation of endogenous nitric oxide (NO) in the brainstem after facial nerve transection and to explore whether this effect has relevance to the survival of facial motor neurons. Guinea pig facial nerves were transected at the tympanic segment, and half were administered with MPSS, while the other half were given a vehicle of saline solution. Post operation NO formation in the brainstem at different time points was directly measured with a NO/ozone chemiluminescence technique. The surviving motor neurons were counted in histological coronal frozen sections of facial motor nuclei. The present results revealed that facial nerve transection induced a significant increase in NO formation in the brainstem by 1 week in both MPSS and saline treated groups and lasted to the end of the study (4 weeks). Compared to the saline treated group, it appeared that MPSS administration could delay the increase of nitric oxide synthase (NOS) expression and NO formation during the first 1∼2 weeks after facial nerve transection. The survival rate of facial motor neurons was significantly higher in the MPSS treated group than in the saline treated group when examined at 3 or 4 weeks after facial nerve transection. These results indicate that a high dose of MPSS elicited a delayed increase of NO formation and thus may concomitantly enhance the survival time of motor neurons after facial nerve transection.

Effects of the Second National Acute Spinal Cord Injury Study of High-Dose Methylprednisolone Therapy on Acute Cervical Spinal Cord Injury–Results in Spinal Injuries Center

Retrospective single-center study. To evaluate the recovery of motor function and the early complications in patients with acute cervical spinal cord injury after receiving a high dose of methylprednisolone sodium succinate (MPSS) within 8 hours of injury. High-dose MPSS therapy has been demonstrated to improve the neurologic recovery in patients with acute spinal cord injury. However, it remains a controversial treatment. Seventy patients were included in this study: 37 in the MPSS group who were treated with MPSS within 8 hours of their injury according to the Second National Acute Spinal Cord Injury Study protocol, and 33 in non-MPSS group who were not administered with MPSS. Improvements in the American Spinal Injury Association motor score were compared between the MPSS group and the non-MPSS group. In patients with complete motor loss at admission and follow-up periods, improvements of myotomal levels between the MPSS (n = 15) and non-MPSS groups (n = 21) were compared. Early complications within 6 weeks of high-dose MPSS therapy were compared with those of no MPSS therapy. Among the patients with incomplete paralysis at admission, the American Spinal Injury Association motor scores in the MPSS group were improved more significantly than those in the non-MPSS group at 6 weeks and 6 months after injury. Meanwhile, among the patients with complete paralysis at admission, the patients in the MPSS group did not show significantly more change in motor score than those in the non-MPSS group. Improvement in myotomal level had no significant difference between the MPSS and non-MPSS groups. The MPSS group had 10 patients with early complications, while the non-MPSS group had 14. The differences between the 2 groups showed no statistical significance. MPSS should be administered to patients with incomplete cervical spinal cord injury according to the Second National Acute Spinal Cord Injury Study protocol.

Mexiletine treatment—induced inhibition of caspase-3 activation and improvement of behavioral recovery after spinal cord injury

It has been demonstrated in several experimental studies that apoptosis contributes to cellular damage after spinal cord injury (SCI). During apoptosis dying cells secrete additional mediators of apoptosis such as cytokines and free radicals which have additional toxic effects and exacerbate neuronal death. The aim of this laboratory study was to investigate the effects of mexiletine on caspase-3 activation and functional recovery and compare its post-SCI effectiveness with methylprednisolone. The rats were divided into five groups. Animals in the trauma group underwent traumatic interventions after laminectomy. Spinal cord contusion injury was produced using the weight-drop method. Animals in treatment groups received a single dose of methylprednisolone sodium succinate (Group C), single dose of mexiletine (Group D), or vehicle solution (saline; Group E) intraperitoneally immediately after injury. Hind-limb functions were assessed using the inclined plane technique and caspase-3 activity in tissue samples was measured 24 hours after SCI. Traumatic injury was found to increase tissue caspase-3 activity. In both treatment groups the drug prevented an increase in caspase-3 activity. Mexiletine treatment improved early behavioral recovery after SCI. The results obtained in this study demonstrated that mexiletine treatment inhibits caspase-3 activation and preserve/restore better neuronal function compared with methylprednisolone after experimental SCI.

Current Concepts in the Management of Acute Spinal Cord Injury

Acute injury to the spinal cord initiates a sequence of vascular, biochemical, and inflammatory events that result in the development of secondary tissue damage. Experimental studies and clinical trials in humans have demonstrated that the extent of this secondary tissue damage can be limited by pharmacologic intervention at appropriate intervals after injury. High doses of methylprednisolone sodium succinate (MPSS) improve the outcome of acute spinal cord injury in humans if treatment is initiated within 8 hours of injury. Starting therapy more than 8 hours after injury is detrimental to outcome. The clinical efficacy of methylprednisolone in improving the outcome of canine spinal cord injuries has not yet been demonstrated and its use by veterinarians is controversial. Many dogs are not seen by a veterinarian within the 8‐hour window after injury, and these dogs frequently are treated with nonsteroidal anti‐inflammatory drugs or large doses of dexamethasone or prednisone before methylprednisolone treatment can be initiated, thus increasing the risk of severe adverse effects. Other drugs that may provide safer and more effective alternatives to methylprednisolone include thyrotropin‐releasing hormone (TRH), the 21‐aminosteroids, and kappa opioid agonists. Recent studies suggest that modulation of the influx of inflammatory cells and activation of endogenous microglial cells may provide another means of improving the outcome of acute spinal cord injuries. Many drugs being developed to treat acute spinal cord injury have shown promising results when evaluated experimentally. However, any proposed therapeutic strategy should be evaluated in prospective blinded clinical trials before being adopted in clinics.

Efficacy of misoprostol in prevention of gastric hemorrhage in dogs treated with high doses of methylprednisolone sodium succinate

Abstract Objective To determine whether administration of misoprostol prevents gastric hemorrhage in healthy dogs treated with high doses of methylprednisolone sodium succinate (MPSS). Animals 18 healthy hound-type dogs of both sexes. Procedure All dogs were given high doses of MPSS (30 mg/kg of body weight, initially, then 15 mg/kg 2 and 6 hours later, and, subsequently, q 6 h for a total of 48 hours) IV. Dogs were assigned randomly to receive concurrent treatment with misoprostol (4 to 6 μg/kg, PO, q 8 h; n = 9) or an empty gelatin capsule (9). Gastroduodenoscopy was performed before and after treatment. Hemorrhage was graded from none (0) to severe (3) for each cardia, fundus, antrum, and duodenum. A total stomach score was calculated as the sum of the regional stomach scores. Food retention was recorded, and pH of gastric fluid was determined. Gastric and fecal occult blood was measured. Results Gastric hemorrhage was evident in all dogs after MPSS administration, and its severity was similar in both groups. Median total stomach score was 6 for misoprostol-treated dogs and 5.5 for dogs given the gelatin capsule. Difference in gastric acidity, frequency of food retention, and incidence of occult blood in gastric fluid and feces was not apparent between the 2 groups. Conclusions and Clinical Relevance Administration of misoprostol (4 to 6 μg/kg, PO, q 8 h) does not prevent gastric hemorrhage caused by high doses of MPSS. Alternative prophylactic treatment should be considered. (Am J Vet Res 1999;60:982–985)

Current concepts in the management of acute spinal cord injury.

Acute injury to the spinal cord initiates a sequence of vascular, biochemical, and inflammatory events that result in the development of secondary tissue damage. Experimental studies and clinical trials in humans have demonstrated that the extent of this secondary tissue damage can be limited by pharmacologic intervention at appropriate intervals after injury. High doses of methylprednisolone sodium succinate (MPSS) improve the outcome of acute spinal cord injury in humans if treatment is initiated within 8 hours of injury. Starting therapy more than 8 hours after injury is detrimental to outcome. The clinical efficacy of methylprednisolone in improving the outcome of canine spinal cord injuries has not yet been demonstrated and its use by veterinarians is controversial. Many dogs are not seen by a veterinarian within the 8-hour window after injury, and these dogs frequently are treated with nonsteroidal anti-inflammatory drugs or large doses of dexamethasone or prednisone before methylprednisolone treatment can be initiated, thus increasing the risk of severe adverse effects. Other drugs that may provide safer and more effective alternatives to methylprednisolone include thyrotropin-releasing hormone (TRH), the 21-aminosteroids, and kappa opioid agonists. Recent studies suggest that modulation of the influx of inflammatory cells and activation of endogenous microglial cells may provide another means of improving the outcome of acute spinal cord injuries. Many drugs being developed to treat acute spinal cord injury have shown promising results when evaluated experimentally. However, any proposed therapeutic strategy should be evaluated in prospective blinded clinical trials before being adopted in clinics.

Medical care of the neurosurgical patient.

Proper medical care before and after surgery play an important role in the overall care of patients requiring neurosurgery and will have an impact on the neurological recovery. Prevention of spinal cord destruction resulting from the cascade of events which occur secondary to central nervous system trauma is a critical part of a patient's preoperative care. High doses of methylprednisolone sodium succinate given within the first 8 hours of trauma are currently recommended to provide protection to neural tissue after trauma. Other promising drugs for patients with spinal trauma, such as 21-aminosteroids and GM-1 gangliosides, may become available in the near future. Knowledge of potential complications after surgery and methods to prevent complications from occurring is an important part of the postoperative care of neurosurgical patients. This includes management of micturition and defecation dysfunction, management of postoperative pain, physical therapy to speed recovery, and providing good supportive care to the recumbent patient.

Effects of methylprednisolone sodium succinate on the growth of hard tissues in the young rat.

The present study was performed to obtain direct eviden ce of MPNSS (methylprednisolone sodium succinate) on the growth retardation of hard tissues in rats. For this purpose, different doses of MPNSS were injected intraperitoneally to the rat (daily administration of 2.0 mg/kg, 14 times and alternate-day administration of 10.0 mg/kg, 14 times). To the age-matched control animals, 0.9 % NaCl solution was injected. The body weight was measured daily. Wet weight of the adrenal gland was measured and the lengths of upper jaw (diastema) and tibia were also measured with dial calipers. In addition, the rate of the incisal dentine formation was measured with a chronological-labelling method using tetracycline. The right tibia was used for measuring the defatted -dry weight and the ash weight. To detect changes in calcium homeostasis, contents of calcium and phosphorus in the plasma were analysed. Following treatment with MPNSS, the weight loss, atrophy of the adrenal gland and retardation of bone growth were detected in both experimental groups.On the other hand, osteoporosis could not be recognized by contact-microradiography. It was confirmed that reduction of the growth rates was greater in the daily injected group than in the alternate-day injected one. In conclusion, the present study showed a direct inhibitory effect of MPNSS on bone growth in growing young rats. It is suggested that a larger dose of glucocorticoids could be given more effectively with less side effects of the drug by an alternate-day administration.

Steroids protect the β-adrenergic system during reperfusion after ischemia: Effects of methylprednisolone on the β-adrenergic response system

Methylprednisolone sodium succinate (MPSS) administered during reperfusion may improve myocardial function. These effects have been related to adrenergic stimulation. The present study investigated (1) the effects of ischemia and reperfusion on the β-adrenergic response system and (2) the ability of MPSS to modify the ischemic effects on the β-adrenergic system. Isolated perfused rat hearts were used. The ischemic protocol consisted of aerobic perfusion (20 minutes) followed by total, global normothermic (37°C) ischemia (30 minutes) and reperfusion (30 minutes) with MPSS (0, 100, 500, or 1,000 mg/L). The non-ischemic protocol consisted of aerobic perfusion (20 minutes) followed by aerobic perfusion (20 minutes) with MPSS (0, 100, 500, or 1,000 mg/L). At the end of the experiments all hearts were rapidly frozen in liquid nitrogen. Crude sarcolemmal membranes were prepared and stimulated at the β-receptor, at the coupling (G s- or N-) protein, or directly at the adenylate cyclase enzyme (AC). Results were assessed by cyclic adenosine monophosphate (cAMP) production. Tissue specimens were analyzed for myocardial content of cAMP and methylprednisolone (MP). In the ischemic protocol, the responsiveness of the β-adrenergic system was significantly reduced at the G s-protein level. The treatment with MPSS (100 or 500 mg/L) during reperfusion preserved the β-adrenergic response. MPSS (1,000 mg/L) offered no protection. In the non-ischemic protocol, MPSS reduced the response of the β-adrenergic system in a dose-dependent manner at the same level. The hearts in the ischemic protocol had significantly higher contents of MP than the hearts in the non-ischemic protocol at corresponding concentrations of MPSS. The present study suggests that postischemic cardiac failure may result in part from β-adrenergic dysfunction. This loss of function, probably at the level of the protein connecting the receptor and AC, can successfully be prevented by an optimal dose of MPSS during reperfusion after ischemia.

Effects of the 21-aminosteroid U74006F on posttraumatic spinal cord ischemia in cats.

The ability of a single intravenous dose of the 21-aminosteroid U74006F to affect the development of posttraumatic spinal cord ischemia was examined in pentobarbital-anesthetized cats. After surgical preparation, each animal received a 300 gm-cm contusion injury to the exposed L-3 vertebral segment, followed by a single bolus injection of vehicle or U74006F (3 or 10 mg/kg) at 30 minutes postinjury. Spinal cord white matter blood flow (SCBF) was measured by hydrogen clearance in the dorsolateral funiculus in the center of the injured segment before and at various times up to 4 hours after injury. In vehicle-treated cats, there was a progressive decline in SCBF over the course of the experiment. By 4 hours postinjury, SCBF had decreased from a preinjury value of 15.9 +/- 2.4 ml/100 gm/min (mean +/- standard error of the mean) to 5.8 +/- 0.8 ml/100 gm/min, representing a decline of 63.5%. In contrast, the SCBF measured 4 hours postinjury in cats that were treated with a single 10-mg/kg dose of U74006F was 13.6 +/- 1.7 ml/100 gm/min (p less than 0.001 vs. vehicle). Animals that received a 3-mg/kg intravenous dose of U74006F displayed a drop in SCBF equal to that of vehicle-treated cats. However, when a 3-mg/kg dose of U74006F was given to four vehicle-treated cats at the end of the experiment, a partial reversal of ischemia was recorded. Blood flow increased within 30 minutes from a mean of 4.5 +/- 0.8 to 7.4 +/- 1.0 ml/100 gm/min or an increase of 64.4% (p less than 0.05). This rather surprising effect of U74006F in reversing posttraumatic ischemia once it has developed significantly is not shared by a 30-mg/kg intravenous dose of methylprednisolone sodium succinate (MP), although MP has previously been shown to attenuate the posttraumatic drop in SCBF when given before the SCBF drop occurs. The mechanism of action of U74006F in antagonizing posttraumatic ischemia development is believed to involve the ability of the compound to inhibit iron-dependent lipid peroxidation in central nervous system tissue.

Attenuation of progressive brain hypoperfusion following experimental subarachnoid hemorrhage by large intravenous doses of methylprednisolone

Experimental subarachnoid hemorrhage was produced in chloralose-anesthetized cats by slow injection of 0.5 ml/kg autologous arterial blood into the cisterna magna. As a result, there was an initial (within 5 min) 25.1% decrease in caudate nuclear blood flow as measured by hydrogen clearance. Between 5 min and 3 h postinjection, there was a further and progressive 25.9% decline in caudate blood flow. The hemorrhage also caused a slow increase in intracranial pressure, a decrease in cerebral perfusion pressure, and an increase in caudate vascular resistance. In contrast, the administration of a single 30 mg/kg i.v. dose of methylprednisolone sodium succinate 30 min after the acute hemorrhage resulted in stabilization of caudate blood flow and vascular resistance and some restoration of those parameters toward prehemorrhage values. This effect was not correlated with a decrease in intracranial pressure or an increase in cerebral perfusion pressure. A 15 mg/kg i.v. dose of the drug had only a slight effect on caudate blood flow. A 60 mg/kg i.v. dose, while initially supportive, lost its effect during the later stages of the experiment, indicating a sharp biphasic dose-response relationship for the effect of methylprednisolone on caudate blood flow after subarachnoid hemorrhage. However, of the three doses, only 60 mg/kg significantly decreased the slow posthemorrhage rise in intracranial pressure. The beneficial effect of the 30 mg/kg i.v. dose of the drug on caudate blood flow, separate from an effect on the slow rise in intracranial pressure, suggests that the steroid support of caudate perfusion is due to a direct protective effect of the drug on the microvasculature. Based on previous studies showing an identical dose-response pattern for the ability of methylprednisolone to prevent posttraumatic lipid peroxidation of central nervous system tissue and progressive ischemia development, the possibility of the drug's inhibition of hemorrhage-initiated vasoconstrictor prostanoid action and microvascular lipid peroxidation is proposed.

Attenuation of hemorrhagic shock by the non-glucocorticoid 21-aminosteroid U74006F

The ability of the novel non-glucocorticoid 21-aminosteroid U74006F to protect against the development of hemorrhagic shock was examined in pentobarbital-anesthetized cats. The animals were hemon-haged to a mean arterial blood pressure (MAP) of 45–50 mm Hg where they were held for 2 h. At the end of the hemorrhage period, either vehicle, a 30 mg/kg dose of methylprednisolone sodium succinate, or a 10 mg/kg dose of U74006F was administered i.v. followed by reinfusion of the shed blood. In vehicle-treated animals, there was a progressive post-remfasion decline in the MAP over the subsequent 2 h. In the methylprednisolone-treated cats, the post-reinfusion decrease in the MAP was only slightly and not significantly better. In contrast, U74006F administration resulted in a significant mainte-nance of the MAP. These results suggest that U74006F may be efficacious for the attenuation of hemorrhagic shock and superior to conventional high dose glucocorticoid therapy in that context.

Effects of aerosolized methylprednisolone on experimental neurogenic pulmonary injury.

We examined the effects of graded doses of methylprednisolone sodium succinate (MPSS)--0.05 (low), 0.5 (medium), and 5 mg/kg/hour (high)--on the development of neurogenic pulmonary injury in rabbits. The aerosolized drug was administered intratracheally for 5 hours beginning 10 minutes after a 2-minute elevation of the cerebrospinal fluid pressure (Pcsf) to 250 mm Hg. Compared to untreated control animals, the percentage of increase in pulmonary capillary permeability, as determined by 51Cr-labeled ethylenediaminetetraacetic acid clearance, was significantly less in the low and high dose MPSS groups. However, high dose MPSS was also associated with a significant decrease in compliance and increase in tissue hemorrhage (quantified by visual inspection). These results indicate biphasic effect of MPSS on alveolar capillary integrity after elevated Pcsf. The low dose minimized the extent of lung hemorrhage, pulmonary capillary leakage, and loss of lung compliance. In contrast, the high dose accelerated tissue hemorrhage and compliance loss, even though pulmonary capillary permeability was maintained near base line rates.

Morphometric assessment of drug effects in experimental spinal cord injury.

The effect of large doses of methylprednisolone sodium succinate (MPSS) and two protease inhibitors, leupeptin and bestatin, on experimental acute spinal cord injury was evaluated by morphometric analysis of degenerating axons with the aid of an automated image analyzer. Spinal cord injury was produced by epidural compression with a surgical clip on the T-11 segment in rats. The extent of axonal damage was assessed in Rexed's lamina VIII in the L-6 segment by measuring the amount of silver grains, representing degenerating axons and their terminals, using the Fink-Heimer method. The severity of axonal damage was expressed as the degeneration index: that is, the amount of silver grains in experimental animals/the amount of silver grains in cord-transected animals. When examined on the 7th postoperative day, axonal degeneration in MPSS-treated rats was significantly decreased, with an average degeneration index difference of 6 (p less than 0.05). Increased preservation of axons was seen in the leupeptin-treated rats sacrificed 7, 10, and 14 days after trauma. The difference in the degeneration index between the leupeptin-treated and untreated groups was 16 on Day 7 (p less than 0.001), 12 on Day 10 (p less than 0.001), and 13 on Day 14 (p less than 0.01). Bestatin had no beneficial effect. The implications for the use of calcium-activated neutral protease inhibitors in acute spinal cord injury are discussed.