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Biomedical subjects

J M McCall

Publications and source records attributed to J M McCall.

At least 19 recordsLinked to original sources
PubMed1998

Effects of the lazaroid, tirilazad mesylate, on sepsis-induced acute lung injury in minipigs.

OBJECTIVE: To assess the effects of the lazaroid, tirilazad mesylate, a potent lipid peroxidation inhibitor, in an animal model of Pseudomonas sepsis. DESIGN: Comparison of four experimental groups: a) saline control; b) Pseudomonas sepsis control; c) tirilazad mesylate control; and d) sepsis with tirilazad mesylate pre treatment. SETTING: University animal laboratory. SUBJECTS: Hanford minipigs (20 to 25 kg), anesthetized with pentobarbital and mechanically ventilated on an FIO2 of 0.4. INTERVENTIONS: Sepsis was induced by infusing Pseudomonas aeruginosa at 1 x 10(6) colony-forming units/kg/min over 120 mins. The tirilazad mesylate-treated group received a 5-mg/kg bolus 30 mins before, and a 3-mg/kg bolus 3 hrs after, the onset of sepsis. Hemodynamics, PaO2, and neutrophil counts were measured for 6 hrs. Thiobarbituric acid reactive material (TBARM) in tissue (lung, liver, and intestine), lung wet/dry weight ratio, lung myeloperoxidase activity, plasma tumor necrosis factor (TNF)-alpha concentrations, protein content, and percent neutrophils in bronchoalveolar lavage fluid were evaluated at the time the animals were killed (6 hrs). MEASUREMENTS AND MAIN RESULTS: Sepsis induced significant systemic hypotension, pulmonary hypertension, hypoxemia, and neutropenia. Sepsis also significantly increased TBARM content, lung wet/dry weight ratio, myeloperoxidase activity, plasma TNF-alpha concentrations, and bronchoalveolar lavage neutrophil percentage. Treatment with tirilazad mesylate significantly attenuated hypoxemia and decreased TBARM content, lung wet/dry weight ratio, myeloperoxidase activity, bronchoalveolar lavage protein, and bronchoalveolar lavage neutrophil percentage, but did not affect sepsis-induced hemodynamics, including systemic hypotension and pulmonary hypertension, plasma TNF-alpha concentrations, or neutropenia. CONCLUSIONS: Pretreatment with the tirilazad mesylate did not change P. aeruginosa sepsis-induced hemodynamic consequences. However, tirilazad mesylate attenuated sepsis-induced acute lung injury.

Animals↗
PubMed1997

Abdominal radical trachelectomy: a new surgical technique for the conservative management of cervical carcinoma.

Traditionally radical hysterectomy has formed the mainstay of treatment for early stage cervical carcinoma. More recently radical trachelectomy and laparoscopic lymphadenectomy have been introduced to allow preservation of fertility. We present a new approach to fertility-sparing surgery, namely abdominal radical trachelectomy. The technique is similar to a standard radical hysterectomy and lymphadenectomy. In our technique the ovarian vessels are not ligated and, following lymphadenectomy and skeletonisation of the uterine arteries, the cervix, parametrium and vaginal cuff are excised. The residuum of the cervix is then sutured to the vagina and the uterine ateries re-anastomosed.

Anastomosis, Surgical↗
PubMed1996

Objectively assessing nursing practices: a curricular development.

In preparation for the changing needs of undergraduate nursing students undertaking a Project 2000 degree, it was necessary to rethink the nursing skills programme. After studying the literature a nursing skills laboratory was designed which provided both an institutional and a domestic setting. A progressive programme was developed, to help the students learn nursing practices, which was based on the Objective Structured Clinical Evaluation (OSCE). A small pilot study was set up using second and third-year students from the traditional nursing studies degree. A number of stations were set up comprising various nursing scenarios. The students who were being assessed rotated through these. Other students acted as patients, examiners and some volunteered to be novices being taught by the more senior students. A set of marking criteria was drawn up for each station to enable each student to be assessed objectively. One of the stations was filmed to provide the students with personal feedback. By the end of the session the students had rotated through each of the stations and received the marked criteria as feedback. At the end of the session a focused group interview took place with all the students and the two lecturers involved in setting up the project. Students were positive and felt the process had potential for future development as a means of integration and consolidation of skills prior to clinical experience. The early introduction of filming to the programme was though to be of benefit by reducing stress levels through regular use. Students felt that the role of teaching the 'novice' helped them focus on their knowledge and performance. This process is resource intensive in human and non-human terms but enables small groups of students to learn in a realistic but safe, non-threatening environment and encourages them to take responsibility for their own learning.

Clinical Competence↗
PubMed1996

The efficacy of percutaneous cholecystostomy in critically ill patients.

Percutaneous cholecystostomy (PC) has been proposed as a method of biliary decompression in critically ill patients with acute cholecystitis. We evaluated the efficacy of PC in this setting. The charts of 33 critically ill patients (mean age 52, range 5-87) who underwent PC for suspected acute cholecystitis were retrospectively examined. Univariate analysis was performed to identify which patients might benefit from PC. PC was technically successful in all patients with no direct mortality or major complications. Failure to improve within 24 hours was associated with increased mortality (P = 0.02). A total of 22/33 patients improved, 17/33 survived, and 8/33 required surgery. PC delayed definitive operation in two patients. Cholelithiasis was associated with surgical intervention (P = 0.01) but not increased mortality. Favorable prognosticators for survival included gallbladder dilatation (P = 0.01), pericholecystic fluid (P = 0.01), and absence of a pulmonary artery catheter (P = 0.02). Predictors of improvement included gallbladder nonvisualization on hepatobiliary scan (P = 0.047), positive bile cultures (P = 0.017), and initial drainage of < / = 100 cc (P = 0.009). Age, laboratory data, the use of total parenteral nutrition, and intubation did not predict outcome. Nine positive bile cultures prompted antibiotic changes in five cases. Finally, PC was less expensive than open cholecystostomy ($1620 versus $3155). PC is a safe, cost-effective, minimally invasive procedure that has diagnostic and therapeutic value in critically ill patients with acute cholecystitis. The involvement of a general surgeon is important to ensure that those patients who do not improve within 24 hours receive early surgical intervention and provide long-term definitive care for those patients with cholelithiasis.

Acute Disease↗
PubMed1994

Tirilazad mesylate protects stored erythrocytes against osmotic fragility.

The hypoosmotic lysis curve of freshly collected human erythrocytes is consistent with a single Gaussian error function with a mean of 46.5 +/- 0.25 mM NaCl and a standard deviation of 5.0 +/- 0.4 mM NaCl. After extended storage of RBCs under standard blood bank conditions the lysis curve conforms to the sum of two error functions instead of a possible shift in the mean and a broadening of a single error function. Thus, two distinct sub-populations with different fragilities are present instead of a single, broadly distributed population. One population is identical to the freshly collected erythrocytes, whereas the other population consists of osmotically fragile cells. The rate of generation of the new, osmotically fragile, population of cells was used to probe the hypothesis that lipid peroxidation is responsible for the induction of membrane fragility. If it is so, then the antioxidant, tirilazad mesylate (U-74,006f), should protect against this degradation of stored erythrocytes. We found that tirilazad mesylate, at 17 microM (1.5 mol% with respect to membrane lecithin), retards significantly the formation of the osmotically fragile RBCs. Concomitantly, the concentration of free hemoglobin which accumulates during storage is markedly reduced by the drug. Since the presence of the drug also decreases the amount of F2-isoprostanes formed during the storage period, an antioxidant mechanism must be operative. These results demonstrate that tirilazad mesylate significantly decreases the number of fragile erythrocytes formed during storage in the blood bank.

Antioxidants↗
PubMed1994

Kinetic evaluation of lipophilic inhibitors of lipid peroxidation in DLPC liposomes.

The authors have developed a kinetic method that allows one to obtain relative reactivity constants for lipophilic antioxidants in free radical systems. Two experimental model systems were developed: (a) a methanolic solution using AMVN as the free radical initiator and linoleic acid as the substrate, and (b) a multilamellar vesicle system composed of dilinoleoylphosphatidylcholine and AAPH as the substrate and the initiator, respectively. The use of these two systems allows researchers not only to determine the intrinsic reactivity of a potential antioxidant, but also to evaluate its potency in a membranous system where the contribution of the physical properties of the antioxidant to the inhibition of lipid peroxidation is important. These results show that all antioxidants tested acted in these systems as free radical scavengers, and they validate the synergism between intrinsic scavenging ability and membrane affinity and/or membrane-modifying physical properties in the inhibition of lipid peroxidation.

Amidines↗
PubMed1993

Iron-initiated tissue oxidation: lipid peroxidation, vitamin E destruction and protein thiol oxidation. Inhibition by a novel antioxidant, U-78517F.

Oxidative injury was initiated by addition of ferrous ammonium sulfate (FAS) to a suspension of whole rat brain homogenate in Krebs buffer. After FAS addition, tissue vitamin E dropped sharply over a 30-sec interval and then recovered marginally for 5 min. After 5 min, vitamin E levels dropped to a low and constant level. Also after 5 min, TBARS (thiobarbituric acid reactive substances, a color test for lipid peroxidation) showed a statistically significant (P < or = 0.05) increase that continued through the remainder of the 30-min experiment. Reduced protein thiols decreased significantly (P < or = 0.05) at 15 min post FAS addition. This suggests that, in this model of iron-initiated lipid peroxidation (LP), the endogenous antioxidant vitamin E is first depleted before membrane lipids and membrane bound proteins show evidence of oxidative injury. A novel antioxidant, U-78517F, inhibited the destruction of vitamin E, LP and protein thiol oxidation in this model. The efficacy of the compound after different times of addition is described.

Animals↗
PubMed1992

Antioxidant effects in brain and spinal cord injury.

Oxygen radical-mediated lipid peroxidation appears to be a critical factor in posttraumatic neuronal degeneration. Thus, numerous studies have evaluated the neuroprotective efficacy of pharmacologic agents with lipid antioxidant activity in models of spinal cord and brain injury. Intensive pretreatment of animals with the endogenous lipid peroxyl radical scavenger alpha tocopherol (i.e., vitamin E) has been shown to decrease posttraumatic spinal cord ischemia and to enhance chronic neurologic recovery. However, the slow CNS tissue uptake of vitamin E requires chronic dosing, making it an impractical agent for the treatment of acute neural injury. The glucocorticoid steroid methylprednisolone has been shown to possess significant antioxidant efficacy and, when administered to animals or humans in antioxidant dosages, improves chronic neurologic recovery after spinal cord injury. This activity of methylprednisolone is independent of the steroid's glucocorticoid receptor-mediated actions. Novel antioxidant 21-aminosteroids have been developed that are devoid of glucocorticoid activity but have greater antioxidant efficacy than methylprednisolone. One of these, U74006F or tirilazed mesylate, has been shown to be effective in animal models of brain and spinal cord injury and is currently undergoing phase II clinical trials. Compounds that combine the amino functionality of the 21-aminosteroids with the peroxyl radical scavenging chromanol portion of vitamin E (i.e., 2-methylaminochromans) have also recently shown promise as neuroprotective agents. The consistent benefit afforded by antioxidant compounds adds further support to the concept that lipid peroxidation is an important therapeutic target for acute pharmacologic neuroprotection.

Animals↗
PubMed1991

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.

Animals↗
PubMed1990

Novel 21-aminosteroids that inhibit iron-dependent lipid peroxidation and protect against central nervous system trauma.

A novel class of 21-aminosteroids has been developed. Compounds within this series are potent inhibitors of iron-dependent lipid peroxidation in rat brain homogenates with IC50's as low as 3 microM. Furthermore, selected members enhance early neurological recovery and survival in a mouse head injury model. Significant improvement in the 1 h post-head-injury neurological status (grip test score) by as much as 168.6% of the control has been observed. The most efficacious compound in this assay (30) showed an increase in the 1-week survival of 78.6% as compared to 27.3% for the vehicle-treated mice in the head-injury model. Based on its biological profile, 21-[4-(2,6-di-1-pyrrolidinyl-4-pyrimidinyl)-1-piperazinyl]-16 alpha- methylpregna-1,4,9(11)-triene-3,20-dione monomethanesulfonate (30) was selected for further evaluation and is currently entering phase I clinical trials for the treatment of head and spinal trauma.

Amines↗
PubMed1990

Effects of a 21-aminosteroid (U-74006F) on cerebral metabolites and edema after severe experimental head trauma.

U-74006F, a 21-aminosteroid, is a potent inhibitor of CNS tissue LP in vitro. In this study it was tested for effects on brain edema and metabolites after impact injury to the closed skull. Anesthetized cats were blindly treated with U-74006F or vehicle at 30 min (1 mg/kg) and 2.5 hr (0.5 mg/kg) after head or sham injury. They were sacrificed 4 hr after injury by in situ fixation of the brain. Head-injured cats were selected for unilateral (left) cerebral contusion. Metabolites (enzyme fluorometry) and edema (specific gravity) were measured in the cerebral cortex and white matter bilaterally. Cerebral hemisphere, contusion, and vasogenic edema volumes were morphometrically measured. Magnitude of edema and metabolites in tissue with vasogenic edema was similar in vehicle- and drug-treated cats. By contrast, the cortex and nonedematous white matter neighboring contusion in drug-treated cats had lactate, glucose, and glycogen levels that suggested an improved metabolic state over vehicle treatment. Most metabolites were not affected by trauma or treatment in the uncontused hemisphere. These results suggest that postinjury treatment with the nonglucocorticoid steroid U-74006F may benefit the metabolism of nonedematous tissue adjacent to contusion.

Animals↗
PubMed1989

Comparative neuroanatomical distribution of the kappa and mu opioid receptors in guinea pig brain sections.

The opiate family of receptors is believed to consist of the mu, delta, kappa and sigma subtypes. Autoradiographic studies have been conducted to define the distribution of the mu and delta receptors. However, due to the lack of a selective ligand definitive studies have not been reported for the kappa receptor. Recently such a ligand was discovered and characterized. Results are presented in which the distribution of kappa receptors in guinea pig brain slices were determined using autoradiographic techniques and its distribution compared to that of a typical mu ligand. The results demonstrate numerous differences between the two opioid systems. The kappa receptors predominate in the prefrontal cortex, the nucleus accumbens, and deep cortex; whereas the mu receptors have a more intense, broader and different distribution.

Animals↗
PubMed1988

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 hemorrhaged 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-reinfusion 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 maintenance 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.

Animals↗
PubMed1988

Arylformamidines with antinociceptive properties.

A series of formamidines structurally related to clonidine were synthesized and investigated as potential nonopiate analgesics. Several of these compounds showed potent analgesic activity (ED50 on HCl writhing less than 1.0 mg/kg) with low potential for hypotensive effects. A qualitative description of the structure-activity relationship of this series reveals that the 2,4- and 2,6-dimethylphenyl compounds are more potent analgesics than are the corresponding dichlorophenyl compounds.

Analgesia↗