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Biomedical subjects

E Brady

Publications and source records attributed to E Brady.

At least 19 recordsLinked to original sources
PubMed2001

The in vitro fate of rabbit fetal brain cells after acute in vivo hypoxia.

In the investigation of ischemia-induced brain damage, traditional methods using histopathology estimate brain cell death at a time remote from ischemic insult. These observations fail to take into account endogenous repair processes or ongoing injury cascades like apoptosis. The cells that are injured but not killed initially are the population most amenable to rescue. The hypothesis was that in vivo uterine ischemia-reperfusion would result in more cell death and apoptosis in fetal brain cells cultured in vitro. Near-term, 29 d gestation, pregnant New Zealand White rabbits were subjected to repetitive uterine ischemia for a cumulative time of 40 min ischemia and 20 min reperfusion. Immediately after uterine ischemia, the fetal brains were removed and dissociated into a cell suspension. The ischemic group had more cell death than non-ischemic controls as assessed by Trypan Blue exclusion and propidium iodide (PI) uptake on a flow cytometer. Aliquots of cells were plated and cultured for 24 and 48 hr. The ischemic group had significantly more cell death (propidium iodide) than non-ischemic controls at 24 hr and significantly more apoptosis, as assessed by annexin-V binding in cells at 24 hr and caspase-3 activity at 48 hr. Fewer cells attached to the culture plates at 48 hr in the ischemia group. After uterine ischemia, certain fetal brain cells die immediately, and other cells undergo ongoing damage resulting in necrosis and apoptosis that is manifest later. This method offers insight into the fate of those cells and provides a tool for assessing interventions to decrease cell injury.

Acute Disease↗
PubMed2001

Beta(3)-adrenoceptor agonist-induced increases in lipolysis, metabolic rate, facial flushing, and reflex tachycardia in anesthetized rhesus monkeys.

The effects of two beta(3)-adrenergic receptor agonists, (R)-4-[4-(3-cyclopentylpropyl)-4,5-dihydro-5-oxo-1H-tetrazol-1-yl]-N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]benzenesulfonamide and (R)-N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)- ethyl]amino]ethyl]phenyl]-1-(4-octylthiazol-2-yl)-5-indolinesulfonamide, on indices of metabolic and cardiovascular function were studied in anesthetized rhesus monkeys. Both compounds are potent and specific agonists at human and rhesus beta(3)-adrenergic receptors. Intravenous administration of either compound produced dose-dependent lipolysis, increase in metabolic rate, peripheral vasodilatation, and tachycardia with no effects on mean arterial pressure. The increase in heart rate in response to either compound was biphasic with an initial rapid component coincident with the evoked peripheral vasodilatation and a second more slowly developing phase contemporaneous with the evoked increase in metabolic rate. Because both compounds exhibited weak binding to and activation of rhesus beta(1)-adrenergic receptors in vitro, it was hypothesized that the increase in heart rate may be reflexogenic in origin and proximally mediated via release of endogenous norepinephrine acting at cardiac beta(1)-adrenergic receptors. This hypothesis was confirmed by determining that beta(3)-adrenergic receptor agonist-evoked tachycardia was attenuated in the presence of propranolol and in ganglion-blocked animals, under which conditions there was no reduction in the evoked vasodilatation, lipolysis, or increase in metabolic rate. It is not certain whether the beta(3)-adrenergic receptor-evoked vasodilatation is a direct effect of compounds at beta(3)-adrenergic receptors in the peripheral vasculature or is secondary to the release or generation of an endogenous vasodilator. Peripheral vasodilatation in response to beta(3)-adrenergic receptor agonist administration was not attenuated in animals administered mepyramine, indomethacin, or calcitonin gene-related peptide(8-37). These findings are consistent with a direct vasodilator effect of beta(3)-adrenergic receptor agonists.

Adenylyl Cyclases↗
PubMed2000

Activation of insulin signal transduction pathway and anti-diabetic activity of small molecule insulin receptor activators.

We recently described the identification of a non-peptidyl fungal metabolite (l-783,281, compound 1), which induced activation of human insulin receptor (IR) tyrosine kinase and mediated insulin-like effects in cells, as well as decreased blood glucose levels in murine models of Type 2 diabetes (Zhang, B., Salituro, G., Szalkowski, D., Li, Z., Zhang, Y., Royo, I., Vilella, D., Diez, M. T. , Pelaez, F., Ruby, C., Kendall, R. L., Mao, X., Griffin, P., Calaycay, J., Zierath, J. R., Heck, J. V., Smith, R. G. & Moller, D. E. (1999) Science 284, 974-977). Here we report the characterization of an active analog (compound 2) with enhanced IR kinase activation potency and selectivity over related receptors (insulin-like growth factor I receptor, epidermal growth factor receptor, and platelet-derived growth factor receptor). The IR activators stimulated tyrosine kinase activity of partially purified native IR and recombinant IR tyrosine kinase domain. Administration of the IR activators to mice was associated with increased IR tyrosine kinase activity in liver. In vivo oral treatment with compound 2 resulted in significant glucose lowering in several rodent models of diabetes. In db/db mice, oral administration of compound 2 elicited significant correction of hyperglycemia. In a streptozotocin-induced diabetic mouse model, compound 2 potentiated the glucose-lowering effect of insulin. In normal rats, compound 2 improved oral glucose tolerance with significant reduction in insulin release following glucose challenge. A structurally related inactive analog (compound 3) was not effective on insulin receptor activation or glucose lowering in db/db mice. Thus, small molecule IR activators exert insulin mimetic and sensitizing effects in cells and in animal models of diabetes. These results have implications for the future development of new therapies for diabetes mellitus.

Animals↗
PubMed2000

NPS 1506, a moderate affinity uncompetitive NMDA receptor antagonist: preclinical summary and clinical experience.

NPS Pharmaceuticals, Inc. (NPS) has synthesized a series of open-channel blockers with varying potencies at the NMDA receptor. NPS 1506 (Fig. 1) is a moderate affinity antagonist that inhibits NMDA/glycine-induced increases in cytosolic calcium in cultured rat cerebellar granule cells (IC50 = 476nM) and displaces the binding of [3H]MK-801 to rat cortical membranes (IC50 = 664nM).

Adolescent↗
PubMed1999

Efficacy of a filter device in the prevention of embolic events during carotid angioplasty and stenting: An ex vivo analysis.

OBJECTIVE: Although percutaneous angioplasty and stenting (PTAS) of carotid bifurcation lesions is feasible and appropriate for surgically inaccessible lesions, its general role and comparative value remain unclarified. Moreover, the acceptance of carotid PTAS has been limited by its potential for producing embolic debris. This study used an ex vivo model to evaluate the efficacy of a novel filter device to entrap emboli during PTAS of human carotid plaques. METHODS: Eight carotid bifurcation plaques were obtained from patients who underwent carotid endarterectomy for high-grade atherosclerotic stenosis (>90%). The mean age of the patients was 63 years, and six patients were symptomatic. Each plaque was encased with polytetrafluoroethylene material to simulate adventitia and was connected to a perfusion circuit, which provided continuous flow through the plaque. The filter device consisted of an expandable polymeric membrane with multiple micro pores that was attached to the distal end of a 0.014-in wire with a shapeable tip. This filter was encased in a delivery catheter. With fluoroscopic guidance, the filter wire was passed through the stenosis and the delivery catheter was then retracted to open the filter to capture particles released into the distal internal carotid artery. PTAS with a self-expandable stent then was carried out over the filter wire. The particles released during the initial filter passage, those captured in the filter, and those that flowed through or around the filter (missed) were collected and analyzed with light microscopy. RESULTS: Filter deployment, PTAS, and filter retrieval were achieved successfully with each lesion. Because the filter has a low crossing profile, it passed through the stenoses smoothly and only produced occasional small particles. PTAS improved the angiographic stenosis from 96.2% +/- 3.7% to 1.3% +/- 1.6%. The mean number and the maximum size of the particles that were released during initial filter passage, missed, and captured by the filter device were 3.1 and 500 microm, 2.8 and 360 microm, 20.1 and 1100 microm, respectively. Most of the particles and those of large size were released during PTAS. The filter captured 88% of these particles. CONCLUSION: These study results show that this filter device, at least in this model, did not add complexity to the interventional procedure itself. Furthermore, the filter may markedly decrease embolic events during carotid PTAS and expand the indications for this procedure.

Aged↗
PubMed1999

Severe peristomal pyoderma gangrenosum: a case study.

Pyoderma gangrenosum is an autoimmune disease that often manifests itself as painful ulcers. When these ulcers occur in the peristomal area, symptom management and wound care must be balanced against the need to pouch the stoma. Although the treatment of pyoderma gangrenosum is not standardized, systemic steroid therapy is frequently used as first-line therapy. The WOC nurse is often asked to manage both the pouching needs and topical therapy of the patient with peristomal pyoderma ulcerations. This article describes the management of severe pyoderma gangrenosum ulcerations in a 59-year-old woman with a long-standing ileostomy.

Bandages↗
PubMed1999

NPS 1506, a novel NMDA receptor antagonist and neuroprotectant. Review of preclinical and clinical studies.

NPS 1506 is a moderate affinity, uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist. NPS 1506 is neuroprotective in rodent models of ischemic stroke, hemorrhagic stroke, and head trauma, with a 2-hr window of opportunity. Neuroprotectant doses of NPS 1506 ranged from approximately 0.1-1.0 mg/kg, with peak plasma concentrations ranging from 8-80 ng/mL. Even at doses producing behavioral toxicity, NPS 1506 did not elicit MK-801-like behaviors, did not generalize to phencyclidine (PCP), and did not elicit neuronal vacuolization. In a Phase I study, intravenous (i.v.) doses of NPS 1506 from 5-100 mg were well tolerated and provided plasma concentrations in excess of those required for neuroprotection in rodents. Adverse events at the 100-mg dose included mild dizziness and lightheadedness, and mild to moderate ataxia. Neither PCP-like psychotomimetic effects nor cardiovascular effects were noted. The long plasma half-life of NPS 1506 (approximately 60 hr) suggests that a single i.v. dose will provide prolonged neuroprotection in humans.

Adolescent↗
PubMed1991

The pharmacokinetics of benazepril relative to other ACE inhibitors.

Benazepril is a prodrug that, following rapid conversion to benazeprilat, is a potent nonsulfhydryl inhibitor of angiotensin-converting enzyme. The absorption, bioactivation, distribution, and elimination of benazepril and benazeprilat have been evaluated in healthy subjects, hypertensive patients, and patients with characteristics known to alter the pharmacokinetic disposition of ACE inhibitors, such as renal impairment, hepatic impairment, and advanced age. Following oral administration, benazepril is absorbed and transformed into benazeprilat in the liver. Coadministration of benazepril with food delays absorption slightly but does not affect the ultimate bioavailability of benazeprilat. Severe hepatic impairment slows conversion of benazepril to benazeprilat but does not affect the overall bioavailability of benazeprilat; thus dosage adjustment is not necessary in the hepatically impaired population. Mild-to-moderate renal impairment (creatinine clearance greater than 30 ml/min) slightly increases benazeprilat concentrations; severe renal impairment (creatinine clearance less than 30 ml/min) reduces benazeprilat elimination and requires dosage reduction. In elderly patients, benazepril disposition is the same as in younger patients, although benazeprilat clearance is slightly reduced. No clinically significant drug-drug interactions occur with benazepril and many other medications commonly prescribed to elderly hypertensive patients. The pharmacokinetic characteristics of benazepril are stable over a wide range of conditions, and dosage adjustments for pharmacokinetic reasons are required infrequently.

Absorption↗
PubMed1989

Design of a selective insulin receptor tyrosine kinase inhibitor and its effect on glucose uptake and metabolism in intact cells.

An inhibitor of the insulin receptor tyrosine kinase (IRTK), (hydroxy-2-naphthalenyl-methyl) phosphonic acid, was designed and synthesized and was shown to be an inhibitor of the biological effects of insulin in vitro. With a wheat germ purified human placental insulin receptor preparation, this compound inhibited the insulin-stimulated autophosphorylation of the 95-kDa beta-subunit of the insulin receptor (IC50 = 200 microM). The ability of the kinase to phosphorylate an exogenous peptide substrate, angiotensin II, was also inhibited. Half-maximal inhibition of basal and insulin-stimulated human placental IRTK activity was found at concentrations of 150 and 100 microM, respectively, with 2 mM angiotensin II as the peptide substrate. The inhibitor was found to be specific for tyrosine kinases over serine kinases and noncompetitive with ATP. The inhibitor was converted into various (acyloxy)methyl prodrugs in order to achieve permeability through cell membranes. These prodrugs inhibited insulin-stimulated autophosphorylation of the insulin receptor 95-kDa beta-subunit in intact CHO cells transfected with human insulin receptor. Inhibition of insulin-stimulated glucose oxidation in isolated rat adipocytes and 2-deoxyglucose uptake into CHO cells was observed with these prodrugs. Our data provide additional evidence for the involvement of the insulin receptor tyrosine kinase in the regulation of glucose uptake and metabolism. These results and additional data reported herein suggest that this class of prodrugs and inhibitors will be useful for modulating the activity of a variety of tyrosine kinases.

Adipose Tissue↗
PubMed1984

Effects of topical applications of phosphonoacetate on colonization of mouse trigeminal ganglia with herpes simplex virus type 1.

The effects of topical application of phosphonoacetic acid on the colonization of mouse trigeminal ganglia by herpes simplex virus type 1 were examined. The results showed that the extent of colonization of ganglia by virus is related to the time elapsed between virus inoculation and application of this agent. In most cases, treatment started up to 12 h after inoculation prevented invasion of ganglia by virus. When started up to 24 h after inoculation, treatment reduced and stabilized the amount of virus detectable in trigeminal ganglia during the acute phase of the ganglionic infection. Treatments started 24 h after virus inoculation had little influence on total virus accumulations in trigeminal ganglia. The data also indicate that virus titers in specimens of inoculated and treated skin sites are less affected by topical phosphonoacetic acid treatment than virus titers in ganglia. The experiments may represent a model system for testing effects of other antiviral compounds on colonization of ganglia by virus and may provide some clues regarding the pathogenic mechanism of herpes simplex virus infections.

Administration, Topical↗
PubMed1981

Effect of acyclovir on latent herpes simplex virus infections in trigeminal ganglia of mice.

The inhibition by acyclovir of the in vitro reactivation of herpes simplex virus from latently infected ganglion explant cultures is dependent on the continuous presence of this drug. Administration of acyclovir subcutaneously, orally, or by continuous perfusion to mice with established latent infections did not eliminate latent virus from the trigeminal ganglia.

Acyclovir↗
PubMed1980

Experimental skin infection with an acyclovir resistant herpes simplex virus mutant: response to antiviral treatment and protection against reinfection.

Skin infections induced in hairless mice with an Acyclovir resistant herpes simplex virus (HSV) mutant were not followed by the death of the animals, and the survivors had no evidence of latent infections in their sensory ganglia. However, mutant virus was detected in the ganglia during the acute phase of the infection. Mice inoculated with the mutant were fully protected against the fatal outcome of the infection when subsequently challenged with the relatively pathogenic parental virus. In addition the frequency of latent infections established after challenge was significantly reduced. Phosphonoacetic acid treatment of the primary mutant-induced infection abolished the protection against reinfection with parental virus. Acyclovir treatment of the primary infection with the mutant virus did not affect the protection against reinfection with parental virus. The results indicate that drug-resistant, latency-negative, HSV mutants are a promising starting point for the development of an attenuated HSV vaccine.

Acyclovir↗
PubMed1979

Latent infections of sensory ganglia as influenced by phosphonoformate treatment of herpes simplex virus-induced skin infections in hairless mice.

Topical treatment with 3% phosphonoformate of herpes simplex virus type 1 (HSV)-induced skin infections of hairless mice reduced the severity of skin lesions when the treatment was initiated 3 h after virus inoculation in the lumbosacral area or 3 and 24 h after inoculation in the orofacial area. The mortality was significantly reduced in lumbosacral-infected mice and was completely prevented in orofacial-infected mice when the treatment was initiated with a delay of 24 h after virus inoculation. However, phosphonoformate did not prevent the establishment of latent herpes simplex virus type 1 infections in the spinal and trigeminal ganglia, even when treatment was initiated as early as 3 h after infection.

Animals↗
PubMed1978

Latent herpes simplex virus in ganglia of mice after primary infection and reinoculation at a distant site.

Herpes simplex virus (HSV)-infected hairless mice with evidence of latent infection in spinal ganglia did not develop latent HSV infections in trigeminal ganglia upon reinfection in the oro-facial area. HSV-infected and PAA-treated mice without evidence of latent HSV infection in spinal ganglia were resistant to reinfection in the lumbar region, but not to that performed in the oro-facial area.

Animals↗
PubMed1976

Immunoglobulin content and antibody activity in an artificial body cavity.

Artificial body cavities (ABC) were created by the insertion of hollow polyethylene balls in the subcutaneous tissue of rabbits. After two months no inflammatory reaction could be detected, the ABC was enveloped by a membranous structure, and the cavity contained about 20 ml of fluid. The protein concentration was about 3 times, and the IgG about 8 times, lower in the ABC fluids than in the corresponding serum. At the same time the antibody titers against sheep red blood cells (SRBC), human IgG and herpes simplex virus type 1 (HSV) were about 20 200 times lower than in the corresponding serum samples. The IgG molecules appeared to be undamaged as shown by the presence of various allotypes and by the elution pattern from G-200 column. Testing the protective activity of ABC fluids and of serum against HSV infection showed that ABC fluids had no protective activity. The experiments suggest that the membranous structure selected among classes of Ig and probably among other serum proteins. In addition, the IgG molecules with antibody activity against various inoculated antigens were selectively excluded to penetrate in the ABC. The ABC might be considered analogous to virtual cavities of the body surrounded by membranes and possibly to the extravascular compartment.

Animals↗