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Biomedical subjects

D W Morgan

Publications and source records attributed to D W Morgan.

At least 37 records · Page 2Linked to original sources
PubMed2000

Audit of headache following resection of acoustic neuroma using three different techniques of suboccipital approach.

A retrospective case notes review using pain visual analogue scale (VAS) and assessment of analgesia required by patients in the post-operative period at 1, 3, 6, 12 and over 12 months following acoustic neuroma resection was performed. Glasgow Benefit Inventory (GBI) score was used to assess the change of quality of life and its relationship to pain following surgery. Questionnaires of 71 patients were included in the study, 23 of whom underwent wide craniotomy including dissection of upper cervical musculature (CE), 25 wide craniotomy with replacement of bone flap (CO) and 23 minimally invasive, approximately 2 x 2 cm, minicraniectomy (MCE). The minicraniectomy resulted in significantly diminished pain from third month post surgery as compared with wide craniectomy (p < 0.05) and patients required less analgesia. Similarly, CO patients have experienced significantly less pain than CE patients (p < 0.05), but only after 12 months following surgery. Although consistently less in absolute visual analogue scores, there was no statistically significant difference between the amount of pain recorded by CO and MCE patients. There was no correlation between gender or age and the VAS pain score. The mean Glasgow Benefit Inventory score for all patients was -6.6, and there was no significant difference between operation types, genders or age. Although bone flap replacement appears to diminish the amount of post-operative pain, minimal invasive technique resulted in least pain following acoustic neuroma resection in our patients.

Female↗
PubMed1999

Enhancement of the surface expression of tumor necrosis factor alpha (TNFalpha) but not the p55 TNFalpha receptor in the THP-1 monocytic cell line by matrix metalloprotease inhibitors.

The monocytic cell line THP-1 can be induced to express and release tumor necrosis factor alpha (TNFalpha) and both TNFalpha receptors (p55 and p75) upon exposure to bacterial lipopolysaccharide (LPS). The broad-spectrum matrix metalloprotease (MMP) inhibitors [4-(N-hydroxyamino)-2R-isobutyl-3S-(phenylthiomethyl)succinyl]-L-p henylalanine-N-methylamide (GI-129471) and marimastat [2S-[N4(R*),2R*,3S*]]-N4[2,2-dimethyl-1-[(methylamino)carbonyl]propyl]-N 1,2-dihydroxy-3-(2-methylpropyl)butanediamide (BB-2516) were effective inhibitors of LPS-induced TNFalpha (soluble) release with IC50 values of 0.2 and 4.0 microM, respectively. Upon LPS stimulation, the expression of pro-TNFalpha (membrane associated) on the cell surface (FACS analysis) could not be observed. However, in the presence of GI-129471, a concentration-dependent increase in TNFalpha surface expression was observed. Peak expression (percentage of cells expressing pro-TNFalpha and mean fluorescence units) in the presence of GI-129471 was at 2 hr, and steadily declined to return to near control levels by 8 hr. This time course was similar to TNFalpha release, which also peaked at 2-4 hr after LPS exposure and then declined. Stimulation of THP-1 cells with LPS + phorbol myristate acetate increased the percentage of cells expressing pro-TNFalpha by 10-fold. In the presence of GI-129471, these increases were augmented further and peaked between 2 and 4 hr, but also returned to near control levels of expression by 24 hr. This was in contrast to the release of soluble TNFalpha, which continued to accumulate over a 24-hr time course. TNFalpha receptor I (p55, TNFRI) and II (p75, TNFRII) shedding was also inhibited by GI-129471 (IC50 = 1.5 and 3.1 microM, respectively) and BB-2516 (IC50 = 14 and 15 microM, respectively). Unlike pro-TNFalpha surface expression, surface expression of both TNFalpha receptors steadily increased over 72 hr. In contrast to pro-TNFalpha surface expression, TNFRI surface expression was not augmented by these MMP inhibitors in THP-1 cells after LPS stimulation. Surface expression of TNFRII was augmented by these MMP inhibitors. These results suggest that even in the continued presence of LPS stimulation and an inhibitor of TNFalpha processing, the augmented surface expression of TNFalpha is transient. The potential "deleterious" implications of high levels of surface pro-TNFalpha expression in the presence of these inhibitors may be lessened by its transient nature.

Cell Line↗
PubMed1998

The design, synthesis, and structure-activity relationships of a series of macrocyclic MMP inhibitors.

A series of succinate-derived hydroxamic acids incorporating a macrocyclic ring were designed, synthesized, and evaluated as inhibitors of matrix metalloproteinases. The inhibitors were designed based on the published X-ray crystal structure of batimastat (1) complexed with human neutrophil collagenase (MMP-8). The synthesized compounds were shown to inhibit selected MMPs in vitro with low nanomolar potency.

Collagenases↗
PubMed1998

Discovery and evaluation of a series of 3-acylindole imidazopyridine platelet-activating factor antagonists.

Studies conducted with the goal of discovering a second-generation platelet-activating factor (PAF) antagonist have identified a novel class of potent and orally active antagonists which have high aqueous solubility and long duration of action in animal models. The compounds arose from the combination of the lipophilic indole portion of Abbott's first-generation PAF antagonist ABT-299 (2) with the methylimidazopyridine heterocycle moiety of British Biotechnology's BB-882 (1) and possess the positive attributes of both of these clinical candidates. Structure-activity relationship (SAR) studies indicated that modification of the indole and benzoyl spacer of lead compound 7b gave analogues that were more potent, longer-lived, and bioavailable and resulted in the identification of 1-(N, N-dimethylcarbamoyl)-4-ethynyl-3-[3-fluoro-4-[(1H-2-methylimidazo[4,5-c] pyrid-1-yl)methyl]benzoyl]indole hydrochloride (ABT-491, 22 m.HCl) which has been evaluated extensively and is currently in clinical development.

Animals↗
PubMed1998

Influence of positive life events on blood pressure in adolescents.

It has been reported that adults suffering from refractory essential hypertension experience significantly fewer positive life events than healthy peers. However, the influence of positive life events on blood pressure (BP) in adolescents has been largely ignored. Therefore, we examined the relationship between self-reported positive life events and BP in 69 sixth graders with a mean age of 11.7 years. Positive life events were assessed with the Adolescent Perceived Events Scale and resting blood pressure was measured with a mercurial sphygmomanometer. Correlational analyses showed an inverse relationship between positive life events and diastolic BP, suggesting that adolescents experiencing more positive life events were more likely to have lower diastolic BP's. Hierarchical regression analyses revealed that physical activity level, dietary sodium-to-potassium ratio, parental history of hypertension, and measures of body composition predicted 24.6% of the variance in systolic BP and 34.6% of the variance in diastolic BP. Moreover, positive life events predicted an additional 4.3% of the variance in diastolic BP when statistically controlling these established risk factors for hypertension. These results suggest that increased perceptions of positive life events may act as a buffer to elevated BP in adolescents.

Adolescent↗
PubMed1998

Relationship between 800-m running performance and accumulated oxygen deficit in middle-distance runners.

PURPOSE: To determine whether there is a significant relationship between accumulated oxygen deficit (AOD) and 800-m running performance in a group of runners of homogeneous ability. METHODS: Nine well-trained male middle and long distance runners (age = 24.7 +/- 4.5 yr, body mass = 69.4 +/- 8.5 kg, VO2max = 64.8 +/- 4.5 mL.kg-1.min-1) underwent treadmill testing to determine maximum oxygen uptake (VO2max), running economy (RE) at 1% and 10.5% treadmill gradient, and AOD at 1% and 10.5% treadmill gradient; 800-m running performance was determined by time trials on an outdoor 440-yd track, for which the average time was 132 +/- 4 s. For the AOD test, subjects were required to run on the treadmill at supramaximal speeds until volitional exhaustion. The AOD value was calculated using linear (LIN) and curvilinear (CUR) extrapolation procedures. RESULTS: Mean AOD values using LIN and CUR were 45.0 +/- 6.9 and 59.3 +/- 10.1 mL.kg-1 at a 1% treadmill gradient and 63.2 +/- 10.6 and 93.6 +/- 19.7 mL.kg-1 at a 10.5% gradient, respectively. No significant relationship was found between 800-m run time and AOD at 1% gradient or 10.5% gradient or when AOD was estimated from a linear or curvilinear fit of the VO2 data. Other variables measured in this study (e.g., VO2max and running economy) were not found to be predictive of 800-m run time. CONCLUSION: Among a homogeneous group of well-trained male middle- and long-distance runners, AOD measured at a 1% and 10.5% treadmill gradient is not significantly related to 800-m running performance.

Adolescent↗
PubMed1998

Modulation of arachidonic acid metabolism: focus on phospholipase A2(S).

New information has challenged our traditional concepts that the forms and functions of PLA(2) are highly homologous, suggesting now that distinct PLA(2)s may be assigned distinct functions in normal and pathological processes. The nonpancreatic type II 14-kDa PLA(2) and the recently identified type IV "cytosolic" 85-kDa PLA(2) are the two forms most studied in inflammation. Observations in the past suggested that the type II 14-kDa PLA2 is a secreted enzyme that functions extracellularly. Evidence is now emerging that the type II 14-kDa PLA(2) or its recently discovered low-molecular-weight isoforms may be localized and act intracellularly. In view of this, a more complex notion of distinctly functioning PLA(2)s in arachidonic acid release and/or eicosanoid generation can be envisioned. A comparison of the structural and biochemical features of the type II 14-kDa and the 85-kDa PLA(2)s reveals that the enzymes are more distinct than similar. These two enzymes would appear to have distinctly different genetic and biochemical regulatory mechanisms, suggesting that their functions could be quite distinct. Inhibitors of the 14-kDa PLA(2) and to a lesser extent the 85-kDa PLA(2) have been used to obtain a greater understanding of their cellular roles. The concept that the two distinct enzymes might hydrolyze arachidonic acid from different pools and/or supply distinct metabolizing systems in a single cell system has emerged. At this time an intriguing hypothesis can be formed suggesting distinct functional modalities for the two the PLA(2) enzymes in a single cell system. Evidence continues to build implicating the role of the type II 14-kDa PLA(2) in disease, providing a strong rationale for targeting this enzyme in designing novel antiinflammatory therapeutics.

Journal Article↗
PubMed1998

The role of platelet-activating factor (PAF) and the efficacy of ABT-491, a highly potent and selective PAF antagonist, in experimental allergic rhinitis.

Platelet-activating factor (PAF) may be an important mediator of allergic rhinitis. In the present study we evaluated the effectiveness of a recently described PAF antagonist (ABT-491) in rat and guinea pig models of allergic rhinitis. PAF, when perfused through the nasal passages of anesthetized Brown Norway rats, provoked an acute increase, measured as dye leakage, in nasal vascular permeability evident within 15 min after exposure to PAF. ABT-491, given orally 1 hr before PAF challenge, inhibited the response in a dose-related manner (ED50 = 0.3 mg/kg). Intranasal perfusion with ovalbumin in rats sensitized to the antigen 18 to 21 days before challenge also induced an increase in vascular permeability. The antigen-induced leakage was inhibited a maximum of 74% (P < or = .001) by pretreatment with ABT-491 (3 mg/kg p.o.). An antihistamine (mepyramine, 10 mg/kg i.p.), a serotonin antagonist (methysergide) and a 5-lipoxygenase inhibitor (A-79175) also exhibited efficacy in this model (56%, 87% and 65% inhibition, respectively). Nearly complete inhibition (93%, P < or = .001) of the response was achieved by coadministration of ABT-491 and methysergide. In guinea pigs intranasal administration of PAF resulted in increased airway resistance that was inhibited in a dose-dependent manner by oral administration of ABT-491 (ED50 = 1 mg/kg). Antigen-induced nasal airway resistance, triggered by exposure of sensitized animals to aerosolized ovalbumin, was also inhibited by ABT-491 (maximum inhibition 64%, P < or = .05, 10 mg/kg p.o.). The effectiveness of the antagonist was increased to 80% protection by coadministration with either an antihistamine or a 5-lipoxygenase inhibitor, agents which were separately insignificant in blocking the response to antigen. These results suggest a therapeutic utility for ABT-491, perhaps in combination with other anti-inflammatory agents, in the treatment of allergic rhinitis.

Airway Resistance↗
PubMed1998

Violent versus nonviolent stalkers.

Medical records of 42 pretrial detainees charged with stalking in South Carolina from January 1992 to January 1996 were reviewed. The group was divided into 22 nonviolent and 20 violent stalkers. Stalkers were classified as violent if they had associated charges involving bodily harm to their victims or if they met the criteria for South Carolina's legal definition of aggravated stalking. Variables compared included age, sex, marital status, level of education, substance abuse, Axis I diagnosis, military history, organicity, and whether the victim was a casual associate or had a previous attachment to the stalker. There were no statistically significant differences between the groups. Approaching statistical significance was the finding that violent stalkers were more likely to have had a previous attachment to their victims, and nonviolent stalkers were more likely to be casually associated with their victims.

Adult↗
PubMed1998

Capital versus noncapital murderers.

This study compares three groups of murderers: those who have received a death sentence (n = 18), those who were eligible to receive a death sentence but did not have it sought against them (n = 18), and those who were not eligible for the death penalty (n = 18). A retrospective record review of these 54 pretrial detainees in South Carolina who underwent court-ordered competency and criminal responsibility evaluations was completed comparing the following variables: age, race, marital status, educational level, prior legal history, relationship to the victim, race of the victim, existence of a codefendant, prior psychiatric history, psychiatric diagnoses, substance abuse history, use of substances at the time of the crime, Wechsler Adult Intelligence Scale (WAIS) or WAIS-Revised Full Scale IQ, and evidence of organic impairment. Statistically significant findings included race of the murderer, race of the victim, relationship to the victim, and existence of a codefendant. Death row inmates were more likely to be Caucasian and much more likely to have murdered a Caucasian than a non-Caucasian victim. Death row inmates were less likely to know their victims and more likely to have a codefendant. Psychiatric and organic findings did not differ among the groups, but the rate of organic findings and substance abuse was high in all three groups.

Adult↗
PubMed1997

Pharmacology of ABT-491, a highly potent platelet-activating factor receptor antagonist.

ABT-491 (4-ethynyl-N, N-dimethyl-3-[3-fluoro-4-[(2-methyl-1H-imidazo-[4,5-c]pyridin-1-yl)methy l]benzoyl]-1H- indole-1-carboxamide hydrochloride) is a novel PAF (platelet-activating factor) receptor antagonist with a K(i) for inhibiting PAF binding to human platelets of 0.6 nM. Binding kinetics of ABT-491 to the PAF receptor is consistent with a relatively slow off-rate of the antagonist when compared to PAF. Inhibition of PAF binding is selective and is correlated with functional antagonism of PAF-mediated cellular responses (Ca2+ mobilization, priming, and degranulation). Administration of ABT-491 in vivo leads to potent inhibition of PAF-induced inflammatory responses (increased vascular permeability, hypotension, and edema) and PAF-induced lethality. Oral potency (ED50) was between 0.03 and 0.4 mg/kg in rat, mouse, and guinea-pig. When administered intravenously in these species, ABT-491 exhibited ED50 values between 0.005 and 0.016 mg/kg. An oral dose of 0.5 mg/kg in rat provided > 50% protection for 8 h against cutaneous PAF challenge. ABT-491 administered orally was also effective in inhibiting lipopolysaccharide-induced hypotension (ED50 = 0.04 mg/kg), gastrointestinal damage (0.05 mg/kg, 79% inhibition), and lethality (1 mg/kg, 85% vs. 57% survival). The potency of this novel antagonist suggests that ABT-491 will be useful in the treatment of PAF-mediated diseases.

Acute Disease↗
PubMed1997

Ex vivo inhibition of beta-thromboglobulin release following administration to man of ABT-299, a novel prodrug of a potent platelet activating factor antagonist.

OBJECTIVE AND DESIGN: ABT-299 is a prodrug that is converted by serum esterase to a potent platelet activating factor (PAF) antagonist (A-85783). In order to evaluate the pharmacological activity of this antagonist in man the effect of ABT-299 given to healthy volunteers on ex vivo PAF-induced beta-thromboglobulin (beta-TG) release in blood was assessed. SUBJECTS: 37 healthy male volunteers, age 18 to 40 (mean age of 23.6 years) and free of medication, participated in the study. TREATMENT: Subjects were administered intravenously 0.8 mg, 2 mg, or 70 mg doses of ABT-299 (6-7 subjects per group) or placebo (9 subjects, pooled). METHODS: Peripheral blood taken over 12 h after dosing was used for ex vivo beta-TG release and, in the case of the 70 mg dose, measurement of plasma drug concentration. Data were compared by Student's t-test. RESULTS: All three doses produced highly significant inhibition (p < 0.005 compared to predose values) of PAF-induced beta-TG release (units/ml plasma +/- SEM) 12 h after drug administration (54 +/- 14 vs. 405 +/- 51, n = 8; 79 +/- 23 vs. 480 +/- 127, n = 7; 21 +/- 10 vs. 327 +/- 72, n = 6, respectively) whereas there was no significant difference in beta-TG release in the placebo group (449 +/- 90 vs. 307 +/- 49, n = 9). Inhibition was associated with the rapid appearance in plasma of A-85783 and the pyridine N-oxide metabolite of A-85783. Within 2 h, the plasma concentration of the metabolite exceeded that of the parent drug. Both the parent drug and the metabolite exhibited potent in vitro inhibition of PAF-induced beta-TG release (A2 values of 4 and 1 nM respectively). CONCLUSIONS: These studies are the first to illustrate the utility of the beta-TG release assay for assessing ex vivo activity of PAF antagonists. These studies also demonstrate that the administration of ABT-299 to man results in potent, long lasting inhibition of PAF-mediated platelet activation, due in part to the pyridine-N-oxide metabolite, and support the potential therapeutic utility of this prodrug in treating PAF-mediated diseases.

Adolescent↗
PubMed1997

Stalkers: the South Carolina experience.

Medical records of 18 pretrial detainees charged with stalking were evaluated at a forensic unit in Columbia, South Carolina from January 1992 to December 1994 and their records were compared with those of 18 offenders in the same unit randomly matched for sex, race, and whether associated crimes were violent or not. Compared variables included age, marital status, level of education, substance abuse, Axis I diagnosis, prior psychiatric hospitalizations, military history, and organicity. Significant findings show that alleged stalkers were better educated, less likely to be married or to abuse substances, and more likely to have military training and organicity when compared with other offenders. The prototypical stalker in this study is a single, educated male who is likely to have military training as well as some degree of organicity. He is less likely than other offenders to abuse substances. Replication studies are needed.

Adolescent↗