Search PubMed⌕ Search

Biomedical subjects

J S Kerr

Publications and source records attributed to J S Kerr.

At least 19 recordsLinked to original sources
PubMed2002

Acute dystonic reaction in an elderly patient with mood disorder after titration of paroxetine: possible mechanisms and implications for clinical care.

The administration of a serotonin reuptake inhibitor may lead to extra pyramidal signs, as reported in the literature. The risk seems to be increased in elderly people. We describe a case of acute dystonic reaction to paroxetine treatment in an elderly patient, who presented with a bipolar affective disorder. The underlying mechanism, possibly generated in the subcortical motor areas, is linked to changes that occur in the pharmacokinetic variables, the decreased neuroplasticity of ageing neurones and to previous exposure to neuroleptic medications.

Aged↗
PubMed2001

Alpha(v)beta(3) integrin in angiogenesis and restenosis.

Various integrins are thought to be intimately involved in several pathological processes, including cancers (solid tumors and metastasis), cardiovascular diseases (stroke and heart failure), inflammatory diseases (rheumatoid arthritis) and ocular pathologies. The mechanism of the involvement of integrins in these acute and chronic disease states is slowly being elucidated. Recently, various therapeutic candidates, including antibodies, cyclic peptides and peptidomimetics, have been clinically evaluated and have been shown to successfully modulate certain disease processes. This review focuses on the key role of the alpha(v) integrin (alpha(v)beta(3)) in the angiogenic processes in diseases such as cancer, restenosis following percutaneous transluminal coronary angioplasty, stroke, ocular disease and rheumatoid arthritis.

Journal Article↗
PubMed2000

Antiangiogenesis efficacy of nitric oxide donors.

Angiogenesis is a complex process involving endothelial cell migration, proliferation, invasion, and tube formation. Inhibition of these processes might have implications in various angiogenesis-mediated disorders. Because nitric oxide (NO) is known to play a key role in various vascular diseases, the present study was undertaken to determine the role of NO in angiogenesis-mediated processes using the NO donor, S-nitroso N-acetyl penicillamine (SNAP) and S-nitroso N-acetyl glutathione (SNAG). The antiangiogenic efficacy of these NO donors was examined using in vivo and in vitro model systems. The in vitro studies demonstrated the ability of SNAP to inhibit cytokine fibroblast growth factor (FGF2)-stimulated tube formation and serum-induced cell proliferation. The inhibitory effect on cell proliferation by SNAP concentrations above the millimolar range was associated with significant shifts in the concentration of NO metabolites. Furthermore, using the mouse Matrigel implant model and the chick chorioallantoic membrane (CAM) models, SNAP demonstrated maximal inhibitory efficacy (85-95% inhibition) of cytokine (FGF2)-induced neovascularization in both in vivo models. SNAP and SNAG resulted in 85% inhibition of FGF2-induced neovascularization in the mouse Matrigel model when given at 5 mg/kg/day infusion in minipumps during 14 days and 87% inhibition of angiogenesis induced by FGF2 in the CAM when administered a single dose of 50 microg. Thus, NO donors might be a useful tool for the inhibition of angiogenesis associated with human tumor growth, or neovascular, ocular, and inflammatory diseases.

Angiogenesis Inhibitors↗
PubMed2000

Small molecule alpha(v) integrin antagonists: novel anticancer agents.

The members of the integrin family are targets that potentially provide both therapeutic and diagnostic opportunities. Advances in the understanding of the signalling pathways, transcriptional regulation and the structure/function relationships of the adhesion molecules to extracellular matrix proteins have all contributed to these opportunities. The role of the integrins in pathological processes in both acute and chronic diseases, include ocular, cancer (solid tumours and metastasis), cardiovascular (stroke and heart failure) and inflammatory (rheumatoid arthritis) conditions. Various therapeutic candidates, including antibodies, cyclic peptides and peptidomimetics, have been identified. This review will focus on the key role of the alpha(v) integrin (alpha(v)beta(3) and alpha(v)beta(5)) in angiogenic processes in tumours, including its potential use in cancer diagnostics and therapy.

Angiogenesis Inhibitors↗
PubMed2000

Tumor biology: use of tiled images in conjunction with measurements of cellular proliferation and death in response to drug treatments.

Tumor growth is dependent on the balance between cell proliferation and cell death, and these events occur heterogenously within an individual tumor. We present a methodology that provides integrative information about cell kinetics, cell death, and cell growth within individual tumors in animals treated with cytotoxic chemotherapeutic agents. Using HCT-116 and NCI-H460 cells, human colonic adenocarcinoma and non-small cell lung cells, respectively, traditional xenograft studies were performed. The tumor-bearing animals were treated with cyclophosphamide (Cytoxan), gemcitabine (Gemzar), or mitomycin C, and extensive analysis of the tumors was studied. Cell kinetics were evaluated by measuring the apoptotic and proliferation indices. The ability to image an entire tumor section using "tiling" by creating a large montage from many high-resolution images makes it possible to identify regional differences within areas of tumor and to demonstrate differences in these tumor regions after treatment with selected chemotherapeutic agents. Two specific areas within tumors have been identified: (a) areas of viable cells within the cell cycle, determined by bromodeoxyuridine and/or morphological characteristics determined by hematoxylin staining; and (b) areas of necrosis determined by the absence of bromodeoxyuridine and proliferating cell nuclear antigen-labeled cells coupled with morphological changes. By standardizing the tumor size to 100 mm2, different patterns of tumor responses to chemotherapeutic agents were determined. By creating such tiled images and by quantitating cell cycle kinetics, it is possible to gain a more complete understanding of tumor growth and response to treatment, leading to the development of more reliable methods for assessing the clinical behavior of anticancer drugs.

Adenocarcinoma↗
PubMed1997

The characterization of potent novel warfarin analogs.

Racemic sodium warfarin, Coumadin, is widely used in the prevention of thromboembolic disease. The present study was undertaken to characterize three novel classes of warfarin analogs, and to compare them with the warfarin enantiomers. All three classes of compounds inhibit vitamin K epoxide reductase, the enzyme inhibited by racemic warfarin. The alcohol and the ester analogs have reduced protein binding compared with R-(+)-warfarin. The ester and the fluoro-derivatives have similar in vivo anticoagulant activity in the rat to that of S-(-)-warfarin. Thus, it is possible to synthesize novel warfarin analogs that differ from racemic warfarin or its enantiomers in certain selected properties.

Animals↗
PubMed1997

Involvement of endothelial PECAM-1/CD31 in angiogenesis.

The adhesive interactions of endothelial cells with each other and the adhesion receptors that mediate these interactions are probably of fundamental importance to the process of angiogenesis. We therefore studied the effect of inhibiting the function of the endothelial cell-cell adhesion molecule, PECAM-1/ CD31, in rat and murine models of angiogenesis. A polyclonal antibody to human PECAM-1, which cross-reacts with rat PECAM-1, was found to block in vitro tube formation by rat capillary endothelial cells and cytokine-induced rat corneal neovascularization. In mice, two monoclonal antibodies against murine PECAM-1 prevented vessel growth into subcutaneously implanted gels supplemented with basic fibroblast growth factor (bFGF). Taken together these findings provide evidence that PECAM-1 is involved in angiogenesis and suggest that the interactions of endothelial cell-cell adhesion molecules are important in the formation of new vessels.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1996

The effects of reboxetine and amitriptyline, with and without alcohol on cognitive function and psychomotor performance.

Reboxetine is a novel antidepressant that has been shown to be effective in the treatment of major depressive disorders. The present experiment was designed to assess whether it affects the cognitive and psychomotor skills necessary for optimum function in everyday life. Ten healthy male volunteers received reboxetine 0.5 mg, 1 mg or 4 mg, amitriptyline 25 mg, or matched placebo with and without alcohol (0.6 mg kg-1) in a double-blind 10-way crossover study. A psychometric test battery was administered at baseline and at 1, 2.25, 3.5, 6 and 9 h post-dose. The results showed that reboxetine had little or no effect on performance at any dose, compared with placebo. Amitriptyline, however, with and without alcohol, lowered critical flicker fusion threshold compared with placebo and/or reboxetine at all test points (e.g. at 3.5 h: 28.51 vs 30.33 Hz; P < 0.05); increased reaction time (e.g. 619 vs 540 ms; P < 0.05); increased tracking error (e.g. 16.34 vs 8.54 RMS units; P < 0.05); and slowed short-term memory scanning (e.g. 742 vs 590 ms; P < 0.05). It is concluded that reboxetine at doses of 4 mg and below is free from disruptive effects on cognitive function and psychomotor performance, and that it does not act synergistically with alcohol, in contrast to amitriptyline.

Adolescent↗
PubMed1995

Early murine Lyme carditis has a macrophage predominance and is independent of major histocompatibility complex class II-CD4+ T cell interactions.

To compare the role of macrophages and CD4+ T lymphocytes in early Lyme carditis, immunohistochemical techniques were used to analyze cardiac infiltrates in immunocompetent mice infected with Borrelia burgdorferi spirochetes. Macrophages predominated in the infiltrate during the first 4 weeks after infection. CD4+ and CD8+ lymphocytes each constituted < 5% of the infiltrate; B lymphocytes were rare. Infected mice deficient in class II major histocompatibility complex (MHC) antigen and depleted of CD4+ lymphocytes developed similar infiltrates, suggesting that class II MHC-CD4+ lymphocyte interactions do not play a critical role in disease initiation. Expression of mRNA encoding JE within areas of cardiac inflammation implicates this chemokine in the recruitment and activation of macrophages in this disease. These data demonstrate that early murine Lyme carditis requires neither class II antigen expression nor presentation of antigen to CD4+ T lymphocytes and suggest a direct response of macrophages to cardiac tissue invasion by B. burgdorferi.

Animals↗
PubMed1994

EDU pretreatment decreases polymorphonuclear leukocyte migration into rat lung airways.

Pretreatment with the heterocyclic compound EDU (N-[2-(2-oxo-1-imidazolindinyl)ethyl]-N'-phenylurea) has previously been shown to reduce polymorphonuclear leukocyte (PMN) infiltration into the airways of ozone-exposed rats. The present study further examined the effects of 1 and 2 days EDU pretreatment on rat lung inflammatory responses by determining PMN infiltration in response to intratracheal instillation with the chemoattractant formyl-norleucine-leucine-phenylalanine (fNLP). Maximal recovery of PMNs by bronchoalveolar lavage was observed 4 hr after fNLP instillation with no alteration in the numbers of recoverable macrophages and lymphocytes. Although 1-day pretreatment with EDU did not affect PMN recovery from fNLP-instilled rat lungs, 2 days of EDU pretreatment prevented PMN infiltration as indicated by PMN recoveries that were similar to those obtained from saline-instilled lungs. Measurements of lung-marginated and interstitial pools of inflammatory cells using collagenase tissue digestion demonstrated no effect of 2 days EDU pretreatment. Although 2 days EDU pretreatment alone did not alter blood PMN content, lung permeability, and the lavage recoveries of inflammatory cells, blood PMN responses to chemotactic stimuli in vitro were impaired. In addition, EDU was shown to directly inhibit PMN chemotaxis and superoxide anion generation in vitro. These data demonstrated that EDU acts by interfering with PMN activation and migration rather than by decreasing PMN availability. EDU, by modulating the inflammatory response, represents a useful compound for preventing PMN-associated amplification of acute lung injuries.

Animals↗
PubMed1994

The psychomotor and cognitive effects of a new antihistamine, mizolastine, compared to terfenadine, triprolidine and placebo in healthy volunteers.

Eighteen healthy volunteers received mizolastine 5 mg, 15 mg or 45 mg, terfenadine 60 mg, triprolidine 10 mg or placebo in a 6-way crossover, double blind study. Following each dose, subjects performed a series of tests of cognitive function and psychomotor performance at 1, 3, 5, 8 and 24 hours post-dose. The test battery included critical flicker fusion, choice reaction time, tracking, Stroop and Sternberg memory tests and assessment of subjective sedation. Sedative effects and a concomitant reduction in psychomotor and cognitive function were observed following triprolidine, terfenadine and the highest dose of mizolastine, 45 mg, e.g. triprolidine reduced CFF threshold by 1.5 Hz and increased reaction time by 50 ms, impairments comparable to those caused by blood alcohol concentrations of 50 mg%, the legal limit in many countries. Mizolastine 5 mg did not differ significantly from placebo and at 15 mg differed only at one test point at one time. It may be concluded that mizolastine (5 mg and 15 mg) is free from disruptive effects on cognitive function and psychomotor performance, in contrast to terfenadine 60 mg, triprolidine 10 mg and mizolastine 45 mg.

Adolescent↗
PubMed1994

EDU decreases polymorphonuclear leukocyte production of reactive oxygen intermediates.

The ability of the heterocyclic compound EDU (N-[2-(2-oxo-1-imidazolindinyl)-ethyl]-N'-phenylurea) to affect polymorphonuclear leukocyte (PMNL) activation was examined by measuring superoxide anion, hydrogen peroxide and hydroxyl radical release from human PMNLs stimulated by phorbol ester. Results demonstrated that EDU effectively interferes with PMNLs reactive oxygen intermediate production, making it a potentially useful compound to be used to modulate PMNL-associated oxidant damage of inflamed tissues.

Antioxidants↗
PubMed1993

2'-substituted chalcone derivatives as inhibitors of interleukin-1 biosynthesis.

A series of 2'-substituted chalcone derivatives has been found to show potent inhibition of the production of IL-1 beta from human peripheral blood monocytes stimulated with lipopolysaccharide (LPS), with IC50 values in the 0.2-5.0-microM range. Some members of the series have also shown inhibition of septic shock induced in mice by injection of LPS, although with low potency. Qualitative structure-activity relationships have shown that the enone is required for activity, which may be mediated by conjugate addition of a biological nucleophile to the chalcone. Electron-poor aromatic rings beta to the ketone give enhanced potency. Although electronic effects in the other ring (directly attached to the ketone) are minimal, this ring must possess an ortho substituent for good activity without cytotoxicity, suggesting a degree of selectivity which would not be expected for simple, nonspecific alkylating agents.

Animals↗
PubMed1993

Amnestic effects of triazolam and other hypnotics.

1. The effects of a number of hypnotics were compared to a range of results collected for triazolam on objective measures of CNS sedation (critical flicker fusion) and short-term memory function (memory scanning). 2. Assessments taken after the drugs had been administered but prior to the onset of sleep showed that in comparison to placebo most of the compounds were effective sedatives and this correlated highly (r = 0.734, p < 0.04) with amnestic effects found at the same time, suggesting that general CNS sedation is a major component of anterograde amnesia. 3. Residual effects assessed the morning after the hypnotics had been used showed a similar relationship (r = 0.896, p < 0.005). 4. The distribution of results indicates that 0.25 mg triazolam has an acute amnestic profile which is similar to other hypnotics, but possesses a distinct lack of residual effects.

Adolescent↗
PubMed1993

The effects of moclobemide on psychomotor performance and cognitive function.

Sixteen young male volunteers received single doses of moclobemide 200 mg, moclobemide 400 mg, amitriptyline 50 mg and placebo in a double-blind crossover study. Subjects then completed a test battery which is sensitive to the effects of psychoactive drugs at 1, 2, and 4 h post-dose. The test battery included tasks of choice reaction time, tracking, critical flicker fusion threshold and memory scanning. Subjective feelings were assessed using the Leeds sleep evaluation questionnaire (LSEQ) and line analogue rating scales (LARS). The results show that the positive internal control (amitriptyline) has a sedative effect in that it increased critical flicker fusion threshold, reaction time and tracking error. Moclobemide 400 mg increased reaction time in the tracking task but neither dose of moclobemide impaired psychomotor performance or cognitive ability in any of the other tests.

Adult↗