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Biomedical subjects

J S Kennedy

Publications and source records attributed to J S Kennedy.

At least 19 recordsLinked to original sources
PubMed2001

Potent antagonism of 5-HT(3) and 5-HT(6) receptors by olanzapine.

The interaction of the psychotropic agent olanzapine with serotonin 5-HT(3) and 5-HT(6) receptors was investigated. Olanzapine did not contract the isolated guinea pig ileum, but blocked contractions induced by the 5-HT(3) receptor agonist 2-methyl serotonin (2-CH(3) 5-HT) with a pK(B) value of 6.38+/-0.03, close to the affinity of the 5-HT(3) receptor antagonist ondansetron. The atypical antipsychotic risperidone (1 microM) did not significantly inhibit 2-CH(3) 5-HT-induced contractions. Olanzapine had high affinity (pK(i)=8.30+/-0.06) for human 5-HT(6) receptors in radioligand binding studies. Olanzapine did not stimulate [35S]guanosine-5'-O-(3-thio)triphosphate ([35S]GTPgammaS) binding to the G protein G(s) in cells containing human 5-HT(6) receptors, but inhibited 5-HT-stimulated [35S]GTPgammaS binding (pK(B)=7.38+/-0.16). Among other antipsychotics investigated, clozapine antagonized 5-HT(6) receptors with a pK(B)=7.42+/-0.15, ziprasidone was three-fold less potent, and risperidone, quetiapine and haloperidol were weak antagonists. Thus, olanzapine was not an agonist, but was a potent antagonist at 5-HT(6) receptors and had marked antagonism at 5-HT(3) receptors.

Animals↗
PubMed2001

The central cholinergic system profile of olanzapine compared with placebo in Alzheimer's disease.

OBJECTIVE: The objective of this analysis was to compare the treatment-emergent central anticholinergic-like adverse events experienced during treatment with olanzapine versus placebo in patients with psychosis and/or agitation due to Alzheimer's disease (AD). In addition, changes in cognition were assessed in a subgroup of patients with mild to moderate cognitive impairment. METHODS: Double-blind data were compared for placebo and three fixed olanzapine dosages (5 mg/day, 10 mg/day, and 15 mg/day) in 206 nursing home-residing patients with AD for five a priori selected central nervous system anticholinergic-like adverse events: confusion, delirium, delusions, hallucinations, abnormal thinking. Mean change from baseline to endpoint on the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog) was measured for a subgroup of 43 patients who had mild to moderate cognitive impairment at baseline. RESULTS: There were no significant differences in central anticholinergic-like adverse events at any olanzapine dose compared to placebo. Additionally, in the 43-patient subgroup, there were no significant differences in mean change in ADAS-Cog scores between placebo and the three olanzapine dose subgroups. CONCLUSION: Olanzapine did not differ significantly from placebo for any of the five central nervous system anticholinergic events nor on the ADAS-Cog. Olanzapine's initially reported potent in vitro muscarinic receptor affinity is not consistent with this clinical study of central nervous system anticholinergic-like adverse events in patients with AD.

Aged↗
PubMed2001

A current review of olanzapine's safety in the geriatric patient: from pre-clinical pharmacology to clinical data.

OBJECTIVE: Olanzapine (OLZ) is unique among currently available antipsychotic medications in its antagonism of a range of receptor systems including dopamine, norepinephrine, serotonin, acetylcholine, and histamine. Olanzapine's mechanistic complexity provides a broad efficacy profile in patients with schizophrenia and acute, pure or mixed mania. Patients experience symptomatic relief of mania, anxiety, hallucinations, delusions, and agitation/aggression and reduced depressive, negative, and some cognitive symptoms. This paper will review the safety profile of OLZ, focusing on the elderly, where data are available. METHOD: Preclinical and clinical studies of OLZ are reviewed, with emphasis on its possible effects on the cholinergic system and the histamine H(1) receptor. Weight change and related metabolic considerations, cardiac and cardiovascular safety, and motor function during treatment with OLZ are also reviewed. RESULTS AND CONCLUSION: In vitro receptor characterization methods, when done using physiologically relevant conditions allow accurate prediction of the relatively low rate of anticholinergic-like adverse events, extrapyramidal symptoms, and cardiovascular adverse events during treatment with OLZ. Currently available clinical data suggest olanzapine is predictably safe in treating adult patients of any age with schizophrenia and acute bipolar mania, as well as in treatment of patients with some types of neurodegenerative disorders.

Adverse Drug Reaction Reporting Systems↗
PubMed1999

Signaling scaffolds in immune cells.

Of the past several years progress in understanding TCR signal transduction has led to the discovery of new kinases, adapter molecules and multiple signaling pathways. The study of molecules such as LAT, SLP-76, FYB, SKAP-55 and VAV have revealed multiple mechanisms with which to control the activation of downstream signaling pathways through RAS, PLC gamma-1 and ERK/MAPK. Signaling through SLP-76 can play a role in TCR-induced cytoskeleton changes through activation of effector molecules in the RAC/RHO-family of GTPases. In addition, SLP-76 through its association with FYB/FYN-T appears to play a role in IL-2 gene transcription following TCR activation. Finally, these newly identified adaptor molecules, such as LAT, may be crucial in T-cell activation by enhancing the recruitment of critical kinases to glycolipid-enriched microdomains of the activated T-cell receptor complex.

Animals↗
PubMed1999

Preferential cerebrospinal fluid acetylcholinesterase inhibition by rivastigmine in humans.

This study sought to examine the feasibility of prolonged assessment of acetylcholinesterase (AChE) activity in the cerebrospinal fluid (CSF) of volunteers and to test the hypothesis that rivastigmine (ENA-713; Exelon, Novartis Pharma AG, Basel, Switzerland) selectively inhibits AChE in CSF in humans at a dose producing minimal inhibition of the peripheral enzyme. Lumbar CSF samples were collected continuously (0.1 mL x min(-1)) for 49 hours from eight healthy volunteers who took either placebo or a single oral dose of rivastigmine (3 mg). CSF specimens and samples of blood cells and blood plasma were analyzed at intervals for rivastigmine and its metabolite NAP 226-90 ([-] [3-([1-dimethylaminolethyl)-phenol]), erythrocyte AChE activity, CSF AChE activity, and plasma and CSF butyrylcholinesterase (BuChE) activity. Safety evaluations were performed 23 hours after drug dosing and at the end of the study. Evaluable data were obtained from six subjects. The mean time to maximal rivastigmine plasma concentration (tmax) was 0.83 +/- 0.26 hours, the mean maximal plasma concentration (Cmax) was 4.88 +/- 3.82 ng x mL(-1), the mean plasma area under the concentration versus time curve (AUC0-infinity) was 7.43 +/- 4.74 ng x hr x mL(-1), and the mean plasma t1/2 was 0.85 +/- 0.115 hours. The concentration of rivastigmine in CSF was lower than the quantification limit for assay (0.65 ng x mL(-1)), but NAP 226-90 reached a mean Cmax of 3.14 +/- 0.57 ng x mL(-1). Only minimal inhibition of erythrocyte AChE activity (approximately 3%) was observed. Inhibition of AChE in the CSF after rivastigmine administration was significantly greater than after placebo for up to 8.4 hours after the dose and was maximal (40%) at 2.4 hours. Plasma BuChE activity was significantly lower after rivastigmine than after placebo, but this was not clinically relevant. BuChE activity in CSF was significantly lower after rivastigmine than after placebo for up to 3.6 hours after dosing, but this difference was not sustained. This study confirms the feasibility of using continuous measurement of AChE activity in CSF over prolonged periods, that rivastigmine markedly inhibits CSF AChE after a single oral dose of 3 mg, and that the inhibition of central AChE is substantially greater than that of peripheral AChE or BuChE.

Acetylcholinesterase↗
PubMed1999

Treatment of major depression with nortriptyline and paroxetine in patients with ischemic heart disease.

OBJECTIVE: This study compared the efficacy, tolerability, and safety of paroxetine and nortriptyline in depressed patients with ischemic heart disease. METHOD: After a 2-week, single-blind placebo lead-in phase, 81 outpatients with DSM-III-R-defined nonpsychotic unipolar major depression and ischemic heart disease were randomly assigned to double-blind treatment with paroxetine or nortriptyline for 6 weeks. Paroxetine was administered at a fixed-flexible dose of 20-30 mg/day. Nortriptyline dose was adjusted with the use of blood-level monitoring to reach a plasma concentration of 50-150 ng/ml. RESULTS: Twenty-seven of the 41 patients who started treatment with paroxetine and 29 of the 40 patients who started treatment with nortriptyline had an improvement of at least 50% in their Hamilton Depression Rating Scale scores. Significantly more patients taking nortriptyline discontinued treatment prematurely (35% versus 10%), and more patients taking nortriptyline had adverse events resulting in termination (25% versus 5%). CONCLUSIONS: Both treatments were efficacious. Sixty-three percent of all patients improved at least 50%, and of these, 90% met the criteria for remission. Paroxetine was better tolerated than nortriptyline and less likely to produce cardiovascular side effects.

Adult↗
PubMed1998

Comparison of paroxetine and nortriptyline in depressed patients with ischemic heart disease.

CONTEXT: Depression and ischemic heart disease often are comorbid conditions and, in patients who have had a myocardial infarction, the presence of depression is associated with increased mortality. Patients with heart disease need a safe and effective treatment for depression. OBJECTIVE: To compare the efficacy, cardiovascular effects, and safety of a specific serotonin reuptake inhibitor, paroxetine, with a tricyclic antidepressant, nortriptyline hydrochloride, in depressed patients with ischemic heart disease. DESIGN: Two-week placebo lead-in followed by a double-blind randomized 6-week medication trial. SETTING: Research clinics in 4 university centers. PATIENTS: Eighty-one outpatients meeting Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for major depressive disorder and with documented ischemic heart disease. INTERVENTIONS: Treatment with either paroxetine, 20 to 30 mg/d, or nortriptyline targeted to a therapeutic plasma level, 190 to 570 nmol/L (50-150 ng/mL), for 6 weeks. MAIN OUTCOME MEASURES: For effectiveness of treatment, a decline in the score of the Hamilton Rating Scale for Depression by 50% and final score of 8 or less; for cardiovascular safety, heart rate and rhythm, supine and standing systolic and diastolic blood pressures, electrocardiogram conduction intervals, indexes of heart rate variability, and rate of adverse events. RESULTS: By intent-to-treat analysis, 25 (61%) of 41 patients improved during treatment with paroxetine and 22 (55%) of 40 improved with nortriptyline. Neither drug significantly affected blood pressure or conduction intervals. Paroxetine had no sustained effects on heart rate or rhythm or indexes of heart rate variability, whereas patients treated with nortriptyline had a sustained 11% increase in heart rate from a mean of 75 to 83 beats per minute (P<.001) and a reduction in heart rate variability, as measured by the SD of all normal R-R intervals over a 24-hour period, from 112 to 96 (P<.01). Adverse cardiac events occurred in 1 (2%) of 41 patients treated with paroxetine and 7 (18%) of 40 patients treated with nortriptyline (P<.03). CONCLUSIONS: Paroxetine and nortriptyline are effective treatments for depressed patients with ischemic heart disease. Nortriptyline treatment was associated with a significantly higher rate of serious adverse cardiac events compared with paroxetine.

Adrenergic Uptake Inhibitors↗
PubMed1998

High-burst-strength, feedback-controlled bipolar vessel sealing.

BACKGROUND: The inherent tedium of intracorporeal knot tying has stimulated greater interest in energy-based and mechanical alternatives for hemostasis. METHODS: Three hundred thirty-one arteries and veins were sealed by application of precisely controlled electrothermal energy and physical pressure, allowing for brief cooling in compression, in experimental animals and fresh abattoir vessels. These seals were compared for bursting strength with occlusions by ultrasonic and bipolar coagulation, surgical clips, and ligatures. RESULTS: Ultrasonic and bipolar occlusions were significantly less likely to have burst strengths greater than 400 mmHg as compared with seals, clips, and ligatures (p < 0.001). Seal competence could be visually assessed by its translucence. CONCLUSIONS: Precise energy control with physical compression, including a brief cooldown, produces a distinctive, translucent seal of partially denatured protein that can typically be transected after a single application. These seals have bursting strengths comparable to those of clips and ligatures and resist dislodgement because they are intrinsic to the vessel wall structure.

Animals↗
PubMed1998

Feasibility of retrospective assessments of behavioral symptoms in Alzheimer's disease: a preliminary study of postmortem caregiver reports.

Studies of the behavioral symptoms in Alzheimer's disease (AD) would be facilitated if reliable reports could be obtained retrospectively, especially about symptoms in the final months of life when concurrent assessment is often not feasible. To evaluate such a method, we compared results of a telephone interview conducted after the patient's death with information provided by the same informant earlier, while the patient was living. Agreement between in-life and retrospective assessments was higher for psychotic symptoms than for depressive behaviors, suggesting that retrospective assessment of specific behavioral symptoms in AD is not uniformly reliable. More symptoms were retrospectively reported as the length of time between the last in-life evaluation and date of death increased, suggesting that there may be increased variety of behavioral symptoms observed by caregivers in the final stages of the disease.

Aged↗
PubMed1996

Clinical, hematologic, and immunologic effects of interleukin-10 in humans.

We conducted a double-blind, placebo-controlled study to investigate the safety, pharmacokinetics, and immunological properties of interleukin-10 (IL-10) administration in healthy humans. Volunteers received a single intravenous bolus injection of recombinant human IL-10 (1, 10, or 25 micrograms/kg) or placebo. Cytokine production in whole blood and peripheral blood mononuclear cells (PBMC) was assessed before and 3, 6, 24, and 48 hr after the injection. Peak serum concentrations of IL-10 (15 +/- 1.1, 208 +/- 20.1, and 505 +/- 22.3 ng/ml) occurred after 2-5 min for 1, 10, and 25 micrograms/kg IL-10, respectively. The terminal-phase half-life was 3.18 hr. A transient leukocytosis (24-63% above baseline) was observed 6 hr after injection, which coincided with a dose-dependent decrease (12-24%) in neutrophil superoxide generation. There was a marked inhibition (60-95%) of endotoxin-induced IL-6 production from whole blood in each group receiving IL-10. Production of IL-8 in endotoxin-stimulated blood was reduced in the 10 micrograms/kg group. In PBMC stimulated with phytohemagglutinin and phorbol ester, there was a decrease (72-87%) in interferon-gamma (IFN gamma) production 6 hr after IL-10 with a return to pre-IL-10 levels after 24 hr. This reduction was only partially associated with a decrease in the number of CD2-bearing cells. We conclude that IL-10 administration into humans is without significant side effects, and a single injection reduces ex vivo production of IL-6, IL-8, and IFN gamma.

Adolescent↗
PubMed1995

A randomized, controlled trial of IL-10 in humans. Inhibition of inflammatory cytokine production and immune responses.

In vitro, IL-10 inhibits T cell proliferation and LPS-induced monocyte production of IL-1, TNF-alpha, IL-6, and IL-8. We studied the safety and immunomodulatory effects of IL-10 administration in humans. Seventeen healthy volunteers received a single i.v. bolus injection of either human IL-10 (1, 10, or 25 micrograms/kg) or placebo. Routine safety parameters, lymphocyte phenotypes, T cell proliferative responses, and stimulus-induced cytokine production were assessed before and 3, 6, 24, and 48 h after injection. There were no adverse symptoms or signs after IL-10 administration. A transient neutrophilia and monocytosis that peaked at 6 h (45-160% above base line) was observed. However, lymphocyte counts fell by 25% 3 and 6 h after the injection (p < 0.01). In particular, lymphocytes expressing the T cell surface markers CD2, CD3, CD4, CD7, and CD8 were significantly decreased. Mitogen-induced T cell proliferation was suppressed by up to 50% (p < 0.01) in the two higher dose groups. Significant dose-dependent inhibition (65-95%) of TNF-alpha and IL-1 beta production from whole blood stimulated ex vivo with endotoxin occurred after each dose of IL-10. In contrast, there was no reduction in the production of their respective antagonists, TNF soluble receptor p55 or IL-1 receptor antagonist. We conclude that a single intravenous injection of IL-10 is safe in humans, has inhibitory effects on T cells, and suppresses production of the pro-inflammatory cytokines TNF-alpha and IL-1 beta.

Adolescent↗
PubMed1993

The relationship of clinical psychopathologic rating and cognitive factors to clinical dementia staging.

1. Sixty-six patients were assessed by one of three physicians employing CERAD assessment and were staged by CDR criteria. 2. The same day, trained raters completed the Brief Psychiatric Rating Scale, the Cornell Scale for Depression in Dementia and the Mini-mental State Examination. 3. Clinician's Global Rating of the CDR is strongly related to the Mini-mental State Examination Score. 4. The CDR is insensitive to mild psychopathology in this population.

Alzheimer Disease↗
PubMed1992

A technique for extracorporeal suturing.

Advances in laparoscopic surgical procedures will be facilitated by the ability to perform suturing efficiently and effectively. A simple technique of extracorporeal suturing is described, which permits rapid and reliable knot placement for a wide variety of laparoscopic procedures.

Humans↗
PubMed1991

Validity of self-reports of caffeine use.

The relationship between self-reports of caffeine ingestion on two occasions and measured plasma concentrations of caffeine and its major metabolites was examined. A subject population [25 men and 25 women, age 20-45 years (mean: 28.7 yr)] that was enrolled in a benzodiazepine pharmacokinetic study underwent general medical screening on two occasions, each including detailed caffeine histories. Before beginning their scheduled study, plasma samples were obtained and evaluated by HPLC for caffeine, paraxanthine, theophylline, and theobromine. These values were compared with estimates of caffeine consumption in mg/day generated from both histories. There was no significant difference between plasma levels of caffeine, metabolites, or caffeine plus metabolites for categories corresponding to reports of low, intermediate or high caffeine use. A self-reported caffeine consumption of greater than 300 mg/day (high) did correlate, however, with a significant smoking history. The authors conclude that self-reports of caffeine ingestion do not accurately reflect acute exposure, and that if caffeine use is of importance in a given setting, reports should be confirmed by biochemical means.

Adult↗
PubMed1990

On the application of a constitutive equation for whole human blood.

In consideration of the pulsatile blood flow in a conduit, the constitutive equation for the whole human blood of F. J. Walburn and D. J. Schneck (Biorheology, Vol. 13, 1976, pp. 201-210) is utilized. Governing equations are solved numerically yielding the velocity and the shear stress distributions. These results are discussed and compared with the Newtonian fluid, Casson's fluid, and Bingham fluid applications.

Blood Flow Velocity↗