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N J Macdonald

Publications and source records attributed to N J Macdonald.

12 recordsLinked to original sources
PubMed2000

Tumor necrosis factor-alpha and nerve growth factor synergistically induce iNOS in pheochromocytoma cells.

Inducible nitric oxide synthase (iNOS) has been reported in tangle-bearing neurons of patients with Alzheimer's disease (AD), and can be induced by tumor necrosis factor-alpha (TNFalpha). High CNS levels of TNFalpha are associated with neurodegenerative diseases such as AD, where neurons dependent on neurotrophins such as nerve growth factor (NGF) are particularly affected. In this study we determined the effect of TNFalpha on iNOS in NGF-responsive pheochromocytoma (PC12) cells. We found that while TNFalpha and NGF alone were unable to induce iNOS, their simultaneous addition resulted in iNOS induction and the release of nitric oxide. Our results suggest that synergistic iNOS induction by TNFalpha and NGF may occur in selective population of NGF-responsive neurons in the presence of elevated CNS levels of TNFalpha.

Adrenal Gland Neoplasms↗
PubMed2000

Cytokine/neurotrophin interaction in the aged central nervous system.

Age-associated neurodegenerative diseases such as Alzheimer's disease are characterised by neuronal impairment that leads to cognitive deficits. As certain affected neurons depend on trophic factors such as neurotrophins (NTs), impairment in NT function has been suggested to be a component of neuronal damage associated with such disorders. Age-related neurodegenerative diseases are also characterised by high levels of proinflammatory cytokines such as tumour necrosis factor alpha (TNFalpha) in the CNS. Because TNFalpha receptors and certain NT receptors share a high degree of homology and are capable of activating similar signalling pathways, one possibility is that altered cytokine levels may affect NT function in the aged or diseased CNS. Here we wish briefly to review the evidence suggesting a role for cytokine and NT in the onset of age-associated neurodegenerative diseases. We propose that cytokine/NT interactions may alter neuronal homeostasis, thus possibly contributing to some of the neuronal degeneration occurring during such age-associated CNS diseases.

Aged↗
PubMed1999

NGF-resistant PC12 cell death induced by arachidonic acid is accompanied by a decrease of active PKC zeta and nuclear factor kappa B.

Inflammation and the associated release of inflammatory cytokines such as tumor necrosis factor alpha (TNFalpha) may be a component of neurodegenerative diseases associated with aging or chronic HIV-1 infection. Most of the neurons that are affected under these conditions require a constant supply of trophic factors such as nerve growth factor (NGF) for survival. NGF acts via binding to a specific tyrosine kinase receptor (TrkA). NGF also binds to the common neurotrophin receptor (p75(NTR)), a member of the TNFalpha receptor (TNFR-I) superfamily, whose function may be to modulate apoptosis via the release of ceramide and the activation of the transcription factor nuclear factor kappa B (NFkappaB). The similarity between p75(NTR) and TNFR-I signal transduction pathways suggests that one of the mechanisms by which TNFalpha affects neuronal survival is by impacting upon these pathways that normally promote NGF support of neurons. Here we show that arachidonic acid (AA), a signaling lipid potentially associated with TNFR-I signal cascade, induces apoptosis in PC12 cells through inhibition of both protein kinase C zeta (PKCzeta) and NFkappaB activity. We also show that apoptosis induced by AA cannot be prevented by NGF. These data support the idea that PKCzeta and NFkappaB are both essential signaling elements for mediating NGF-promoted rescue from apoptosis. Our results also suggest that AA, an inflammatory signal lipid induced by TNFalpha via binding to TNFR-I, may reduce neuronal survival by inhibiting elements of the signal cascade induced by NGF.

Animals↗
PubMed1993

A comparison in young and elderly subjects of the pharmacokinetics and pharmacodynamics of single and multiple doses of benazepril.

1. The pharmacokinetics and pharmacodynamics of single and multiple oral doses of the ACE inhibitor benazepril were investigated in young and elderly normotensive subjects. 2. Following multiple doses the trough concentrations were significantly higher in the elderly and the areas under the plasma concentration-time curves (AUC0-24) were significantly greater, by approximately 23%. 3. The fall in blood pressure tended to be greater in the elderly subjects but this is likely to be attributable to their higher initial blood pressures, although it may reflect the small differences in pharmacokinetics. 4. The age related differences in kinetics and dynamics following multiple dosing are quantitatively similar to those obtained with single doses. However, there appears to be a quantitative difference between benazepril and other ACE inhibitors in that the age related increases were of a relatively smaller magnitude.

Administration, Oral↗
PubMed1993

The effects of age on the pharmacokinetics and pharmacodynamics of single oral doses of benazepril and enalapril.

1. Eighteen healthy, normotensive subjects (nine young and nine elderly) participated in a double-blind, 3-way, crossover study to compare aspects of the pharmacokinetics and pharmacodynamics of single oral doses of 10 mg benazepril, 10 mg enalapril and placebo. 2. The hypotensive effect was similar after both drugs but the absolute reductions were greater in the elderly who had higher initial levels of blood pressure. 3. The AUCs for both benazeprilat and enalaprilat were higher in the elderly but by a significantly greater amount for enalaprilat (+ 113% vs 40%; P < 0.01). 4. The AUCs for both drugs tended to be highest in subjects with the lowest creatinine clearance. 5. The changes in kinetics and dynamics observed in the elderly after benazepril are qualitatively similar to those with other ACE inhibitors. The clinical significance of the quantitative differences requires further investigation.

Administration, Oral↗
PubMed1992

Dose responses and pharmacokinetics for the angiotensin converting enzyme inhibitor quinapril.

Single doses of the angiotensin converting enzyme (ACE) inhibitor quinapril were administered to salt replete normotensive men to investigate pharmacokinetics and dose responses. Maximal ACE inhibition was produced by the 2.5, 5, and 20 mg doses (but not by 0.5 mg), but there was evidence of dose-dependency only for the duration of ACE inhibition. Quinaprilat was detectable in plasma up to 72 hours after all doses and the terminal phase half-life was calculated at 26 +/- 7 hours. Although there were dose-related increases in area under the curve (AUC), the relationships between dose and both AUC and maximum concentration were nonlinear. These findings suggest that quinapril displays the same prolonged terminal phase half-life that is characteristic of other ACE inhibitor drugs. The failure of doses above 2.5 mg to produce any further increase in the magnitude of ACE inhibition is consistent with an maximum effect dose-response relationship, with the obvious implication that higher doses will increase only the duration not the magnitude of response.

Adult↗
PubMed1991

Combined lipid-lowering and antihypertensive treatment as part of a strategy of multiple risk factor intervention.

Thirty-six patients with treated mild to moderate hypertension and hypercholesterolaemia (greater than 6.5 mmol/l) entered a 12 week study to evaluate the efficacy and patient tolerability of combined lipid-lowering and antihypertensive treatment as part of a strategy of multiple risk factor intervention. The principal effects on the plasma lipid profiles were significant reductions of 30-40% in total and LDL cholesterol. These reductions were achieved without loss of blood pressure control. There was no significant impact on HDL cholesterol or on lipoprotein Lp(a). These preliminary results suggest that substantial reductions in total and LDL cholesterol can be achieved without compromising blood pressure control which remained satisfactory at 144/82 supine and 143/80 mmHg standing. Furthermore, these changes were achieved without any problems of patient tolerability or interference with patient compliance with drug treatment. Overall, therefore, substantial reductions in CHD risk can be achieved with an acceptable combination of lipid lowering and antihypertensive treatments.

Aged↗
PubMed1989

Hypernatraemic dehydration in patients in a large hospital for the mentally handicapped.

OBJECTIVE: To determine the prevalence of hypernatraemic dehydration and to assess the hydration and nutritional state of patients in a large hospital for the mentally and physically handicapped; also to assess the efficacy of an intervention programme to reduce the prevalence of hypernatraemic dehydration in the hospital. DESIGN: Prospective study of patients admitted with hypernatraemic dehydration from a large hospital for mentally and physically handicapped patients (hospital A) to a district general hospital between 1986 and 1988. In 1986 the hydration and nutritional state of a random sample of patients from hospital A was compared with a random sample of patients from a small hospital for the physically and mentally handicapped (hospital B) and with control groups from the community. The hydration of the patients from hospital A examined in 1986 was reassessed in 1988. PATIENTS: 12 Patients were admitted from hospital A to the district general hospital during 1986-8 (seven women, five men; age range 29-82). In 1986, 72 patients were randomly selected for the assessment of hydration and nutritional state from hospital A, 33 who required help with feeding and 39 who could feed independently. Fifty patients were similarly selected from hospital B, half of them requiring help with feeding. In 1988 the hydration state of 60 of the 72 patients from hospital was reassessed. Control values were taken from two published studies. INTERVENTIONS: In 1987 nursing staff in hospital A were asked to provide between 2.5 and 3.0 litres of fluid daily for all patients. The use of hypertonic enemas was discontinued, and the ratio of staff to patients was increased. MAIN OUTCOME MEASURES: Serum concentrations of urea and electrolytes (hydration) and body mass index (nutritional state). RESULTS: Of the 10 patients admitted with hypernatraemic dehydration from hospital A to the district general hospital in 1986, four died of intercurrent infection. No patients were admitted from hospital B with hypernatraemic dehydration during the same time. In 1986 the hydration and nutritional state of patients in hospital A were inferior to those in patients from hospital B and control subjects from the community (serum urea concentrations were 6.1 (SD 1.8) mmol/l v 5.5 (1.9) and 5.6 (0.4) mmol/l, respectively) 50% (36/72) of patients in hospital A had a body mass index less than or equal to 20 compared with 34% (17/50) of patients from hospital B and 12% (1141/9434) of control subjects). After the initiation of the preventive programme only one patient was admitted with hypernatraemic dehydration in each of the years 1987 and 1988. The mean serum urea concentration of the 60 patients who were reassessed in 1988 fell significantly between 1986 and 1988 from 6.1 (SD 1.8) mmol/l to 5.7 (2.1) mmol/l, the value in a control group matched for age and sex. CONCLUSIONS: Hypernatraemic dehydration, subclinical underhydration, and undernutrition were common in a large hospital for the mentally and physically handicapped. The problem of hypernatraemic dehydration was successfully dealt with by the hospital management team. Similar problems may be encountered in hospitals for patients who are mentally and physically handicapped and mentally ill, including psychogeriatric units.

Adult↗
PubMed1989

Angiotensin-converting enzyme inhibitors in the elderly.

Although early studies suggested little role for angiotensin-converting enzyme (ACE) inhibitors in older hypertensive patients, more careful evaluation has confirmed their efficacy and good tolerability. Although the elderly tend to have low plasma renin levels, the fall in blood pressure after ACE inhibitors is at least as great (and in several studies greater) than in younger age groups. Because several ACE inhibitors, including captopril and enalaprilat, are eliminated by the kidneys, there are predictable age-related effects on pharmacokinetics. Reduced renal clearance will contribute, at least in part, to the enhanced intensity and duration of action seen in elderly patients. However, not all the effects of age on the kinetics and dynamics of ACE inhibitors are predictable. Studies with perindopril and benazepril in the elderly confirm the efficacy of this group of drugs but highlight other pharmacokinetic differences. ACE inhibitors are effective in reducing blood pressure and can be considered for wider use in elderly hypertensives.

Aged↗