Dietary Supplement Use in Older People Attending Memory Clinics in Australia.

BACKGROUND: Dietary supplement use is common in older adults. There has been limited research in people attending memory clinics. OBJECTIVES: To explore the use of dietary supplements in older people attending Australian memory clinics. DESIGN: Cross-sectional analysis of baseline data from the Prospective Research In MEmory clinics (PRIME) study. PARTICIPANTS: Community-dwelling older people who attended nine memory clinics and had a diagnosis of mild cognitive impairment (MCI) or dementia. MEASUREMENTS: Dietary supplement was defined as a product that contains one or more: vitamin, mineral, herb or other botanical, amino acid or other dietary substance. Non-prescribed supplement was defined as a supplement that is not usually prescribed by a medical practitioner. Polypharmacy was defined as use of five or more medications. RESULTS: 964 patients, mean age 77.6 years, were included. Dietary supplements were used by 550 (57.1%) patients; 353 (36.6%) used two or more. Non-prescribed supplements were used by 364 (36.8%) patients. Supplement use was associated with older age (OR: 1.12, 95% CI: 1.03-1.21), lower education level (OR: 1.53, 95% CI: 1.01-2.32) and a diagnosis of MCI rather than dementia (OR: 1.52, 95% CI: 1.05-2.21). Potential drug-supplement interactions were identified in 107 (11.1%) patients. Supplement users had increased prevalence of polypharmacy compared to non-users (80.5% vs. 48.1%, p<0.001). CONCLUSIONS: Dietary supplements, including non-prescribed supplements, were commonly used by people attending memory clinics. Supplement use increased the prevalence of polypharmacy and resulted in potential supplement-drug interactions. Further research is required to assess the clinical outcomes of supplement use.

Meat consumption and the risk of incident distal colon and rectal adenoma.

BACKGROUND: Most studies of meat and colorectal adenoma have investigated prevalent events from a single screening, thus limiting our understanding of the role of meat and meat-related exposures in early colorectal carcinogenesis. METHODS: Among participants in the screening arm of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial who underwent baseline and follow-up sigmoidoscopy (n=17,072), we identified 1008 individuals with incident distal colorectal adenoma. We calculated odds ratios (ORs) and 95% confidence intervals (95% CIs) for associations between meat and meat-related components and incident distal colorectal adenoma using multivariate logistic regression. RESULTS: We observed suggestive positive associations for red meat, processed meat, haeme iron, and nitrate/nitrite with distal colorectal adenoma. Grilled meat (OR=1.56, 95% CI=1.04-2.36), well or very well-done meat (OR=1.59, 95% CI=1.05-2.43), 2-amino-1-methyl-6-phenyl-imidazo[4,5-b]pyridine (PhIP) (OR=1.75, 95% CI=1.17-2.64), benzo[a]pyrene (OR=1.53, 95% CI=1.06-2.20), and total mutagenic activity (OR=1.57, 95% CI=1.03-2.40) were positively associated with rectal adenoma. Total iron (diet and supplements) (OR=0.69, 95% CI=0.56-0.86) and iron from supplements (OR=0.65, 95% CI=0.44-0.97) were inversely associated with any distal colorectal adenoma. CONCLUSION: Our findings indicate that several meat-related components may be most relevant to early neoplasia in the rectum. In contrast, total iron and iron from supplements were inversely associated with any distal colorectal adenoma.

A comparative study in rats of the in vitro and in vivo pharmacology of the acetylcholinesterase inhibitors tacrine, donepezil and NXX-066.

The in vitro and in vivo effects of the novel acetylcholinesterase inhibitors donepezil and NXX-066 have been compared to tacrine. Using purified acetylcholinesterase from electric eel both tacrine and donepezil were shown to be reversible mixed type inhibitors, binding to a similar site on the enzyme. In contrast, NXX-066 was an irreversible non-competitive inhibitor. All three compounds were potent inhibitors of rat brain acetylcholinesterase (IC50 [nM]; tacrine: 125 +/- 23; NXX-066: 148 +/- 15; donepezil: 33 +/- 12). Tacrine was also a potent butyrylcholinesterase inhibitor. Donepezil and tacrine displaced [3H]pirenzepine binding in rat brain homogenates (IC50 values [microM]; tacrine: 0.7; donepezil: 0.5) but NXX-066 was around 80 times less potent at this M1-muscarinic site. Studies of carbachol stimulated increases in [Ca2+]i in neuroblastoma cells demonstrated that both donepezil and tacrine were M1 antagonists. Ligand binding suggested little activity of likely pharmacological significance with any of the drugs at other neurotransmitter sites. Intraperitoneal administration of the compounds to rats produced dose dependent increases in salivation and tremor (ED50 [micromol/kg]; tacrine: 15, NXX-066: 35, donepezil: 6) with NXX-066 having the most sustained effect on tremor. Following oral administration, NXX-066 had the slowest onset but the greatest duration of action. The relative potency also changed, tacrine having low potency (ED50 [micromol/kg]; tacrine: 200, NXX-066: 30, donepezil: 50). Salivation was severe only in tacrine treated animals. Using in vivo microdialysis in cerebral cortex, both NXX-066 and tacrine were found to produce a marked (at least 30-fold) increase in extracellular acetylcholine which remained elevated for more than 2 h after tacrine and 4 h after NXX-066.

The effects of Ca2+ antagonists and hydralazine on central 5-hydroxytryptamine biochemistry and function in rats and mice.

1. The effects of calcium antagonists on behaviour mediated by 5-hydroxytryptamine (5-HT) have been studied in rats and mice together with an investigation of the effects of these drugs on 5-HT synthesis in rat brain and endogenous 5-HT release from brain slices. 2. Administration of felodipine (35 mg kg-1 i.p.) to rats pretreated with tranylcypromine (20 mg kg-1, i.p.) resulted in the animals displaying the complete 5-HT-mediated behavioural syndrome (including head weaving, reciprocal forepaw treading and hind limb abduction) 75 min later. No evidence was obtained for the rate of 5-HT synthesis in brain regions differing between control and felodipine-treated rats. 3. Pretreatment with felodipine (10 or 35 mg kg-1) enhanced the 5-HT-mediated behavioural syndrome induced by injection of tranylcypromine and L-tryptophan. The rate of 5-HT accumulation in the brain was similar in both groups. Administration of Bay K 8644 (1 mg kg-1, i.p.) did not prevent the enhanced behaviour induced by felodipine (10 mg kg-1). 4. The 5-HT behavioural syndrome induced by injection of the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) was unaltered by either acute injection of felodipine (35 mg kg-1) or administration of felodipine twice daily for 3 days. 5. Felodipine (10 microM), verapamil (10 microM) and Bay K 8644 (10 microM) did not alter either basal release of endogenous 5-HT from slices prepared from frontal cortex or hind brain, or release following addition of K+ at a concentration of 20 mM, or 35 mM. 6. Verapamil (25mgkg-', i.p.), nicardipine (25mgkg-1, i.p.) and nifedipine (20mgkg-1, i.p.) all markedly inhibited the 5-HT2 receptor-mediated head twitch response in mice produced by injection of 5- methoxy-N,N-dimethyl-tryptamine (5-MeODMT). Felodipine had the same effect with an ED50 of 2.6mgkg-'. Bay K 8644 did not reverse this effect. Both verapamil (IC50:2.5 microM) and nicardipine (IC50:8 microM) were 5-HT2 antagonists as indicated by inhibition of [3H]-ketanserin binding in mouse frontal cortex. However felodipine and nifedipine antagonized 5-HT2 receptor binding only in the millimolar range.7. Hydralazine (5mg kg 1, i.p.) induced the 5-HT behavioural syndrome in tranylcypromine pretreated rats, enhanced the tranylcypromine/L-tryptophan behavioural syndrome, inhibited 5-MeODMT-induced head twitch behaviour in mice and was not a 5-HT2 receptor antagonist. 8. These data indicate that at a high dose, Ca2+ antagonists produce complex changes in 5-HT function in rodents which are similar to those produced by lithium administration. The data with hydralazine suggest that the effects seen are not related to an action at Ca2 + channels.

Frontal cortical and left temporal glutamatergic dysfunction in schizophrenia.

Glutamatergic mechanisms have been investigated in postmortem brain samples from schizophrenics and controls. D-[3H]Aspartate binding to glutamate uptake sites was used as a marker for glutamatergic neurones, and [3H]kainate binding for a subclass of postsynaptic glutamate receptors. There were highly significant increases in the binding of both ligands to membranes from orbital frontal cortex on both the left and right sides of schizophrenic brains. The changes are unlikely to be due to antemortem neuroleptic drug treatment, because no similar changes were recorded in other areas. A predicted left-sided reduction in D-[3H]aspartate binding was refuted at 5% probability, but not at 10%. Previously reported high concentrations of dopamine in left amygdala were strongly associated with low concentrations of D-[3H]aspartate binding in left polar temporal cortex in the schizophrenics. The findings are compatible with an overabundant glutamatergic innervation of orbital frontal cortex in schizophrenia. The results also suggest that schizophrenia may involve left-sided abnormalities in the relationship between temporal glutamatergic and dopaminergic projections to amygdala.

Reduced high-affinity glutamate uptake sites in the brains of patients with Huntington's disease.

The binding of D-[3H]aspartic acid to the high-affinity glutamate uptake system was studied in membrane preparations of postmortem brains from controls and Huntington's disease (HD) subjects. The groups were matched for age and postmortem delay. A large (60-72%) and significant reduction in D-[3H]aspartate binding was observed in both the caudate nucleus and putamen, but not in the frontal cortex of the HD brains. The loss of striatal D-[3H]aspartate binding may reflect a loss of the high-affinity glutamate uptake system contained on the terminals of corticostriatal afferents. In contrast, the binding of [3H]paroxetine to the serotonin uptake system was marginally increased in the caudate nucleus and unchanged in the putamen. It is suggested that the reduction of high-affinity glutamate uptake sites may contribute to the production of the striatal lesion in HD.

Elevation of neuropeptide Y (NPY) in substantia innominata in Alzheimer's type dementia.

Concentrations of neuropeptide Y (NPY) have been determined in 12 areas of control brains and compared to those found in brains from patients with Alzheimer's type dementia (ATD). The distribution of NPY in the control brains was compared with those reported previously. Highest concentrations were identified in the subcortical structures, in particular, nucleus accumbens (203 +/- 21.7 pmol/g), amygdala (136.7 +/- 15.8 pmol/g), and substantia innominata (109.0 +/- 12.6 pmol/g). A significant elevation in NPY concentrations was identified in the region of the substantia innominata of Alzheimer brains (controls: 109.0 +/- 12.6 pmol/g, ATD: 206 +/- 28.2 pmol/g, P less than 0.001). This change in NPY concentration was similar to the increase in somatostatin concentration in this region of ATD brain. In contrast, although cortical concentrations of somatostatin were reduced in ATD, no change was found in the concentrations of NPY in the 4 regions of cerebral cortex and the remaining subcortical areas examined.