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Biomedical subjects

N Pomara

Publications and source records attributed to N Pomara.

At least 19 recordsLinked to original sources
PubMed2005

Changes in cerebral neurotransmitters and metabolites induced by acute donepezil and memantine administrations: a microdialysis study.

Cholinesterase inhibitors including donepezil, rivastigmine, and galantamine and the N-methyl-D-aspartate (NMDA) antagonist, memantine are the medications currently approved for the treatment of Alzheimer's disease (AD). In addition to their beneficial effects on cognitive and functional domains typically disrupted in AD, these agents have also been shown to slow down the emergence of behavioral and psychotic symptoms associated with this disease. However, the underlying mechanisms for these therapeutic effects remain poorly understood and could involve effects of these medications on non-cholinergic or non-glutamatergic neurotransmitter systems respectively. These considerations prompted us to initiate a series of investigations to examine the acute and chronic effects of donepezil (Aricept (+/-)-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-1 hydrochloride and memantine (1-amino-3,5-dimethyladamantane hydrochloride C12H21N.HCl)). The present study focuses on the acute effects of donepezil and memantine on brain extracellular levels of acetylcholine, dopamine, serotonin, norepinephrine and their metabolites. We assayed changes in the ventral and dorsal hippocampus and the prefrontal and medial temporal cortex by microdialysis. Memantine resulted in significant increases in extracellular dopamine (DA), norepinephrine (NE), and their metabolites, in the cortical regions, and in a reduction of DA in the hippocampus. Donepezil produced an increase in extracellular DA in the cortex and in the dorsal hippocampus. Norepinephrine increased in the cortex; with donepezil it increased in the dorsal hippocampus and the medial temporal cortex, and decreased in the ventral hippocampus. Interestingly both compounds decreased extracellular serotonin (5HT) levels. The metabolites of the neurotransmitters were increased in most areas. We also found an increase in extracellular acetylcholine (ACh) by memantine in the nucleus accumbens and the ventral tegmental area. Our results suggest both region and drug specific neurotransmitter effects of these agents as well as some similarities. We conclude that drugs influencing cognitive mechanisms induce changes in a number of neurotransmitters with the changes being both region and drug specific. Release and metabolism are altered and extracellular neurotransmitter levels can be increased or decreased by the drugs. Other studies are in progress to determine the pharmacological effects associated with chronic treatment with these compounds, which may be more pertinent to the clinical situation in which patients take these medications for months or years.

Acetylcholine↗
PubMed2001

White matter abnormalities in HIV-1 infection: a diffusion tensor imaging study.

Diffuse white matter pallor is the most frequent neuropathological feature of HIV-1 infection and has been found to be particularly prominent in the advanced stages of the disease. The purpose of this study was to determine whether subtle white matter abnormalities can be detected in medically stable, ambulatory HIV-1 patients, in vivo, using diffusion tensor imaging (DTI). DTI is a magnetic resonance imaging (MRI) technique that is uniquely suited for the study of subtle white matter abnormalities. DTI was performed in six HIV-1 patients and nine controls. The two groups were similar in age. Abnormal fractional anisotropy was found in the white matter of the frontal lobes and internal capsules of the HIV-1 patients, in the absence of group differences in mean diffusivity, computed proton density, and computed T2. DTI may be more sensitive than conventional MRI methods for detecting subtle white matter disruptions in HIV-1 disease.

Acquired Immunodeficiency Syndrome↗
PubMed2001

Sex-related differences in nortriptyline-induced side-effects among depressed patients.

1. Men and women may differ in their pharmacokinetic responses to tricyclic antidepressants (TCAs), in a number of autonomic indices, and in various adrenergic receptor mediated responses. Emerging evidence also suggests that women may have a lower rate of serotonin synthesis in brain and a greater sensitivity to the depressant effects of tryptophan depletion, relative to men. However, sex-related differences in TCA-induced side-effects, including increases in heart rate (HR), dry mouth, constipation, and difficulty urinating, has not been systematically investigated. 2. The authors examined potential sex-related differences in the pattern of side-effects during treatment with nortriptyline (NT), a TCA that is still widely used. Seventy-eight healthy outpatients who met Research Diagnostic Criteria and DSM-III-R criteria for major depression participated in a double-blind, randomized parallel trial of NT versus placebo. 3. Each subject was acutely challenged with either placebo or 50 mg NT prior to and after a 6-week treatment with NT. NT doses were adjusted weekly to maintain therapeutic plasma levels. Patients were assessed at multiple time points to detect the presence of NT-induced side-effects. 4. The initial, single (50 mg) dose of NT significantly increased supine HR. Six-week treatment with NT was found to significantly increase supine and sitting HRs, irrespective of sex. In rechallenge with the single NT dose, there were no significant effects on HR. 5. When sex-related differences were examined, HR increases were greater in men than women during weeks 4 through 6 of the NT treatment, although no sex-related differences were present in plasma NT levels or metabolites. In addition, there was a significant NT to placebo difference in self-rated dry mouth for women during all 6-weeks of treatment, whereas men showed a significant NT-placebo difference during weeks 3 and 5. 6. The results suggest the presence of sex-related differences in elevated supine HR response during the course of 6-week NT treatment. Depressed men may be more susceptible to NT-induced increases in supine HR than women.

Adult↗
PubMed1999

Risperidone in the treatment of elderly patients with psychotic disorders.

The authors evaluated the safety, tolerability, and efficacy of risperidone in 103 elderly patients (mean age, 71 years) with schizophrenia (75%) or schizoaffective disorder (25%). Using the Extrapyramidal Symptoms Rating Scale (ESRS), Positive and Negative Syndrome Scale (PANSS), and Clinical Global Impression (CGI) scale, they conducted a prospective, open-label, 12-week trial in 14 psychiatric centers in the United States. Patients' symptoms were assessed at baseline and over a 12-week period. At endpoint, ESRS scores were significantly reduced, as were PANSS total and subscale scores. There were no clinically significant changes in electrocardiograms, laboratory test results, or vital signs. Risperidone was well tolerated and efficacious in elderly patients with schizophrenia or schizoaffective disorder.

Aged↗
PubMed1998

Decreases in plasma A beta 1-40 levels with aging in non-demented elderly with ApoE-epsilon 4 allele.

This report examines plasma amyloid beta proteins A beta 40 and A beta 42 and apolipoprotein E (apoE) levels and their relationships with age in non-demented older adults with (N = 32) or without the apoE-epsilon 4 allele (N = 94). A beta levels did not differ between the groups whereas the epsilon 4 allele was associated with a significant reduction in plasma apoE. In subjects with the epsilon 4 allele, increasing age was associated with significant reduction in plasma A beta 40. Subjects without the epsilon 4 allele showed a significant positive correlation between A beta 40 and A beta 42 levels. There was also a significant correlation between plasma A beta 40 and apoE levels in all subjects.

Aging↗
PubMed1998

The acute and chronic performance effects of alprazolam and lorazepam in the elderly: relationship to duration of treatment and self-rated sedation.

We examined the acute performance and sedative effects of single high and low doses of alprazolam and lorazepam, both before and after chronic, 3-week b.i.d. treatment in elderly adults. The effects of chronic treatment also were examined in this parallel, double-blind, placebo-controlled study. Initial acute low doses significantly impaired total recall and increased intrusion errors. High doses also impaired delayed recall and critical flicker fusion threshold (CFF). Only chronic treatment with high-dose alprazolam increased intrusions and self-rated sedation. Single-dose rechallenge after chronic treatment was associated with significantly less impairment than the initial challenge in memory tasks but not in the discriminant reaction time (DRAT) task. For most memory measures, the development of tolerance was only partial; rechallenge still produced significant deficits in relation to placebo. The development of tolerance was task-specific and depended on drug type and dosage. Despite impairments in various memory functions, CFF, and DRAT, volunteers did not report significant drug-induced changes in sedation.

Aged↗
PubMed1997

Immunocytochemical detection of anti-hippocampal antibodies in Alzheimer's disease and normal cerebrospinal fluid.

Immunocytochemical staining was performed to investigate the presence of anti-hippocampal antibodies in cerebrospinal fluid (CSF) from patients with probable Alzheimer's disease (AD) (n = 19), aged normal controls (n = 9), and young normal controls (n = 10). Marked staining of neurons in the granule cell layer of the dentate gyrus and in pyramidal neurons in CA1-3 of the rat hippocampus was observed in 5 AD CSF samples (26%), 1 aged control sample (11%), and 1 young control sample (10%). These differences were not statistically significant. One of the immunoreactive AD CSF specimens also contained high concentrations of C5b-9, the membrane attack complex. The infrequent occurrence of anti-hippocampal antibodies in AD CSF, and the detection of similar immunoreactivity in control CSF specimens, suggest that these antibodies are unlikely to play a role in the neurodegenerative process in most individuals with AD. However, elevated C5b-9 concentration in an AD CSF specimen with marked immunoreactivity to hippocampal neurons suggests the possibility that anti-neuronal antibodies may contribute to complement activation in some AD patients.

Adult↗
PubMed1994

Ceruloplasmin is increased in cerebrospinal fluid in Alzheimer's disease but not Parkinson's disease.

Although the pathophysiology of Alzheimer's disease (AD) and Parkinson's disease (PD) is unknown, altered brain antioxidative mechanisms have been found in both disorders. Ceruloplasmin (CP) and transferrin (TF) interact to limit concentrations of free ferrous iron (Fe2+), and thus play an important role in antioxidant defense in serum; both proteins are also produced in brain, where their significance as antioxidants is unknown. We quantified concentrations of CP and TF by immunoassay in AD (n = 17) and PD (n = 12) cerebrospinal fluid (CSF) to determine whether these proteins could serve as disease markers. CP was increased versus aged normal subjects (n = 11) in AD (p < 0.05) but not PD CSF, whereas TF concentrations did not differ between groups. CP levels have been reported to be elevated in some brain regions in AD, and increased CP in AD CSF may reflect this finding. Systemic inflammation and oxidative stress are major factors stimulating hepatic CP synthesis, and it remains to be determined whether increased CP concentrations in AD CSF and brain follow from similar mechanisms.

Adult↗
PubMed1993

Aging, emotional states, and memory.

OBJECTIVE: This study compared the relation between negative mood states and memory in young and elderly subjects. METHOD: Forty-five normal, healthy young volunteers (ages 19-35 years) and 45 normal, healthy elderly volunteers (ages 60-78 years) were administered a verbal list-learning task and self-rated scales of affective states. RESULTS: The elderly group, but not the young group, consistently exhibited significant correlations between their performance on verbal recall measures and their ratings of their anxiety, depression, and withdrawal; i.e., within the elderly group, higher levels of negative affective states were associated with poorer memory. CONCLUSIONS: These findings indicate that aging modulates the relation between emotional state and memory functions, and they are consistent with the hypothesis that the elderly are more vulnerable than the young to the adverse effects of negative emotional states on memory. Therefore, even in normal elderly individuals without diagnosable psychopathology, negative affective states (such as anxiety and depression) may interfere with memory functioning.

Adult↗
PubMed1992

Increased CSF HVA response to arecoline challenge in Alzheimer's disease.

The effects of the muscarinic agonist, arecoline, on the concentration of homovanillic acid (HVA) in the cerebrospinal fluid of patients with Alzheimer's disease (AD) and controls were examined. Patients and controls received intravenous infusions of arecoline and a lumbar puncture was performed four hours after the infusion began. Arecoline induced a significant increase in the concentration of HVA in cerebrospinal fluid of Alzheimer's disease patients (p < .01) but not in controls. The differential HVA response to a muscarinic agonist in Alzheimer's disease is suggestive of an alteration in muscarinic receptor response. This finding may have potential implications for the pathophysiology and treatment of Alzheimer's disease.

Aged↗
PubMed1992

Milacemide: a placebo-controlled study in senile dementia of the Alzheimer type.

OBJECTIVE: Milacemide, a MAO-B inhibitor that is also a prodrug for glycine, was tested as a treatment for senile dementia of the Alzheimer type (SDAT) because of its potential for enhancing cognition in animal models of impaired learning and memory. DESIGN: Double-blind, placebo-controlled, randomized clinical trial. SETTING: Sixteen study sites, both university-affiliated and private. PATIENTS: A total of 228 outpatients (116 men and 112 women) with SDAT, ranging in age from 49-93 years. INTERVENTION: 1200 mg/day milacemide treatment for 1 month (113 patients received milacemide, and 115 patients received placebo). MAIN OUTCOME MEASURES: Alzheimer's Disease Assessment Scale and the Mini-Mental State Examination. RESULTS: Milacemide-treated SDAT patients did not show significant improvement in any of the outcome measures used. Significant elevations in liver enzymes in four subjects were of sufficient magnitude to necessitate withdrawal from the study. CONCLUSIONS: Milacemide does not appear to be an effective treatment in enhancing cognition in SDAT patients.

Acetamides↗
PubMed1992

Glutamate and other CSF amino acids in Alzheimer's disease.

The authors compared CSF amino acid levels of 10 patients with mild to moderate dementia and probable Alzheimer's disease who had never received antidepressant or neuroleptic medication with those of 10 normal subjects of similar age. The Alzheimer's patients had significantly higher levels of CSF glutamate. This finding was not related to age, sex, or severity of dementia. Elevated CSF glutamate may reflect greater glutamatergic activity early in the course of Alzheimer's disease. The authors speculate that the excitotoxic effects of glutamate may contribute to progressive neuronal loss in Alzheimer's disease.

Age Factors↗
PubMed1991

Pretreatment postural blood pressure drop as a possible predictor of response to the cholinesterase inhibitor velnacrine (HP 029) in Alzheimer's disease.

The failure of cholinesterase inhibitors to produce noticeable improvement in about half of patients with Alzheimer's disease (AD) may result from heterogeneity of neurotransmitter abnormalities in this disorder. This study examined whether pretreatment postural blood pressure (BP) drop, which presumably reflects sympathetic response, differed in patients who were responders or nonresponders to the cholinesterase inhibitor, HP 029. Twenty-three AD patients completed a double-blind dose-finding phase of a clinical trial in which four doses of HP 029 and placebo were administered. Evaluation for efficacy occurred after 7 days of treatment at each dose. Of the 23 patients, 12 were classified as responders in the dose-ranging phase of the study. Nonresponders demonstrated significantly greater decreases in pretreatment systolic postural BPs when going from a supine to sitting position than did responders. The greater postural BP drop in nonresponders may identify a subgroup of AD patients that responds poorly to cholinesterase inhibitors.

Aged↗