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Treatment approaches to symptoms associated with frontotemporal degeneration.

A systematic review of the literature reveals few randomized, controlled trials for drug therapy in frontotemporal degeneration (FTD). Although there is evidence to support a serotonergic deficit, and clinicians frequently prescribe selective serotonin reuptake inhibitors to patients with FTD, only paroxetine and trazodone have been studied. There is Class II evidence for use of rivastigmine in FTD behavioral disturbances, although there is no consistent evidence of cholinergic deficit in this illness.

Aphasia↗

The effect of dimethylaminoadamantane on neuronal membranes.

The effect of dimethylaminoadamantane (DMAA), an amantadine derivative with an anti-Parkinson property, on rat sensory nerve fibres was studied with the sucrose gap method. DMAA 10(-4) M in normal Locke solution reduced the spike amplitude without changing the resting potential, increased the membrane resistance and depressed repetitive spike activity elicited by depolarizing currents. From experiments performed with changed concentrations of sodium, potassium, calcium and chloride ions in the suspension medium it appears that the permeability of sodium, potassium and chloride ions is reduced by DMAA. The possible implication of the membrane effects of the drug in its action on dopaminergic transmission in the brain is discussed.

Amantadine↗

Re-examination for pharmacological properties of serotonin-induced tachycardia in isolated guinea-pig atrium.

In the presence of 10(-6) M atropine, 5-HT induced a positive chronotropic and inotropic effect in isolated guinea-pig atrium preparation. Both propranolol, a beta-adrenoceptor blocker, and imipramine, a 5-HT uptake inhibitor, did not affect the response induced by 5-HT, indicating that a tyramine-like mechanism is not involved. The positive chronotropic effect of 5-HT was mimicked by several 5-HT3 receptor agonists. N omega-Methyl-5-HT, reported to have a high affinity for 5-HT1B recognition sites, was found to act as a 5-HT3 receptor agonist with higher efficacy. The other 5-HT receptor agonists tested did not produced any responses. The positive chronotropic effect of 5-HT was inhibited by various 5-HT3 receptor antagonists, such as tropisetron, granisetron, ondansetron, cisapride and zacopride, but it was unaffected by various 5-HT receptor antagonists which are not selective for 5-HT3 receptor. Thus, the positive chronotropic response to 5-HT is a direct effect, and it was suggested to be mediated by 5-HT3 receptor subtype with rather an atypical profile.

Adrenergic Uptake Inhibitors↗

Topical and systemic drug delivery to the posterior segments.

The posterior segments of the eye are exquisitely protected from the external environment. This poses unique and fairly challenging hurdles for drug delivery. It is somewhat dogmatic that topical ocular delivery is insufficient to achieve therapeutic drug levels in the posterior segments. However, some drugs are currently challenging this dogma. In this review we investigate the constraints and challenges of drug delivery to the posterior segment. Additionally, we outline several potential absorption pathways that may potentially be exploited to deliver drug to the back of the eye. Data on several compounds that achieve therapeutic posterior segment concentrations after topical dosing is presented. Finally, the issues surrounding systemic delivery to the posterior segment are reviewed.

Administration, Topical↗

Altered synaptic function in Alzheimer's disease.

Alzheimer's disease is the leading cause of dementia in the elderly, presenting itself clinically by progressive loss of memory and learning. Since synaptic density correlates more closely with cognitive impairment than any other pathological lesion observable in the disease pathology, an increased understanding of the mechanisms behind synaptic disconnection is of vital importance. Our lab investigated the neurotransmitter-specific status of distinct cortical presynaptic bouton populations in various transgenic mouse models of the Alzheimer's-like amyloid pathology in order to assess their involvement throughout the progression of the pathology. These studies have revealed that the amyloid pathology appears to progress in a neurotransmitter-specific manner where the cholinergic terminals appear most vulnerable, followed by the glutamatergic terminals and finally by the somewhat more resilient GABAergic terminals. This review will discuss additional studies which also provide evidence of a neurotransmitter-specific pathology as well as comment on the potential explanations for the observed vulnerabilities, touching upon metabolic demand, trophic support and receptor mediated activation.

Alzheimer Disease↗

Current status and future promise of pharmacotherapeutic strategies for Alzheimer's disease.

BACKGROUND AND OBJECTIVE: The pharmacotherapy of Alzheimer's disease (AD) is evolving rapidly. Unless new discoveries continue to emerge to facilitate prevention and effective treatment of the disease, the anticipated burden of this disease on caregivers and society at large will overwhelm resources. The objective of this paper is to review the state of development of approaches likely to yield effective interventional measures with regard to AD in the future. DESIGN: A comprehensive systematic search of MEDLINE using focused search criteria, a search of reference lists from these studies and reviews, a review of the Cochrane Database of Systematic Reviews, and a hand search of relevant journals was conducted. Selection of articles was based on the clinical focus. Additional inclusion criteria preferentially selected key articles that contained higher-level evidence in accordance with explicit, validated criteria. RESULTS: Pharmaceutical interventions are being developed and tested that confer neuroprotective benefits by targeting causative mechanisms. CONCLUSION: The paradigm that AD is pharmacologically unresponsive is shifting. Our understanding of the molecular mechanisms of neurodegeneration will soon allow us to more specifically target and interrupt the processes that contribute to this dementia.

Activities of Daily Living↗

Dementia assessment and management.

Dementia is a common yet potentially underdiagnosed illness in the long-term care setting. Targeted screening for dementia should be routine practice, as a diagnosis of dementia will have benefits to the care of the patient. Assessment of dementia should proceed in a step-wise approach and should be tailored to the needs of the individual patient. Management of dementia involves care for the cognitive changes, behavioral changes, functional changes, and emotional issues. It also involves the management of other illnesses in light of the dementia, consideration of the needs and well-being of the caregiver, and particular attention to advanced care planning. Management techniques and goals should evolve as the patient's illness progresses. This comprehensive approach to management of dementia may reduce morbidity and mortality associated with this illness. This model of care provides patients and families with needed information and resources, a clear view of prognosis, and necessary attention to quality of life issues.

Activities of Daily Living↗

Alzheimer's treatment in nursing homes: room for improvement.

Managing Alzheimer's disease (AD) continues to challenge long-term care physicians and administrators. Although pharmacologic treatment can substantially benefit AD patients in the nursing home setting, common misconceptions and skepticism about its value are barriers to treatment use. Aggressive treatment for AD maximizes patient function and independence and is cost-effective. Herein we discuss state-of-the-art treatment of AD with a view to providing nursing home physicians a framework from which to make treatment decisions.

Activities of Daily Living↗

A multicenter in vivo proton-MRS study of HIV-associated dementia and its relationship to age.

OBJECTIVE: Differences in diagnostic criteria and methods have led to mixed results regarding the metabolite pattern of HIV-associated brain injury in relation to neurocognitive impairment. Therefore, a multicenter MRS consortium was formed to evaluate the neurometabolites in HIV patients with or without cognitive impairment. METHODS: Proton magnetic resonance spectroscopy (MRS) at short-echo time (30 ms) was assessed in the frontal white matter, basal ganglia, and parietal cortex of 100 HIV patients [61 with AIDS dementia complex (ADC) and 39 neuroasymptomatic (NAS)] and 37 seronegative (SN) controls. RESULTS: Compared to SN, NAS had higher glial marker myoinositol-to-creatine ratio (MI/Cr) in the white matter (multivariate analyses, adjusted P=0.001), while ADC showed further increased MI/Cr in the white matter and basal ganglia (both P<0.001), and increased choline compounds (Cho)/Cr in white matter (P=0.04) and basal ganglia (P<0.001). Compared to NAS, ADC showed a reduction in the neuronal marker N-acetyl compound (NA)/Cr in the frontal white matter (P=0.007). CSF, but not plasma, viral load correlated with MI/Cr and Cho/Cr in white matter and NAA/Cr in parietal cortex. HIV infection and aging had additive effects on Cho/Cr and MI/Cr in the basal ganglia and white matter. CONCLUSIONS: The results suggest that glial activation occurs during the NAS stages of HIV infection, whereas further inflammatory activity in the basal ganglia and neuronal injury in the white matter is associated with the development of cognitive impairment. Aging may further exacerbate brain metabolites associated with inflammation in HIV patient and thereby increase the risk for cognitive impairment.

AIDS Dementia Complex↗

Two blocking sites of amino-adamantane derivatives in open N-methyl-D-aspartate channels.

Using whole-cell patch-clamp techniques, we studied the blockade of open N-methyl-D-aspartate (NMDA) channels by amino-adamantane derivatives (AADs) in rat hippocampal neurons acutely isolated by the vibrodissociation method. The rapid concentration-jump technique was used to replace superfusion solutions. A kinetic analysis of the interaction of AAD with open NMDA channels revealed fast and slow components of their blockade and recovery. Mathematical modeling showed that these kinetic components are evidence for two distinct blocking sites of AADs in open NMDA channels. A comparative analysis of different simplest models led us to conclude that these AAD blocking sites can be simultaneously occupied by two blocker molecules. The voltage dependence of the AAD block suggested that both sites were located deep in the channel pore.

Adamantane↗

Chronic multichannel recordings from organotypic hippocampal slice cultures: protection from excitotoxic effects of NMDA by non-competitive NMDA antagonists.

In vitro neuronal damage has traditionally been evaluated by biochemical or anatomical but not by electrophysiological techniques. In the present study, we combined two newly developed technologies, an 8 x 8 multi-electrode array (MED-64) and cultured hippocampal slices, to demonstrate the potential use of electrophysiological measures as index of neuronal damage. We first demonstrated the stability of electrophysiological recordings over prolonged periods of time (up to 14 days) in field CA1 of cultured hippocampal slices following electrical stimulation of the Schaffer collateral pathway. We then assessed the neurotoxic properties of NMDA and AMPA and determined that the time-course, potency, and efficacy of these two neurotoxins were similar to those assessed by other experimental approaches. We also compared the efficacy and potency of two non-competitive NMDA receptor antagonists to protect against NMDA-mediated neurotoxicity. Again, the results matched well with the results obtained from traditional techniques. Thus, this new technology might provide a new and powerful method to study the chronic effects of drugs or other experimental manipulations in an in vitro preparation.

Animals↗