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Biomedical subjects

K L Davis

Publications and source records attributed to K L Davis.

At least 307 records · Page 17Linked to original sources
PubMed1983

Experimental pharmacology of Alzheimer disease.

Evidence for a major role of acetylcholine in the pathogenesis of AD is provided by the dramatic decrease in the hippocampus and frontal cortex of choline acetyltransferase and the marked reduction in cholinergic neuron counts in the nucleus basalis in post-mortem studies of AD brains. The ChAT deficit correlates with histopathologic changes and psychologic test scores. Pharmacologic mimicking by anti-cholinergics of the core symptoms of AD, and modest enhancement of memory and cognition by cholinomimetic agents support a cholinergic-deficit theory in AD. These findings strongly support therapeutic cholinergic strategies. A presynaptic approach utilizing acetylcholine precursors alone has been discouraging; however, precursor loading coupled with an agent that accelerates acetylcholine release shows promise. At the synaptic level, improvement in the encoding of new information into long-term memory in AD during parenteral administration of acetylcholinesterase inhibitors should enable psychopharmacologists to focus on the development of practical chronic oral treatments. Postsynaptic cholinergic receptor agonists bypass the degenerating presynaptic cholinergic neuron and increase cholinergic neurotransmission at the intact muscarinic receptor. Trials evaluating the effects of cholinergic neuromodulators on cognition provide another tactic in the fight against the disabling consequences of this disorder.

Acetylcholine↗
PubMed1983

Acetylcholinesterase activity in CSF in schizophrenia, depression, Alzheimer's disease and normals.

Acetylcholinesterase (AChE) activity and protein were measured in the CSF of patients with Alzheimer's disease, depression, schizophrenia with and without tardive dyskinesia, and control subjects. AChE activity was assayed by a radioenzymatic method involving the direct extraction of hydrolyzed 3H-acetate into a toluene-based scintillation fluid followed by liquid scintillation spectrometry. AChE activity was proportional to the amount of CSF protein. Greater than 90% of AChE activity in CSF could be inhibited by 10(-3) M eserine. In addition, activity remained stable despite repeated freeze-thawing in an acetone-dry ice bath. Age was found to be positively correlated with CSF protein and AChE activity expressed per volume CSF, but not with AChE measured per milligram protein. No differences between diagnostic groups were found on either measure of AChE when the extraneous factors of age and CSF protein concentrations were controlled, nor were any differences found between groups for CSF protein when age was controlled.

Acetylcholinesterase↗
PubMed1982

Dopamine autoreceptor and postsynaptic receptor blocking potency of neuroleptics.

Neuroleptic drugs have been shown to block brain dopamine (DA) receptors. The relative potency of neuroleptics at blocking DA postsynaptic receptors (PSRs) and autoreceptors (ARs) is less clear. To examine this question, the potency of 5 neuroleptics at inhibiting receptors (PSRs) and autoreceptors (ABs) is less clear. To examine this question, the potency of 5 neuroleptics at inhibiting the augmentation of mouse climbing behavior induced by a high dose of apomorphine (2.5 mg/kg) (presumably mediated by DA PSRs) was compared with their potency at inhibiting the suppression of climbing behavior induced by a low dose of apomorphine (0.45 mg/kg) (presumably mediated by DA Ars). Haloperidol and molindone had no AR-blocking ability even at doses that substantially blocked DA PSRs. Metoclopramide and fluphenazine had AR-blocking ability only at doses that produced substantial PSR blockade. Sulpiride blocked DA ARs at doses that had relatively litter PSR effect. It is concluded that neuroleptic drugs differ substantially in their relative potency at blocking DA ARs and PSRs.

Animals↗
PubMed1982

A signal detectability analysis of the effect of physostigmine on memory in patients with Alzheimer's disease.

Ten patients with clinically diagnosed Alzheimer's disease were given tests of recognition memory while receiving placebo or physostigmine, a cholinesterase inhibitor, given intravenously over 30 min. Doses of 0.0, 0.125, 0.25, and 0.5 mg were given in random order on 4 separate days. All patients had their best performance following one of the doses of physostigmine rather than saline although dose-response curves varied from one patient to another. The dose associated with the best performance in each patient was compared with saline in a replication study using a double-blind cross-over design. In the replication study the total number of correct responses on the recognition memory task was significantly greater following physostigmine than following saline. To determine whether this improvement in performance was a result of an increase in the amount of information stored in memory or was secondary to a change in the patients' criteria for saying that they recognized an item, the results were subjected to a signal detectability analysis. This analysis indicated that studied items and new items were more discriminable following physostigmine, as evidenced by an increase in d', and that the criteria for saying which items had been studied also changed following physostigmine, as evidenced by an increase in C. The increase in d' indicates that physostigmine enhanced storage of information in memory while the change in C is consistent with the view that patients altered their decision criteria to maximize the number of correct responses in both conditions.

Aged↗
PubMed1982

A rationale for studying the transmissibility of Alzheimer's disease.

Despite extensive chemical, epidemiological, histopathological and pharmacological investigations of Alzheimer's disease (AD), its etiology remains elusive. This article describes studies supporting a rationale for exploring a transmissible slow viral etiology of at least some forms of AD. To date, a major limitation in these studies has been reliance upon induction of AD histopathology as the outcome measure of successful transmission. Future studies should consider novel outcome measures for the detection of successful, although histopathologically inapparent, transmissible infection. In addition, the need to inoculate a diverse variety of rationally selected, potential hosts is stressed.

Alzheimer Disease↗
PubMed1982

Research subject recruitment for gerontological studies of pharmacological agents.

Elderly subjects were recruited for a study of the effect of intravenous physostigmine on the memory disturbance of Alzheimer's Disease. Approximately one out of every twelve people screened was suitable for the study. Subjects were ruled out either because they did not meet research diagnostic criteria for AD, because they could not cooperate with the studies or because of medical contraindications. The data indicate that large numbers of potential subjects are required to select relatively small groups for pharmacological studies. The implications of some of these developments for future research are discussed.

Aged↗
PubMed1982

The use of cholinergic precursors in neuropsychiatric diseases.

Preclinical data suggest that cholinergic precursors such as choline or lecithin, increase levels of acetylcholine in specific brain structures, and under certain conditions may enhance cholinergic neurotransmission. A variety of neuropsychiatric diseases including tardive dyskinesia. Huntington's chorea, ataxias, Tourette's syndrome, schizophrenia, affective illness, and senile dementia of the Alzheimer type, has been implicated with a general underactivity of central cholinergic mechanisms. Recent studies have investigated the possibility that cholinergic precursor loading strategies may provide viable treatments for these disorders of presumed cholinergic underactivity. Extensive data demonstrate that the symptoms of tardive dyskinesia can be reduced by choline or lecithin, whereas investigations in other disorders have met with mild success, at best, or are still in preliminary stages. Further controlled studies with choline or lecithin using broader dose ranges, longer durations of treatment, and concomitant administration of agents which may increase the release of acetylcholine are warranted.

Acetylcholine↗
PubMed1982

Enhancement of memory processes in Alzheimer's disease with multiple-dose intravenous physostigmine.

Physostigmine (.125 mg, .25 mg, or .50 mg) or placebo was administered intravenously to 10 neuroleptic-free patients with Alzheimer's disease over a 30-minute period. All patients performed better on a recognition memory task while receiving physostigmine. When placebo or the dose of physostigmine previously associated with an improvement in memory was readministered, physostigmine again enhanced performance on a recognition memory task. These results indicate that the acute augmentation of cholinergic activity in some patients with Alzheimer's disease can partially reverse the memory deficit of that disorder and may provide an approach to the eventual therapy of this condition.

Aged↗
PubMed1982

The neuropharmacology of tardive dyskinesia, spontaneous dyskinesia, and other dystonias.

Most classifications of movement disorders emphasize their differential diagnosis and epidemiology according to clinical history and neurological examination. This review of movement disorders is organized according to the hypothesis of basal ganglia neurotransmitter imbalance in order to emphasize current research based on the pharmacology of these disorders. Specifically, dopamine (DA) excess and acetylcholine (ACh) deficiency may characterize part of the pathology of several hyperkinetic movement disorders including tardive dyskinesia, Huntington disease, Gilles de la Tourette syndrome, l-dopa dyskinesias, tardive Tourette syndrome, and toxic Tourette syndrome. The mirror image of this paradigm, namely DA deficiency and ACh excess, may characterize several rigid-dystonic movement disorders including Parkinson disease, drug-induced dystonias, and dystonia musculorum deformans. Finally, the unique combination of DA excess with ACh excess may characterize idiopathic orofacial dyskinesia (also known as Meige dystonia, Brueghel syndrome, and blepharospasm-oromandibular dystonia). Evidence supporting this formulation of movement disorders is reviewed, the limitations of this hypothesis are discussed, and new data from our own studies are presented.

Acetylcholine↗