Neuroprotective properties of valproate

Neuropsychiatric disturbances are extremely common in Alzheimer’s disease (AD), and represent integral features of the illness, as well as appropriate targets for therapy. We are interested in designing trials aimed at preventing or delaying the emergence of psychopathology in AD. For symptomatic treatment of agitation, mood stabilizers, particularly sodium valproate, have proved to be beneficial in some patients. Since these effects take several weeks to emerge, we considered that they might be dependent on potentially neuroprotective actions of valproate, such as inhibition of apoptosis and slowing of neurofibrillary tangle formation. In this article we present the rationale for testing the neuroprotective potential of valproate experimentally in mouse models of tauopathy and in a clinical trial of patients with AD who lack psychopathology at baseline. Together, these studies will provide important tests of the hypothesis that valproate, either through inhibition of tau phosphorylation or some other mechanism, is a useful therapeutic agent to modify disease progression in AD.     

Selective anorexigenic effects of corticotropin releasing hormone in the rhesus monkey

1. Rhesus monkeys were equipped with a novel intracerebroventricular (i.c.v.) cannula system and trained to respond under operant schedules of food presentation or termination of stimuli associated with the delivery of shock (escape). 2. CRH decreased food-maintained behavior in a dose-related manner over the range of (0.3-10 micrograms/kg) but did not affect escape responding, demonstrating a selective effect on food-maintained responding. 3. This selective effect was related to the tendency for responding to stop after delivery of a food pellet when higher doses of CRH were given, consistent with the notion that a conditioned aversion to food was established in the presence of CRH. 4. This may suggest that in hyperaroused clinical states such as depression and anorexia nervosa, focus is shifted away from appetitive tasks as a result of increased levels of CRH.     

Pharmacological properties of fluphenazine-mustard, an irreversible calmodulin antagonist

We describe an improved synthesis and properties of fluphenazine-mustard, a potent phenothiazine having an alkylating chlorethylamine chain in its structure. The drug possesses anticalmodulin activity equivalent to the parent compound, but unlike fluphenazine dihydrochloride, the mustard derivative irreversibly antagonizes the ability of calmodulin to activate cyclic nucleotide phosphodiesterase. This property is partially calcium-dependent and can be overcome by coincubation with excess fluphenazine dihydrochloride. The compound irreversibly inactivated calmodulin when incubated with intact cells and caused single-stranded breakage of DNA. Fluphenazine-mustard possesses potent antiproliferative and cytotoxic properties against malignant cell lines that are likely to be mediated through both of these actions.     

'Reprofessionalization' or 'occupational imperialism'?: some reflections on pharmacy in Britain

Drawing upon preliminary research findings, this paper considers whether pharmacists in Britain face a crisis in their occupational status and identity as a result of changes in their work and market situations. It further examines some of the ways in which they are responding to the challenges and opportunities presented. The paper also comments on the utility of the concepts of 'reprofessionalization' and 'occupational imperialism' in the study of British pharmacy.     

Antibodies to HTLV-1 in saliva of seropositive individuals from Japan

Secretory antibodies protect mucosal surfaces against transmission of many viruses. Human T-lymphotropic Virus, Type I (HTLV-I) is transmitted via blood products and via sexual contact across mucosal surfaces. We investigated the presence of HTLV-I-specific antibodies in whole saliva samples from 10 seronegative and 28 seropositive volunteers from a hospital in southern Japan. Antibodies directed to HTLV-I antigens were found in the salivas from 22 of 28 (79%) of the seropositive subjects. None of the seronegative individuals showed evidence of salivary antibodies. Antibodies directed to the envelope antigens of the virus were found in 21 of 22 positive saliva samples. Secretory antibodies may be important in preventing mucosal transmission.