Muscarinic agonists and antagonists in the treatment of Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by cognitive impairment and personality changes. The development of drugs for the treatment of the cognitive deficits of AD has focused on agents which counteract loss in cholinergic activity. Although symptoms of AD have been successfully treated with acetylcholinesterase inhibitors (tacrine, donepezil. rivastigmine, galanthamine), limited success has been achieved with direct M1 agonists, probably due to their lack of selectivity versus other muscarinic receptor subtypes. Muscarinic M2 antagonists have been reported to increase synaptic levels of acetylcholine after oral administration to rats (e.g. BIBN-99, SCH-57790), but their selectivity versus other muscarinic receptor subtypes is modest. Exploration of a series of piperidinylpiperidines has yielded the potent and selective M2 antagonist SCH-217443. This antagonist has excellent bioavailability in rats and dogs and shows activity in a rat model of cognition.

Affective reactions to auditory hallucinations in psychotic, evangelical and control groups.

OBJECTIVES: Building on recent work on the similarities and differences in delusional ideation between psychotic and religious populations (Peters, Day, McKenna, & Orbach, 1999), the experiences of auditory hallucinations in psychotic, evangelical and control groups were examined in this study. METHOD: The incidence and subjective experiences of hearing voices were assessed using questionnaire methods in psychotic out-patients, evangelical Christians and controls (non-psychotic, non-evangelical). RESULTS: Incidence of auditory hallucinations differed significantly across the three groups with psychotics showing the highest levels and controls the lowest levels. The experiences of the evangelical group were significantly more positive than those of the control group, which in turn were significantly more positive than those of the psychotic group. The most recent experience of hearing voices was rated more positively than the first experience by the psychotic and religious groups but not by the control group. These findings were much stronger for affective reactions to the experiences than for perceptions of the voices. CONCLUSION: These results provide only partial support for the findings of Peters et al. (1999) on differences in delusional ideation and possible reasons for this are discussed. The findings for religious and psychotic individuals are discussed further in terms of interpretational and coping mechanisms.

Inactivation of Bacillus cereus 569/H beta-lactamase I by 6-beta-(trifluoromethane sulfonyl)amidopenicillanic acid sulfone and its N-methyl derivative.

6-beta-(Trifluoromethane sulfonyl)amidopenicillanic acid sulfone and its N-methyl derivative were found to be potent inhibitors of Bacillus cereus 569/H beta-lactamase I. The rate of the inactivation of the enzyme by both compounds was found to increase with the decreasing pH of the reaction medium. The reaction of the enzyme with 6-beta-(trifluoromethane sulfonyl)amidopenicillanic acid sulfone was found to be irreversible at the pH values investigated. In contrast, the reaction with the N-methyl derivative at neutral pH was consistent with the partitioning of the acyl enzyme intermediate in three pathways which included (a) deacylation to yield active enzyme, (b) conversion to a transiently inhibited species, and (c) conversion to an irreversibly inactive form. The amino acid composition of the chromophoric peptide obtained from the enzyme inactivated by either of the compounds was consistent with the occurrence of an initial acylation of serine-70 of the protein.