Verbal working memory and solvent exposure: a positron emission tomography study.

Neuropsychological studies have documented frontal dysfunction in patients with a history of exposure to organic solvents. The deficits typically observed in these patients appear to be related to working memory (WM). This study used [15O] water positron emission tomography (PET) to examine the pattern of neural activation during verbal working memory in patients with a history of exposure to solvents. Six individuals with solvent exposure were compared with 6 age- and education-matched controls. On the 2 WM tasks examined with PET, with equivalent task performance, participants with solvent exposure demonstrated frontal peaks that were atypical for the tasks, whereas the posterior peaks were typical for the tasks. The results support frontal dysfunction and compensatory use within anterior regions of the WM system in patients with solvent exposure.

Occupational asthma: a review.

Occupational asthma is the most common form of occupational lung disease in the developed world at the present time. In this review, the epidemiology, pathogenesis/mechanisms, clinical presentations, management, and prevention of occupational asthma are discussed. The population attributable risk of asthma due to occupational exposures is considerable. Current understanding of the mechanisms by which many agents cause occupational asthma is limited, especially for low-molecular-weight sensitizers and irritants. The diagnosis of occupational asthma is generally established on the basis of a suggestive history of a temporal association between exposure and the onset of symptoms and objective evidence that these symptoms are related to airflow limitation. Early diagnosis, elimination of exposure to the responsible agent, and early use of inhaled steroids may play important roles in the prevention of long-term persistence of asthma. Persistent occupational asthma is often associated with substantial disability and consequent impacts on income and quality of life. Prevention of new cases is the best approach to reducing the burden of asthma attributable to occupational exposures. Future research needs are identified.

Phosphodiesterase-IV inhibition, respiratory muscle relaxation and bronchodilation by WAY-PDA-641.

The ability of 1-[3-(cyclopentyloxy)-4-methoxyphenyl]ethanone (E)-O-(aminocarbonyl) oxime) (WAY-PDA-641) to inhibit cyclic AMP-metabolizing phosphodiesterases (PDEs) and to relax respiratory muscle was explored as part of a program to identify a PDE-IV inhibitor for potential use in the treatment of asthma. WAY-PDA-641 was identified as a preferential inhibitor of PDE-IV, possessing 36 times greater potency versus canine trachealis PDE-IV than PDE-III (IC50, 4.2 x 10(-7) M and 1.5 x 10(-5) M, respectively). The classification of WAY-PDA-641 as a preferential PDE-IV inhibitor was supported in radioligand binding studies, which demonstrated that 10 microM WAY-PDA-641 did not displace ligands from a large number of receptors, and in functional studies, which used isolated guinea pig tracheal rings. Under conditions in which tracheal rings were made sensitive to the relaxant effects of PDE-IV or PDE-III inhibitors, WAY-PDA-641 induced relaxation with IC50S of 2.6 x 10(-8) M (PDE-IV) and 3.2 x 10(-5) M (PDE-III). Moreover, PDE-IV inhibitory concentrations of WAY-PDA-641 significantly potentiated the relaxant effects of albuterol. WAY-PDA-641 reversed tracheal contractions induced by prostaglandin F2 alpha, leukotriene D4 or histamine in a biphasic manner consistent with its activity as a preferential PDE-IV inhibitor. The IC50S for reversal of each spasmogen were similar, which confirmed that WAY-PDA-641 is a functional antagonist of respiratory muscle contraction.(ABSTRACT TRUNCATED AT 250 WORDS)

Antihyperglycemic activity of novel naphthalenyl 3H-1,2,3,5-oxathiadiazole 2-oxides.

A series of naphthalenyl 3H-1,2,3,5-oxathiadiazole 2-oxides was prepared and tested for antihyperglycemic activity in the db/db mouse, a model for type 2 (non-insulin dependent) diabetes mellitus. Substitution at the 1-, 5-, or 8-positions of the naphthalene ring with a halogen was found to be beneficial to antihyperglycemic activity. 4-[(5-Chloronaphthalen-2-yl)methyl]-3H-1,2,3,5-oxathiadiazole++ + 2-oxide (45), one of the most potent compounds in this series, was selected for further pharmacological evaluation.