Interaction of Soman with {beta}-Cyclodextrin

Interaction of Soman with ß-CycIodextrin. DESIRE,B., AND SAINT-ANDRE, S. (1986). Fun-dam. Appl. Toxicol. 7, 646-657.Of the following neurotoxic agents, pinacolyl methylphospho-nofluoridate(soman), isopropyl methylphosphonofluoridate (sarin) and ethylN, N-dimethyl-phosphoramidocyanidate (tabun), only soman wasinactivated appreciably at pH 7.40 by ß-cyclodextrin.The interaction of soman, a mixture of four stereoisomers designatedas C(+)P(–), C(–)P(–), C(+)P(+), and C(–)P(+),with cyclodextrins was revealed by methods based on (i) theirreversible inhibition of acetylcholinesterase (AChE) thatis phosphonylated chiefly by P(–)-isomers of racemic somanand (ii) continuous titration of fluoride ions released by somanusing a fluoride-specific electrode. Soman and ß-cyclodextrinform a 1:1 complex. At pH 7.40 and 25°C the dissociationconstant Kd of this complex and the rate constant k2 of cleavageof soman by ß-cyclodextrin are (0.53 ± 0.05)mM and (5.9 ± 0.6) x 10² min¹, respectively. The rateconstant k₂^max for the cleavage of soman by monoionized ß-cyclodextrinhas a value of 2.8 x 103 min¹ and the second order rate constantk₂^max/K_d 5.3 x 106 M^–1 min^–1. Consequently, somanis hydrolyzed about 2500 times faster by the monoanion of ß-cyclodextrin,than by the hydroxide ion. The cleavage of P(–)-somanby ß-cyclodextrin as estimated by AChE inhibitionproceeds apparently at the same rate for the C(–)P(–)-and C(+)P(–)-isomers. However, the release of fluorideions indicated a stereospecific rate of reaction, the P(-Hsomersreacting faster than the P(+)-isomers. At pH 7.40, the inactivationrate of soman by ß-cyclodextrin was as fast in humanplasma in vitro as in Tris buffer. This interaction betweensoman and ß-cyclodextrin, and other data from theliterature, suggests that the introduction of catalytic or noncatalyticgroups on ß-cyclodextrin might possibly make it abetter catalyst for soman inactivation through improvement inthe catalytic or in the binding process.     

Duloxetine in the treatment of women with stress urinary incontinence: results from DESIRE (Duloxetine Efficacy and Safety for Incontinence in Racial and Ethnic populations)

ABSTRACT

Objective: To evaluate the effectiveness and safety of duloxetine for the treatment of African– American and Hispanic women with stress urinary incontinence.

Research design and methods: The 10‐week (a 2‐week lead in period followed by 8 weeks of active treatment), open-label, multicenter study of duloxetine 40?mg twice daily included women with stress urinary incontinence or stress predominant mixed incontinence. Efficacy was measured by the median percent change from baseline to endpoint of weekly incontinence episode frequency. The primary objective assessed the treatment response in a pre-specified group of women (n = 2960; 2321 Caucasian, 271 African–American, and 368 Hispanic) with similar baseline incontinence and comorbidity characteristics as the subjects enrolled in the placebo-controlled trials of duloxetine for the treatment of stress urinary incontinence. The efficacy in African–American and Hispanic women was compared with Caucasians using a predefined non-inferiority subpopulation analysis. Safety measures included adverse events, laboratory test results, and vital signs.

Results: All three subgroups reported significant (all p < 0.001) median percent decreases in weekly incontinence episode frequency: –65.7% (African–American), –73.0% (Hispanic), and –75.0% (Caucasian). Non-inferior efficacy was demonstrated for African–American and Hispanic women compared to the Caucasian women. Common adverse events included nausea (21.8%, 28.0%, 25.3%), dry mouth (7.7%, 11.4%, 11.9%), and fatigue (9.2%, 5.7%, 11.6%) for the African–American, Hispanic, and Caucasian groups, respectively.

Conclusion: Duloxetine was efficacious and well tolerated for the treatment of African–American, Hispanic, and Caucasian women with stress urinary incontinence. The trial design was successful in enrolling a diverse population of patients. The most important limitations include the lack of placebo control, the short study duration, and the exclusion of patients with less than seven incontinence episodes per week.