Pentoxifylline increases erythrocyte flexibility, reduces blood viscosity, and inhibits platelet aggregation and is thus used in the treatment of peripheral vascular disease. It is transformed into at least seven phase I metabolites, of which two, M1 and M5, are active. The reduction of the keto group of pentoxifylline to a secondary alcohol in M1 takes place chiefly in erythrocytes, is rapidly reversible, and creates a chiral center. The aims of this study were: to develop HPLC methods to separate the enantiomers of M1, to investigate the kinetics of the reversible biotransformation of pentoxifylline to (R)- and (S)-M1 in hemolysed erythrocyte suspension, and to quantify the formation of the enantiomers of M1 (as well as M4 and M5) after intravenous and oral administration of pentoxifylline to human volunteers. (R)- and (S)-M1 could be separated preparatively on a cellobiohydrolase column, while determination in blood or plasma was by HPLC after chiral derivatization with diacetyl-L-tartaric acid anhydride. The metabolism of pentoxifylline to (R)-M1 in suspensions of hemolysed erythrocytes followed simple Michaelis-Menten kinetics (K(m) = 11 mM), while that to (S)-M1 was best described by a two-enzyme model (K(m) = 1.1 and 132 mM). Studies with inhibitors indicated that the enzymes were of the carbonyl reductase type. At a therapeutic blood concentration of pentoxifylline, the calculated rate of formation of (S)-M1 is 15 times higher than that of the (R)-enantiomer. Back-conversion of M1 to pentoxifylline was 3-4 times faster for the (S)- than for the (R)-enantiomer. In vivo, the R:S plasma concentration ratio of M1 ranged from 0.010-0.025 after intravenous infusion of 300 or 600 mg of pentoxifylline, and from 0.019-0.037 after oral administration of 600 mg. The biotransformation of pentoxifylline to M1 was thus highly stereoselective in favor of the (S)-enantiomer both in vitro and in vivo.

Objectives: Depressive symptoms in the elderly have been shown to be associated with increased mortality. The purpose of this study was to examine symptoms of depression in octogenarian men and their association with all-cause mortality, and whether physical, cognitive and social factors influence this association. Methods: Out of the 703 initially included 55-years-old men, from the prospective cohort study "Men born in 1914", we studied 163 survivors who could take a part in a survey at age 81, and followed them until their death. Results: Those men who had at least mild depressive symptoms, defined with Zung Self-rating Depression Scale, were found to have an increased mortality risk (HR ¼ 1.52; CI ¼1.10-2.08; p ¼ 0.01). This association persisted significantly after adjusting for: education, global cognition at age 81, cognitive abilities at age 68, vascular risk factors and comorbidities. Instead, it was attenuated after adjustments for Activities of Daily Life (ADL)dependency and for a grade of Satisfaction with Participation in daily life. Conclusion: In octogenarian men with survival above the average, mild depressive symptoms predict all-cause mortality. Neither cognitive capacity nor vascular comorbidity explained this association, but lower Satisfaction with Participation in daily life, especially in combination with moderate ADL-dependency.

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