and never-married people (OR 1.32) had a higher risk for depression. Among elderly unmarried people, widowed people had a higher risk for depression than those who never married (OR 1.51). In conclusion, being unmarried was an important risk factor for depression in elderly people.

The synthesis and CRF receptor binding affinities of several new series of N-aryltriazolo- and -imidazopyrimidines and -pyridines are described. These cyclized systems were prepared from appropriately substituted diaminopyrimidines or -pyridines by nitrous acid, orthoester, or acyl halide treatment. Variations of amino (ether) pendants and aromatic substituents have defined the structure-activity relationships of these series and resulted in the identification of a variety of high-affinity agents (Ki's < 10 nM). On the basis of this property and lipophilicity differences, six of these compounds (4d,i,n,x, 8k, 9a) were initially chosen for rat pharmacokinetic (PK) studies. Good oral bioavailability, high plasma levels, and duration of four of these compounds (4d,i,n,x) prompted further PK studies in the dog following both iv and oral routes of administration. Results from this work indicated 4i,x had properties we believe necessary for a potential therapeutic agent, and 4i1 has been selected for further pharmacological studies that will be reported in due course.

BackgroundPostnatal developmental changes of human renal membrane transporters, which are key players of disposition of renally cleared drugs and endogenous substrates, are largely unknown. This study aimed to characterize the ontogeny of 11 human renal transporters to understand changes in the renal clearance of substrate drugs in children.Methods mRNA levels of known renal transporters: BCRP, MATE1, MATE2-K, MDR1, MRP2, MRP4, URAT1, GLUT2, OAT1, OAT3 and OCT2, and the transcription factor PXR were measured with RT-qPCR in 184 human postmortem frozen renal cortical tissues (preterm newborns - adults; 1 day-75 yrs old) from individuals of European and African descent. Protein expression of all but MRP2, MRP4 and PXR was quantified with LC-MS/MS SRM in 62 of those samples (term newborns - adults; 1 day-29 yrs old). Localization of MRP4 was tested with immunohistochemistry.ResultsExpression levels of MDR1, URAT1, OAT1, OAT3, and OCT2 increased with age, but levels of MATE1 and GLUT2 were stable from birth. Protein levels of MATE2-K and BCRP showed no difference from newborns to adults despite age-related changes in mRNA expression. MRP2, MRP4 and PXR expression levels were stable. MRP4 localization in pediatric samples was similar to that in adult samples.ConclusionRenal drug transporters exhibited different rates and patterns of maturation, suggesting that renal handling of both endogenous and exogenous compounds may change with age. It is important to consider ontogeny of renal transporters during pediatric drug development.Disclosure(s)The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Views expressed in this paper are those of authors and do not necessarily reflect the official views or policies of the FDA; nor does any mention of trade names, commercial practices, or organization imply endorsement by the U.S. Government.*Contributed equally,**Contributed equally