Oxytocin (OT) modulates the expression of social and emotional behaviors and consequently has been proposed as a pharmacologic treatment of psychiatric diseases, including autism spectrum disorders and schizophrenia; however, endogenous OT has a short half-life in plasma and poor permeability across the blood-brain barrier. Recent efforts have focused on the development of novel drug delivery methods to enhance brain penetration, but few efforts have aimed at improving its half-life. To explore the behavioral efficacy of an OT analog with enhanced plasma stability, we developed PF-06655075 (PF1), a novel non–brain-penetrant OT receptor agonist with increased selectivity for the OT receptor and significantly increased pharmacokinetic stability. PF-06478939 was generated with only increased stability to disambiguate changes to selectivity versus stability. The efficacy of these compounds in evoking behavioral effects was tested in a conditioned fear paradigm. Both central and peripheral administration of PF1 inhibited freezing in response to a conditioned fear stimulus. Peripheral administration of PF1 resulted in a sustained level of plasma concentrations for greater than 20 hours but no detectable accumulation in brain tissue, suggesting that plasma or cerebrospinal fluid exposure was sufficient to evoke behavioral effects. Behavioral efficacy of peripherally administered OT receptor agonists on conditioned fear response opens the door to potential peripheral mechanisms in other behavioral paradigms, whether they are mediated by direct peripheral activation or feed-forward responses. Compound PF1 is freely available as a tool compound to further explore the role of peripheral OT in behavioral response.

Water soluble derivatives of cellulose are widely used in various biomedical and biotechnological applications. Sodium carboxymethyl cellulose was insolubilized in the form of microspheres using aluminium chloride as the crosslinking agent. It was observed that, depending on the preparation medium pH, the spherical product could either be a microsphere with an ionotropic interior or a microcapsule. Various microspheres with different crosslinker, biopolymer, and drug (2',7'-dichlorofluorescein and aldicarb) contents were prepared and their structures, properties, swelling behaviour and release kinetics investigated. The release kinetics could not be described by typical Fickian or non-Fickian approaches.

Modulators of P-glycoprotein (P-gp) can enhance or limit the permeability of a number of therapeutic agents that are considered substrates of this efflux pump protein. The modulatory effect of amlodipine (4-dihydropyridine calcium antagonist) on P-gp efflux activity has not been fully elucidated. We have studied the concentration dependency of its modulatory effect and compared it qualitatively with tamoxifen (a non-esteroid anti-estrogen). The investigation was conducted on transmembrane efflux of doxorubicin at a fixed concentration of 5 microM across a Caco-2 monolayer in the presence of various concentrations of amlodipine or tamoxifen. The maximum flux of doxorubicin from basolateral to apical (ba) occurred at 4.5 microM amlodipine and at 0.02 microM tamoxifen. At higher concentrations, the apical to basolateral (ab) flux and the net flux of doxorubicin (ba - ab) declined steadily in a concentration-dependent manner. We analysed the observed net flux data by fitting different mathematical models to the data. A composite sigmoidal Emax/Imax (stimulatory/inhibitory) model was found to be the most appropriate to define the system. The observed and calculated parameters supported the modulatory role of both compounds and clearly indicated that the stimulation and inhibition of transmembrane efflux occurred simultaneously in the presence of amlodipine or tamoxifen. It was concluded that amlodipine, similar to tamoxifen, modulated the transporter-dependent transmembrane flux of the P-gp substrate in a concentration-dependent manner.

The effect of TAM on DOX accumulation in the myocardial tissue and the increase in cardiotoxicity can be related to the net inhibitory effect of TAM on the efflux activity of Pgp in the heart. The results of the present study supported the hypothesis of the project that multiple regimen pretreatment with Pgp modulator TAM increases the DOX accumulation in the heart and promotes DOX-induced cardiotoxicity.

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