Relative receptor affinity comparisons among inhaled/intranasal corticosteroids: perspectives on clinical relevance

<p>Abstract</p> <p>Background</p> <p>Pharmacokinetic properties, dosing regimen, and potency at the site of action are among the factors that influence activity of a corticosteroid. The potency of a corticosteroid at the site of action is determined significantly by its affinity to the glucocorticoid receptor. Recent literature on topical corticosteroids reveals an increasing emphasis on comparative relative receptor affinity values as a key method of differentiating among various corticosteroid compounds, particularly with regard to clinical efficacy.</p> <p>Methods</p> <p>A response was formulated to: Valotis A, Högger P: Human receptor kinetics and lung tissue retention of the enhanced-affinity glucocorticoid fluticasone furoate. Respir Res 2007, 8:54.</p> <p>Results</p> <p>Relative receptor binding affinities, while often showing significant variability across different laboratories, are a valid parameter when a comparison of the pharmacological activity of various glucocorticoids at the site of action is desired. Unfortunately within this context, scientific literature including the article from Valotis and Högger, confuse differences in potency (concentration or dose necessary to achieve a certain effect) with differences in efficacy (a quantitative difference in the overall maximum effect, even if all the receptors are occupied). All glucocorticoids will show the same efficacy as long as the selected dose will occupy the same number of receptors.</p> <p>Conclusion</p> <p>While relative receptor affinities are useful for comparing in vitro potencies of corticosteroids, these data are not representative of physiologic conditions and should not be used as a basis for comparing the presumed effectiveness of compounds in a clinical situation.</p

Cholestenoic acid, an endogenous cholesterol metabolite, is a potent γ-secretase modulator.

BackgroundAmyloid-β (Aβ) 42 has been implicated as the initiating molecule in the pathogenesis of Alzheimer's disease (AD); thus, therapeutic strategies that target Aβ42 are of great interest. γ-Secretase modulators (GSMs) are small molecules that selectively decrease Aβ42. We have previously reported that many acidic steroids are GSMs with potencies ranging in the low to mid micromolar concentration with 5β-cholanic acid being the most potent steroid identified GSM with half maximal effective concentration (EC50) of 5.7 μM.ResultsWe find that the endogenous cholesterol metabolite, 3β-hydroxy-5-cholestenoic acid (CA), is a steroid GSM with enhanced potency (EC50 of 250 nM) relative to 5β-cholanic acid. CA i) is found in human plasma at ~100-300 nM concentrations ii) has the typical acidic GSM signature of decreasing Aβ42 and increasing Aβ38 levels iii) is active in in vitro γ-secretase assay iv) is made in the brain. To test if CA acts as an endogenous GSM, we used Cyp27a1 knockout (Cyp27a1-/-) and Cyp7b1 knockout (Cyp7b1-/-) mice to investigate if manipulation of cholesterol metabolism pathways relevant to CA formation would affect brain Aβ42 levels. Our data show that Cyp27a1-/- had increased brain Aβ42, whereas Cyp7b1-/- mice had decreased brain Aβ42 levels; however, peripheral dosing of up to 100 mg/kg CA did not affect brain Aβ levels. Structure-activity relationship (SAR) studies with multiple known and novel CA analogs studies failed to reveal CA analogs with increased potency.ConclusionThese data suggest that CA may act as an endogenous GSM within the brain. Although it is conceptually attractive to try and increase the levels of CA in the brain for prevention of AD, our data suggest that this will not be easily accomplished

Nanosistema Dextrano/Quitosano con potencial aplicación oftalmológica

La administraci&oacute;n de productos intrav&iacute;treo constituye un riesgo al paciente, lo que ha conducido al desarrollo denue vas estrategias de f&aacute;rmacos y sistemas transportadores que disminuyan la frecuencia de administraci&oacute;n. Esta in -ves tigaci&oacute;n tuvo como objetivo desarrollar y caracterizar nanopart&iacute;culas de Quitosano como sistema de liberaci&oacute;nprolongada, empleando pol&iacute;meros biodegradables, hidrosolubles y compatibles a nivel ocular, para formar un nanosistemacombinado: pol&iacute;mero terap&eacute;utico/nanopart&iacute;cula (hemisuccinato de metilprednisolona Dextrano/Quitosano).Las nanopart&iacute;culas de quitosano se elaboraron por el m&eacute;todo de gelificaci&oacute;n i&oacute;nica empleando tripolifosfato s&oacute;dicocomo agente entrecruzante y se dispersaron con lactosa mediante el secado por atomizaci&oacute;n. Se evalu&oacute; morfolog&iacute;a,dis tribuci&oacute;n del tama&ntilde;o de las part&iacute;culas, contenido y eficacia de captura del f&aacute;rmaco as&iacute; como, su liberaci&oacute;n invitro. Las part&iacute;culas esf&eacute;ricas presentaron superficies lisas y uniformes donde el pH del medio tuvo influencia en eltama&ntilde;o de las mismas. El Quitosano fue capaz de encapsular el conjugado f&aacute;rmaco-pol&iacute;mero y crear una nueva formulaci&oacute;ncon una buena dispersabilidad en agua y de caracter&iacute;sticas deseables para el sistema ocular, que podr&iacute;aevidenciar un eficiente nanosistema de liberaci&oacute;n prologada in vivo que reduzca la frecuencia de administraci&oacute;n,ofreciendo una excelente alternativa que proporcione un mayor grado de satisfacci&oacute;n y mejore la calidad de vidapara los pacientes