Influence of Plasma Protein Binding on Pharmacodynamics: Estimation of In Vivo Receptor Affinities of beta Blockers Using a New Mechanism-Based PK-PD Modelling Approach

The objective of this investigation was to examine in a systematic manner the influence of plasma protein binding on in vivo pharmacodynamics. Comparative pharmacokinetic-pharmacodynamic studies with four beta blockers were performed in conscious rats, using heart rate under isoprenaline-induced tachycardia as a pharmacodynamic endpoint. A recently proposed mechanism-based agonist-antagonist interaction model was used to obtain in vivo estimates of receptor affinities (K(B),(vivo)). These values were compared with in vitro affinities (K(B),(vitro)) on the basis of both total and free drug concentrations. For the total drug concentrations, the K(B),(vivo) estimates were 26, 13, 6.5 and 0.89 nM for S(-)-atenolol, S(-)-propranolol, S(-)-metoprolol and timolol. The K(B),(vivo) estimates on the basis of the free concentrations were 25, 2.0, 5.2 and 0.56 nM, respectively. The K(B),(vivo)-K(B),(vitro) correlation for total drug concentrations clearly deviated from the line of identity, especially for the most highly bound drug S(-)-propranolol (ratio K(B),(vivo)/K(B),(vitro) similar to 6.8). For the free drug, the correlation approximated the line of identity. Using this model, for beta-blockers the free plasma concentration appears to be the best predictor of in vivo pharmacodynamics. (C) 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:3816-3828, 2009

On the Upper Cretaceous age and affinities of Neocyprideis lusitanicus (Ostracoda)

Guernet & Lauverjat (1986) described a new species, Neocyprideis lusitanicus, from sediments deposited near Aveiro, Portugal. For these authors, some associated fossils (Molluscs, planktonic Foraminifera) indicated a Pliocene age. That seemingly was the first record of Neocyprideis in post-Miocene sediments in Europe. A recent study of Upper Cretaceous material from the same region showed an abundant Neocyprideis fauna, associated with Charophyta. These Neocyprideis could be assigned without any doubt to N. lusitanicus. Therefore, N. lusitanicus appears as an Upper Cretaceous species, reworked in much later sediments, not Pliocene but Quaternary, as indicated by the planktonic Foraminifera assemblage. This interpretation is supported by: 1 - the incompatibility of the Neocyprideis (restricted to lacustrine-lagoonal environments) with abundant planktic Foraminifera; 2 - the occurrence of N. lusitanicus with Charophytes and non marine, cretaceous vertebrates but without the same Foraminifera. Neocyprideis lusitanicus is a valid species, clearly different from the other late Cretaceous species (N. coudouxensis and N. murciensis) as well as the Early Miocene described species (N. aquitanica, N. janoscheki).

Catalogue of birds of the Americas and the adjacent islands in Field Museum of Natural History. including all species and subspecies known to occur in North America, Mexico, Central America, South America, the West Indies, and islands of the Caribbean Sea, the Galapagos Archipelago, and other islands which may properly be included on account of their faunal affinities /

v.13:pt.2:no.1(1918)

A manual of the infusoria, including a description of all known flagellate, ciliate, and tentaculiferous protozoa, British and foreign and an account of the organization and affinities of the sponges by W. Saville Kent, 3 vol.

1

A manual of the infusoria, including a description of all known flagellate, ciliate, and tentaculiferous protozoa, British and foreign and an account of the organization and affinities of the sponges by W. Saville Kent, 3 vol.

3

A manual of the infusoria, including a description of all known flagellate, ciliate, and tentaculiferous protozoa, British and foreign and an account of the organization and affinities of the sponges by W. Saville Kent, 3 vol.

2

The birds of Sibuyan Island, Romblon Province, Philippines : with particular reference to elevational distribution and biogeographic affinities / Steven M. Goodman, David E. Willard, Pedro C. Gonzales.

n.s. no.82(1995)

A remarkable new mouse (Muridae: Sigmodontinae) from southeastern Peru : with comments on the affinities of Rhagomys rufescens (Thomas, 1886) / Lucía Luna, Bruce D. Patterson.

n.s. no.101(2003)

Fauna of the Vale and Choza : Diadectes, Xenacanthus, and specimens of uncertain affinities / Everett Claire Olson --

v.10:no.27(1956)