Pharmacokinetic-Pharmacodynamic Modeling of the Antinociceptive Effect of Diclofenac in the Rat 1

ABSTRACT The relationship between the pharmacokinetics and the antinociceptive effect of diclofenac was evaluated using the paininduced functional impairment model in the rat. Male Wistar rats were injected with uric acid in the knee joint of the right hind limb, which induced its dysfunction. Once the dysfunction was complete, animals received a p.o. dose of 0.56, 1, 1.8, 3.2, 5.6 or 10 mg/kg of sodium diclofenac, and the antinociceptive effect and drug blood concentration were simultaneously evaluated at selected times for a period of 6 h. Diclofenac produced a dose-dependent antinociceptive effect, measured as a recovery of the functionality of the injured limb. However, the onset of the antinociceptive effect was delayed with respect to blood concentrations. Moreover, the effect lasted longer than expected from pharmacokinetic data. Therefore, when functionality index was plotted against diclofenac blood concentration, an anticlockwise hysteresis loop was observed for all doses. Hysteresis collapse was achieved using the effect-compartment model, and the plot of functionality index against diclofenac concentration in the effect-compartment data was well fitted by the sigmoidal E max model. Our data suggest slow equilibrium kinetics between diclofenac concentration in blood and at its site of action, which leads to a delayed onset of the antinociceptive effect as well as a longer duration of the response resulting from drug accumulation in synovial fluid. Diclofenac is an NSAID that has been shown to be effective for relieving pain in rheumatic and nonrheumatic diseases On the other hand, it has been established that the relationship between pharmacokinetic properties and pharmacologic effect is the basis for a more rational drug regimen design, because it allows prediction of the time course of the intensity of the effect There are reports wherein the anti-inflammatory and antinociceptive effect of diclofenac cannot be directly explained by circulating concentrations in animals Materials and Methods Animals. Male Wistar rats (weighing, 180-220 g) from our own breeding facilities [Crl:(WI)BR], were used in this study. Animals were housed in a room with controlled temperature (22 Ϯ 1°C) for at least 2 days before the study. Food was withheld for 12 h before the Received for publication May 10, 1996. 1 This work is supported by CONACYT, grant 0250-M. ABBREVIATIONS: AUC, area under the blood concentration-time curve; AUC E , area under the functionality index-time curve; C, blood concentration; C max , maximal concentration; E max , maximal effect; E max obs , maximal observed effect; Ke0, transference rate constant from site effect; PIFIR, pain-induced functional impairment model in the rat; PE, polyethylene; NSAID, nonsteroidal anti-inflammatory drug; FI, functionality index

Increased Endoparasite Infection in Late-Arriving Individuals of a Trans-Saharan Passerine Migrant Bird

Abstract Earlier migration in males than in females is the commonest pattern in migrating passerines and is positively related to size dimorphism and dichromatism. The early arrival of males is a costly trait that may confer reproductive advantages in terms of better territories and/or mates. Given the physiological cost of migration, early migrants are those in best condition and accordingly the prevalence, load, and/or diversity of parasites is expected to increase in both sexes for late migrants. To test this hypothesis, we sampled 187 trans-Saharan migrant garden warblers Sylvia borin and 64 resident serins Serinus serinus (as a control for potential circannual patterns in parasite load) during spring migration in Spain. We assessed the prevalence of blood parasites (Haemoproteus, Plasmodium, and Leucocytozoon) and the prevalence and load of intestinal parasites (mainly coccidians and spirurids). The relationship between parasite (prevalence, load, and richness) and the timing of passage through a stopover area was tested using generalized linear models. Protandry occurs in the monomorphic garden warbler and males migrated on average 5.5 days before females. Intestinal parasite richness increased with the date of migration. The timing of migration was unrelated to the presence or load of the other parasite groups analyzed. Our results support the idea that the timing of migration is a condition-dependent trait and suggests that multiple intestinal parasite infestations could delay migration in birds. Even in monomorphic species parasites may play a role in sexual selection by delaying the arrival of the most infected individuals at breeding grounds, thereby further increasing the benefits of mating with early-arriving individuals

Sequence and phylogenetic analysis of genome segments

Abstract Mal de Río Cuarto virus (MRCV) is a newly described species of the genus Fijivirus , family Reoviridae . The nucleotide sequence of four MRCV genome segments was determined. MRCV S1, S2, S3 and S6 were predicted to encode proteins of 168.4, 134.4, 141.7 and 90 kDa, respectively. MRCV S1 encodes a basic protein that contains conserved RNA-dependent RNA polymerase motifs, and is homologous to Rice black streaked dwarf virus (RBSDV), Fiji disease virus (FDV) and Nilaparvata lugens reovirus (NLRV) polymerases as well as to corresponding proteins of members of other genera of the Reoviridae . MRCV S2 codes for a protein with intermediate homology to the ones coded by RBSDV S4 and FDV S3 'B' spike, which is presumably the B-spike protein. MRCV S3 most probably encodes the major core protein and is highly homologous to corresponding proteins of RBSDV S2 and FDV S3. MRCV S6-encoded protein has low homology to the proteins of unknown function coded by RBSDV S6 and FDV S6. The identity levels between all analyzed MRCV coded proteins and their RBSDV counterparts varied between 84.5 and 44.8%. The analysis of the reported sequences allowed a phylogenetic comparison of MRCV with other reovirus and supported its taxonomic status within the genus.