The Artemisinin class of compounds is the most rapidly acting of all antimalarials. Two artemisinin derivatives, artemether and artesunate have been most widely used in the treatment of multi-drug resistant falciparum malaria. Artesunate (AS) and most other artemisinin derivatives (artemether, arteether) are biotransformed to dihydroartemisinin (DHA), the major active metabolite. Dihydroartemisinin is the most potent member of the class in in vitro test system. It is synthesized by chemical reduction of artemisinin extracted from the Chinese herb and is used as the starting material for the manufacture of artesunate, aitemether, and arteether. Since DHA is the most potent and least expensive to manufacture, it has the potential to be developed as an antimalarial drug in the market. Aiiesunate is readily biotransformed to dihydroartemisinin and, therefore, measurement of antimalarial activity in blood provides a critical pharmacodynamics endpoint. Quantitative determination of plasma total antimalarial activity can be performed by the use of an in vitro Plasmodium falciparum bioassay method, which has been validated to measure drug in serum or plasma samples from patients given artemisinin compounds. The plasma antimalarial activity is reported as the concentration equivalent to DHA. In other words, the antimalarial activity of AS is reported as the concentration of DHA that produces the same antimalarial activity as AS. Data from the bioassay provides information on the pharmacokinetic pharmacodynamic or the effect kinetic profile of the drugs. As part of the drug development process, the pharmacokinetic-pharmacodynamic properties of oral dihydroru·temisinin were compared with oral artesunate (4 mg/kg) in a crossover study in Thai healthy volunteers (n=20) and in patients with acute, uncomplicated malaria (n=20) admitted to the Hospital of Tropical diseases, Bangkok. The drugs were given sequentially once daily (day 1 DHA, day 2 AS or vice versa). For patients, mefloquine (MQ) 25 mg/kg was administered as a split dose on the third day to complete the treatment. The maximum effect (Cmax) associated with DHA (1,576 nM) is less than that of AS (4,042 nM) in normal volunteers (p 0.05), there are wide variation in the half-live's associated with AS in patients compared to volunteers (0.5 - 4.0 h). The areas under the effect-time curves corrected for molar dose (AUC/D) of DHA in both volunteers and patients (0.394 and 0.804 h.kg.L - 1 , respectively) are less than AS (0.654 and 1.114 h.kg.L -1 , respectively; p < 0.001). The relative bioavailability of the effect associated with DHA is 70% and 80% of AS in volunteers and patients, respectively. The apparent volume of distribution (Vz/f) of the effect associated with DHA is 2 fold greater than AS (6.8 VS 2.7 L.kg -1 in normal volunteers, p = 0.001; and 2.6 VS 1.6 L.kg -1 in patients, p = 0.005). The clearance (Cl/f) of the DHA effect is faster than that of AS in normal volunteers (3.0 VS 1.7 L.kg -1 .h -1 , p < 0.001) but it is not clinically different in patients (1.3 VS 1.0 L.kg -1 .h -1 , p = 0.01). The volume of distribution and clearance associated with DHA are reduced by half in patients with malaria compared to volunteers (6.79 VS 2.57 L.kg - 1 and 3.03 VS 1.33 L. kg -1 .h -1 , p = 0.001 and < 0.001, respectively). Both parameters for AS are also reduced in patients but to a lesser extent than DHA (2.68 VS 1.59 L.kg·1 and 1.72 VS 1.01L. kg -1 .h -1 , p=0.004 and= 0.006, respectively). In summary, effect kinetic bioavailability of oral DHA is 80% of oral AS in patients. If the production cost of DHA is, in fact significantly less than AS, DHA can be regarded as comparable to or economically better than AS.
Classical population genetics theory predicts that selection should deplete heritable genetic variance for fitness. We show here that, consistent with this prediction, there was a negative correlation between the heritability of a trait and its association with fitness in a wild population of red deer (Cervus elaphus) and there was no evidence of significant heritability of total fitness. However, the decline in heritability was caused, at least in part, by increased levels of residual variance in longevity and, hence, in total fitness: in this population, longevity is known to be heavily influenced by environmental factors. Other life history traits that were not associated with longevity, such as average annual breeding success, had higher heritabilities. Coefficients of additive genetic variance differed markedly between traits, but highly skewed measures, such as male breeding success, generally had greater coefficients of variance than morphometric traits. Finally, there were significant maternal effects in a range of traits, particularly for females.
No abstract is provided for this article.
In reviewing this book I am going to say some harsh things about it. From this one might think that I did not like the book. In fact, one would be wrong to think so. For this reason I wish to state up front that I did like the book. It was an ambitious undertaking and I think that the author has, for the most part, pulled it off. This extremely broad and rich book will allow those non-specialists with a sufficiently long attention span to obtain a good understanding of what cosmic rays are and what cosmic ray research is all about. I have pointed out things that bothered me because I believe that the book is good enough for a second edition and I hope that these matters can be addressed at that time.
This long-awaited study of the most enigmatic figure of Greek philosophy reclaims Socrates' ground-breaking originality. Written by a leading historian of Greek thought, it argues for a Socrates who, though long overshadowed by his successors Plato and Aristotle, marked the true turning point in Greek philosophy, religion and ethics. The quest for the historical figure focuses on the Socrates of Plato's earlier dialogues, setting him in sharp contrast to that other Socrates of later dialogues, where he is used as a mouthpiece for Plato's often anti-Socratic doctrine. At the heart of the book is the paradoxical nature of Socratic thought. But the paradoxes are explained, not explained away. The book highlights the tensions in the Socratic search for the answer to the question 'How should we live?' Conceived as a divine mandate, the search is carried out through elenctic argument, and dominated by an uncompromising rationalism. The magnetic quality of Socrates' personality is allowed to emerge throughout the book. Clearly and forcefully written, philosophically sophisticated but entirely accessible to non-specialists, this book will be of major importance and interest to all those studying ancient philosophy and the history of Western thought.
The evolution of cooperative behavior is a major area of research among evolutionary biologists and behavioral ecologists, yet there are few estimates of its heritability or its evolutionary potential, and long-term studies of identifiable individuals are required to disentangle genetic and nongenetic components of cooperative behavior. Here, we use long-term data on over 1800 individually recognizable wild meerkats (Suricata suricatta) collected over 30 years and a multigenerational genetic pedigree to partition phenotypic variation in three cooperative behaviors (babysitting, pup feeding, and sentinel behavior) into individual, additive genetic, and other sources, and to assess their repeatability and heritability. In addition to strong effects of sex, age, and dominance status, we found significant repeatability in individual contributions to all three types of cooperative behavior both within and across breeding seasons. Like most other studies of the heritability of social behavior, we found that the heritability of cooperative behavior was low. However, our analysis suggests that a substantial component of the repeatable individual differences in cooperative behavior that we observed was a consequence of additive genetic variation. Our results consequently indicate that cooperative behavior can respond to selection, and suggest scope for further exploration of the genetic basis of social behavior.
No abstract is provided for this article.
No abstract is provided for this article.
