Population pharmacokinetics of gabapentin in infants and children.

PURPOSE: To characterize gabapentin pharmacokinetics in infants and children using a population approach and to identify important demographic and/or physiologic determinants of gabapentin disposition. METHODS: Gabapentin was administered in single doses of 10 mg/kg (N=48 healthy subjects, age 1 month-12 years) or in multiple doses of 10-65 mg/kg per day (N=205 patients with epilepsy, age 2 months-13 years) at 08:00, 14:00, and 20:00. Serial concentration-time data from the healthy subjects were combined with sparse data obtained in patients and were modeled using NONMEM. RESULTS: Gabapentin oral clearance (l/h) was directly related to creatinine clearance (ml/min) with a slope of 0.116. The slope of the relationship was 36% greater in blacks than in subjects of other races. When oral clearance was normalized for body weight, young children (<5 years) had higher and more variable values than older children. Volume of distribution was related to body weight and appeared to differ between subjects and patients. Intersubject variability was approximately 30% for oral clearance and volume of distribution and was larger for the absorption rate constant and lag time. Residual variability, a measure of intrasubject variability and measurement error, was smaller in subjects than in patients. CONCLUSIONS: On a weight basis, 33% larger doses would be required in younger children (<5 years) to achieve the same exposure as older children.

Sexual conflict: males with highest mating success convey the lowest fertilization benefits to females.

In natural populations of a coral reef fish (the bluehead wrasse, Thalassoma bifasciatum), males with the highest daily mating success produce the fewest sperm per mating, and this is reflected in significantly lower fertilization rates. The average amount released by males in pair-mating was 3.3 x 10(6) spermatozoa, resulting in a fertilization rate of 96%. Sperm released per spawn declined with increasing mating success, so that females mating with the most successful males had less than 93% of their eggs fertilized. It is unlikely that high mating-success males are physiologically incapable of increasing sperm production, because younger males with different mating strategies have absolutely larger testes and higher daily sperm output. Feeding experiments suggest that high-success males are diverting energy from gamete production to other fitness-enhancing activities such as mate guarding. Females incur the cost of low sperm release by having fewer of their eggs fertilized. There are no obvious compensatory benefits to females from mating with high-success males.

The occurrence of the transposable element pogo in Drosophila melanogaster.

We examined the genomic occurrence of the transposable element pogo in over 120 strains of Drosophila melanogaster, from around the world and from different eras. All had multiple copies of a 2.1 kilobase (kb) pogo element, and multiple copies of several size classes between 1.0 and 1.8 kb. There were differences between strains in intensities or presences of deletion-derivative size classes, suggesting current or recent mobility in the species. We were unable to find any pogo-hybridization in eight other species in the genus, in three subgenera, or in the related Scaptomyza pallida. The pogo element may be a 'middle-aged' element in the genome of D. melanogaster, having entered the species since its divergence from its sibling species, but long before the P and hobo elements.

Plasticity of gonadal development and protandry in fishes.

Sexual differentiation in eutherian mammals follows a simple governing paradigm: development proceeds in a female direction unless a masculinizing mechanism intervenes. Sexual development in fishes is much more plastic than in mammals. It permits the intervention of environmental factors and follows several different types of sequences that produce successive hermaphrodites and alternative pathways for the development of the same final sex. In spite of this plasticity, the primacy of female development is suggested by the initial ovarian phase in the development of gonads of both sexes in some gonochoristic fishes and by protogynous sex change. One barrier to the application of this principle to fishes generally is the existence of protandric hermaphrodites. Recent evidence suggests a reinterpretation of gonadal differentiation in a protandric anemonefish and a protandric sparid. In both cases, testicular development is both preceded and followed by ovarian development. These patterns are interpreted to mean that female development is primary and that male development is a temporary phase initiated by a masculinizing mechanism and terminated by its cessation.

Sex-changing fish as a manipulable system for the study of the determination, differentiation, and stability of sex in vertebrates.

Two fundamental questions concerning vertebrate sexuality are what controls the stability of gender throughout the life of an individual and what are the genetic, immunological, and endocrine factors controlling sex determination and differentiation. Significant aspects of both issues cannot readily be examined experimentally in standard laboratory vertebrates partly because these species are gonochores and provide no opportunity to examine plasticity in sexual systems, and partly because few means have yet been found experimentally to manipulate immunogenetic factors, such as sex-specific DNA or cell-surface antigens, thought to be involved in the determination and differentiation of sex. Behaviorally induced adult sex change in hermaphroditic fishes constitutes a unique system of controlled sexual plasticity in which these issues can be addressed. Several species of tropical marine fishes satisfy the requirements for an appropriate laboratory experimental animal. Sex change in them is known to involve alterations in external coloration, behavior, gonadal structure, hormonal enzyme activity, levels of circulating steroid hormones, and concentrations of H-Y antigen. Genetic, immunological, endocrine, and behavioral factors interact with one another causally in ways permitting relatively simple manipulations simultaneously to analyze the network of sequential causes for sex change and to address the above-stated fundamental issues concerning sexuality generally in vertebrates. Since sex change can be started at will, these fish species become powerful model systems for the analysis of basic mechanisms of sex determination, differentiation, and long-term stability.

Increased H-Y antigen levels associated with behaviorally induced, female-to-male sex reversal in a coral-reef fish.

It has been proposed that H-Y antigen is the synthetic product of sex-determining genes, and that H-Y antigen controls ontogenetic differentiation of the heterogametic sex throughout vertebrates. The coral-reef fish Anthias squamipinnis is a protogynous hermaphrodite in which all individuals mature initially as females. Males result when adult females change sex as a consequence of alterations in behavioral interactions within social groups. Three assay methods were used to measure H-Y antigen levels in the spleens, gonads, and epidermal tissue of 16 adult females and in 16 males that had been induced to change sex from a prior female phase by the removal of a pre-existing male from each of 16 social groups. In 15 male-female pairs, the H-Y antigen levels were higher in male than in female spleen, gonad, and epidermis tissues. The precise temporal relationship between the onset of sex change and the increase in the H-Y antigen level was not examined. If, as we strongly suspect, the temporal relationship proves to be close, the inference will be that the behavioral cues inducing sex change also influence the synthetic activity of genes controlling H-Y antigen production.

Distinguishing behavioral interactions from visual cues as causes of adult sex change in a coral reef fish.

Two experiments tested the hypothesis that adult female-to-male sex reversal in protogynous fish is induced by the loss of close-contact behavioral interactions between males and females, and not by the loss of simple visual cues from the male. Twenty-six laboratory groups of Anthias squamipinnis were manipulated so that females within each group (1) retained chemical and acoustic access to a male, (2) were denied behavioral access to a male, and (3) were either allowed or denied visual access to a male alone or to a male interacting with another female. At least one female subsequently changed sex in each of 22 groups. While acoustic and chemical cues were not completely eliminated as possible causes, sex change is apparently induced by loss of male-female behavioral interaction in combination with continued interaction between females.

Serial female sex changes after simultaneous removal of males from social groups of a coral reef fish.

The simultaneous removal of three to nine males from large social groups of Anthias squamipinnis led to close to a one-to-one replacement of the removed males by sex-reversing females. The females changed sex serially within each group with a mean interval between successive onset times of 1.9 days. The timing of sex change is thus not independent for each fish but is influenced by the events surrounding other sex reversals within the group.