Strong hybrid male incompatibilities impede the spread of a selfish chromosome between populations of a fly.

Meiotically driving sex chromosomes manipulate gametogenesis to increase their transmission at a cost to the rest of the genome. The intragenomic conflicts they produce have major impacts on the ecology and evolution of their host species. However, their ecological dynamics remain poorly understood. Simple population genetic models predict meiotic drivers will rapidly reach fixation in populations and spread across landscapes. In contrast, natural populations commonly show spatial variation in the frequency of drivers, with drive present in clines or mosaics across species ranges. For example, Drosophila subobscura harbors a sex ratio distorting drive chromosome (SRs) at 15-25% frequency in North Africa, present at less than 2% frequency in adjacent southern Spain, and absent in other European populations. Here, we investigate the forces preventing the spread of the driver northward. We show that SRs has remained at a constant frequency in North Africa, and failed to spread in Spain. We find strong evidence that spread is impeded by genetic incompatibility between SRs and Spanish autosomal backgrounds. When we cross SRs from North Africa onto Spanish genetic backgrounds we observe strong incompatibilities specific to hybrids bearing SRs. The incompatibilities increase in severity in F2 male hybrids, leading to almost complete infertility. We find no evidence supporting an alternative hypothesis, that there is resistance to drive in Spanish populations. We conclude that the source of the stepped frequency variation is genetic incompatibility between the SRs chromosome and the genetic backgrounds of the adjacent population, preventing SRs spreading northward. The low frequency of SRs in South Spain is consistent with recurrent gene flow across the Strait of Gibraltar combined with selection against the SRs element through genetic incompatibility. This demonstrates that incompatibilities between drive chromosomes and naïve populations can prevent the spread of drive between populations, at a continental scale.

Relationships between CSF drug concentrations, receptor binding characteristics, and pharmacokinetic and pharmacodynamic properties of selected 1,4-substituted benzodiazepines.

Pharmacokinetic profiles of the 1,4-substituted benzodiazepines are defined by their absorption, distribution, metabolism, and excretion characteristics. An ability to cross the blood-brain barrier and the onset of pharmacological activity have been associated with the physiochemical properties of the benzodiazepines. In addition, drug concentrations in the CSF correlate with the unbound drug concentrations in blood or plasma. Duration of pharmacological activity of the benzodiazepines in humans is associated with the affinity of these compounds for the benzodiazepine receptors in human brain. Therefore, benzodiazepines with high affinity for the benzodiazepine receptor sites in human brain tend to exhibit prolonged half-lives of elimination from the CSF which correlate with the prolonged duration of clinical and pharmacological effects and lower therapeutic doses of these drugs in vivo.

Pharmacokinetic model for diazepam and its major metabolite desmethyldiazepam following diazepam administration.

A five-compartment open model was used to simulate the blood concentration profiles of diazepam and its metabolite, desmethyldiazepam, following single- and multiple-dose administrations of diazepam. The parameter estimates for diazepam were previously reported literature values. The parameters estimates for the metabolite were calculated from literature values of blood concentrations of desmethyldiazepam following the administration of clorazepate. The five-compartment open model suggests that approximately 50% of the administered diazepam is biotransformed to desmethyldiazepam, and that the elimination profile of the metabolite is not altered by the presence of the drug. The model may also be readily adapted to predict the concentrations of diazepam and desmethyldiazepam in cerebrospinal fluid following the administration of diazepam by simply correcting the blood or plasma concentrations of the drug and metabolite for the degree of plasma protein binding.

A pharmacokinetic/pharmacodynamic/receptor binding model to predict the onset and duration of pharmacological activity of the benzodiazepines.

Ex vivo receptor binding as a function of time was determined in Charles River rats. The pharmacokinetic and protein binding parameters in man as well as the ex vivo receptor binding parameters in rat brain for three benzodiazepine induction agents, diazepam, lorazepam and midazolam, were used to develop and test a pharmacokinetic/pharmacodynamic/receptor binding model. The model was subsequently used to predict changes in receptor binding and pharmacodynamics as a function of changes in pharmacokinetics. The model was found to be a good predictor of the relative onset and duration of the sedative and amnesic properties in normal subjects as well as in the presence of certain patho-physiological conditions and certain drug interactions.

Bumetanide: radioimmunoassay and pharmacokinetic profile in humans.

A simple, specific, and sensitive radioimmunoassay was developed for the determination of the diuretic bumetanide in plasma and urine. Antiserum to bumetanide was obtained from rabbits immunized with an immunogen prepared by covalently coupling the glycine conjugate of bumetanide to bovine serum albumin. Following extraction of the sample at pH 5.5 with ether, radioimmunoassay of the residue from the ether extract allows for the determination of bumetanide with a limit of sensitivity of about 1 ng/ml using 0.1 ml of plasma or urine. The specificity of the radioimmunoassay was established by comparison with specific radiometric and spectrofluorometric techniques. The pharmacokinetic profile of bumetanide in eight human subjects receiving single 2-mg oral doses of the drug was elucidated using the radioimmunoassay. The peak plasma levels ranged from 39 to 50 ng/ml at 1-4 hr after administration and declined with a mean apparent half-life of 1.17 hr. The mean plasma clearance rate was calculated to be 255 ml/min. During the first 24 hr, a mean of 43% of the bumetanide dose was excreted in the urine as intact drug.