Quantification of Efavirenz Hydroxymetabolites in Human Plasma Using LC-HRMS/MS.

BACKGROUND: Efavirenz (EFV) is a drug used to treat HIV. Low plasma concentrations of EFV result in suboptimal viral suppression, whereas high concentrations can cause adverse neuropsychiatric side reactions. Some studies have identified a correlation between the plasma concentrations of EFV metabolites and neurotoxicity. To our knowledge, no studies have investigated the metabolism of EFV in young children and its effect on treatment outcomes. Therefore, the aim of this study was to develop and validate a method for quantifying EFV and its metabolites in human plasma derived from children. METHODS: Sample preparation was performed using protein precipitation of 100 µL plasma. Thereafter, an aliquot of the supernatant was used to quantify EFV, 7-hydroxyefavirenz (7-OH-EFV), 8-hydroxyefavirenz (8-OH-EFV), and a newly discovered metabolite ("EFAdeg") associated with 8-OH-EFV. A second aliquot of the supernatant was hydrolyzed using ß-glucuronidase/arylsulfatase and used with the first aliquot to quantify phase II metabolites. The analyses were performed using a Dionex Ultimate 3000RS LC-system coupled with a Q Exactive Orbitrap mass spectrometer. RESULTS: The method has a measuring range of 100-50,000 ng/mL (EFV, 8-OH-EFV), 125-25,000 ng/mL (7-OH-EFV), and 200-10,000 ng/mL ("EFAdeg"). All criteria of the European Medicines Agency guidelines regarding precision, accuracy, and selectivity were met. Of note, carryover must be considered for 8-OH-EFV. Overall, the validated method was successfully applied to plasma samples obtained from children and confirmed the presence of the newly discovered metabolite, "EFAdeg." CONCLUSIONS: An LC-HRMS/MS method for the quantification of EFV and its phase I and II metabolites was developed and validated. This method is suitable for analyzing plasma samples from children. Furthermore, studies using this method identified an additional metabolite that may influence the concentration of 8-OH-EFV in patient samples.

Homecare workers - an untapped resource in preventing emergency department visits among older individuals? A qualitative interview study from Sweden.

BACKGROUND: Older individuals with functional decline and homecare are frequent visitors to emergency departments (ED). Homecare workers (HCWs) interact regularly with their clients and may play a crucial role in their well-being. Therefore, this study explores if and how HCWs perceive they may contribute to the prevention of ED visits among their clients. METHODS: In this qualitative study, 12 semi-structured interviews were conducted with HCWs from Sweden between July and November 2022. Inductive thematic analysis was used to identify barriers and facilitators to prevent ED visits in older home-dwelling individuals. RESULTS: HCWs want to actively contribute to the prevention of ED visits among clients but observe many barriers that hinder them from doing so. Barriers refer to care organisation such as availability to primary care staff and information transfer; perceived attitudes towards HCWs as co-workers; and client-related factors. Participants suggest that improved communication and collaboration with primary care and discharge information from the ED to homecare services could overcome barriers. Furthermore, they ask for support and geriatric education from primary care nurses which may result in increased respect towards them as competent staff members. CONCLUSIONS: HCWs feel that they have an important role in the health management of older individuals living at home. Still, they feel as an untapped resource in the prevention of ED visits. They deem that improved coordination and communication between primary care, ED, and homecare organisations as well as proactive care would enable them to add significantly to the prevention of ED visits.

Profiling chronic diseases and hospitalizations in older home care recipients: a nationwide cohort study in Sweden.

BACKGROUND: Older adults with home care (HC) often have complex disease patterns and use healthcare extensively. Increased understanding is necessary to tailor their care. To our knowledge, this is the first study to describe patterns of morbidity and hospitalizations among community-dwelling older HC recipients nationwide and in subgroups defined by age, sex, and amount of HC, and to compare patterns to community-dwelling older adults without HC. METHODS: Nationwide register-based cohort study in community-dwelling adults aged 70 and older receiving publicly funded HC in Sweden on January 1st 2019 and an age-and-sex matched comparison group ("non-HC recipients"). Using register data from inpatient and specialized outpatient care, we assessed the prevalence of sixty chronic diseases, frailty, multimorbidity and hospitalizations, calculated incidence rates and explored reasons for hospitalizations during two years of follow-up. RESULTS: We identified 138,113 HC recipients (mean age 85, 66% women, 57% ≥5 chronic diseases). The most prevalent diseases were hypertension (55%) and eye conditions (48%). Compared to non-HC recipients, HC recipients had a higher prevalence of almost all diseases, with an overrepresentation of neurological (26.1 vs. 9.5%) disease and dementia (9.3 vs. 1.5%). 61% of HC recipients were hospitalized at least once during two years, which was 1.6 times as often as non-HC recipients. One third of HC recipients´ hospitalizations (37.4%) were due to injuries, infections, and heart failure. Hospitalizations for chronic obstructive pulmonary disease, confusion, infections, and breathing difficulties were 3-5 times higher among HC recipients compared to non-HC recipients. CONCLUSION: Compared to non-HC recipients, HC recipients more often live alone, have higher degrees of frailty, suffer from more chronic diseases, especially neurological disease, and are hospitalized almost twice as often. The results provide a thorough description of HC recipients, which might be useful for targeted healthcare interventions including closer collaboration between primary care, neurologists, and rehabilitation.

Proud but Powerless: A Qualitative Study of Homecare Workers´ Work Experiences and Their Suggestions for How Care for Homebound Older Adults Can Be Improved.

Many older adults with complex care needs live at home due to ageing-in-place policies. This study explored homecare workers' experiences and suggestions for improvements of care. Twelve semi-structured interviews were analyzed thematically, and revealed pride, capability, and satisfaction in their work, yet they feel undervalued and lack support. They advocate for integrated care models, recognition of their competence, flexible work approaches, and committed leadership. This would enhance patient care and address their own working conditions, addressing concerns from being relegated to the bottom of the hierarchy. They emphasize the need for comprehensive approaches, spanning from housekeeping to end-of-life palliative care.

The interactive effect of ambient temperature and brood size manipulation on nestling body mass in blue tits: an exploratory analysis of a long-term study.

BACKGROUND: Relatively few studies have examined the interactive effects of ecological factors on physiological responses in wild animals. Nearly all of them have been short-term investigations that did not include experimental manipulations, limiting our ability to understand how climate change will affect natural populations. Using a 10-year brood size manipulation experiment in wild blue tits (Cyanistes caeruleus), we quantified the impact of weather conditions and brood competition on the body mass and structural size (tarsus length) of nestlings just prior to leaving the nest. RESULTS: We found that variation in nestling body mass on day 14 after hatching was explained by an interactive effect between average ambient temperature experienced during nestling period and brood size treatment. Specifically, in control broods nestling body mass was correlated with temperature in a non-linear manner (concave) with the vertex point (maximum body mass) at ca. 13 °C. In contrast, in enlarged broods nestling body mass permanently increased (also non-linearly) as temperature advanced. CONCLUSIONS: Our results highlight the importance of considering the effects of brood rearing conditions alongside other environmental factors experienced during growth while investigating early-life environmental effects on body condition.

Differential effects of steroid hormones on levels of broad-sense heritability in a wild bird: possible mechanism of environment × genetic variance interaction?

Genetic variation is one of the key concepts in evolutionary biology and an important prerequisite of evolutionary change. However, we know very little about processes that modulate its levels in wild populations. In particular, we still are to understand why genetic variances often depend on environmental conditions. One of possible environment-sensitive modulators of observed levels of genetic variance are maternal effects. In this study we attempt to experimentally test the hypothesis that maternally transmitted agents (e.g. hormones) may influence the expression of genetic variance in quantitative traits in the offspring. We manipulated the levels of steroid hormones (testosterone and corticosterone) in eggs laid by blue tits in a wild population. Our experimental setup allowed for full crossing of genetic and rearing effects with the experimental manipulation. We observed that birds treated with corticosterone exhibited a significant decrease in broad-sense genetic variance of tarsus length, and an increase in this component in body mass on the 2nd day post-hatching. Our study indicates, that maternally transmitted substances such as hormones may have measurable impact on the levels of genetic variance and hence, on the evolutionary potential of quantitative traits.

Density-Dependent Adaptive Topography in a Small Passerine Bird, the Collared Flycatcher.

AbstractAdaptive topography is a central concept in evolutionary biology, describing how the mean fitness of a population changes with gene frequencies or mean phenotypes. We use expected population size as a quantity to be maximized by natural selection to show that selection on pairwise combinations of reproductive traits of collared flycatchers caused by fluctuations in population size generated an adaptive topography with distinct peaks often located at intermediate phenotypes. This occurred because r- and K-selection made phenotypes favored at small densities different from those with higher fitness at population sizes close to the carrying capacity K. Fitness decreased rapidly with a delay in the timing of egg laying, with a density-dependent effect especially occurring among early-laying females. The number of fledglings maximizing fitness was larger at small population sizes than when close to K. Finally, there was directional selection for large fledglings independent of population size. We suggest that these patterns can be explained by increased competition for some limiting resources or access to favorable nest sites at high population densities. Thus, r- and K-selection based on expected population size as an evolutionary maximization criterion may influence life-history evolution and constrain the selective responses to changes in the environment.

Genomic inference of contemporary effective population size in a large island population of collared flycatchers (Ficedula albicollis).

Due to its central importance to many aspects of evolutionary biology and population genetics, the long-term effective population size (Ne ) has been estimated for numerous species and populations. However, estimating contemporary Ne is difficult and in practice this parameter is often unknown. In principle, contemporary Ne can be estimated using either analyses of temporal changes in allele frequencies, or the extent of linkage disequilibrium (LD) between unlinked markers. We applied these approaches to estimate contemporary Ne of a relatively recently founded island population of collared flycatchers (Ficedula albicollis). We sequenced the genomes of 85 birds sampled in 1993 and 2015, and applied several temporal methods to estimate Ne at a few thousand (4000-7000). The approach based on LD provided higher estimates of Ne (20,000-32,000) and was associated with high variance, often resulting in infinite Ne . We conclude that whole-genome sequencing data offers new possibilities to estimate high (>1000) contemporary Ne , but also note that such estimates remain challenging, in particular for LD-based methods for contemporary Ne estimation.

Silver-spoon upbringing improves early-life fitness but promotes reproductive ageing in a wild bird.

Early-life conditions can have long-lasting effects and organisms that experience a poor start in life are often expected to age at a faster rate. Alternatively, individuals raised in high-quality environments can overinvest in early-reproduction resulting in rapid ageing. Here we use a long-term experimental manipulation of early-life conditions in a natural population of collared flycatchers (Ficedula albicollis), to show that females raised in a low-competition environment (artificially reduced broods) have higher early-life reproduction but lower late-life reproduction than females raised in high-competition environment (artificially increased broods). Reproductive success of high-competition females peaked in late-life, when low-competition females were already in steep reproductive decline and suffered from a higher mortality rate. Our results demonstrate that 'silver-spoon' natal conditions increase female early-life performance at the cost of faster reproductive ageing and increased late-life mortality. These findings demonstrate experimentally that natal environment shapes individual variation in reproductive and actuarial ageing in nature.

Differential effects of early growth conditions on colour-producing nanostructures revealed through small angle X-ray scattering and electron microscopy.

The costs associated with the production and maintenance of colour patches is thought to maintain their honesty. Although considerable research on sexual selection has focused on structurally coloured plumage ornaments, the proximate mechanisms of their potential condition dependence, and thus their honesty, is rarely addressed, particularly in an experimental context. Blue tit (Cyanistes caeruleus) nestlings have ultraviolet (UV)-blue structurally coloured tail feathers, providing a unique opportunity for investigation of the causes of variation in their colour. Here, we examined the influence of early growing conditions on the reflectance and structural properties of UV-blue-coloured tail feathers of blue tit nestlings. We applied a two-stage brood size manipulation to determine which stage of development more strongly impacts the quality of tail feather colouration and microstructure. We used small-angle X-ray scattering (SAXS) and electron microscopy to characterise the nanoscale and microscale structure of tail feather barbs. Nestlings from the broods enlarged at a later stage of growth showed a sex-specific rectrix development delay, with males being more sensitive to this manipulation. Contrary to predictions, treatment affected neither the quality of the barbs' nanostructures nor the brightness and UV chroma of feathers. However, at the microscale, barbs' keratin characteristics were impaired in late-enlarged broods. Our results suggest that nanostructure quality, which determines the UV-blue colour in tail feathers, is not sensitive to early rearing conditions. Furthermore, availability of resources during feather growth seems to impact the quality of feather microstructure more than body condition, which is likely to be determined at an earlier stage of nestling growth.

Born to be young? Prenatal thyroid hormones increase early-life telomere length in wild collared flycatchers.

The underlying mechanisms of the lifelong consequences of prenatal environmental condition on health and ageing remain little understood. Thyroid hormones (THs) are important regulators of embryogenesis, transferred from the mother to the embryo. Since prenatal THs can accelerate early-life development, we hypothesized that this might occur at the expense of resource allocation in somatic maintenance processes, leading to premature ageing. Therefore, we investigated the consequences of prenatal TH supplementation on potential hallmarks of ageing in a free-living avian model in which we previously demonstrated that experimentally elevated prenatal TH exposure accelerates early-life growth. Using cross-sectional sampling, we first report that mitochondrial DNA (mtDNA) copy number and telomere length significantly decrease from early-life to late adulthood, thus suggesting that these two molecular markers could be hallmarks of ageing in our wild bird model. Elevated prenatal THs had no effect on mtDNA copy number but counterintuitively increased telomere length both soon after birth and at the end of the growth period (equivalent to offsetting ca 4 years of post-growth telomere shortening). These findings suggest that prenatal THs might have a role in setting the 'biological' age at birth, but raise questions about the nature of the evolutionary costs of prenatal exposure to high TH levels.

Parents' perspectives on dried blood spot self-sampling from children with epilepsy: A mixed-method study.

AIM: Children with epilepsy often have concomitant diagnoses. Dried blood spot samples for drug monitoring can be collected by parents at home as an alternative to traditional sampling. This mixed-method study aimed to understand the parents' perspectives on blood self-sampling from their children and to identify factors contributing to successful sampling. METHOD: Parents who had collected a sample from their child during a visit to the neuropediatric clinic were asked to fill in a questionnaire. To get in-depth information and individual perspectives, parents and nurses participated in semi-structured interviews and analysed with thematic analysis. RESULTS: The results from questionnaires (n = 64) and interviews (n = 9) were interpreted together. Watching an instruction video and practical training contributed to successful sampling. 97% of the parents managed to collect a sample, 72% thought it was easy to perform, and 80% found self-sampling at home desirable. Factors for success were as follows: high motivation, prepared parents with pre-understanding, a pragmatic attitude, flexible education, effective communication and willingness to take on the role as a performer. Risk factors were as follows: conflict, fear, unprepared parents, confused or worried children. CONCLUSION: Voluntary self-sampling at home for parents of children with epilepsy is feasible and can reduce stress factors in everyday life.

Pretreatment HIV drug resistance predicts accumulation of new mutations in ART-naïve Ugandan children.

AIM: To assess the prevalence of pretreatment drug resistance (PDR) and its association with virologic outcomes after 24 weeks of antiretroviral therapy (ART), within an urban cohort of Ugandan children. METHODS: Prospective observational study. Baseline and 24-week assessments of viral load (VL) and genotypic drug resistance to nucleoside reverse transcriptase inhibitors (NRTI) and non-nucleoside reverse transcriptase inhibitors (NNRTI) were performed. RESULTS: Ninety-nine ART-naïve children (3-12 years) initiated efavirenz-based ART 2015-2016 and 18/90 (20%) had baseline NRTI/NNRTI associated drug resistance mutations (DRMs). By 24 weeks, 72/93 (77%) children had VL < 40 copies/mL and a total of 23 children had DRMs. Children with PDR accumulated new DRMs with a mean number (SD) of 1.4 (2.35) new mutations compared to 0.26 (0.98) in 67 children with wild-type virus (P = .003). High pretreatment VL and PDR (number of baseline DRMs) predicted viremia (P = .003; P = .023) as well as acquired drug resistance (P = .02; P = .04). CONCLUSION: Pretreatment drug resistance to NNRTI/NRTI was common among ART-naïve Ugandan children and predicted viremia and new resistance mutations after only 24 weeks of efavirenz-based therapy. PDR may compromise long-term ART outcomes-especially when access to resistance testing and VL monitoring is poor. The long-term importance of PDR for non-NNRTI-based regimens needs further evaluation.

A full annual perspective on sex-biased migration timing in long-distance migratory birds.

In many taxa, the most common form of sex-biased migration timing is protandry-the earlier arrival of males at breeding areas. Here we test this concept across the annual cycle of long-distance migratory birds. Using more than 350 migration tracks of small-bodied trans-Saharan migrants, we quantify differences in male and female migration schedules and test for proximate determinants of sex-specific timing. In autumn, males started migration about 2 days earlier, but this difference did not carry over to arrival at the non-breeding sites. In spring, males on average departed from the African non-breeding sites about 3 days earlier and reached breeding sites ca 4 days ahead of females. A cross-species comparison revealed large variation in the level of protandry and protogyny across the annual cycle. While we found tight links between individual timing of departure and arrival within each migration season, only for males the timing of spring migration was linked to the timing of previous autumn migration. In conclusion, our results demonstrate that protandry is not exclusively a reproductive strategy but rather occurs year-round and the two main proximate determinants for the magnitude of sex-biased arrival times in autumn and spring are sex-specific differences in departure timing and migration duration.

Birds with high lifetime reproductive success experience increased telomere loss.

Lifetime reproductive success (LRS) is what counts in terms of evolution, but investments in reproduction entail costs for an organism. The idea that telomere dynamics may be shaped in response to such costs is already established; however, we still lack information on whether this relation translates to overall fitness. Here, we quantified LRS (number of fledged young) and longitudinal telomere dynamics of small passerine birds-the blue tits ( Cyanistes caeruleus). We found that individual telomere erosion rate was positively associated with lifetime fledgling number. Birds with more fledged young experienced increased telomere attrition. We show that telomere attrition rate, but not telomere length, is related to individual fitness and suggest that telomere dynamics may underlie reproductive costs experienced by animals as a consequence of prioritizing their lifetime fitness. This is the first study, to our knowledge, to provide evidence that more pronounced telomere erosion is associated with higher fitness gain.

Dried Blood Spot Self-Sampling by Guardians of Children With Epilepsy Is Feasible: Comparison With Plasma for Multiple Antiepileptic Drugs.

BACKGROUND: Dried blood spot (DBS) is an attractive matrix alternative to plasma for the measurement of antiepileptic drug concentrations with the possibility of self-sampling at home. The aim of this study was to evaluate whether DBS concentrations from a children population could be used as an alternative to plasma concentrations in a clinical routine laboratory. METHODS: Children with epilepsy using carbamazepine (CBZ), lamotrigine (LTG), levetiracetam (LEV), or valproic acid (VPA) had capillary blood collected for routine plasma analysis. DBS samples were collected by guardians or nurses, and the quality of sampling was compared between the groups. DBS samples were analyzed with liquid chromatography-tandem mass spectrometry methods and plasma samples with immunochemical methods. In the comparison between DBS and plasma concentrations, previously analyzed sample data were pooled with data in this study and resulted in 190 comparison pairs. A bioanalytical cross-validation according to European Medicines Agency was performed. Clinicians evaluated the results to understand if a DBS concentration was linked to a different clinical dose recommendation for the patient in comparison with plasma concentrations. RESULTS: Comparison of DBS sample quality showed that 2.3% of the capillary DBS collected by guardians were rejected and 8.0% of the capillary DBS collected by nurses. For DBS, a conversion factor of 0.85 for CBZ and 1.65 for VPA was applied for the comparison with plasma. LTG and LEV results were directly comparable. In the cross-validation, 88% of CBZ, 75% of LTG, 74% of LEV, and 94% of VPA comparisons were within 20% of the difference of the mean, although LEV had a few major differences (+31% to -40%). In 4 of the 190 comparisons, the clinical evaluation indicated a risk of conflicting decisions regarding the need for dose adjustment when using DBS concentrations. However, the risk of negative patient outcomes was considered negligible. CONCLUSIONS: Our study demonstrates that a combination of bioanalytical cross-validation and clinical evaluation is an effective way to describe the applicability of DBS as an alternative to plasma, taking into account how therapeutic drug monitoring is used in specific patient groups. For LTG, converted CBZ and VPA, DBS is a feasible alternative for self-sampling at home. DBS for LEV can only be recommended for nonadherence queries due to the high variability of the plasma/DBS concentration ratios.

Sex-specific effects of parasites on telomere dynamics in a short-lived passerine-the blue tit.

Parasitic infections potentially drive host's life-histories since they can have detrimental effects on host's fitness. Telomere dynamics is a candidate mechanism to underlie life-history trade-offs and as such may correlate with observed fitness reduction in infected animals. We examined the relationship of chronic infection with two genera of haemosporidians causing avian malaria and malaria-like disease with host's telomere length (TL) in a longitudinal study of free-ranging blue tits. The observed overall infection prevalence was 80% and increased with age, constituting a potentially serious selective pressure in our population. We found longer telomeres in individuals infected with a parasite causing lesser blood pathologies i.e. Haemoproteus compared to Plasmodium genus, but this only held true among males. Female TL was independent of the infection type. Our results indicate that parasitic infections could bring about other types of costs to females than to males with respect to TL. Additionally, we detected linear telomere loss with age, however a random regression analysis did not confirm significant heterogeneity in TL of first breeders and telomere shortening rates in further life.

Breeding consequences of flavivirus infection in the collared flycatcher.

BACKGROUND: The breeding consequences of virus infections have rarely been studied in avian natural breeding populations. In this paper we investigated the links between humoral immunity following a natural flavivirus infection and reproduction in a wild bird population of collared flycatcher (Ficedula albicollis). We analyzed plasma from 744 birds for antibodies and correlated these results to a number of reproductive components. RESULTS: Nearly one third (27.8%) of the sampled collared flycatchers were found seropositive for flavivirus. Males had significantly more frequently flavivirus antibodies (32.3%) than females (25.1%). Seropositive females differed significantly from seronegative females in four traits: they had earlier lay date, higher body weight, higher survival rate and were older than seronegative females. The females did not differ in clutch size, number of fledged young or number of recruited young. Seropositive males had female partners with earlier lay date, i.e. the males bred earlier and they also produced more fledged young than seronegative males. In contrast, the males did not differ in clutch size, number of recruited young, male weight, age or survival. Interestingly, seropositive males had larger ornament, forehead badge size, than seronegative males. CONCLUSIONS: Collared flycatchers with an antibody response against flavivirus were more successful than birds with no antibody response, for any of the measured life history traits. The positive link between flavivirus antibody presence and life-history trait levels suggest that it is condition dependent in the collared flycatcher.

Sex-biased gene expression, sexual antagonism and levels of genetic diversity in the collared flycatcher (Ficedula albicollis) genome.

Theoretical work suggests that sexual conflict should promote the maintenance of genetic diversity by the opposing directions of selection on males and females. If such conflict is pervasive, it could potentially lead to genomic heterogeneity in levels of genetic diversity an idea that so far has not been empirically tested on a genomewide scale. We used large-scale population genomic and transcriptomic data from the collared flycatcher (Ficedula albicollis) to analyse how sexual conflict, for which we use sex-biased gene expression as a proxy, relates to genetic variability. Here, we demonstrate that the extent of sex-biased gene expression of both male-biased and female-biased genes is significantly correlated with levels of nucleotide diversity in gene sequences and that this correlation extends to diversity levels also in intergenic DNA and introns. We find signatures of balancing selection in sex-biased genes but also note that relaxed purifying selection could potentially explain part of the observed patterns. The finding of significant genetic differentiation between males and females for male-biased (and gonad-specific) genes indicates ongoing sexual conflict and sex-specific viability selection, potentially driven by sexual selection. Our results thus indicate that sexual antagonism could potentially be considered as one viable explanation to the long-standing question in evolutionary biology of how genomes can remain so genetically variable in face of strong natural and sexual selection.

Combined Recirculatory-compartmental Population Pharmacokinetic Modeling of Arterial and Venous Plasma S(+) and R(-) Ketamine Concentrations.

WHAT WE ALREADY KNOW ABOUT THIS TOPIC: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: The pharmacokinetics of infused drugs have been modeled without regard for recirculatory or mixing kinetics. We used a unique ketamine dataset with simultaneous arterial and venous blood sampling, during and after separate S(+) and R(-) ketamine infusions, to develop a simplified recirculatory model of arterial and venous plasma drug concentrations. METHODS: S(+) or R(-) ketamine was infused over 30 min on two occasions to 10 healthy male volunteers. Frequent, simultaneous arterial and forearm venous blood samples were obtained for up to 11 h. A multicompartmental pharmacokinetic model with front-end arterial mixing and venous blood components was developed using nonlinear mixed effects analyses. RESULTS: A three-compartment base pharmacokinetic model with additional arterial mixing and arm venous compartments and with shared S(+)/R(-) distribution kinetics proved superior to standard compartmental modeling approaches. Total pharmacokinetic flow was estimated to be 7.59 ± 0.36 l/min (mean ± standard error of the estimate), and S(+) and R(-) elimination clearances were 1.23 ± 0.04 and 1.06 ± 0.03 l/min, respectively. The arm-tissue link rate constant was 0.18 ± 0.01 min, and the fraction of arm blood flow estimated to exchange with arm tissue was 0.04 ± 0.01. CONCLUSIONS: Arterial drug concentrations measured during drug infusion have two kinetically distinct components: partially or lung-mixed drug and fully mixed-recirculated drug. Front-end kinetics suggest the partially mixed concentration is proportional to the ratio of infusion rate and total pharmacokinetic flow. This simplified modeling approach could lead to more generalizable models for target-controlled infusions and improved methods for analyzing pharmacokinetic-pharmacodynamic data.