Enantioselective disposition of (R,R)-formoterol, (S,S)-formoterol and their respective glucuronides in urine following single inhaled dosing and application to doping control

Formoterol is a long‐acting beta2‐adrenoceptor agonist (LABA) used for treatment of asthma and exercise‐induced bronchoconstriction. Formoterol is usually administered as a racemic (rac‐) mixture of (R,R)‐ and (S,S)‐enantiomers. While formoterol is restricted by the World Anti‐Doping Agency (WADA), inhalation of formoterol is permitted to a predetermined dose (54 μg/24 hours) and a urine threshold of 40 ng/mL. However, chiral switch enantiopure (R,R)‐formoterol is available, effectively doubling the therapeutic advantage for the same threshold. The aim of this study was to investigate whether formoterol exhibits enantioselective urinary pharmacokinetics following inhalation. Six healthy volunteers were administered a 12 μg inhaled dose of rac‐formoterol. Urine was collected over 24‐hours and analysed by enantioselective UPLC‐MS/MS assay. Total (free drug plus conjugated metabolite) median (min‐max) rac‐formoterol urine levels following inhalation were 1.96(1.05‐13.4) ng/mL, 1.67(0.16‐9.67) ng/mL, 0.45(0.16‐1.51) ng/mL, 0.61(0.33‐0.78) ng/mL, and 0.17(0.08‐1.06) ng/mL at 2, 4, 8, 12 and 24 hours, respectively, well below the 2019 urine threshold. The proportion of conjugation differed between enantiomers with glucuronide conjugation much greater for (R,R)‐formoterol (around 30‐60% of total) compared to (S,S)‐formoterol (0‐30%). There was clear evidence of inter‐individual enantioselectivity observed in the ratios of (R,R):(S,S)‐formoterol, where (S,S)‐ was predominant in free formoterol, and (R,R)‐ predominant in the conjugated metabolite. In conclusion, rac‐formoterol delivered by inhalation exhibits enantioselective elimination in urine following single dose administration. Enantioselective assays should be employed in doping control to screen for banned beta2‐agonist chiral switch products such as (R,R)‐formoterol, and total hydrolysed rac‐formoterol is warranted to account for inter‐individual differences in enantioselective glucuronidation

Abdominal examination during pregnancy may enhance relationships between midwife, mother and child : a qualitative study of pregnant women's experiences

Background: Abdominal examination is a routine procedure performed by midwives several times during pregnancy to monitor the growth and well-being of the baby. Literature and instructions regarding abdominal examination focus on the technical performance, with limited attention paid to the women’s experience of the examination or the bonding-related aspects between the mother and baby. The aim of the study was to explore how pregnant women experience the abdominal examination and how the examination affects maternal–fetal attachment. Methods: Participant observation and semi-structured interviews with 10 pregnant women. We used thematic analysis to identify themes across the empirical material. Results: We identified the following four central themes: an essential examination, the baby becomes real, the importance of being involved and different senses provide different experiences. These themes describe how the women regarded the abdominal examination as an essential part of the midwifery consultation and considered it the occasion when the baby became real and tangible. Being prepared and involved before and during the examination were pivotal for how the examination was experienced by the women. The abdominal examination was crucial to the pregnant women because it provided them with important sensory aspects that were not obtained from ultrasound examination. Conclusion: The abdominal examination is regarded as essential in midwifery consultations and has the potential for supporting a woman’s bodily sensation of her baby, which is reinforced by the midwife’s manual palpation. Touch can be a way for a pregnant woman to become acquainted with her unborn child, which provides midwives a profound potential to facilitate the process of maternal–fetal attachment

Cardiological health in patients with schizophrenia. A prospective cohort study

INTRODUCTION: Patients with schizophrenia have a four-fold increased all-cause and a doubled cardiovascular mortality rate as compared to the general population. OBJECTIVES: The study overall investigates the point-prevalence and prospective changes in cardiovascular risk factors in patients with schizophrenia, with baseline demographics of participants presented here. METHODS: A prospective study of patients diagnosed with schizophrenia divided into two subpopulations consisting of newly diagnosed (≤2 years from baseline in study (group A)) or chronic (diagnosed ≥10 years from baseline in study (group B)). RESULTS: A total of 199 patients (57 diagnosed ≤2 years preceding baseline and 142 diagnosed ≥10 years ago) were included. Group A had been diagnosed for an average of 1.13±0.58 years and 21.19±7.62 years in group B. The majority (n=135 (67.8%)) were diagnosed with paranoid schizophrenia. At baseline PANSS total (median[Q1;Q3]) for group A was 61.0[51.0;76.0] and 60.0[48.0;76.0] for group B, with PANNS Positive being 17.0[13.0;20.0] and 15.0[12;19], PANSS Negative being 16.0[11.0;20.0] and 14.5[10.0;20.0], and PANSS General being 28.0[22.0;35.0] and30.0 [25.0;37.0], respectively. No difference in Clinical Global Impression was observed between groups ((median[Q1;Q3): 4.0[3.0;4.0] in both groups). Lastly, global assessment of function was similar between groups ((median[Q1;Q3): group A symptom: 38.5[37.0;46.0] and group B 41.0[37.0;52.0], and with function being 48.0[44.5;53.5] in group A and 45.5[41.0;53.0] in group B). CONCLUSIONS: Prospective studies investigating prevalence of and prospective changes in cardiovascular risk in patients with schizophrenia are essential to understand the increased all-cause and cardiovascular specific mortality. Demographic descriptions of participants are essential to estimate generalizability in different treatment settings. DISCLOSURE: No significant relationships

Mechanisms underlying enhancements in muscle force and power output during maximal cycle ergometer exercise induced by chronic beta(2)-adrenergic stimulation in men

The study was a randomized placebo-controlled trial investigating mechanisms by which chronic beta(2)-adrenergic stimulation enhances muscle force and power output during maximal cycle ergometer exercise in young men. Eighteen trained men were assigned to an experimental group [oral terbutaline 5 mg/30 kg body weight (bw) twice daily (TER); n = 9] or a control group [placebo (PLA); n = 9] for a 4-wk intervention. No changes were observed with the intervention in PLA. Isometric muscle force of the quadriceps increased (P <= 0.01) by 97 +/- 29 N (means +/- SE) with the intervention in TER compared with PLA. Peak and mean power output during 30 s of maximal cycling increased (P <= 0.01) by 32 +/- 8 and 25 +/- 9 W, respectively, with the intervention in TER compared with PLA. Maximal oxygen consumption ((V) over dotO(2)max) and time to fatigue during incremental cycling did not change with the intervention. Lean body mass increased by 1.95 +/- 0.8 kg (P <= 0.05) with the intervention in TER compared with PLA. Change in single fiber cross-sectional area of myosin heavy chain (MHC) I (1,205 +/- 558 mu m(2); P <= 0.01) and MHC II fibers (1,277 +/- 595 mu m(2); P <= 0.05) of the vastus lateralis muscle was higher for TER than PLA with the intervention, whereas no changes were observed in MHC isoform distribution. Expression of muscle proteins involved in growth, ion handling, lactate production, and clearance increased (P <= 0.05) with the intervention in TER compared with PLA, with no change in oxidative enzymes. Our observations suggest that muscle hypertrophy is the primary mechanism underlying enhancements in muscle force and peak power during maximal cycling induced by chronic beta(2-)adrenergic stimulation in humans