Frequency and associated symptoms of isthmoceles in women 6 months after caesarean section: a prospective cohort study.

PURPOSE: The purpose of this study was to determine the frequency of detection of isthmoceles by ultrasound 6 months after caesarean section (CS) and which symptoms associated with isthmocele formation occur after CS. Subsequently, it was determined how often the ultrasound finding "isthmocele" coincided with the presence of complaints. METHODS: A prospective multicentre cohort study was conducted with 546 patients from four obstetric centres in Berlin, who gave birth by primary or secondary CS from October 2019 to June 2020. 461 participants were questioned on symptoms 3 months after CS; 329 participants were included in the final follow-up 6 months after CS. The presence of isthmoceles was determined by transvaginal sonography (TVS) 6 months after CS, while symptoms were identified by questionnaire. RESULTS: Of the 329 women, 146 (44.4%) displayed an isthmocele in the TVS. There was no statistically significant difference in the manifestation of symptoms between the two groups of women with and without isthmocele; however, when expressed on a scale from 1 to 10 the intensity of both scar pain and lower abdominal pain was significantly higher in the set of women that had shown to have developed an isthmocele (p = 0.014 and p = 0.031, respectively). CONCLUSION: The prevalence of isthmoceles 6 months after CS was 44.4%. Additionally, scar pain and lower abdominal pain were more pronounced when an isthmocele was also observed in the TVS. TRIAL REGISTRATION: Trial registration number DRKS00024977. Date of registration 17.06.2021, retrospectively registered.

Dosing regimens, FVIII levels and estimated haemostatic protection with special focus on rFVIIIFc.

AIM: To use Pharmacokinetic (PK) simulations to illustrate potential differences in clinical outcomes between prophylaxis with conventional recombinant factor VIII (rFVIII) and rFVIIIFc, an extended half-life rFVIII covalently fused to the Fc domain of human IgG1. METHODS: Population PK estimates from 180 (rFVIIIFc) and 46 (rFVIII) severe haemophilia A patients were used to simulate FVIII activity over time at various rFVIIIFc dosing regimens compared to rFVIII 30 IU kg(-1) three times weekly in a typical adult patient. RESULTS: rFVIII dosed 3x30 IU kg(-1) weekly gave trough levels of 2.7, 2.8 and 0.7 IU dL(-1) , and time spent below 1, 3 and 5 IU dL(-1) of 0.2/1.2/2.3 days week(-1) . rFVIIIFc 2 x 45 IU kg(-1) gave higher troughs (4.4 and 1.7 IU dL(-1) ) and shorter time spent below 1, 3 and 5 IU dL(-1) (0/0.6/1.3 days week(-1) ), with same total factor consumption. rFVIIIFc 2 x 30 IU kg(-1) gave similar troughs (3.0 and 1.2 IU kg(-1) ) and time spent below 1, 3 and 5 IU dL(-1) (0/1.0/2.1 days week(-1) ), despite total factor consumption being reduced by one-third. The same dose and interval of rFVIIIFc (3 x 30 IU kg(-1) ) gave substantially higher troughs (7.8, 8.5 and 3.3 IU dL(-1) ) and markedly shorter time spent below 1, 3 and 5 IU dL(-1) (0/0/0.4 days week(-1) ). CONCLUSION: The lower clearance of rFVIIIFc compared to conventional rFVIII gives rFVIIIFc the potential of improved bleed prevention and reduced injection frequency at similar factor consumption. Although additional clinical data are required to confirm the conclusions, the simulations clearly show the potential of rFVIIIFc of increased flexibility to tailor treatment to the individual patient, and to advance the standard of care in haemophilia.

Serum protein binding of tolterodine and its major metabolites in humans and several animal species.

The aim of this study was to determine in vitro protein binding of tolterodine and its 5-hydroxymethyl (5-HM) and N-dealkylated metabolites in serum from humans and several animal species at concentrations similar to those obtained in clinical and preclinical studies. Binding of tolterodine and the two metabolites to human serum albumin and alpha1-acid glycoprotein (AAG) was also assessed, as was binding of tolterodine to red blood cells. Ex vivo protein binding of tolterodine and 5-HM was determined in serum samples from healthy volunteers treated with oral tolterodine 4 mg twice daily for 8 days. Tolterodine exhibited high protein binding in human serum; the unbound fraction (f(u)) was 3.7%. The unbound fraction of tolterodine in cat and dog serum (1.5 and 2.1%, respectively) was lower compared with human serum; f(u) was higher in the other species investigated (rat, 22%; mouse, 16-17%; rabbit, 39%). The unbound fraction of 5-HM was much higher in serum from humans (36%) and all animal species investigated (mouse, 72%; rabbit, 68%; cat, 32%; dog, 45%). Binding of N-dealkylated tolterodine to proteins in human serum was intermediate (f(u) 14%). AAG was the major binding protein for tolterodine and 5-HM, and the degree of binding increased with increasing concentration of the protein. The association constant of 5-HM for AAG was lower than that of tolterodine (1.3 x 10(5) M(-1) versus 2.1 x 10(6) M(-1)). The blood:plasma tolterodine concentration ratio was 0.6 in both humans and dog; thus, a minor fraction of tolterodine was present in red blood cells compared with plasma (0.18 and 0.36, respectively). In the mouse, tolterodine was equally present in blood and plasma. In ex vivo samples, f(u) values for tolterodine (pH adjusted) varied between 1.6 and 4.9% (mean 2.8%), which could be explained by differences in AAG concentrations. There was good correlation between observed f(u) values for tolterodine and those predicted on the basis of AAG levels. Similar findings were observed for 5-HM.

Pharmacokinetic-pharmacodynamic modeling of the immunomodulating agent susalimod and experimentally induced tumor necrosis factor-alpha levels in the mouse.

The main objective of this study was to explore the concentration-effect relationship between the immunomodulating agent susalimod and lipopolycaccharide (LPS)-induced elevated serum levels of the proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha). Bacterial LPS (1 mg/kg) was given i.p. along with different doses of susalimod (0, 25, 50, 100, and 200 mg/kg) to female CD-1 mice. Blood samples were drawn at different time points (15-300 min), and serum was analyzed with respect to susalimod and TNF-alpha. The concentration-effect relationship was explored by modeling the data from all dose levels simultaneously using specially written program models, i.e., a three-compartment pharmacokinetic model, including biliary excretion, and an indirect mechanistically based pharmacodynamic model. The models, which were successfully fitted to the experimental data, showed that LPS induced the TNF-alpha synthesis during approximately 70 min and that during this time course, the synthesis rate was governed by the serum phamacokinetics of susalimod. Because the results supported the assumption that the maximum inhibitory effect was equal to full inhibition of the synthesis, the in vivo potency (IC(50)) of susalimod could be estimated to 293 microM. In conclusion, susalimod decreased the LPS-induced TNF-alpha mouse serum levels in a concentration-related manner. The compound is suggested to inhibit the synthesis of TNF-alpha. The integrated pharmacokinetic-pharmacodynamic model estimated the in vivo potency of susalimod in the mouse to be 293 microM.