Prediction of Phase I single-dose pharmacokinetics using recombinant cytochromes P450 and physiologically based modelling

1. Ten compounds from the Merck Research Laboratories pipeline were selected to evaluate the utility of using intrinsic clearance derived from recombinantly expressed cytochromes P450 (CYP) and physiologically based pharmacokinetic modelling to predict Phase I pharmacokinetics using simCYP. The compounds selected were anticipated to be eliminated predominantly by P450 metabolism.

2. There was a reasonable agreement between the predicted and actual clinical exposure with 80% of the predicted exposures being within three-fold of the observed values. Furthermore, prediction of C(t) (plasma concentration at a specified time point) and T_max were acceptable with greater than or equal to 70% of the predicted data being within three-fold of the observed values. However, prediction of C_max was unreliable and may have been due to error in predicting the time-dependent change in volume of distribution and/or error in estimating absorption rate.

3. Although it is acknowledged that research is needed to improve predictive performance, the data presented are supportive of using recombinant P450 intrinsic clearance and physiologically based pharmacokinetic modelling to predict Phase I pharmacokinetics for compounds eliminated by P450 metabolism.

     

Self-administered measurement of symphysis-fundus heights

BACKGROUND: Antenatal identification of infants small for gestational age (SGA) improves their perinatal outcome. Repeated measurement of symphysis-fundus (SF) heights performed by midwives is the most widespread screening method for detection of SGA. However, the inefficiency of this method necessitates improved practices. Earlier start and more frequent SF measurements, which could be accomplished by self-administered measurements, might improve the ability to detect deviant growth. The present study was set up to evaluate whether pregnant women can reliably perform SF measurements by themselves. METHOD: Forty healthy women with singleton and ultrasound-dated pregnancies from 2 antenatal clinics in Uppsala, Sweden, were asked to perform 4 consecutive SF measurements once every week, from 20 to 25 weeks of gestation until delivery. The self-administered SF measurements were recorded and systematically compared with midwives' SF measurements. RESULTS: Thirty-three pregnant women performed self-administered SF measurements over a 14-week period (range: 1-21). The SF curves constructed from self-administered SF measurements had the same shape as previously constructed population-based reference curves. The variance for self-administered SF measurements was higher than that of the midwives. CONCLUSIONS: Pregnant women are capable of measuring SF heights by themselves, but with higher individual variance than midwives. Repeated measurements at each occasion can compensate for the higher variance. The main advantage of self-administered SF measurements is the opportunity to follow fetal growth earlier and more frequently.     

Impaired Quality of Life 5 Years After Bile Duct Injury During Laparoscopic Cholecystectomy: A Prospective Analysis

OBJECTIVE: To assess the impact of bile duct injury (BDI) sustained during laparoscopic cholecystectomy on physical and mental quality of life (QOL). SUMMARY BACKGROUND DATA: The incidence of BDI during laparoscopic cholecystectomy has decreased but remains as high as 1.4%. Data on the long-term outcome of treatment in these patients are scarce, and QOL after BDI is unknown. METHODS: One hundred six consecutive patients (75 women, median age 44 +/- 14 years) were referred between 1990 and 1996 for treatment of BDI sustained during laparoscopic cholecystectomy. Outcome was evaluated according to the type of treatment used (endoscopic or surgical) and the type of injury. Objective outcome (interventions, hospital admissions, laboratory data) was evaluated, a questionnaire was filled out, and a QOL survey was performed (using the SF-36). Risk factors for a worse outcome were calculated. RESULTS: Median follow-up time was 70 months (range 37-110). The objective outcome of endoscopic treatment (n = 69) was excellent (94%). The result of surgical treatment (n = 31) depended on the timing of reconstruction (overall success 84%; in case of delayed hepaticojejunostomy 94%). Five patients underwent interventional radiology with a good outcome. Despite this excellent objective outcome, QOL appeared to be both physically and mentally reduced compared with controls (P <.05) and was not dependent on the type of treatment used or the severity of the injury. The duration of the treatment was independently prognostic for a worse mental QOL. CONCLUSIONS: Despite the excellent functional outcome after repair, the occurrence of a BDI has a great impact on the patient's physical and mental QOL, even at long-term follow-up.     

Reactive angioendotheliomatosis presenting as cellulitis

Reactive angioendotheliomatosis (RAE) is a diagnostically challenging condition characterized by multiple possible clinical presentations, which makes diagnosis challenging. We present a rare case of RAE mimicking cellulitis in a 74‐year‐old woman with a valvular disease and also end‐stage renal disease, for which she was being treated with haemodialysis.     

Clinical and microbiological properties of Staphylococcus lugdunensis skin infections

Staphylococcus lugdunensis is an emerging pathogen in skin and soft tissue infections that was previously considered a commensal. The aim of this study was to elucidate the characteristics of skin infections by S. lugdunensis and its appropriate management, in a tertiary referral medical center. The clinical files, bacterial cultures and histopathology reports of all S. lugdunensis isolates from skin infections over a period of 8 years (September 2009–September 2017) were reviewed. S. lugdunensis was isolated from 29 patients with skin infections, aged 7–89 years (mean 33.3 years). A state of immune suppression (drug‐induced, malignancy or diabetes) was present in five patients (17%). Folliculitis and cutaneous pustulosis were the most common presentations (16 cases, 55%), followed by secondary infection of hidradenitis suppurativa (five cases, 17%). Other sources of isolation were infected molluscum contagiosum (two cases), folliculitis decalvans (one case), dissecting cellulitis (one case), abscess (one case), cyst (one case), impetigo (one case) and granuloma after trauma (one case). The in vitro antibiotic sensitivity tests showed susceptibility to most tested antibiotics, although a few isolates were resistant to gentamycin, penicillin and oxacillin. In 19 of 20 patients for whom follow ups were available, cutaneous manifestations improved or resolved with proper local and/or oral antibiotic therapy. S. lugdunensis may play a role as a primary or secondary pathogen in various skin infections, most commonly folliculitis and pustulosis. Proper antibiotic therapy may lead to improvement or resolution.