A Novel Method for Studying the Pharmacokinetics of [(14) C]Umeclidinium After Application to the Axilla or Palm of Healthy Male Subjects.

Umeclidinium (UMEC), a long-acting muscarinic antagonist approved for chronic obstructive pulmonary disease (COPD), was investigated for primary hyperhidrosis as topical therapy. This study evaluated the pharmacokinetics, safety, and tolerability of a single dose of [(14) C]UMEC applied to either unoccluded axilla (UA), occluded axilla (OA), or occluded palm (OP) of healthy males. After 8 h the formulation was removed. [(14) C]UMEC plasma concentrations (Cp) were quantified by accelerator mass spectrometry. Occlusion increased systemic exposure by 3.8-fold. Due to UMEC absorption-limited pharmacokinetics, Cp data from the OA were combined with intravenous data from a phase I study. The data were described by a two-compartment population model with sequential zero and first-order absorption and linear elimination. Simulated systemic exposure following q.d. doses to axilla was similar to the exposure from the inhaled therapy, suggesting that systemic safety following dermal administration can be bridged to the inhaled program, and offering the potential for a reduced number of studies and/or subjects.

Mood and cognitive performance effects of "energy" drink constituents: caffeine, glucose and carbonation.

Three studies using healthy volunteers (n = 271) investigated the effects of caffeine, carbohydrates and carbonation in functional "energy" drinks (EDs) with the aim of determining their benefit in every-day life. The results showed caffeine to be the main ED constituent responsible for the effects found, with possible minor, relatively weak effects of carbohydrates. EDs were found to improve and/or maintain mood and performance during fatiguing and cognitively demanding tasks relative to placebo. In terms of absolute values, EDs maintained levels of arousal compared to a deterioration in arousal where placebo was consumed. These effects were found in caffeine-deprived participants, and so may be largely due to "withdrawal reversal". There were only minor differences in the effects of water vs. "sensory-matched" placebo, supporting previous findings indicating that the type of placebo does not alter the conclusions drawn about the effects of the full ED. Finally, carbonation had various effects on mood, some of which were present immediately following consumption, others were consistent with slower absorption of caffeine (and possibly carbohydrates) from carbonated drinks.

Establishment and maintenance of parasegmental compartments.

Embryos of higher metazoans are divided into repeating units early in development. In Drosophila, the earliest segmental units to form are the parasegments. Parasegments are initially defined by alternating stripes of expression of the fushi-tarazu and even-skipped genes. How fushi-tarazu and even-skipped define the parasegment boundaries, and how parasegments are lost when fushi-tarazu or even-skipped fail to function correctly, have never been fully or properly explained. Here we show that parasegment widths are defined early by the relative levels of fushi-tarazu and even-skipped at stripe junctions. Changing these levels results in alternating wide and narrow parasegments. When shifted by 30% or more, the enlarged parasegments remain enlarged and the reduced parasegments are lost. Loss of the reduced parasegments occurs in three steps; delamination of cells from the epithelial layer, apoptosis of the delaminated cells and finally apoptosis of inappropriate cells remaining at the surface. The establishment and maintenance of vertebrate metameres may be governed by similar processes and properties.

The development of a long, dual-platform triaxial walkway for the measurement of forces and temporal-spatial data in the clinical assessment of gait.

Force-plate measurement of the ground reaction force (GRF) has, for many years, been considered a vital component of the comprehensive assessment of human gait in the clinical context. For example, the data can be used in the adjustment of prostheses and orthoses and in identifying the mechanisms underlying a gait dysfunction. However, commercial force plates are usually only capable of measuring GRF data from one step in a single traverse. That can lead to problems of 'targeting' and, with less able subjects, fatigue before the necessary data have been collected. Previous work at the University of Surrey resulted in a prototype dual-platform force walkway capable of measuring the vertical component of the GRF and estimating the position of application of that force for multiple foot contacts in a single traverse. In addition, temporal-spatial information, e.g. speed and step length, could also be determined. This paper describes the development of a longer walkway that can measure the three orthogonal components of the GRF and provide and a more accurate estimate of the position of application of that force. Software to allow the rapid reduction of gait data to useful clinical information has also been developed.

The dissolution of urinary catheter encrustation.

OBJECTIVES: To identify the optimum volume of acidic bladder washout solution to dissolve catheter encrustations and to compare the effectiveness of different bladder washout delivery devices. MATERIALS AND METHODS: Urinary catheter encrustation was generated in vitro using a model of the catheterized bladder adapted from previous work. An acidic bladder washout solution (Suby G) was applied via the catheter in the model and retained for 15 min. The amount of encrusting material dissolved was measured by colorimetric analysis of the magnesium and calcium content of the solution returned after the washout procedure. The relative effectiveness of different volumes of washout solution and different washout delivery devices (Optiflow, Bard Ltd, Crawley; UroTainer, B/Braun Medical Ltd, Aylesbury; and a bladder syringe) in dissolving catheter encrustations was compared to the 'standardized' conditions commonly used in practice. RESULTS: There was no statistically significant difference between washouts with 100 mL and washouts with 50 mL for any of the delivery devices tested. Gentle agitation with 50 mL Suby G did not significantly improve the dissolution of encrustation but the total amount of material dissolved when two washouts with 50 mL Suby G were used sequentially was significantly better than a single washout with either 100 mL or 50 mL. CONCLUSIONS: Under controlled laboratory conditions, smaller volumes of acidic bladder washout solution (50 mL) are as effective as the 100 mL commonly used in practice, but two sequential washouts with 50 mL are more effective than a single washout. The newly designed Optiflow delivery device is at least as effective as the other devices tested. This study provides new evidence which may contribute to decision-making by practitioners in relation to catheter care.

Finite element analysis of bone stress and strain around a distal osseointegrated implant for prosthetic limb attachment.

Direct skeletal attachment techniques have recently been identified as an alternative method for percutaneous attachment of prosthetic limbs. Osseointegrated implants for prosthetic attachments are subjected to a complex load condition. This finite element study investigates the effect of varying geometries of the implant on the stress and strain distribution in the area of the bone/implant interface. Simplified three-dimensional axisymmetric models of the femur and seven implants with different core diameters, external diameters, implant lengths and thread pitches were derived. The resulting stress and strain distributions were compared. The significance of each implant geometry was identified for improving implant design in the light of benefit to the bone/implant osseointegration and the bone remodelling of the femur.

Active and inhibitory components of the insulin-like growth factor binding protein-3 protease system in adult serum, interstitial, and synovial fluid.

Circulating insulin-like growth factor binding protein-3 (IGFBP-3) proteolytic activity is normally low but increases in serum from pregnant women and from patients with various pathologies. In contrast, we have recently reported that outside the circulation, such activity is normally high but decreases in various pathologies. We have now compared components of the IGFBP-3 proteolytic system revealed after size fractionation of serum and extravascular fluids with different intrinsic levels of such activity. Normal serum, serum from pregnant women, and synovial fluid from patients with rheumatoid arthritis revealed high and low molecular weight (MW) areas of activity. However, only the low MW activity was apparent in interstitial fluid from normal skin (N Inst F) or psoriatic lesions (P Inst F) and in synovial fluid from normal volunteers (N Syn F) or patients with osteoarthritis (OA Syn F). Addition of inhibitors revealed both areas to comprise more than one enzyme, including serine proteases and metalloproteinases; both could also be inhibited by P Inst F, NS, RA Syn F, and inhibitory fractions from the separation of the latter two. These findings demonstrate low and high MW regions of proteolytic activity, which may contribute to the IGFBP-3 protease system, the former always present, whereas the latter seems to be retained within the circulation apart from inflammatory conditions. The variations apparent in IGFBP-3 protease activity in the intact samples related to the presence of an inhibitor, which may protect IGFBP-3 from proteolysis, rather than to changes in the component proteases.

Intravenous remifentanil: placental transfer, maternal and neonatal effects.

BACKGROUND: Remifentanil has not been studied in obstetric patients. This study evaluates the placental transfer of remifentanil and the neonatal effects when administered as an intravenous infusion. METHODS: Nineteen parturients underwent nonemergent cesarean section with epidural anesthesia and received 0.1 microg kg(-1) x min(-1) remifentanil intravenously, which was continued until skin closure. Maternal arterial (MA), umbilical arterial (UA), and umbilical venous (UV) blood samples were obtained at delivery for analysis of drug concentrations of remifentanil, its metabolite, and blood gases. Maternal vital signs were monitored continuously, and pain and sedation levels were assessed intermittently. Apgar scores were obtained at 1, 5, 10, and 20 min, and Neonatal and Adaptive Capacity Scores were noted 30 and 60 min after delivery. Parturients and newborns were observed for at least 24 h after surgery for side effects. RESULTS: The means and SDs of UV:MA and UA:UV ratios for remifentanil were 0.88+/-0.78 and 0.29+/-0.07, respectively. Mean clearance was 93 ml x min(-1) kg(-1). The mean UV:MA and UA:MV ratios for remifentanil acid were 0.56+/-0.29 and 1.23+/-0.89, respectively. The mean MA (remifentanil acid):MA (remifentanil) ratio was 2.92+/-3.65. There were no adverse effects on the neonates, but there was a sedative effect and respiratory depressant effect on the mothers. CONCLUSIONS: Remifentanil crosses the placenta but appears to be rapidly metabolized, redistributed, or both. Maternal sedation and respiratory changes occur, but without adverse neonatal or maternal effects.

Growth hormone therapy in patients with cirrhosis: a pilot study of efficacy and safety.

BACKGROUND & AIMS: The protein catabolic state of cirrhosis is associated with severe growth hormone (GH) resistance, with low levels of insulin-like growth factor (IGF)-I and its major binding protein (IGFBP)-3. The aim of this study was to conduct a randomized, double-blind, placebo-controlled pilot study of GH therapy in 20 cirrhotic patients to assess the reversibility of GH resistance and subsequent impact on protein economy and safety. METHODS: Patients were treated with GH (0.25 IU/kg body wt) or placebo for 7 days. Serum levels of GH, IGF-I, IGFBP-3, and insulin were measured by radioimmunoassay and 24-hour urinary nitrogen by the Kjeldahl technique. RESULTS: IGF-I levels increased only in the GH-treated group (mean, 69.2 +/- SE 7.0 to 170.6 +/- 48.8 ng/mL; P < 0.05) together with IGFBP-3 (1.65 +/- 0.3 to 2.94 +/- 0.6 mg/L; P < 0.005). Cumulative nitrogen balance similarly improved only in the GH group (2.87-24.16 g; P < 0.05). No significant side effects of GH were observed. CONCLUSIONS: GH therapy can overcome the GH resistance of cirrhosis. The resulting improvement in nitrogen economy and possible influences on clinical outcomes will need to be confirmed in controlled studies of longer duration.

The insulin-like growth factors (IGFs) in follicular fluid are predominantly bound in the ternary complex.

The presence of IGFs and their associated binding proteins (IGFBPs) in human follicular fluid is well documented. Furthermore, most of the constituents of the IGF system in follicular fluid have been found to vary, either in total amount or by proteolytic cleavage, depending on the health status of the follicle. In this study we have examined the acid-labile subunit (ALS) and found that levels in follicular fluid (mean 146 nmol/l) were almost 50% of those in the circulation. This amount of ALS was considerably greater than that found in other extracirculatory fluids (20.9 for synovial fluid and 31.4 nmol/l for skin blister fluid). As in the circulation, ALS levels were in molar excess and did not vary between atretic and dominant follicles. Although the source of ALS is probably from blood (conditioned medium from ovarian cell cultures had no measurable ALS) it would appear that this glycoprotein is not merely diffusing from the circulation as the capillary endothelium becomes more permeable in dominant follicles and this is not reflected in the level of ALS. Analysis of the distribution of IGF-I, IGF-II and IGFBP-3 in fluid from healthy and atretic follicles revealed that the majority of these growth factors (> 80% of total IGF-II) were in the 150KDa complex, indicating that the ALS present was functional, in that it formed the ternary complex with a molecule of IGFBP-3 and IGF. No free IGF-II was found in any of the follicular fluids analysed nor was there any increase in the amount of unsaturated IGFBP-3 in atretic follicles. In summary, we have shown that the majority of IGF measured in follicular fluid, whether from healthy or atretic follicles, is bound in the ternary complex.