Clinical pharmacokinetics of mycophenolate mofetil

The pharmacokinetics of the immunosuppressant mycophenolate mofetil have been investigated in healthy volunteers and mainly in recipients of renal allografts. Following oral administration, mycophenolate mofetil was rapidly and completely absorbed, and underwent extensive presystemic de-esterification. Systemic plasma clearance of intravenous mycophenolate mofetil was around 10 L/min in healthy individuals, and plasma mycophenolate mofetil concentrations fell below the quantitation limit (0.4 mg/L) within 10 minutes of the cessation of infusion. Similar plasma mycophenolate mofetil concentrations were seen after intravenous administration in patients with severe renal or hepatic impairment, implying that the de-esterification process had not been substantially affected. Mycophenolic acid, the active immunosuppressant species, is glucuronidated to a stable phenolic glucuronide (MPAG) which is not pharmacologically active. Over 90% of the administered dose is eventually excreted in the urine, mostly as MPAG. The magnitude of the MPAG renal clearance indicates that active tubular secretion of MPAG must occur. At clinically relevant concentrations, mycophenolic acid and MPAG are about 97% and 82% bound to albumin, respectively. MPAG at high (but clinically realisable) concentrations reduced the plasma binding of mycophenolic acid. The mean maximum plasma mycophenolic acid concentration (Cmax) after a mycophenolate mofetil 1 g dose in healthy individuals was around 25 mg/L, occurred at 0.8 hours postdose, decayed with a mean apparent half-life (t1/2) of around 16 hours, and generated a mean total area under the plasma concentration-time curve (AUC infinity) of around 64 mg.h/L. Intra- and interindividual coefficients of variation for the AUC infinity of the drug were estimated to be 25% and 10%, respectively. Intravenous and oral administration of mycophenolate mofetil showed statistically equivalent MPA AUC infinity values in healthy individuals. Compared with mycophenolic acid, MPAG showed a roughly similar Cmax about 1 hour after mycophenolic acid Cmax, with a similar t1/2 and an AUC infinity about 5-fold larger than that for mycophenolic acid. Secondary mycophenolic acid peaks represent a significant enterohepatic cycling process. Since MPAG was the sole material excreted in bile, entrohepatic cycling must involve colonic bacterial deconjugation of MPAG. An oral cholestyramine interaction study showed that the mean contribution of entrohepatic cycling to the AUC infinity of mycophenolic acid was around 40% with a range of 10 to 60%. The pharmacokinetics of patients with renal transplants (after 3 months or more) compared with those of healthy individuals were similar after oral mycophenolate mofetil. Immediately post-transplant, the mean Cmax and AUC infinity of mycophenolic acid were 30 to 50% of those in the 3-month post-transplant patients. These parameters rose slowly over the 3-month interval. Slow metabolic changes, rather than poor absorption, seem responsible for this nonstationarity, since intravenous and oral administration of mycophenolate mofetil in the immediate post-transplant period generated comparable MPA AUC infinity values. Renal impairment had no major effect on the pharmacokinetic of mycophenolic acid after single doses of mycophenolate mofetil, but there was a progressive decrease in MPAG clearance as glomerular filtration rate (GFR) declined. Compared to individuals with a normal GFR, patients with severe renal impairment (GFR 1.5 L/h/1.73m2) showed 3-to 6-fold higher MPAG AUC values. In rental transplant recipients during acute renal impairment in the early post-transplant period, the plasma MPA concentrations were comparable to those in patients without renal failure, whereas plasma MPAG concentrations were 2- to 3-fold higher. Haemodialysis had no major effect on plasma mycophenolic acid or MPAG. Dosage adjustments appear to not be necessary either in renal impairment or during dialysis. (ABSTRACT TRUN     

Cisapride reduces neonatal postoperative ileus: randomised placebo controlled trial

AIM: To assess the efficacy of cisapride in reducing ileus persisting to the tenth postoperative day after neonatal abdominal surgery. METHODS: A prospective, randomised, double blind trial comparing rectal cisapride (1.4-2.3 mg/kg/day) with placebo over seven days was undertaken in 33 neonates. RESULTS: Seven of 12 (58%) patients receiving placebo and eight of 11 (73%) receiving cisapride achieved a first sustained feed during treatment. Of those receiving cisapride, the first sustained feed occurred at 2.3 days (SEM 0.6) compared with 4.7 days (SEM 0.8) with placebo. By the seventh day the mean daily net enteral balance was 69 (SEM 18) ml/kg in the cisapride subgroup and 17 (SEM 8) ml/kg for those receiving placebo. Stool was passed on 6.3 (SEM 0.4) treatment days in the cisapride subgroup compared with 4.1 (SEM 1.0) treatment days in the placebo subgroup. CONCLUSION: Cisapride is effective in neonates with a prolonged ileus after abdominal surgery.     

The prevalence of preferential nasal breathing in adults

The prevalence of preferential nasal breathing was studied in an awake adult population. One hundred and ninety-four people consented to gentle manual compression of the nostrils. They were advised to 'breathe in and out', but no further information regarding breathing was given to avoid influencing the patient. One hundred and eighty patients (92.8%) commenced immediate regular relaxed breathing. Fourteen patients (7.2%) had difficulty with oral breathing which ranged from irregular mouth breathing associated with distress to no spontaneous respiration. The prevalence of preferential nasal breathing was strongly associated with increasing age (chi 2 for trend, P = 0.007). In addition, a weakly significant association was demonstrated between a history of asthma and this phenomenon (P = 0.047). These findings suggest a tendency for the elderly person to revert to the infant pattern of obligate nasal breathing. Physicians should be aware of this possibility in the elderly patient, especially prior to any procedure which may induce nasal obstruction.     

Anatomical correction of the exstrophy-epispadias complex: analysis of 34 patients

OBJECTIVE: To evaluate the surgical procedures required for anatomical reconstruction of the bladder and penis in the exstrophy-epispadias complex. PATIENTS AND METHODS: All primary exstrophy-epispadias repairs carried out by one surgeon between 1987 and 1997 were reviewed. Bladder closure consisted of full extraperitoneal mobilization, transpositional omphaloplasty, drainage with ureteric and urethral catheters and immobilization with a 'frog-leg' plaster-cast or 'mermaid' dressings. Osteotomies were always performed when bladder closure was attempted after 37 h of age. Before 1990 the osteotomies were posterior vertical iliac (one patient) and subsequently anterior oblique iliac (10 patients). Pre-peritoneal herniotomies, in the absence of a clinical hernia, were included in the primary procedure after 1992. A modified Cantwell technique was used for epispadias repair and this was undertaken at a median of 16 months after bladder closure (range 6-30). RESULTS: Thirty-four patients (27 male) were reviewed; one patient had a chromosomal abnormality, a deletion in the short arm of chromosome 4. The male infants required a median of four procedures (range 2-5) for bladder closure, epispadias reconstruction and herniotomies, while the females needed a median of two (range 2-5). Complete bladder dehiscence, requiring re-closure with osteotomies, occurred in three cases (9%, two male). There were no dehiscences in the primary osteotomy group. Fistulae after epispadias repair occurred in four patients (17%). The bladder capacity increased to > 60 mL in 10 of 15 males by 36 months after epispadias repair. Only two of seven female infants attained a capacity of > 60 mL. Of the 15 infants who did not undergo herniotomy at primary closure, 13 subsequently developed inguinal hernias (one uni- and 11 bilateral) with incarceration occurring in two. Twelve infants underwent herniotomy at primary closure and six developed subsequent hernias (two uni- and four bilateral; P = 0.05) with documented incarceration in two. CONCLUSIONS: Anatomical correction of the exstrophy-epispadias complex remains challenging, but can be achieved with complication rates of < 20% for each stage. Bladder volumes large enough to permit adequate bladder neck reconstruction can be anticipated after epispadias repair in a large proportion of male infants, but remains small in female infants with low outlet resistance. Inguinal herniotomy at the time of bladder closure significantly reduces the incidence of subsequent herniation, which nevertheless remains high.     

OptaDOS: A tool for obtaining density of states,core-level and optical spectra from electronic structure codes

We present OptaDOS, a program for calculating core-electron and low-loss electron energy loss spectra (EELS) and optical spectra along with total-, projected- and joint-density of electronic states (DOS) from single-particle eigenenergies and dipole transition coefficients. Energy-loss spectroscopy is an important tool for probing bonding within a material. Interpreting these spectra can be aided by first principles calculations. The spectra are generated from the eigenenergies through integration over the Brillouin zone. An important feature of this code is that this integration is performed using a choice of adaptive or linear extrapolation broadening methods which we show produces higher accuracy spectra than standard fixed-width Gaussian broadening. OptaDOS  may be straightforwardly interfaced to any electronic structure code. OptaDOS  is freely available under the GNU General Public licence from http://www.optados.org.     

The effect of the third invariant on the strength and failure of boron carbide and silicon carbide

This article presents new test data to assess the effect the third invariant has on the strength and failure of two ceramic materials: boron carbide and silicon carbide. Two experimental techniques are used: the Brazilian test that produces a biaxial state of stress, and a new technique that uses a high-pressure confinement vessel to load a specially designed dumbbell specimen in triaxial extension. The dumbbell geometry provides two important advantages over the typically used cylindrical specimen: no adhesive is required to bond the specimen to the load cell because the dumbbell geometry naturally takes the specimen into tension, and any loading asymmetries are essentially eliminated due to the axisymmetric geometry. The results show that when the stress state is on the tensile meridian the equivalent stress at failure is constant, independent of the hydrostatic pressure. The average equivalent stress at failure is for boron carbide and for silicon carbide. The Brazilian test was only performed on boron carbide and failed at , much higher than when on the tensile meridian () indicating that the effect of the third invariant is significant (because of the difference in the failure strength) and must be accounted for to accurately predict when failure will occur.     

Slip homogenization in Al-Li alloys by thermomechanical treatment and its effect on mechanical behaviour

The affects of a pre-ageing stretch and of duplex ageing on slip distribution have been examined in the Al-Li-Cu-Mg-Zr alloy 8090 peak aged at 170 °C. Stretching prior to ageing and duplex ageing were found to effectively homogenize the distribution of S in these alloys. In contrast, in unstretched materials that were not duplex aged, precipitation of S was intense on the grain and subgrain boundaries but scarce elsewhere.Tensile, cyclic stress-strain, long fatigue crack growth and small fatigue crack growth data were gathered. These data showed that slip was planar in the unstretched and duplex-aged materials as compared to materials that were stretched prior to ageing. A model is developed to calculate the diameter where Orowan looping of the S precipitates was likely to give way to shearing of those precipitates. Based on this model, it was concluded that, although the distribution of S precipitates was homogeneous in the duplex-aged materials, the precipitates were too fine to effectively homogenize slip. It was also shown that if the artificial ageing temperature was increased to 190 °C the S precipitates were thicker, leading to a change in deformation behaviour.     

Light‐Activated,Multi‐Semiconductor Hybrid Microswimmers

Using a dynamic fabrication process, hybrid, photoactivated microswimmers made from two different semiconductors, titanium dioxide (TiO₂) and cuprous oxide (Cu₂O) are developed, where each material occupies a distinct portion of the multiconstituent particles. Structured light‐activated microswimmers made from only TiO₂ or Cu₂O are observed to be driven in hydrogen peroxide and water most vigorously under UV or blue light, respectively, whereas hybrid structures made from both of these materials exhibit wavelength‐dependent modes of motion due to the disparate responses of each photocatalyst. It is also found that the hybrid particles are activated in water alone, a behavior which is not observed in those made from a single semiconductor, and thus, the system may open up a new class of fuel‐free photoactive colloids that take advantage of semiconductor heterojunctions. The TiO₂/Cu₂O hybrid microswimmer presented here is but an example of a broader method for inducing different modes of motion in a single light‐activated particle, which is not limited to the specific geometries and materials presented in this study.     

Arachidonic acid potentiates the duration of the metabotropic, protein kinase C-mediated, suppression of the inhibitory adenosine A1 receptor pathway in glutamatergic nerve terminals from rat cerebral cortex

Percutaneous US guided nephrostomy is the simplest and most direct technique to drain an obstructed kidney. The indications are included in two groups: temporary drainage and permanent drainage; the former is indicated in the non endoscopically superable ureteral obstruction, in pyonephrosis, in pregnant women and in transplanted kidneys (due to the easier access), the latter is exclusively reserved to neoplastic obstructions. The only real contraindication to the method, besides a documented allergy to local anaesthetics, is represented by a severe coagulopathy. Positioning techniques are the "one shot" technique, in which dilation and positioning are synchronous (it can avoid fluoroscopy but it is more traumatic) and angiographic derived Seldinger's technique, that utilizes fluoroscopy and an instrumentation including a guidewire and a set of Amplatz dilators. Complications are due to the access route; the choice of an intercostal access is always inadvisable, due to the risk of pneumothorax or pulmonary injury; the most frequent complications are vascular (hemorrhage, retroperitoneal hematoma) and usually well controlled; more severe lesions (renal artery laceration and arteriovenous fistula) may require intervention or embolization, but the incidence of nephrectomies due to vascular injury accounts for one per thousand.