Clinical pharmacokinetics of Neoral in pediatric recipients of primary liver transplants

Pediatric liver transplant recipients constitute a population characterized by a particularly unpredictable and poor bioavailability of cyclosporin (CyA). Even though several adult studies show that the new oral formulation of CyA, Neoral (NEO), produces better bioavailability and blood level predictability, few data describe its pharmacokinetics in children. We performed a complete analysis of the pharmacokinetics of NEO in ten small children after primary liver transplantation. Three pharmacokinetic profiles were set up with data obtained from tests taken during i. v. administration of CyA, after the first oral NEO dose, and after the last NEO dose before discharge from the hospital. The mean half-lives obtained were 8.1, 7.7, and 6.9 h, respectively, and the bioavailabilities were 22 % and 21 % for the first and last NEO doses. A large interpatient variability was observed. This was due, in part, to episodes of diarrhea that interfered with the pharmacokinetic evaluation and, in part, to the variability of post-transplant hepatic function. There was a good correlation between CyA trough levels and their related AUCs for both NEO profiles (r = 0.93 and r = 0.74, respectively). We conclude that, even though the pediatric OLT population remains more unpredictable than that of adults, NEO has a relatively rapid half-life and a remarkably improved bioavailability. Received: 29 November 1996 Received after revision: 10 April 1997 Accepted: 15 May 1997     

An investigation into the effects of structured music workshops with adults with mental handicap

This study investigated the effects of structured group workshops for a population with special needs. Twenty subjects, each with a mild or moderate mental handicap, attended a series of 10 weekly 1-hour music workshops on the structured group playing of a Javanese Gamelan. Twenty subjects formed a non-intervention control group. The experimental hypothesis was that participation in the experimental group would produce significant improvements in musical ability as measured by the Rossi test of musical ability, devised and validated for use in this study. Significant gains in communication skills as measured by the Communication Assessment Profile for Adults with a Mental Handicap (CASP) and self-esteem levels measured by the Khalid semantic differential technique were also postulated. It was also suggested that these gains would be significantly correlated. Results show significant gains in musical ability (instrumental rhythm production: t = 5.67, d.f. = 29, p < 0.01 and simple rhythm production: t = 8.42, d.f. = 29, p < 0.01) and communication skills (t = 4.69, d.f. = 29, p < 0.01). Moreover these results are significantly correlated (r = 0.59, p < 0.05, r = 0.75, p < 0.05, r = 0.56, p < 0.05). A ceiling effect was obtained in the measurement of self-esteem. It is suggested that these gains derive from certain aspects of the musical communicative environment at the workshops. Suggestions for future research involve examining the possible influences on these developments.     

Does the Prepubertal Duration of Diabetes Influence the Onset of Microvascular Complications?

This study investigated the relationship between the development of diabetic retinopathy and pubertal status at onset of diabetes in 521 Type 1 diabetic patients diagnosed between 1950 and 1985. Pubertal status was based on age at onset (girls ≧ 11 years and boys ≧ 12 years). Retinopathy (all forms) developed in 112 patients (21.5%; 65 background and 47 proliferative retinopathy). For subjects diagnosed in either the prepubertal or postpuberal period, a similar proportion survived without developing retinopathy for any given duration of diabetes (X² = 0.3822, p = 0.54). However, if only the postpubertal duration of diabetes is considered, then the proportion of patients surviving without retinopathy was significantly less for those diagnosed in the prepubertal period (X² = 14.2, p = 0.002). This study suggests that the prepubertal duration of diabetes is an important phase and that the years prior to puberty do contribute to the risk of developing microvascular injury.     

Cyclophosphamide and etoposide therapy with GM-CSF for VAD-resistant multiple myeloma

Few effective regimens are available for patients with advanced multiple myeloma resistant to or relapsing after both alkylating agents and VAD. We treated 52 patients with advanced and refractory multiple myeloma with the combination of cyclophosphamide (3.0 g/m²) and etoposide (900 mg/m²) followed by GM-CSF at a daily dose of 0.125 mg/m² until recovery of granulocytes. 42% of patients responded with a median time of 19 d for recovery of granulocytes to 0.5 x 10⁹/1 and a 4% mortality rate. Eight responding patients received a second myeloablative treatment supported by either autologous bone marrow (six patients) or blood stem cells (two patients). The median survival time for all patients was 11 months and the median remission time for responding patients was 8 months. The combination of cyclophosphamide and etoposide provided an effective rescue treatment for many patients with advanced multiple myeloma resistant to conventional therapies. This programme also allowed early marrow or blood stem cell collection in support of subsequent myeloablative therapy for selected patients.     

SODIUM EFFECTS ON THE FIBRILLATORYPROPENSITY OF NON-IONIC CONTRAST MEDIA

Removing sodium from standard ionic contrastmedia markedly increases the incidence of ventricu-lar fibrillation in patients undergoing coronary arvgiography. Newer nonionic contrast media, Iopa-midol (IOP), Iohexol (IOH) and Ioversol (IOV),contain only trace amounts of sodium. To determinewhether sodium influences the fibrillatory propen-sity of nonionic contrast media, we measured theprolongation in QT interval and performed program-med electrical stimulation with l,2 and 3 ventricularextra stimuli in 40 dogs during 4 ml intracoronaryinjections of IOP, IOH and IOV. Solutions of eachcontrast media with added NaCI at concentrations of0.225To, 0.45% and 0.970 were compared to stockcontrast media. The addition of NaCI markedlyincreased the amount of QT interval prolongationproduced by each contrast media. With IOP, theamount of QT interval prolongation was 40+11msec with standard IOP but was 58+11 msec with0.225'70 NaCI/IOP, 84+17 msec with 0.45'To NaCI/IOP, and 132+42 msec with 0.970 NaCl/IOP(P相似文献   

Survivin expression predicts poorer prognosis in anaplastic large-cell lymphoma.

PURPOSE: Survivin, a member of the inhibitor of apoptosis (IAP) family, is not detected in normal adult tissues but is overexpressed in various cancers, including some types of lymphoma. The frequency and prognostic significance of survivin expression in anaplastic large-cell lymphoma (ALCL) is unknown. Materials and METHODS: We assessed for survivin expression in 62 ALCL tumors (30 anaplastic lymphoma kinase [ALK]-positive and 32 ALK-negative) obtained before doxorubicin-based chemotherapy. Given that survivin is a target of the STAT3 signaling pathway and STAT3 is activated in ALCL, survivin expression was also correlated with STAT3 activation. RESULTS: Survivin was expressed in 34 tumors (55%) and did not correlate with ALK. A significant association between survivin expression and STAT3 activation was observed (P =.007, Fisher's exact test). For the ALK-positive group, the 5-year failure-free survival (FFS) was 34% for patients with survivin-positive ALCL compared with 100% for patients with survivin-negative ALCL (P =.009, log-rank test). For the ALK-negative group, the 5-year FFS was 46% for patients with survivin-positive tumors compared with 89% for patients with survivin-negative tumors (P =.03, log-rank test). Overall survival was similarly worse for patients with survivin-positive tumors in both the ALK-positive and ALK-negative groups. Furthermore, multivariate analysis confirmed the independent prognostic value of survivin expression, along with age older than 60 years and Ann Arbor stage III or IV. CONCLUSION: Survivin is expressed in approximately half of ALCL tumors and independently predicts unfavorable clinical outcome. Modulation of survivin expression or function may provide a novel target for experimental therapy in patients with ALCL.     

Modification of Blood Vessel Diameter Following Perivascular Application of Botulinum Toxin-A

The purpose of this study was to demonstrate that perivascularly applied botulinum toxin-A (BTX) increases the diameter of treated blood vessels in a rat femoral vessel exposure model. Six adult Sprague–Dawley rats were used and bilateral femoral artery and vein exposures were performed. Five units of BTX were applied to the experimental side and an equal volume of sterile saline was applied to the control side. Digital images of the vessels were obtained at the following time points: pretreatment, immediately posttreatment, and postoperative days (POD) 1, 14, and 28. Vessel diameters were equivalent at baseline and immediately following application of BTX and saline. The BTX artery was significantly larger than the control artery on POD 1 and 14. The BTX treated artery was significantly larger than all other vessels on POD 14 (p < 0.05) as well as all prior time points (p < 0.01). Direct perivascular application of BTX increases the diameter of rat femoral vessels as early as POD 1. The affect is most robust on POD 14 where the artery was significantly larger than all other vessels at all time points. It is likely that the increased diameter of blood vessels results in an increased blood flow across the area of dilation. Such an increase in flow may serve to improve end-organ perfusion in microvascular procedures.     

Modeling spheroid growth, PET tracer uptake, and treatment effects of the Hsp90 inhibitor NVP-AUY922.

For a PET agent to be successful as a biomarker in early clinical trials of new anticancer agents, some conditions need to be fulfilled: the selected tracer should show a response that is related to the antitumoral effects, the quantitative value of this response should be interpretable to the antitumoral action, and the timing of the PET scan should be optimized to action of the drug. These conditions are not necessarily known at the start of a drug-development program and need to be explored. We proposed a translational imaging activity in which experiments in spheroids and later in xenografts are coupled to modeling of growth inhibition and to the related changes in the kinetics of PET tracers and other biomarkers. In addition, we demonstrated how this information can be used for planning clinical trials. METHODS: The first part of this concept is illustrated in a spheroid model with BT474 breast cancer cells treated with the heat shock protein 90 (Hsp90) inhibitor NVP-AUY922. The growth-inhibitory effect after a pulse treatment with the drug was measured with digital image analysis to determine effects on volume with high accuracy. The growth-inhibitory effect was described mathematically by a combined E(max) and time course model fitted to the data. The model was then used to simulate a once-per-week treatment; in these experiments the uptake of the PET tracers (18)F-FDG and 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) was determined at different doses and different time points. RESULTS: A drug exposure of 2 h followed by washout of the drug from the culture medium generated growth inhibition that was maximal at the earliest time point of 1 d and decreased exponentially with time during 10-12 d. The uptake of (18)F-FDG per viable tumor volume was minimally affected by the treatment, whereas the (18)F-FLT uptake decreased in correlation with the growth inhibition. CONCLUSION: The study suggests a prolonged action of the Hsp90 inhibitor that supports a once-per-week schedule. (18)F-FLT is a suitable tracer for the monitoring of effect, and the (18)F-FLT PET study might be performed within 3 d after dosing.