Phase II study of oral platinum drug JM216 as first-line treatment in patients with small-cell lung cancer.

PURPOSE: This multicenter phase II trial was performed to determine tumor efficacy and tolerance of the oral platinum drug JM216 in patients with small-cell lung cancer (SCLC). PATIENTS AND METHODS: Patients with SCLC limited disease unfit for intensive chemotherapy or those with extensive disease received JM216 120 mg/m(2)/d for 5 consecutive days every 3 weeks. Individual dose escalation to 140 mg/m(2)/d was allowed if toxicity was 相似文献   

Surface roughness, porosity and wettability of gentamicin-loaded bone cements and their antibiotic release

In this study, the release of gentamicin as a function of time was measured for six different gentamicin-loaded bone cements and related with the surface roughness, porosity and wettability of the cements. Initial release rates varied little between the six bone cements (CMW1, CMW3, CMW Endurance, CMW 2000, Palacos, and Palamed) and ranged from 8.6 to 14.1 microg/cm2/h. The total amounts of gentamicin released after 1 week varied between 4.0 and 5.3% of the total amount of antibiotic incorporated for the CMW cements and was 8.4% for Palacos. Palamed released after 1 week significantly more of the gentamicin incorporated (17.0%). The wettability of all cements was similar (water contact angles between 70 and 80 degrees), but the surface roughness and the porosity of the cements varied markedly. Initial release rates increased with surface roughness, although the correlation coefficient was low (0.64), while total amounts released increased linearly (correlation coefficient 0.97) with the bulk porosity of the cements. Consequently, it can be concluded that the release kinetics of gentamicin from bone cements is controlled by a combination of surface roughness and porosity.     

Neurophysiological evaluation in children with Friedreich's ataxia

Introduction

In children with Friedreich's ataxia (FRDA children), clinical ataxia outcomes are hardly substantiated by underlying neurophysiological parameters. In young FRDA children, some reports (based upon International Cooperative Ataxia Rating Scale scores (ICARS)) mention transient neurological improvement upon idebenone treatment. However, these outcomes are obtained with adult instead of pediatric reference values. It is unknown whether age-related neurophysiological parameters can really substantiate neurologic improvement.

Aim

In young FRDA children, we aimed to determine longitudinal neurophysiological parameters during idebenone treatment.

Methods

During a two-year study period, 6 genetically proven FRDA children with cardiomyopathy (6-18 years) were longitudinally assessed for neurophysiological parameters [sensory evoked potentials (SEPs), F response, peripheral nerve conduction and dynamometry] in association with age-matched ICARS-scores.

Results

In all FRDA children, SEPs remained absent during the two-year study period. Peroneal nerve conduction velocity declined (from − 1SD to − 2SD; p < .05), whereas F responses remained essentially unaltered. Total muscle force and leg muscle force decreased (from − 2 to − 3SD and − 2.5 to − 3.5SD; both p < .05) and age-related ICARS-scores deteriorated (median increase + 41%; p < .05).

Conclusion

In FRDA children, age-related neurophysiological and ataxia parameters deteriorate during idebenone treatment. Although we cannot exclude some (subjective) disease stabilization, age-related neurophysiological parameters do not substantiate neurologic improvement.     

The relation between the blood benzodiazepine concentration and performance in suspected impaired drivers

Several experimental studies have shown a negative influence of benzodiazepines on driving skills. The objective of this study is to study the relationship between the blood concentration of benzodiazepines and the influence on performance in field sobriety tests. A retrospective case file evaluation was conducted to select cases of drivers, tested positive for benzodiazepines only in the period from January 1999 to December 2004. Drivers were grouped into the categories sub therapeutic, therapeutic or elevated concentrations. The outcome of the tests (walking, walking after turn, nystagmus, Romberg's test, behavior, pupils and orientation) was binomial. A Chi square test was used to assess differences in proportions of the categorized cases. In total 171 cases were included. Observations of behavior (n=137; p<0.01), walking (n=109; p<0.01), walking after turn (n=89; p=0.02) and Romberg's test (n=88; p<0.05) were significantly related to the benzodiazepine concentration. There was no significant relation between benzodiazepine concentration and effect on pupil size, nystagmus or orientation. The results of our study indicate a relation between the concentration of benzodiazepines and the results of some performance tests. More effort is needed to standardize the tests and to determine the sensitivity and selectivity of the tests for benzodiazepines.     

Pharmacokinetics of MEN-10755, a novel anthracycline disaccharide analogue, in two phase I studies in adults with advanced solid tumours

The doxorubicin analogue MEN-10755 has been identified as a compound with promising antitumour activity based on structure-activity studies of a new series of anthracycline disaccharides. The high antitumour activity of MEN-10755 in human tumour xenografts, including doxorubicin-resistant xenografts, and its unique pharmacological and biological properties made this novel disaccharide analogue an interesting candidate for clinical evaluation. Two pharmacokinetic phase I studies with different dosing schedules were performed in adults with solid refractory malignancies. The pharmacokinetics of MEN-10755 were studied after a 15-min i.v. infusion given once every 3 weeks or once every week for 3 weeks followed by 1 week rest. Plasma and urine levels of MEN-10755 were measured by HPLC with fluorescent detection. It was possible to combine the pharmacokinetic results of the two studies because there was no accumulation of MEN-10755 before the next infusion of MEN-10755 in the weekly study with 1 week rest. The administered dose levels on day 1 in this study were all in the lower range from the 3-weekly study. The postinfusion plasma kinetics of MEN-10755 were best described by a triexponential model. The plasma peak levels (Cmax) of MEN-10755 showed a linear relationship with the administered dose. Peak plasma MEN-10755 levels ranged between 474 and 21,587 microg/l. The mean elimination half-life (T(1/2gamma)) was 20.7+/-9.0 h. The AUC(0-infinity) was proportional to the administered dose. The mean plasma clearance of MEN-10755 was 6.0+/-2.2 l/h per m2 with a mean volume of distribution (Vss) of 95.6+/-43.4 l/m2. The mean renal excretion of unchanged drug within 24 h was 4.3+/-1.8%. Compared to epirubicin and doxorubicin, the pharmacokinetics of MEN-10755 were characterized by an approximately twofold shorter terminal half-life, a much lower total plasma clearance and a much smaller volume of distribution.     

4-Aminopyridine (fampridine) effectively treats amlodipine poisoning: a case report

A case of a serious poisoning with the calcium entry blocker amlodipine is described, which was treated effectively with 4-aminopyridine. Calcium is suggested as general treatment of poisoning with calcium entry blockers in many guidelines. The use of intravenous 4-aminopyridine is theoretically useful to treat poisoning from calcium entry blockers and was demonstrated in this case report.     

Vincristine pharmacokinetics is related to clinical outcome in children with standard risk acute lymphoblastic leukemia

Vincristine is a key drug in the treatment of childhood and adult acute lymphoblastic leukemia (ALL), and many other childhood malignancies. Despite decades of wide clinical use, no data on the correlation between vincristine pharmacokinetics and long-term clinical outcome have been published. We here report clinical data (median follow-up time 10·5 years, range 7·3–12 years) for 86 children with B-cell precursor ALL, in whom vincristine kinetics were studied on treatment day 1. The median total plasma clearance was 429 and 331 ml/min per m² and the area under the plasma concentration-time curve (AUC) was 4·49 and 5·40 mg/l × min in relapse and non-relapse patients, respectively (not significant). In standard risk patients, where treatment depends more heavily on vincristine than in other subgroups, the relative risk (RR) of relapse was significantly increased for patients with clearance values above median (RR 5·2; P  = 0·036), or AUC values below median (RR 5·8; P  = 0·025). Our data suggest a relationship between the antileukemic effect and the systemic exposure of the drug, which warrants further studies.     

Morphine pharmacokinetics during venoarterial extracorporeal membrane oxygenation in neonates

Objective To study morphine pharmacokinetics in neonates undergoing venoarterial ECMO and to quantify differences between these neonates and neonates subjected to noncardiac major surgery.Design and setting Observational study in a level III referral center.Patients and methods Pharmacokinetic estimates from 14 neonates undergoing ECMO were compared with findings from a previous study in 0- to 3-year-olds after noncardiac major surgery using a nonlinear mixed effect model. A one-compartment linear disposition model with zero-order input (infusion) and first-order elimination was used to describe all data.Results Clearance in neonates (age <7 days) at the start of ECMO (2.2 l per hour per 70 kg) was lower than that in postoperative neonates (10.5 l per hour per 70 kg) but increased rapidly (maturation half-life 30 and 70 days, respectively) and equaled that of the postoperative group after 14 days. Clearance was affected by size and age only. Exchange transfusion, when used, contributed only 1.1% (CV 46%) of total clearance. Distribution volume increased with age and was 2.5 times (CV 102%) greater in ECMO children than in postoperative children. The between-subject variability values for volume of distribution and clearance were 49.4% and 38.7%. Weight and age information explained 83% of the overall clearance variability and 60% of overall distribution volume variability.Conclusions Morphine clearance is reduced in infants requiring ECMO, possibly reflecting severity of illness. Clearance maturation on ECMO is rapid and normalizes within 2 weeks. Initial morphine dosing may be guided by age and weight, but clearance and distribution volume changes (and their variability) during prolonged ECMO suggests that morphine therapy should be subsequently guided by clinical monitoring.     

Dried blood spots: a new tool for tuberculosis treatment optimization

Tuberculosis (TB) is a high-burden infectious disease, especially in low and middle-income countries. The efforts to eliminate this disease are challenged by the emergence of multidrug resistance and TB-HIV coinfection. The cumulative knowledge on pharmacokinetics/ pharmacodynamics of antituberculosis agents has recently encouraged therapeutic drug monitoring (TDM) in patient care. However, logistical problems related to conventional sampling limit the application of TDM in research-oriented institutions. Dried blood spot (DBS) compared with conventional venous blood sampling has the advantages of easier sampling, storage and transportation, thus enabling the application of TDM even in remote areas. In addition, DBS with its lower biohazardous risk can be safely performed in a high HIV prevalence area, which also tends to have a high TB burden. Another benefit of DBS sampling is that it requires a smaller blood volume than conventional sampling and is highly recommended for application in pediatric TB. A limitation of DBS is that additional considerations are required for analysis method development and validation. The accuracy of the DBS method is influenced by a number of factors that need to be thoroughly examined in method development and validation. Further, the agreement between DBS and plasma/serum concentrations is not always understood and further investigations are required.