Pilot Study of Hyperpolarized 13C Metabolic Imaging in Pediatric Patients with Diffuse Intrinsic Pontine Glioma and Other CNS Cancers.

BACKGROUND AND PURPOSE: Pediatric CNS tumors commonly present challenges for radiographic interpretation on conventional MR imaging. This study sought to investigate the safety and tolerability of hyperpolarized carbon-13 (HP-13C) metabolic imaging in pediatric patients with brain tumors. MATERIALS AND METHODS: Pediatric patients 3 to 18 years of age who were previously diagnosed with a brain tumor and could undergo MR imaging without sedation were eligible to enroll in this safety study of HP [1-13C]pyruvate. Participants received a one-time injection of HP [1-13C]pyruvate and were imaged using dynamic HP-13C MR imaging. We assessed 2 dose levels: 0.34 mL/kg and the highest tolerated adult dose of 0.43 mL/kg. Participants were monitored throughout imaging and for 60 minutes postinjection, including pre- and postinjection electrocardiograms and vital sign measurements. RESULTS: Between February 2017 and July 2019, ten participants (9 males; median age, 14 years; range, 10-17 years) were enrolled, of whom 6 completed injection of HP [1-13C]pyruvate and dynamic HP-13C MR imaging. Four participants failed to undergo HP-13C MR imaging due to technical failures related to generating HP [1-13C]pyruvate or MR imaging operability. HP [1-13C]pyruvate was well-tolerated in all participants who completed the study, with no dose-limiting toxicities or adverse events observed at either 0.34 (n = 3) or 0.43 (n = 3) mL/kg. HP [1-13C]pyruvate demonstrated characteristic conversion to [1-13C]lactate and [13C]bicarbonate in the brain. Due to poor accrual, the study was closed after only 3 participants were enrolled at the highest dose level. CONCLUSIONS: Dynamic HP-13C MR imaging was safely performed in 6 pediatric patients with CNS tumors and demonstrated HP [1-13C]pyruvate brain metabolism.

A model-based meta-analysis of the effect of latanoprost chronotherapy on the circadian intraocular pressure of patients with glaucoma or ocular hypertension.

Several reports have demonstrated that the efficacy of latanoprost is influenced by the time of dosing. This model-based meta-analysis validates previous findings that evening dosing is superior to morning dosing and predicts the optimal time for dosing, based on the quantitative assessment of baseline and latanoprost-treated 24-h circadian intraocular pressure (IOP) curves. The results confirm the importance of the time of dosing as a factor that influences the extent of reduction in IOP and underline the need to take this factor into consideration in the design of glaucoma trials and therapy.

Ritonavir 100 mg does not cause QTc prolongation in healthy subjects: a possible role as CYP3A inhibitor in thorough QTc studies.

To assess the QTc prolongation by ritonavir (RTV) 100 mg and explore its potential use as CYP3A inhibitor in thorough QTc (TQT) studies. Randomized, crossover study of single-dose RTV 100 mg, placebo, and moxifloxacin (MFLX) 400 mg in 65 healthy subjects with serial triplicate electrocardiograms obtained for 12 h post-dose. Largest mean placebo-adjusted QTcF increase from baseline (90% confidence interval (CI)) for RTV 100 mg was noninferior to placebo (0.16 ms (-1.38, 1.69)). Study sensitivity was validated by detecting the largest mean placebo-adjusted QTcF increase from baseline (90% CI) for MFLX of 8.31 ms (6.44, 10.18). A single dose of RTV 100 mg does not cause QTc prolongation in healthy subjects. Based on the potent CYP3A4 inhibition, lack of QTc effect and better safety profile, RTV 100 mg could replace ketoconazole as the CYP3A4 inhibitor in TQT studies.

Pharmacodynamics of glycopeptides in the mouse peritonitis model of Streptococcus pneumoniae or Staphylococcus aureus infection.

The emergence of resistance to various antibiotics in pneumococci leaves the glycopeptides as the only antibiotics against which pneumococci have no resistance mechanism. This situation has led to a renewed interest in the use of glycopeptides. It has not yet been possible to conclude which one or more of the pharmacokinetic or pharmacodynamic (PK/PD) parameters are the most important and best predictors for the effects of treatment with glycopeptides in animal models or in humans. We used the mouse peritonitis model with immunocompetent mice and with Staphylococcus aureus and Streptococcus pneumoniae as infective organisms. A wide spectrum of different treatment regimens with vancomycin and teicoplanin was tested to study the pharmacodynamics of these drugs. In studies in which the single dose that protected 50% of lethally infected mice (ED(50)) was given as one dose or was divided into two doses, survival was significantly decreased when the dose was divided. The only statistically significant correlations between the percentage of survival of the mice after 6 days and each of the PK/PD parameters were for peak concentration (C(max))/MIC and S. aureus and for the free fraction of C(max) (C(max-free))/MIC and S. pneumoniae. For S. pneumoniae, the ED(50) for different dosing regimens increased with the number of doses given; e.g., the single-dose ED(50)s for vancomycin and teicoplanin were 0.65 and 0. 45 mg/kg, respectively, but the ED(50)s for dosing regimens with 2-h doses given for 48 h were 6.79 and 5.67 mg/kg, respectively. In experiments with 39 different vancomycin dosing regimens and 40 different teicoplanin dosing regimens against S. pneumoniae, the different PK/PD parameters were analyzed using logistic regression. The C(max-free)/MIC was one of two parameters that best explained the effect for both drugs; for vancomycin, the other important parameter was the AUC/MIC, and for teicoplanin, the other parameter was the time the free fraction of the drug is above the MIC. The effect analyzed as a function of C(max-free)/MIC disclosed thresholds with shifts from almost no effect to full effect at ratios of five to six for vancomycin and two to three for teicoplanin.

National survey of extended-interval aminoglycoside dosing.

A random sample survey of 500 acute care hospitals in the United States was conducted to evaluate the adoption of extended-interval aminoglycoside dosing (EIAD). The survey revealed that EIAD has been adopted in 3 of every 4 acute care hospitals, a 4-fold increase since 1993. Of the 74.7% of hospitals reporting EIAD, 64% had written guidelines. Equal or less toxicity (87.1%), equal efficacy (76.9%), and cost-savings (65.6%) were common rationales. There has been a trend toward higher adult dosages of gentamicin (e.g., >5 mg/kg/dose) and an increase in the adoption of EIAD across all age groups (neonatal, 11%, and pediatric, 23%). Monitoring of aminoglycoside concentrations has shifted to a single determination of concentration, at 6-18 h after drug administration. The most common methods of dosage adjustment for declining renal function were an interval extension with the same dose (47%) or use of the Hartford nomogram (32%).

National survey of once-daily dosing of aminoglycoside antibiotics.

To evaluate the scope of once-daily dosing of intravenous aminoglycoside antibiotics, a questionnaire was designed and mailed to a random sample of pharmacy directors at 500 acute care hospitals in the United States. The response rate was 68.4%. Nineteen percent of the respondents reported use of once-daily dosing of aminoglycosides. Affiliation with a pharmacy residency program and the presence of a pharmacokinetic consultation service by the pharmacy department were associated with this practice (p < 0.05). No other statistically significant differences were found. Reported indications, contraindications, and dosing were consistent with those found in the literature. The profession of pharmacy, as demonstrated by pharmacy residency programs and pharmacokinetic consultation services, appears to have been instrumental in implementing this method of dosing aminoglycosides.

The effects of cyclosporine on the pharmacokinetics of doxorubicin in patients with small cell lung cancer.

BACKGROUND: The authors compared the pharmacokinetics of doxorubicin when administered with and without concomitant high dose cyclosporine for multidrug resistant (MDR) tumor modulation in small cell lung cancer. METHODS: Eight patients with small cell lung cancer served as their own controls and were studied first during an initial course of doxorubicin without cyclosporine, and then subsequently during a cyclosporine-modulated doxorubicin course. All patients received cyclophosphamide and vincristine in each course. Doxorubicin was administered as a 1-hour infusion after a 2-hour cyclosporine loading infusion, and cyclosporine was infused continuously for the next 48 hours. Serum concentrations of doxorubicin, doxorubicinol, and cyclosporine all were assayed by high-pressure liquid chromatography. Pharmacokinetic analysis of doxorubicin included area under the curve (AUC), clearance, apparent volume of distribution at steady state (Vss), and elimination half-life (T1/2). The percent of change and surviving fraction of leukocyte count and platelets were determined as pharmacodynamic indices. RESULTS: Cyclosporine modulation increased the AUC0-36 of doxorubicin by 48% (P = 0.042) and the AUC0-36 of doxorubicinol by 443% (P = 0.0001), whereas the doxorubicin clearance declined by 37% (P = 0.0495). No difference was found in the Vss or T1/2 for doxorubicin when cyclosporine was added to the regimen. The ratio of the doxorubicinol AUC0-36 to the doxorubicin AUC0-36 increased significantly with cyclosporine modulation (8.88 vs. 2.19; P = 0.001). Drug-related toxicity was also greater with the cyclosporine-modulated course of doxorubicin. A 91% reduction in the leukocyte count followed the modified course, compared with an 84% reduction following the initial course (P = 0.0074). A more prolonged and greater degree of myelosuppression was observed and a significant relationship was found between the systemic exposure to doxorubicin (defined by AUC) and the surviving fraction of the leukocyte count (r = -0.69; P = 0.006). Similarly, the reduction in the platelet count was significantly greater after the cyclosporine-modulated course (72.8%) than after the initial course (36.4%) (P = 0.0016). A significant correlation was found between the AUC of doxorubicinol and the surviving fraction of platelets (r = -0.71; P = 0.004). In addition, patients showed decreased performance status associated with significant weight loss and severe myalgias. CONCLUSIONS: The addition of high dose cyclosporine for MDR modulation resulted in the significant alteration of doxorubicin disposition and remarkable toxicity in all patients. The mechanisms responsible for the decreased doxorubicin clearance may include cyclosporine's ability both to interfere with P-glycoprotein in normal tissues and to selectively inhibit the cytochrome P-450 enzyme system. Further study of this potentially significant drug-drug interaction is warranted.

Teacher feedback to mentally retarded and nonretarded children.

In an effort to understand earlier findings on helplessness of retarded children, we observed feedback given during reading training to retarded and nonretarded children of third- to fourth-grade reading ability. The helplessness-inducing pattern of feedback identified in previous research on learned children were more likely to receive negative feedback than were nonretarded children. The findings suggest that retarded children's susceptibility to helplessness may result partly from the feedback they receive in school.

The social maps of children approaching adolescence: Studying the ecology of youth development.

This article reports the first results of the three-year longitudinal study of the social maps of children beginning the transition to adolescence. This exploratory study is guided by Bronfenbrenner's conception of the ecology of human development, stressing the importance of a phenomenological orientation to development in the context of ecological transitions. The study focuses on characteristics of children's social networks (the web of relationships in which the individual is involved) as a function of neighborhood type, socioeconomic status, and level of physical maturation. The social heterogeneity of the social network (e.g., the relative salience of peers versus adults) is a primary concern. The child's and parent's perceptions of the network, of the people available to help the child, and the child's friends are compared within the context of ecological, socioeconomic, and maturational factors. The results (for 111 sixth-grade children from three contrasting neighborhood schools) shed some light on age segregation and the overall heterogeneity of the social environments of children facing the transition to adolescence. They provide a context and a baseline for the longitudinal study.