Pharmacokinetics of the 13C labeled anticancer agent temozolomide detected in vivo by selective cross-polarization transfer

The anticancer agent temozolomide labeled with ¹³C (8-Carbamoyl-3-13C-methylimidazo-[5,1-d]-1,2,3,5-tetrazin-4-(3H)-one), was noninvasively detected in subcutaneous RIF-1 tumors by a selective cross polarization ¹³C NMR method, at a field strength of 9.4T. Pharmacokinetics of the drug, at a dose of 150 mg/kg, were determined for intravenous and intraperitoneal modes of administration (three animals per mode). The half-life of the drug in the tumors was approximately 60 min. The uptake and clearance of the drug, however, varied significantly between individual hosts, for both modes of administration. These results demonstrate the feasibility of obtaining pharmacokinetics of anticancer agents for individual tumors without the need for a label that might modify drug activity (e.g., fluorine). The variability of the in vivo measurements, even within the same tumor model, demonstrates the necessity of directly monitoring the tumor to evaluate drug pharmacokinetics.     

Reduction of vascular and permeable regions in solid tumors detected by macromolecular contrast magnetic resonance imaging after treatment with antiangiogenic agent TNP-470.

PURPOSE: The availability of noninvasive techniques to detect the effects of antiangiogenic agents is critically important for optimizing treatment of cancer with these agents. Magnetic resonance imaging (MRI) is one such noninvasive technique that is routinely used clinically. EXPERIMENTAL DESIGN: In this study, we have evaluated the use of MRI of the intravascular contrast agent albumin-GdDTPA to detect the effects of the antiangiogenic agent TNP-470 on the vascular volume and permeability of the MatLyLu prostate cancer model. RESULTS: TNP-470-treated tumors demonstrated a significant decrease of vascular volume, as well as a significant reduction in vascular and permeable regions, compared with volume-matched control tumors. Although the fractional volume of permeable regions in the tumor decreased, the average value of tumor permeability did not decrease significantly. This was attributable to increase in permeability in some regions of the tumor. These regions were mostly associated with low vascular volume. ELISA assays of control and treated MatLyLu tumors also detected a significant increase of vascular endothelial growth factor in the TNP-470-treated tumors. CONCLUSION: MRI detected significant changes in tumor vascular characteristics after treatment with TNP-470.     

Targeting choline phospholipid metabolism: GDPD5 and GDPD6 silencing decrease breast cancer cell proliferation,migration, and invasion

Abnormal choline phospholipid metabolism is associated with oncogenesis and tumor progression. We have investigated the effects of targeting choline phospholipid metabolism by silencing two glycerophosphodiesterase genes, GDPD5 and GDPD6, using small interfering RNA (siRNA) in two breast cancer cell lines, MCF‐7 and MDA‐MB‐231. Treatment with GDPD5 and GDPD6 siRNA resulted in significant increases in glycerophosphocholine (GPC) levels, and no change in the levels of phosphocholine or free choline, which further supports their role as GPC‐specific regulators in breast cancer. The GPC levels were increased more than twofold during GDPD6 silencing, and marginally increased during GDPD5 silencing. DNA laddering was negative in both cell lines treated with GDPD5 and GDPD6 siRNA, indicating absence of apoptosis. Treatment with GDPD5 siRNA caused a decrease in cell viability in MCF‐7 cells, while GDPD6 siRNA treatment had no effect on cell viability in either cell line. Decreased cell migration and invasion were observed in MDA‐MB‐231 cells treated with GDPD5 or GDPD6 siRNA, where a more pronounced reduction in cell migration and invasion was observed under GDPD5 siRNA treatment as compared with GDPD6 siRNA treatment. In conclusion, GDPD6 silencing increased the GPC levels in breast cancer cells more profoundly than GDPD5 silencing, while the effects of GDPD5 silencing on cell viability/proliferation, migration, and invasion were more severe than those of GDPD6 silencing. Our results suggest that silencing GDPD5 and GDPD6 alone or in combination may have potential as a new molecular targeting strategy for breast cancer treatment. Copyright © 2016 John Wiley & Sons, Ltd.     

A Systematic Review of Randomized Controlled Trials of Interventions to Improve the Health of Persons During Imprisonment and in the Year After Release

We systematically reviewed randomized controlled trials of interventions to improve the health of people during imprisonment or in the year after release. We searched 14 biomedical and social science databases in 2014, and identified 95 studies.Most studies involved only men or a majority of men (70/83 studies in which gender was specified); only 16 studies focused on adolescents. Most studies were conducted in the United States (n = 57). The risk of bias for outcomes in almost all studies was unclear or high (n = 91). In 59 studies, interventions led to improved mental health, substance use, infectious diseases, or health service utilization outcomes; in 42 of these studies, outcomes were measured in the community after release.Improving the health of people who experience imprisonment requires knowledge generation and knowledge translation, including implementation of effective interventions.Worldwide, more than 11 million people are imprisoned at any given time, and the prison population continues to grow at a rate faster than that of the general population.1 Substantial evidence reveals that people who have experienced imprisonment have poor health compared with the general population, as indicated by the prevalence of mental illness, infectious diseases, chronic diseases, and mortality.2There are several reasons to focus on improving the health of people who experience imprisonment.3 The burden of disease in this population affects the general population directly through increased health care costs and through the transmission of communicable diseases (e.g., HIV, HCV, and tuberculosis) after people are released from detention. Imprisonment has also been associated with worse health in family members of those who are detained, compared with the general population, including chronic diseases4 and poor mental health5,6 in adult relatives and mortality in male children.7 At the community level, higher rates of incarceration have been associated with adverse health outcomes, such as sexually transmitted infections and teen pregnancies.8 There is also evidence that poor health in persons who are released from detention, particularly those with inadequately treated mental illness and substance use disorders,3 may affect public safety and reincarceration rates,3 and that better access to health care is associated with less recidivism.9,10 Finally, the right to health and health care is enshrined in international human rights documents,11,12 and is a legislated responsibility of governments in many countries.Intervening during imprisonment and at the time of release could improve the health of people who experience imprisonment and public health overall.13 Knowledge translation efforts, such as syntheses of effective interventions, could lead to the implementation and further evaluation of interventions,14 and identify areas where further research is needed. To date, only syntheses with a limited focus have been conducted in this population, for example, reviews of interventions related to HIV15 or for persons with serious mental illness.16 Decision makers, practitioners, and researchers in this field would benefit from a broader understanding of the state of evidence regarding interventions to improve health in people who experience imprisonment.To address this gap, we systematically reviewed randomized controlled trials of interventions to improve health in persons during imprisonment and in the year after release. We chose this population because we view imprisonment as a unique opportunity to deliver and to link with interventions for this population, and to highlight interventions that could be implemented by those responsible for the administration of correctional facilities. We limited this study to randomized controlled trials, recognizing that randomized controlled trials provide the highest quality of evidence compared with other study designs.17     

Cost-effectiveness analysis of levonorgestrel-releasing intrauterine system (LNG-IUS) 13.5 mg in contraception

Background

Levonorgestrel-releasing intrauterine system (LNG-IUS) 13.5 mg (total content) is a low-dose levonorgestrel intrauterine system for up to 3 years of use. This analysis evaluated the cost-effectiveness of LNG-IUS 13.5 mg in comparison with short-acting reversible contraceptive (SARC) methods in a cohort of young women in the United States from a third-party payer's perspective.

Study design

A state transition model consisting of three mutually exclusive health states — initial method, unintended pregnancy (UP) and subsequent method — was developed. Cost-effectiveness of LNG-IUS 13.5 mg was assessed vs. SARC methods in a cohort of 1000 women aged 20–29 years. SARC methods comprise oral contraceptives (OC), ring, patch and injections, which are the methods commonly used by this cohort. Failure and discontinuation probabilities were based on published literature, contraceptive uptake was determined by the most recent data from the National Survey of Family Growth, and costs were taken from standard US databases. One-way sensitivity analysis was conducted around key inputs, while scenario analysis assessed a comparison between LNG-IUS 13.5 mg and the existing IUS, LNG-IUS 20 mcg/24 h. The key model output was cost per UP avoided.

Results

Compared to SARC methods, initiating contraception with LNG-IUS 13.5 mg resulted in fewer UP (64 UP vs. 276 UP) and lower total costs ($1,283,479 USD vs. $1,862,633 USD, a 31% saving) over the 3-year time horizon. Results were most sensitive to the probability of failure on OC, the probability of LNG-IUS 13.5 mg discontinuation and the cost of live births. Scenario analysis suggests that further cost savings may be generated with the initiation of LNG-IUS 20 mcg/24 h in place of SARC methods.

Conclusions

From a third-party payer perspective, LNG-IUS 13.5 mg is a more cost-effective contraceptive option than SARC. Therefore, women switching from current SARC use to LNG-IUS 13.5 mg are likely to generate cost savings to third-party health care payers, driven principally by decreased UP-related expenditures and long-term savings in contraceptive costs.     

Effects of blood flow modifiers on tumor metabolism observed in vivo by proton magnetic resonance spectroscopic imaging

Perfusion plays a key role in tumor proliferation and therapeutic response. Tumor heterogeneity necessitates use of the highest spatial resolution to monitor metabolic correlates of blood flow changes. This is best achieved with ¹H NMR spectroscopy, which permits noninvasive acquisition of high resolution spectroscopic images (SI) of subcutaneous tumors in a relatively short scan time (e.g., 12-25 μl voxels with signal-to-noise ratio 7:1 in 30 min at 4.7 T). This study seeks to identify ¹H spectroscopic indices of tumor blood flow. Proton SI of subcutaneous murine RIF-1 tumors were recorded (a) before and after administration of nicotinamide (1 g/kg) to increase blood flow, and (b) before and after hydralazine (10 mg/kg) to decrease flow. Nicotinamide produced a significant decrease in the total choline peak amplitudes, which subsequent high resolution NMR spectroscopy of tumor extracts revealed to be due to decreases in phosphocholine and glycerophosphocholine. The deamidation of nicotinamide to nicotinic acid, which is known to have hypolipidemic effects and to stimulate the formation of prostaglandins, may have sufficiently altered lipid metabolism to affect the in vivo concentration of the NMR-visible choline-containing compounds. The main effect of hydralazine was a significant increase of lactate, which is consistent with a reduction of tumor blood flow.     

Matching Capacity to Demand: A Regional Dashboard Reduces Ambulance Avoidance and Improves Accessibility of Receiving Hospitals

Objectives: Ambulance diversion is a dangerous repercussion of emergency department (ED) crowding and can reflect fragmentation and a lack of coordination in designating optimal patient offload sites for prehospital providers. The objective of this study was to evaluate whether proactive destination selection through the Regional Emergency Patient Access and Coordination (REPAC) program would enhance capacity and ED flow management. Methods: The REPAC system provides a dashboard that synthesizes real‐time capacity and acuity data for all three adult EDs in the city of Calgary, assigning a color code to reflect receiving status. It assigns destination for the next patient transported by emergency medical services (EMS) by categorizing ED sites as having either a favorable (green/yellow) status or unfavorable (orange/red) status. Three time windows were analyzed: a 6‐month window prior to REPAC implementation (pre), the first 6‐month window immediately following (post1), and the second 6‐month period following (post2). Primary outcomes of interest were the proportion of time spent in favorable versus unfavorable status and EMS avoidances for all adult ED sites in the region (percentage of total time with any center on EMS bypass). Information on total number of ED visits, percentage of patients arriving by EMS transports, admission rates, patient acuity (Canadian Triage and Acuity Score), age, and length of stay (LOS) for admitted and discharged patients was collected. The Kruskal‐Wallis test was employed for primary outcome analysis. Results: Implementation of the REPAC system resulted in an increase in the proportion of total time region hospitals reported favorable status (57.5% vs. 64.1%) pre versus post1, an effect that was accentuated at 1 year (post2, 78.7%; p < 0.001 for both comparisons). There was a concomitant decrease in EMS avoidances as a result of the REPAC system, 4.4% to 1.8% (pre vs. post1), also further improved at 1 year to 0.6% (p < 0.001 for both comparisons). Conclusions: Proactive EMS destination selection through a real‐time integrated electronic surveillance system enhances regional capacity and flow management while significantly reducing ambulance diversions. ACADEMIC EMERGENCY MEDICINE 2010; 17:1383–1389 © 2010 by the Society for Academic Emergency Medicine     

Image-guided enzyme/prodrug cancer therapy.

PURPOSE: The success of enzyme/prodrug cancer therapy is limited by the uncertainty in the delivery of the enzyme in vivo. This study shows the use of noninvasive magnetic resonance (MR) and optical imaging to image the delivery of a prodrug enzyme. With this capability, prodrug administration can be timed so that the enzyme concentration is high in the tumor and low in systemic circulation and normal tissue, thereby minimizing systemic toxicity without compromising therapeutic efficiency. EXPERIMENTAL DESIGN: The delivery of a multimodal imaging reporter functionalized prodrug enzyme, cytosine deaminase, was detected by MR and optical imaging in MDA-MB-231 breast cancer xenografts. Stability of the enzyme in the tumor was verified by (19)F MR spectroscopy, which detected conversion of 5-fluorocytosine to 5-flurouracil. The optimal time window for prodrug injection determined by imaging was validated by immunohistochemical, biodistribution, and high-performance liquid chromatographic studies. The therapeutic effect and systemic toxicity of this treatment strategy were investigated by histologic studies and tumor/body weight growth curves. RESULTS: The delivery of the functionalized enzyme in tumors was successfully imaged in vivo. The optimal time window for prodrug administration was determined to be 24 h, at which time the enzyme continued to show high enzymatic stability in tumors but was biodegraded in the liver. Significant tumor growth delay with tolerable systemic toxicity was observed when the prodrug was injected 24 h after the enzyme. CONCLUSION: These preclinical studies show the feasibility of using a MR-detectable prodrug enzyme to time prodrug administration in enzyme/prodrug cancer therapy.     

Developing imidazoles as CEST MRI pH sensors

A series of intra‐molecular hydrogen bonded imidazoles and related heterocyclic compounds were screened for their N–H chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI) contrast properties. Of the compounds, imidazole‐4,5‐dicarboxamides (I45DCs) were found to provide the strongest contrast, with the contrast produced at a large chemical shift from water (7.8 ppm) and strongly dependent on pH. We have tested several probes based on this scaffold, and demonstrated that these probes could be applied for in vivo detection of kidney pH after intravenous administration. Copyright © 2016 John Wiley & Sons, Ltd.