Opportunities for new CT contrast agents to maximize the diagnostic potential of emerging spectral CT technologies.

The introduction of spectral CT imaging in the form of fast clinical dual-energy CT enabled contrast material to be differentiated from other radiodense materials, improved lesion detection in contrast-enhanced scans, and changed the way that existing iodine and barium contrast materials are used in clinical practice. More profoundly, spectral CT can differentiate between individual contrast materials that have different reporter elements such that high-resolution CT imaging of multiple contrast agents can be obtained in a single pass of the CT scanner. These spectral CT capabilities would be even more impactful with the development of contrast materials designed to complement the existing clinical iodine- and barium-based agents. New biocompatible high-atomic number contrast materials with different biodistribution and X-ray attenuation properties than existing agents will expand the diagnostic power of spectral CT imaging without penalties in radiation dose or scan time.

Therapeutic ultrasound: Increased HDL-Cholesterol following infusions of acoustic microspheres and apolipoprotein A-I plasmids.

BACKGROUND: Low levels of HDL-C are an independent cardiovascular risk factor associated with increased premature cardiovascular death. However, HDL-C therapies historically have been limited by issues relating to immunogenicity, hepatotoxicity and scalability, and have been ineffective in clinical trials. OBJECTIVE: We examined the feasibility of using injectable acoustic microspheres to locally deliver human ApoA-I DNA plasmids in a pre-clinical model and quantify increased production of HDL-C in vivo. METHODS: Our novel site-specific gene delivery system was examined in naïve rat model and comprised the following steps: (1) intravenous co-administration of a solution containing acoustically active microspheres (Optison™, GE Healthcare, Princeton, New Jersey) and human ApoA-I plasmids; (2) ultrasound verification of the presence of the microspheres within the liver vasculature; (3) External application of locally-directed acoustic energy, (4) induction of microsphere disruption and in situ sonoporation; (4) ApoA-I plasmid hepatic uptake; (5) transcription and expression of human ApoA-I protein; and (6) elevation of serum HDL-C. RESULTS: Co-administration of ApoA-I plasmids and acoustic microspheres, activated by external ultrasound energy, resulted in transcription and production of human ApoA-I protein and elevated serum HDL-C in rats (up to 61%; p-value < 0.05). CONCLUSIONS: HDL-C was increased in rats following ultrasound directed delivery of human ApoA-I plasmids by microsphere sonoporation. The present method provides a novel approach to promote ApoA-I synthesis and nascent HDL-C elevation, potentially permitting the use of a minimally-invasive ultrasound-based, gene delivery system for treating individuals with low HDL-C.

Biological performance of a size-fractionated core-shell tantalum oxide nanoparticle x-ray contrast agent.

OBJECTIVES: Metal-containing nanoparticles show great promise as x-ray contrast media and could enable reduced radiation dose, increased contrast, and the visualization of smaller anatomic features. In this study, we report progress toward these goals using a size-fractionated core-shell tantalum oxide nanoparticle contrast agent. MATERIALS AND METHODS: A core-shell tantalum oxide nanoparticle contrast agent was synthesized and size fractionated for preclinical investigation of biodistribution, blood half-life, organ retention, and histopathology. Fractionated agent was injected at anticipated clinical dose and at 3 times the anticipated clinical dose to evaluate biological performance. Computed tomography (CT) imaging studies were also performed to evaluate short-term clearance kinetics and new imaging applications. RESULTS: Improved control of 2-diethylphosphatoethylsilane-TaO nanoparticle size resulted in significantly reduced retention of injected tantalum. In vivo and in vitro CT imaging studies demonstrated short-term biodistribution differences in the kidney between small-molecule iodinated contrast media and fractionated 2-diethylphosphatoethylsilane-TaO, as well as preliminary data about new "Ta-only" imaging applications using multienergy CT image acquisition. CONCLUSIONS: Size-fractionated core-shell tantalum oxide nanoparticles with a well-defined particle size distribution have several key features required of clinically viable vascular imaging compounds and may be used in developing multienergy CT imaging applications.

Preclinical assessment of a zwitterionic tantalum oxide nanoparticle X-ray contrast agent.

Tantalum oxide nanoparticles show great potential as the next generation of X-ray contrast media. Recently, we reported advances in tantalum oxide nanoparticles and identified improvements that were required for such particles to progress further. Namely, the viscosity of concentrated particles, the amount of retention in reticuloendothelial (RES) tissues, and the effect of large quantities of particles on the kidneys after administration were all identified as critical factors which needed further study, understanding, and development. Here, we report on a zwitterionic siloxane polymer nanoparticle coating that reduced the viscosity of concentrated solutions of particles by a factor of 5, decreased tissue retention of injected particles by a factor of 10, and, importantly, did not induce pathological responses in the kidneys.

Correlates of nonmedical use of hydromorphone and hydrocodone:results from a national household survey.

Over the past decade, the misuse and abuse of opioid medications in the United States has risen dramatically. Although data show a substantial variation in the nonmedical use of individual opioids, relatively little is known about risk factors for the nonmedical use of specific opioid products. This study compared the prevalence and correlates of the nonmedical use of oral immediate-release hydromorphone (marketed under the brand name of Dilaudid), versus that of hydrocodone combination products using a nationally representative sample of the civilian noninstitutionalized United States population aged 12 years or older. Data were from the 2003 National Survey on Drug Use and Health. An estimated 31.3 million individuals reported lifetime nonmedical use of an opioid analgesic. Of these, 2.9 percent reported lifetime nonmedical use of Dilaudid, and 51.9 percent reported lifetime nonmedical use of hydrocodone combination products exclusive of nonmedical Dilaudid use. Nonmedical Dilaudid users were likely to be older, Caucasian, and to have reported a higher lifetime prevalence of heroin, cocaine and injection drug use, as well as nonmedical use of other opioids. Nonmedical Dilaudid users were at higher risk for engaging in more serious substance abuse-related behaviors than those who reported lifetime nonmedical use of hydrocodone combination products.

Measurement of brain microglial proliferation rates in vivo in response to neuroinflammatory stimuli: application to drug discovery.

Microglial activation is emerging as an important etiologic factor and therapeutic target in neurodegenerative and neuroinflammatory diseases. Techniques have been lacking, however, for measuring the different components of microglial activation independently in vivo. We describe a method for measuring microglial proliferation rates in vivo using heavy water (2H2O) labeling, and its application in screening for drugs that suppress neuro-inflammation. Brain microglia were isolated by flow cytometry as F4/80+, CD11b+, CD45(low) cells, and 2H enrichment in DNA was analyzed by gas chromatography/mass spectrometry. Basal proliferation rate was approximately 1%/week and systemic administration of bacterial lipopolysaccharide (LPS) markedly increased this rate in a dose-dependent manner. Induction of experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice by MOG(35-55) peptide stimulated proliferation of CD45(low) microglia, which could be distinguished from the proliferation of CD45(high) infiltrating monocytes. Minocycline (45 mg/kg/day, i.p.) inhibited resident microglial proliferation in both the LPS and EAE models. Thirteen drugs were then screened for their ability to inhibit LPS-stimulated microglia proliferation. Female C57BL/6 mice were given LPS (1 mg/kg), and concomitant drug treatment while receiving 2H2O label for 7 days. Among the drugs screened, treatment with isotretinoin dose-dependently reduced LPS-induced microglial proliferation, representing an action of retinoids unknown previously. Follow-up studies in the EAE model confirmed that isotretinoin not only inhibited proliferation of microglia but also delayed the onset of clinical symptoms. In conclusion, 2H2O labeling represents a relatively high-throughput, quantitative, and highly reproducible technique for measuring microglial proliferation, and is useful for screening and discovering novel anti-neuroinflammatory drugs.

UK smokers' and ex-smokers' reactions to cigarettes promising reduced risk.

AIMS: This study evaluated the impact of exposure to information about a novel cigarette claiming to reduce exposure to tobacco toxins ('potential reduced exposure product' cigarette or PREP-C) on smokers' and ex-smokers' perceptions of PREP-C, on quit interest among smokers and on interest in resuming smoking among ex-smokers. DESIGN AND PARTICIPANTS: A random digit-dialed telephone survey was conducted in the United Kingdom with 500 current smokers and 106 ex-smokers who had quit within the last 2 years. INTERVENTION: The interviewer described a novel cigarette that claimed to significantly reduce exposure to smoke toxins. MEASUREMENTS: Respondents' interest in purchasing the PREP-C, beliefs about its safety and risk reduction and smokers' quit interest, as measured by stage of change, before and after exposure to PREP-C information. FINDINGS: Among smokers, 76.5% were interested in purchasing PREP-C; interest did not vary by stage of change. Almost all smokers (90.6%) thought PREP-C was safer than regular cigarettes, with 5.4% indicating that the health risks were equivalent to not smoking at all. Exposure to PREP-C description did not change quit interest. Among ex-smokers, 5.6% believed PREP-C carried no health risk and 7.1% expressed purchase interest. CONCLUSIONS: Smokers and ex-smokers interpreted claims of reduced toxin exposure as reduced health risk and responded positively towards PREP-Cs. With the increasing introduction of PREP-Cs world-wide, evaluation of these products and their claims on quitting among smokers and on relapse among ex-smokers is a matter of public health urgency.

Measurement of protein turnover rates by heavy water labeling of nonessential amino acids.

In vivo measurements of protein synthesis using isotope-labeled amino acids (AAs) are hampered by the heterogeneity of AA pools and, for slow turnover proteins, the difficulty and expense of long-term labeling. Continuous oral heavy water (2H2O) labeling can safely maintain stable body water 2H enrichments for weeks or months. 2H is metabolically incorporated into C-H bonds of nonessential AAs (NEAAs) and hence into proteins. No posttranslational label exchange occurs, so 2H incorporation into protein NEAAs, in principle, reports on protein synthesis. Here, we show by mass isotopomer distribution analysis (MIDA) of 2H2O-labeled rodent tissue proteins that metabolic 2H flux into C-H bonds of Ala, Gly, or Gln used for protein synthesis is nearly complete. By 2H2O labeling of rodents, turnover of bone and muscle mixed proteins was quantified and stimulation of liver collagen synthesis by CCl4 was detected. Kinetics of several human serum proteins were also measured, reproducing published t1/2 estimates. Plateau enrichments in Ala varied among different proteins. Moderate amounts of protein, isolated chromatographically or electrophoretically, sufficed for kinetic analyses. In conclusion, 2H2O labeling permits sensitive, quantitative, operationally simple measurements of protein turnover in vivo by the rise-to-plateau approach, especially for proteins with slow constitutive turnover.

Non-medical use of OxyContin Tablets in the United States.

The non-medical use of OxyContin (controlled release oxycodone HCl) Tablets has been widely cited in media reports often leaving the impression that OxyContin was a source of primary or new onset drug abuse. However, no published research to date has examined the drug use history of those reporting non-medical use of OxyContin. This study examined rates of non-medical OxyContin use in the United States and the demographic and drug use profiles of those reporting such use, based on data from the 1999, 2000, and 2001 Substance Abuse and Mental Health Services Administration National Household Survey on Drug Abuse. Reported lifetime non-medical OxyContin use in the United States increased from 0.1% to 0.2% to 0.4% in 1999, 2000, and 2001 suggesting new incidence of 0.1%-0.2% per year. Compared to those reporting non-medical use of prescription analgesics other than OxyContin, non-medical OxyContin users were more likely to show a pattern of more serious drug abuse: they used multiple drugs, used needles for drug injection, and had higher rates of abuse and dependence. Approximately 83% of non-medical OxyContin users reported having used illicit drugs or other prescription medications non-medically prior to their first non-medical use of prescription analgesics. Even compared to those who reported non-medical use of other prescription analgesics, non-medical OxyContin users already had a more significant pattern of drug abuse before they began using prescription analgesics for non-medical purposes, suggesting that non-medical use of OxyContin is rarely the initiating factor leading to the abuse of other drugs.

The effectiveness of nicotine patch and nicotine lozenge in very heavy smokers.

The efficacy of nicotine replacement therapy (NRT) among very heavy and highly dependent smokers was examined in a secondary analysis of two randomized clinical trials of NRT. In the first trial, smokers were assigned to active patch (n=249) or placebo (n=253) plus intensive behavioral treatment. In the second trial, smokers were assigned to active 4-mg nicotine lozenge (n=450) or placebo (n=451) plus brief behavioral treatment. Nicotine patch and lozenge significantly increased 6-month continuous abstinence quit rates in both very heavy (>or=40 cigarettes per day) and highly dependent (Fagerström Tolerance Questionnaire or Fagerström Test for Nicotine Dependence score >7) smokers. The effect of active NRT treatment did not differ significantly by smoking rate or nicotine dependence, with the exception that the nicotine patch was significantly more effective than placebo in highly dependent smokers. The nicotine patch and lozenge are effective (vs. placebo) even in heavy and highly dependent smokers.

Patterns of over-the-counter nicotine gum use: persistent use and concurrent smoking.

AIMS: To examine the occurrence of persistent use (i.e. use beyond 12 weeks) and concurrent use of nicotine gum with cigarettes among consumers who purchase nicotine gum over-the-counter (OTC). DESIGN: Assessment of gum use was conducted in the context of a smoking cessation trial among smokers who purchased Nicorette gum and enrolled in the optional Committed Quitters smoking cessation program. Eligible participants were contacted by telephone 6 weeks and 12 weeks following their self-selected target quit date. Those who reported gum use at 12 weeks were contacted again at week 24. PARTICIPANTS: A total of 2655 current smokers who purchased nicotine gum and enrolled in a clinical efficacy trial of the Committed Quitters program. MEASUREMENTS: Detailed information on smoking and gum use, including frequency of use, amount used and reasons for use was obtained at each of the three follow-up assessments. FINDINGS: At the 24-week assessment, 6% of participants reported current use of nicotine gum (i.e. persistent use). Those engaging in persistent use averaged 4.7 (SD = 2.5) days of gum use per week and 3.2 (SD = 3.5) pieces of gum per day. Sixty-six per cent of persistent users reported at week 24 that they were not currently smoking, and 67% of persistent users reported they were using gum to establish or maintain abstinence. At the 6-, 12- and 24-week assessments, 14%, 10% and 2% of participants, respectively, reported current use of nicotine gum and current cigarette smoking (i.e. concurrent users). Those concurrent users reported at the 12-week follow-up that they did so an average of 4.4 (SD = 2.1) days per week, that they chewed an average of 2.6 (SD = 3.5) pieces of nicotine gum per day and that they smoked an average of 8.7 (SD = 8.6) cigarettes per day. CONCLUSION: Extended use of nicotine gum is rare. Concurrent use with cigarettes is uncommon. In both cases, the amount of gum use is small. OTC marketing of nicotine gum does not appear to have increased use contrary to labeling nor resulted in patterns of use that should warrant clinical or public health concerns.

Real-world efficacy of prescription and over-the-counter nicotine replacement therapy.

AIMS: To assess smoking cessation rates achieved with nicotine gum and patch in simulated over-the-counter (OTC) and actual prescription (Rx) settings. DESIGN: Separate open-label studies with gum and patch in OTC and Rx settings. PARTICIPANTS: There were multiple samples: OTC gum: 2981 smokers; OTC patch: 2367; Rx gum: 324; Rx patch: 669. INTERVENTIONS: All smokers received active nicotine replacement. In the OTC setting, smokers self-selected doses of nicotine gum (2 or 4 mg Nicorette) or patch (21, 14 or 7 mg NicoDerm CQ). No intervention was provided. In the Rx setting, smokers were prescribed gum or patch by their physician. MEASUREMENTS: Biochemically verified continuous smoking abstinence was assessed at 6 weeks (28-day abstinence) and 6 months. FINDINGS: OTC success rates were consistently higher than Rx rates: differences were significant at 6 weeks for both patch [OR = 1.45 (1.05-1.98)] and gum [OR 2.92 (1.58-5.40)], and remained significant at 6 months for patch [OR = 3.63: (1.74-7.61)] but not gum [OR = 1.37: (0.73-2.58)]. Among OTC gum users. 16.1% were abstinent at 6 weeks and 8.4% at 6 months. For Rx gum users, abstinence rates were 7.7% at 6 weeks and 7.7% at 6 months. With OTC patch, 19.0% were abstinent at 6 weeks and 9.2% at 6 months. With Rx patch. abstinence rates were 16.0% at 6 weeks and 3.0% at 6 months. CONCLUSIONS: Smoking cessation rates achieved with nicotine gum and patch under OTC conditions were as good as those under real-world prescribing conditions.