Therapeutic nanoparticles in clinics and under clinical evaluation.

This article reviews nanoparticulate-chemotherapeutic systems that have been developed for human therapy, considering the components of the nanoparticles, the therapeutic agents associated with the nanoparticles and the clinical indications these therapeutic nanoparticles have been developed for. In this evaluation we have put into perspective the types of nanomaterials and their therapeutic indications. We have reviewed the nanoparticulate-chemotherapeutic systems that have been published, approved and marketed and that are currently in clinical use. We have also analyzed the nanoparticulate-chemotherapeutic systems that are in clinical trials and under preclinical development.

Concomitant administration of intravenous drugs in the ICU: evaluation of physico-chemical compatibilities

Background and objective: Patients in the ICU often get many intravenous (iv) drugs at the same time. Even with three-lumen central venous catheters, the administration of more than one drug in the same iv line (IVL) is frequently necessary. The objective of this study was to observe how nurses managed to administer these many medications and to evaluate the proportion of two-drugs associations (TDA) that are compatible or not, based on known compatibility data. Design: Observational prospective study over 4 consecutive months. All patients receiving simultaneously more than one drugs in the same IVL (Y-site injection or mixed in the same container) were included. For each patient, all iv drugs were recorded, as well as concentration, infusion solution, location on the IVL system, time, rate and duration of administration. For each association of two or more drugs, compatibility of each drug was checked with each other. Compatibilities between these pairs of drugs were assessed using published data (mainly Trissel LA. Handbook on Injectable Drugs and Trissel's Tables of Physical Compatibility) and visual tests performed in our quality control laboratory. Setting: 34 beds university hospital adult ICU. Main outcome measures: Percentage of compatibilities and incompatibilities between drugs administered in the same IVL. Results: We observed 1,913 associations of drugs administered together in the same IVL, 783 implying only two drugs. The average number of drugs per IVL was 3.1 ± 0.8 (range: 2-9). 83.2% of the drugs were given by continuous infusion, 14.3% by intermittent infusion and 2.5% in bolus. The associations observed allowed to form 8,421 pairs of drugs (71.7% drug-drug and 28.3% drug-solute). According to literature data, 80.2% of the association were considered as compatible and 4.4% incompatible. 15.4% were not interpretable because of different conditions between local practices and those described in the literature (drug concentration, solute, etc.) or because of a lack of data. After laboratory tests performed on the most used drugs (furosemide, KH2PO4, morphine HCl, etc.), the proportion of compatible TDA raised to 85.7%, the incompatible stayed at 4.6% and only 9.7% remain unknown or not interpretable. Conclusions: Nurses managed the administration of iv medications quite well, as only less than 5% of observed TDA were considered as incompatible. But the 10% of TDA with unavailable compatibility data should have been avoided too, since the consequences of their concomitant administration cannot be predictable. For practical reasons, drugs were analysed only by pairs, which constitutes the main limit of this work. The average number of drugs in the same association being three, laboratory tests are currently performed to evaluate some of the most observed three-drugs associations.

Governor's Office of Drug Control Policy Five-Year Strategic Plan July 1, 2003-June 30, 2008

The Office of the Drug Policy Coordinator is established in Chapter 80E of the Code of Iowa. The Coordinator directs the Governor’s Office of Drug Control Policy; coordinates and monitors all statewide counter-drug efforts, substance abuse treatment grants and programs, and substance abuse prevention and education programs; and engages in other related activities involving the Departments of public safety, corrections, education, public health, and human services. The coordinator assists in the development of local and community strategies to fight substance abuse, including local law enforcement, education, and treatment activities. The Drug Policy Coordinator serves as chairperson to the Drug Policy Advisory Council. The council includes the directors of the departments of corrections, education, public health, public safety, human services, division of criminal and juvenile justice planning, and human rights. The Council also consists of a prosecuting attorney, substance abuse treatment specialist, substance abuse prevention specialist, substance abuse treatment program director, judge, and one representative each from the Iowa Association of Chiefs of Police and Peace Officers, the Iowa State Police Association, and the Iowa State Sheriff’s and Deputies’ Association. Council members are appointed by the Governor and confirmed by the Senate. The council makes policy recommendations related to substance abuse education, prevention, and treatment, and drug enforcement. The Council and the Coordinator oversee the development and implementation of a comprehensive State of Iowa Drug Control Strategy. The Office of Drug Control Policy administers federal grant programs to improve the criminal justice system by supporting drug enforcement, substance abuse prevention and offender treatment programs across the state. The ODCP prepares and submits the Iowa Drug and Violent Crime Control Strategy to the U.S. Department of Justice, with recommendations from the Drug Policy Advisory Council. The ODCP also provides program and fiscal technical assistance to state and local agencies, as well as program evaluation and grants management.

Stress ulcer prophylaxis in non-critically ill patients: a prospective evaluation of current practice in a general surgery department

Objective: There is little evidence regarding the benefit of stress ulcer prophylaxis (SUP) outside critical care setting. Over-prescription of SUP is not devoid of risks. This prospective study aimed to evaluate the use of proton pump inhibitors (PPIs) for SUP in a general surgery department.Methods: Data collection was performed prospectively during an 8-week period on patients hospitalized in a general surgery department (58 beds) by pharmacists. Patients with a PPI prescription for the treatment of ulcers, gastro-oesophageal reflux disease, oesophagitis or epigastric pain were excluded. Patients admitted twice during the study period were not re-included. The American Society of Health-System Pharmacists guidelines on SUP were used to assess the appropriateness of de novo PPI prescriptions.Results: Among 255 consecutive patients in the study, 138 (54%) received a prophylaxis with PPI, of which 86 (62%) were de novo PPI prescriptions. One-hundred twenty-nine patients (94%) received esomeprazole (according to the hospital drug policy). The most frequent dosage was 40 mg/day. Use of PPI for SUP was evaluated in 67 patients. Fifty-three patients (79%) had no risk factors for SUP. Twelve and 2 patients had one or two risk factors, respectively. At discharge, PPI prophylaxis was continued in 34% of patients with a de novo PPI prescription.Conclusion: This study highlights the overuse of PPIs in non-ICU patients and the inappropriate continuation of PPI prescriptions at discharge.Treatment

Utilization of Remote Traffic Monitoring Devices for Urban Freeway Work Zone Assessment Final Report, January 2012

The objective of this project was to promote and facilitate analysis and evaluation of the impacts of road construction activities in Smart Work Zone Deployment Initiative (SWZDI) states. The two primary objectives of this project were to assess urban freeway work-zone impacts through use of remote monitoring devices, such as radar-based traffic sensors, traffic cameras, and traffic signal loop detectors, and evaluate the effectiveness of using these devices for such a purpose. Two high-volume suburban freeway work zones, located on Interstate 35/80 (I-35/I-80) through the Des Moines, Iowa metropolitan area, were evaluated at the request of the Iowa Department of Transportation (DOT).

Evaluation of uptake and transport of ultrasmall superparamagnetic iron oxide nanoparticles by human brain-derived endothelial cells.

Aim: Ultrasmall superparamagnetic iron oxide nanoparticles (USPIO-NPs) are under development for imaging and drug delivery; however, their interaction with human blood-brain barrier models is not known. Materials & Methods: The uptake, reactive oxygen species production and transport of USPIO-NPs across human brain-derived endothelial cells as models of the blood-brain tumor barrier were evaluated for either uncoated, oleic acid-coated or polyvinylamine-coated USPIO-NPs. Results: Reactive oxygen species production was observed for oleic acid-coated and polyvinylamine-coated USPIO-NPs. The uptake and intracellular localization of the iron oxide core of the USPIO-NPs was confirmed by transmission electron microscopy. However, while the uptake of these USPIO-NPs by cells was observed, they were neither released by nor transported across these cells even in the presence of an external dynamic magnetic field. Conclusion: USPIO-NP-loaded filopodia were observed to invade the polyester membrane, suggesting that they can be transported by migrating angiogenic brain-derived endothelial cells.

Combination of carbon isotope ratio with hydrogen isotope ratio determinations in sports drug testing.

Carbon isotope ratio (CIR) analysis has been routinely and successfully applied to doping control analysis for many years to uncover the misuse of endogenous steroids such as testosterone. Over the years, several challenges and limitations of this approach became apparent, e.g., the influence of inadequate chromatographic separation on CIR values or the emergence of steroid preparations comprising identical CIRs as endogenous steroids. While the latter has been addressed recently by the implementation of hydrogen isotope ratios (HIR), an improved sample preparation for CIR avoiding co-eluting compounds is presented herein together with newly established reference values of those endogenous steroids being relevant for doping controls. From the fraction of glucuronidated steroids 5β-pregnane-3α,20α-diol, 5α-androst-16-en-3α-ol, 3α-Hydroxy-5β-androstane-11,17-dione, 3α-hydroxy-5α-androstan-17-one (ANDRO), 3α-hydroxy-5β-androstan-17-one (ETIO), 3β-hydroxy-androst-5-en-17-one (DHEA), 5α- and 5β-androstane-3α,17β-diol (5aDIOL and 5bDIOL), 17β-hydroxy-androst-4-en-3-one and 17α-hydroxy-androst-4-en-3-one were included. In addition, sulfate conjugates of ANDRO, ETIO, DHEA, 3β-hydroxy-5α-androstan-17-one plus 17α- and androst-5-ene-3β,17β-diol were considered and analyzed after acidic solvolysis. The results obtained for the reference population encompassing n = 67 males and females confirmed earlier findings regarding factors influencing endogenous CIR. Variations in sample preparation influenced CIR measurements especially for 5aDIOL and 5bDIOL, the most valuable steroidal analytes for the detection of testosterone misuse. Earlier investigations on the HIR of the same reference population enabled the evaluation of combined measurements of CIR and HIR and its usefulness regarding both steroid metabolism studies and doping control analysis. The combination of both stable isotopes would allow for lower reference limits providing the same statistical power and certainty to distinguish between the endo- or exogenous origin of a urinary steroid.

Statewide Process and Comparative Outcomes Study of 2003 Iowa Adult and Juvenile Drug Courts, August 2009

A statewide evaluation of the six adult and three juvenile drug courts in operation during calendar year 2003 was conducted. Completion rates, recidivism, substance abuse treatment, and supervision and placement (juveniles only) costs were examined by model (Judge and Community Panel) and by Judicial District. In addition, adult drug court participants were compared with a group of offenders who were screened and declined or were rejected by drug court in 2003 (referred) and a sample of offenders starting probation in 2003 (probationer). The adult participant and comparison groups were tracked from their entry into drug court, or the study, through December 31, 2007. This yielded an average post-program follow-up time of almost 3 years (2.9) for drug court participants. For the juvenile portion, drug court participants were compared with a group matched on several demographic and offense variables (Matched Comparison group) and juveniles referred to drug court who did not enter the program (Referred Comparison group). The juvenile participant and comparison groups were tracked from their entry into drug court, or the study, through approximately 16 quarters after program discharge with an end date of December 31, 2007.

Process and Outcome Evaluation of the STAR (Sisters Together Achieving Recovery) Program, September, 2010

In July of 2009, the Division of Criminal and Juvenile Justice Planning (CJJP) received Byrne Justice Assistance Grant/American Recovery and Reinvestment Act funding from the Governor’s Office of Drug Control Policy to conduct a process and outcome evaluation of the STAR (Sisters Together Achieving Recovery) program housed at the Iowa Correctional Institution for Women (ICIW) in Mitchellville, Iowa. The STAR Program is a licensed inpatient substance abuse treatment program that utilizes a Therapeutic Community model (TC). All offenders exiting the STAR program between October 1, 2004 and June 30, 2008 were included in the study (n=173). A comparison sample was drawn of offenders exiting the ICIW during the same release time frame with identified but untreated substance abuse needs (n= 173). March 31, 2010 was designated as the cut-off date for the study. This yielded an average post-program follow-up time of 3.1 years. The STAR group was further divided into two groups by time of program exit. Participants exiting the program between October 1, 2004 and June 30, 2006 were designated as STAR 1 (n=78) and those exiting the program between July 1, 2006 and June 30, 2008 were designated as STAR 2 (n=95). In order to have comparable tracking time between STAR groups, tracking time for STAR 1 concluded July 31, 2008. This yielded an average post release follow-up time of 2.4 years for both groups. Demographic, Program, Intervention, and Outcome data were examined. Comparisons were made between groups as well as categories of participation.

Glucose uptake, utilization, and signaling in GLUT2-null islets.

We previously reported that pancreatic islet beta-cells from GLUT2-null mice lost the first phase but preserved the second phase of glucose-stimulated insulin secretion (GSIS). Furthermore, we showed that the remaining secretory activity required glucose uptake and metabolism because it can be blocked by inhibition of oxidative phosphorylation. Here, we extend these previous studies by analyzing, in GLUT2-null islets, glucose transporter isoforms and glucokinase expression and by measuring glucose usage, GSIS, and glucose-stimulated insulin mRNA biosynthesis. We show that in the absence of GLUT2, no compensatory expression of either GLUT1 or GLUT3 is observed and that glucokinase is expressed at normal levels. Glucose usage by isolated islets was increased between 1 and 6 mmol/l glucose but was not further increased between 6 and 20 mmol/l glucose. Parallel GSIS measurements showed that insulin secretion was not stimulated between 2.8 and 6 mmol/l glucose but was increased by >4-fold between 6 and 20 mmol/l glucose. Stimulation by glucose of total protein and insulin biosynthesis was also markedly impaired in the absence of GLUT2. Finally, we re-expressed GLUT2 in GLUT2-null beta-cells using recombinant lentiviruses and demonstrated a restoration of normal GSIS. Together, these data show that in the absence of GLUT2, glucose can still be taken up by beta-cells, albeit at a low rate, and that this transport activity is unlikely to be attributed to GLUT1 or GLUT3. This uptake activity, however, is limiting for normal glucose utilization and signaling to secretion and translation. These data further demonstrate the key role of GLUT2 in murine beta-cells for glucose signaling to insulin secretion and biosynthesis.

Governor's Office of Drug Control Policy Five-Year Strategic Plan July 1, 2010-June 30, 2015

The Office of the Drug Policy Coordinator is established in Chapter 80E of the Code of Iowa. The Coordinator directs the Governor’s Office of Drug Control Policy; coordinates and monitors all statewide counter-drug efforts, substance abuse treatment grants and programs, and substance abuse prevention and education programs; and engages in other related activities involving the Departments of public safety, corrections, education, public health, and human services. The coordinator assists in the development of local and community strategies to fight substance abuse, including local law enforcement, education, and treatment activities. The Drug Policy Coordinator serves as chairperson to the Drug Policy Advisory Council. The council includes the directors of the departments of corrections, education, public health, public safety, human services, division of criminal and juvenile justice planning, and human rights. The Council also consists of a prosecuting attorney, substance abuse treatment specialist, substance abuse prevention specialist, substance abuse treatment program director, judge, and one representative each from the Iowa Association of Chiefs of Police and Peace Officers, the Iowa State Police Association, and the Iowa State Sheriff’s and Deputies’ Association. Council members are appointed by the Governor and confirmed by the Senate. The council makes policy recommendations related to substance abuse education, prevention, and treatment, and drug enforcement. The Council and the Coordinator oversee the development and implementation of a comprehensive State of Iowa Drug Control Strategy. The Office of Drug Control Policy administers federal grant programs to improve the criminal justice system by supporting drug enforcement, substance abuse prevention and offender treatment programs across the state. The ODCP prepares and submits the Iowa Drug and Violent Crime Control Strategy to the U.S. Department of Justice, with recommendations from the Drug Policy Advisory Council. The ODCP also provides program and fiscal technical assistance to state and local agencies, as well as program evaluation and grants management.

Pharmacokinetic and pharmacodynamic evaluation of valganciclovir in solid organ transplant patients

Goal: To validate oral vatgancictovir (VGC) in the prophylaxis of CMV infection in Lung (Lu) and Liver (L) recipients and in the treatment of CMV infection/disease in solid organ transplant recipients, using pharmacokinetic and pharmacodynamic studies in comparison with i/v gancicLovir (GCV). Methods: patients undergoing organ transpLantation donor or recipient CMV-seropositive receiving VGC prophylaxis for a period of 3 months (D+/R- Lung recipients, 6 months) were enroLLed. Heart (H), Lu, and L recipients received 900mg VGC q.d., adjusted to kidney (K) function. No K recipients received more than 450mg of VGC q.d. GCV trough (Ctrough) and peak (Cpeak = 3 hours after drug administration) LeveLs, and CMV DNA were measured at 7, 30, and 60 days post-transpLant (prophyLactic study). Patients who developed CMV infection/disease after stopping prophylaxis were treated with VGC (1800mg per day adjusted to K function and GCV blood LeveLs). GCV trough and peak LeveLs, and CMV DNA were measured weekly for the first 3 weeks and biweekly thereafter, until therapy cessation (therapeutic study). PLasma concentration of GCV is measured by HPLC. Results: In the first 8 prophyLaxed patients (6 K, and 1 L and 1 H transplant recipient) of 450mg VGC q.d., the average GCV concentration was 0.5±0.3 mg/t at trough, and 3.9±l.0mg/t 3 hours after administration. Inter-patient variability was substantiaL, especiaLLy for Ctrough (63% of total variance), which correlated with the patient's estimated gtomerutar filtration rate (r square = 42%). No CMV DNA was detected during VGC prophy- Laxis. Two patients (1 H and 1 L) were treated for Late CMV disease. Average GCV Cpeak were 8.9±2.3 mg/L and 4.6±0.5 rag/L, and GCV Ctrough were 2.0±0.9 mg/t and 1.6±0.2 mg/t respectively in each patient during induction phase. VGC treatment afforded a decrease in CMV DNA from 5.2 and 4.4 Log copies/10E6 cettutes at week 0, to 3.9 and 3.0 at week 1, and 3.3 and 2.1 at week 3, respectively.

Pharmacokinetic evaluation of losartan.

Introduction: Blockade of the renin-angiotensin system is one of the major therapeutic strategies in the management of patients with essential hypertension, congestive heart failure and diabetic as well as non-diabetic renal diseases. As the first angiotensin II receptor blocker (ARB) on the market, losartan belongs to the most frequently prescribed ARB. Area covered : The present review examines the pharmacokinetics of losartan with a special discussion on the dose of losartan that should be used in clinical practice to obtain the maximal benefits of the drug. Readers are provided with arguments suggesting that the dose of 50 mg losartan is probably too low and that losartan should preferably be prescribed at the dose of 100 mg/day or higher. Expert opinion : Losartan is an effective antagonist of angiotensin II AT(1) receptors which has been shown to provide important clinical benefits in patients with hypertension, congestive heart failure and renal diseases. Losartan should be prescribed at the dose of 100 mg/day and the use of higher doses should be reconsidered in future studies to improve its clinical efficacy.

Evaluation of the new photosensitizer Stakel (WST-11) for photodynamic choroidal vessel occlusion in rabbit and rat eyes.

PURPOSE: To evaluate the photodynamic potential of a new hydrosoluble photosensitizer (WST-11, Stakel; Steba Biotech, Toussus-Le-Noble, France), for use in occlusion of normal choroidal vessels in the rabbit eye and CNV (choroidal neovascularization) in the rat eye. METHODS: Occlusive and nonocclusive parameters of Stakel and verteporfin photodynamic therapy (PDT) were investigated in pigmented rabbits. Eyes were followed by fluorescein angiography (FA) and histology at various intervals after PDT. RESULTS: When occlusive parameters (fluence of 50 J/cm(2), 5 mg/kg drug dose and DLI [distance to light illumination] of 1 minute) were used, Stakel PDT was efficient immediately after treatment without associated structural damage of the RPE and retina overlying the treated choroid in the rabbit eye. Two days later, total occlusion of the choriocapillaries was seen in 100% of the treated eyes, along with accompanying histologic structural changes in the overlying retina. When the occlusive parameters (fluence, 100 J/cm2; drug dose, 12 mg/m2; and DLI, 5 minutes) of verteporfin PDT were used, occlusion of the choriocapillaries was observed in 89% of the treated eyes. Histology performed immediately after treatment demonstrated structural damage of the overlying retina and RPE layer. Weaker, nonocclusive Stakel PDT parameters (25 J/cm2, 5 mg/kg, and DLI of 10 minutes) did not induce choriocapillary occlusion or retinal lesions on FA or histology. Weaker, nonocclusive verteporfin PDT parameters (10 J/cm2, 0.2 mg/kg, and DLI of 5 minutes) did not induce choriocapillary occlusion. However, histology of these eyes showed the presence of damage in the retinal and choroidal tissues. Moreover, preliminary results indicate that selective CNV occlusion can be achieved with Stakel PDT in the rat eye. CONCLUSIONS: Unlike verteporfin PDT, Stakel PDT does not cause direct damage to the RPE cell layer or retina. These observations indicate that Stakel PDT may have a high potential for beneficial therapeutic outcomes in treatment of AMD.