Antimicrobial use in Belgian broiler production.

PubMed

Persoons, Davy; Dewulf, Jeroen; Smet, Annemieke; Herman, Lieve; Heyndrickx, Marc; Martel, An; Catry, Boudewijn; Butaye, Patrick; Haesebrouck, Freddy

2012-08-01

The use of antimicrobials in production animals has become a worldwide concern in the face of rising resistance levels in commensal, pathogenic and zoonotic bacteria. In the years 2007 and 2008 antimicrobial consumption records were collected during two non consecutive production cycles in 32 randomly selected Belgian broiler farms. Antimicrobials were used in 48 of the 64 monitored production cycles, 7 farms did not use any antimicrobials in both production cycles, 2 farms only administered antimicrobials in one of the two production cycles, the other 23 farms applied antimicrobial treatment in both production cycles. For the quantification of antimicrobial drug use, the treatment incidences (TI) based on the defined daily doses (the dose as it should be applied: DDD) and used daily doses (the actual dose applied: UDD) were calculated. A mean antimicrobial treatment incidence per 1000 animals of 131.8 (standard deviation 126.8) animals treated daily with one DDD and 121.4 (SD 106.7) animals treated daily with one UDD was found. The most frequently used compounds were amoxicillin, tylosin and trimethoprim-sulphonamide with a mean TI(UDD) of 37.9, 34.8, and 21.7, respectively. The ratio of the UDD/DDD gives an estimate on correctness of dosing. Tylosin was underdosed in most of the administrations whereas amoxicillin and trimethoprim-sulphonamide were slightly overdosed in the average flock. Copyright © 2012 Elsevier B.V. All rights reserved.

The Association Between the Use of Zolpidem and the Risk of Alzheimer's Disease Among Older People.

PubMed

Cheng, Hui-Ting; Lin, Fang-Ju; Erickson, Steven R; Hong, Jin-Liern; Wu, Chung-Hsuen

2017-11-01

To evaluate the association between zolpidem use and the risk of Alzheimer's disease among older people. A retrospective cohort study using data from 2001 to 2011 from the National Health Insurance Research Database. Taiwan. A total of 6,922 patients aged 65 years or older enrolled from January 2002 to December 2004 (the enrollment period). Zolpidem users were identified as patients who used zolpidem during the enrollment period. The index date was the date of the first zolpidem prescription. Dosage of zolpidem use was defined using cumulative defined daily dose (cDDD) based on the cumulative dosage that patients took within one year after the index date (grouped as: less than 28, 28-90, 91-180, and more than 180 cDDD). The occurrence of Alzheimer's disease was defined as the time period from the end of one year after the index date to the date of the Alzheimer's disease diagnosis. The propensity score was used to adjust the measured confounders of Alzheimer's disease. Cox proportional hazards models were used to evaluate the association between zolpidem use and the incidence of Alzheimer's disease. Zolpidem users with a high cumulative dose (>180 cDDD) in the first year after initiation had a significantly greater risk of Alzheimer's disease than non-zolpidem users (HR = 2.97, 95% CI = 1.61-5.49) and low cumulative dose (<28 cDDD) users (HR = 4.18, 95% CI = 1.77-9.86). We found the use of a high cumulative dose of zolpidem was associated with an increased risk of Alzheimer's disease among older people living in Taiwan. It is advised to use caution when considering long-term use of zolpidem in older patients. © 2017, Copyright the Authors Journal compilation © 2017, The American Geriatrics Society.

Treatment practices and quantification of antimicrobial drug usage in conventional and organic dairy farms in Wisconsin.

PubMed

Pol, M; Ruegg, P L

2007-01-01

The objective of this study was to develop a method to quantify antimicrobial drug usage and treatment practices on conventional and organic dairy farms that had been recruited to represent a broad spectrum of potential exposure to antimicrobial drugs. Data on disease prevalence and treatment practices of organic (n = 20) and conventional (n = 20) farms were obtained during a farm visit using a survey instrument. A standardized estimate of antimicrobial drug usage was developed using a defined daily dose (DDD) of selected compounds. Density of antimicrobial drug usage was expressed as the number of DDD per adult cow per year. Differences in prevalence and management of selected diseases between conventional and organic farms were identified. The overall estimated prevalence of selected diseases was greater for conventional farms compared with organic farms. Organic farmers reported use of a variety of nonantimicrobial compounds for treatment and prevention of disease. Conventional farmers reported that penicillin was the compound most commonly used for dry cow therapy and cephapirin was most commonly used for treatment of clinical mastitis. On conventional farms, the estimated overall exposure to antimicrobial drugs was 5.43 DDD per cow per year composed of 3.58 and 1.85 DDD of intramammary and parenteral antimicrobial drugs, respectively. Of total intramammary antimicrobial drug usage, treatment of clinical mastitis contributed 2.02 DDD compared with 1.56 DDD attributed to the use of dry cow therapy. Of total parenteral treatments, the distribution of exposure was 0.52 (dry cow therapy), 1.43 (clinical mastitis treatment), 0.39 (treatment of foot disease), 0.14 (treatment of respiratory disease), and 0.32 (treatment of metritis) DDD. For treatments of foot infections (0.33 DDD), respiratory infections (0.07 DDD), and metritis (0.19 DDD), the mean density of ceftiofur usage was significantly greater compared with other compounds.

Comparison of adherence to generic multi-tablet regimens vs. brand multi-tablet and brand single-tablet regimens likely to incorporate generic antiretroviral drugs by breaking or not fixed-dose combinations in HIV-infected patients.

PubMed

Rwagitinywa, Joseph; Lapeyre-Mestre, Maryse; Bourrel, Robert; Montastruc, Jean-Louis; Sommet, Agnès

2018-03-05

Adherence to antiretroviral (ARV) is crucial to achieve viral load suppression in HIV-infected patients. This study aimed to compare adherence to generic multi-tablet regimens (MTR) vs. brand MTR likely to incorporate ARV drugs without breaking fixed-dose combinations (FDC) and brand single-tablet regimens (STR) likely to incorporate generics by breaking the FDC. Patients aged of 18 years or over exposed to one of the generic or the brand of lamivudine (3TC), zidovudine/lamivudine (AZT/TC), nevirapine (NVP), or efavirenz (EFV), or the brand STR of efavirenz/emtricitabine/tenofovir (EFV/FTC/TDF). Adherence was measured by medication possession ratio (MPR) using both defined daily dose (DDD) and daily number of tablet recommended for adults (DNT). Adherence to generic MTR vs. brand MTR and brand STR was compared using Kruskal-Wallis. The overall median adherence was 0.97 (IQR 0.13) by DNT method and 0.97 (0.14) by DDD method. Adherence in patients exposed to generic MTR (n = 165) vs. brand MTR (n = 481) and brand STR (n = 470) was comparable by DNT and DDD methods. In conclusion, adherence to generic MTR was high and comparable with adherence to brand MTR and to STR. Utilization of DDD instead DNT to measure the MPR led to small but nonsignificant difference that has no clinical impact. © 2018 Société Française de Pharmacologie et de Thérapeutique.

Efficacy of Management for Rational Use of Antibiotics in Surgical Departments at a Multi-Disciplinary Hospital: Results of a 7-year Pharmacoepidemiological Research.

PubMed

Korableva, A A; Yudina, E V; Ziganshina, L E

Irrational medicine use including excessive use and abuse of antibiotics remains a crucial problem for the healthcare systems. In this regard, studies examining approaches to improving the clinical use of medicines are highly important. to assess the efficacy rate of management for the rational use of antibiotics in surgical departments of a multi-disciplinary hospital. The intervention complex combined the research, educational, and methodological activities: local protocols for perioperative antibiotic prophylaxis (PABP) for various surgical departments were developed; local PABP protocols were discussed with the physicians of specialized surgical departments; official order on implementation of PABP was issued; the list of drug prescriptions for registration of the first pre-operative antibiotic dose was changed; audit and feedback processes were introduced as well as consultations of a clinical pharmacologist were implemented. We assessed the efficacy rate of the interventions basing on the changes in consumption of antibiotics (both quantitatively and qualitatively) at surgical departments of a hospital using ATC/DDD methodology. Comparison of the studied outcomes was performed before and after the intervention implementation and between the departments (vascular and abdominal surgery). The consumption of antibacterial agents (ATCJ01) was measured as a number of defined daily doses (DDD) per 100 bed-days (DDD/100 bed-days, indicator recommended by the World Health Organization, WHO) and DDD per 100 treated patients (DDD/100 treated patients). From 2006 to 2012, a decrease in antibacterial consumption in surgical departments by 188 DDD/100 treated patients was observed. We obtained the opposite results when using an indicator of DDD/100 bed-days (increase by 2.5 DDD/100 bed-days) which could be explained by the dependence on indices of overall hospital work and its changes during the examined period. Observed changes in antibacterial consumption varied in different surgical departments. The most pronounced positive changes were noted in the department of vascular surgery: decrease in total antibacterial consumption by 298 DDD/100 treated patients, decrease in the use of cephalosporins of the III generation from 141 to 38 DDD/100 treated patients. These positive changes were accompanied by the same (low) level of consumption/use of reserve antibiotics. In the department of abdominal surgery, there was no decrease in total antibiotic consumption, as well as in consumption of broad-spectrum cephalosporins of the III generation and fluoroquinolones, and we observed an increase in the use of reserve antibiotics (carbapenems) during the study period. Positive changes in antibiotic consumption were associated with the positive attitude of the manager/head of the department towards interventions: we observed the most pronounced decrease in antibiotic consumption straight after the publication of the administrative order on perioperative antibacterial prophylaxis. The combination of scientific, educational, and methodological interventions is effective for improving antibiotic application. The study results provide the rationale for analyzing the drug consumption using the DDD/100 treated patients measure in addition to the WHO-recommended indicator of DDD/100 bed-days which depends on overall hospital performance.

Seventeen-Year Nationwide Trends in Antihypertensive Drug Use in Denmark.

PubMed

Sundbøll, Jens; Adelborg, Kasper; Mansfield, Kathryn E; Tomlinson, Laurie A; Schmidt, Morten

2017-12-15

Recent trends in use of antihypertensive drugs are unknown. From Danish nationwide prescription data, we obtained information on primary care use of angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, beta blockers, diuretics, aldosterone receptor antagonists, and calcium channel blockers. During 1999 to 2015, the use of antihypertensive drugs per 1,000 inhabitants/day increased from 184 to 379 defined daily doses (DDD), corresponding to a rise in the prevalence proportion of users from ≈20% to ≈35%. From 1999 to 2015, a notable increase was observed for angiotensin-converting enzyme inhibitors (from 29 to 105 DDD per 1,000 inhabitants/day ≈260%) and angiotensin II receptor blockers (from 13 to 73 DDD per 1,000 inhabitants/day ≈520%). For diuretics the use remained stable, with a slight decrease (from 89 to 81 DDD per 1,000 inhabitants/day ≈-10%). The use of aldosterone receptor antagonists increased until 2007 and remained unchanged at around 3.5 DDD per 1,000 inhabitants/day thereafter (average change ≈65%). The use of beta blockers doubled during the study period (from 17 to 34 DDD per 1,000 inhabitants/day ≈100%), entirely driven by increasing use of metoprolol. Similar trends were observed for calcium channel blockers (from 34 to 82 DDD per 1,000 inhabitants/day ≈140%), where amlodipine drove the overall increase. In conclusion, antihypertensive drug use has increased remarkably during the past 2 decades. Copyright © 2017 Elsevier Inc. All rights reserved.

Medication usage in Majuro, Marshall Islands.

PubMed

Harding, Andrew

2005-03-01

To conduct a drug utilisation study to determine the top 50 drugs by prescription count, top 50 drugs by cost to government and the top 30 drugs by consumption for Majuro Atoll, Marshall Islands for the year 2003. Data was collected from the Majuro Hospital computer dispensing system. All outpatient prescriptions dispensed in the year 2003 were included. The defined daily dose (DDD) methodology was employed. Drug consumption was presented as DDD/1000 population/day. The top 5 drugs by consumption in Majuro for 2003 were glibenclamide (glyburide), enalapril, ferrous sulphate, amoxycillin and ascorbic acid. Values for the DDD/1000 population/day were on average lower than many other countries. This is the first local study of medication usage in the Marshall Islands. It provided some useful baseline data.

Prescription patterns of diuretics in Dutch community-dwelling elderly patients

PubMed Central

Van Kraaij, Dave J W; Jansen, René W M M; De Gier, Johan J; Gribnau, Frank W J; Hoefnagels, Willibrord H L

1998-01-01

Aims To describe age-and gender-related prescription patterns of diuretics in community-dwelling elderly, and to compare diuretics to other cardiovascular (CV) medications. Methods Cross-sectional study of patient-specific prescription data derived from a panel of 10 Dutch community pharmacies. Determination of proportional prescription rates and prescribed daily dose (PDD) of diuretics, cardiac glycosides, nitrates, angiotensin converting enzyme (ACE) inhibitors, β-adrenoceptor blockers, and calcium channel blockers in all 5326 patients aged 65 years or older dispensed CV medications between August 1st, 1995 and February 1st, 1996. Results Diuretics were prescribed to 2677 of 5326 patients (50.3%), 1325 patients (24.9%) using thiazides and 1198 patients (22.5%) using loop diuretics. Prescription rates of loop diuretics increased from 15.1% in patients aged 65–74 years to 37.2% in patients aged 85 years or older. Rates also increased for digoxin and nitrates. Rates for thiazide diuretics remained unchanged with age; rates for β-adrenoceptor blockers, ACE inhibitors and calcium channel blockers declined with age. Thiazides were prescribed to 30.1% of women compared with 16% of men (P<0.001). Average PDD was 135±117% of defined daily dose (DDD) for loop diuretics, and highest for bumetanide (245±2.01% of DDD, equivalent to 2.5±2.0 mg). Average PDD was 74±40% of DDD for thiazides, and highest for chlorthalidone (100±49% of DDD, equivalent to 25±12 mg). Conclusions Important characteristics of diuretic usage patterns in this elderly population were a steep increase in loop diuretic use in the oldest old, a large gender difference for thiazide use, and high prescribed doses for thiazides. PMID:9803990

Trends in the Outpatient Utilization of Antipsychotic Drugs in the City of Zagreb in the Ten-Year Period as a Tool to Assess Drug Prescribing Rationality.

PubMed

Polić-Vižintin, Marina; Tripković, Ingrid; Štimac, Danijela; Šostar, Zvonimir; Orban, Mirjana

2016-12-01

The aim was to determine distribution and trends in the outpatient utilization of antipsychotics to evaluate the rationality of antipsychotic drug prescribing during the ten year period. The epidemiological method of descriptive and analytical observation was used. Data on drug utilization from Zagreb Municipal Pharmacy were used to calculate the number of defined daily doses (DDD) and DDD per 1000 inhabitants per day (DDD/TID) using the World Health Organization Anatomical-Therapeutic-Chemical methodology. The ratio of typical versus atypical antipsychotics served as an indicator on assessing the rationality of the utilization. Data on the use of anticholinergics in the treatment of neuroleptic side effects were also included. Outpatient utilization of antipsychotics showed a declining pattern from 14.17 in 2001 to 8.42 DDD/TID in 2010. The utilization of atypical antipsychotics increased by 60% (from 3.68 to 5.89 DDD/TID), while the utilization of typical antipsychotics decreased by 76% (from 10.49 to 2.53 DDD/TID). The drugs showing the largest increase were olanzapine (from 1.21 to 2.78 DDD/TID) and quetiapine (from 0 to 0.68 DDD/TID). The typical/atypical antipsychotic ratio changed from 1:0.4 in 2001 to 1:2.3 in 2010. A 2.3-fold decrease was recorded in the utilization of anticholinergics (from 2.05 to 0.91 DDD/TID). Total consumption of neuroleptics significantly decreased. A decrease was also recorded in the utilization of anticholinergics. Study results pointed to two favorable features, i.e. low use of typical antipsychotics and the ratio of typical and atypical antipsychotics. Implementation of the new clinical guidelines for nervous system disorders and updating of the list of reimbursable drugs with the addition of new ones contributed to the observed improvement in the prescribing patterns during the study period. Using the WHO ATC/DDD methodology and rationality indicators in the assessment of trends in the outpatient utilization of psychopharmaceuticals over a ten-year period proved efficient in the evaluation of prescribing rationality.

Comparative drug dose and drug combinations in patients that present to hospital due to self-poisoning.

PubMed

Armstrong, Thomas M; Davies, Matthew S; Kitching, Gary; Waring, W Stephen

2012-11-01

Self-poisoning is a common reason for acute presentation to hospital. Commonly involved drugs have been reported, but few data exist concerning the different combinations of agents or comparative doses ingested. The present study sought to better characterise the typical patterns of drug overdose that may present via the emergency department. Consecutive adults ≥16 years of age that presented to York Hospital owing to self-poisoning were studied for 2010-2011 inclusive. The primary outcome measure was reported dose, expressed as a multiple of the defined daily dose (DDD) to allow comparison between different agents. There were 1024 patients, including 622 women (60.7%), and median age was 32 years (range, 16 to 92 years). Overdose in men was associated with a higher overall quantity of drugs: arithmetic mean of 20 DDD multiples (95% CI, 15-26) versus 13 (11-15), p = 0.001. Overdose involved a single agent only in 538 patients (52.5%). The mean paracetamol dose was 4.0 (95% CI, 3.7-4.3) DDD multiples; the doses of antidepressants (19.4, 17.0-21.7, p < 0.0001) and benzodiazepines (18.0, 12.8-23.2, p < 0.0001) were comparatively higher. The types of agents involved in self-poisoning and common combinations of agents are characterised. Psychotropic medications were ingested in comparatively larger quantities than analgesic agents and had worse clinical outcome. Further work is required to understand the factors that determine the quantity of drug ingested in patients at risk of drug overdose so as to minimise the risk of significant toxicity. © 2012 The Authors Basic & Clinical Pharmacology & Toxicology © 2012 Nordic Pharmacological Society.

The Risk of TB in Patients With Type 2 Diabetes Initiating Metformin vs Sulfonylurea Treatment.

PubMed

Pan, Sheng-Wei; Yen, Yung-Feng; Kou, Yu Ru; Chuang, Pei-Hung; Su, Vincent Yi-Fong; Feng, Jia-Yih; Chan, Yu-Jiun; Su, Wei-Juin

2017-12-16

Metformin and the sulfonylureas are common initial antidiabetic agents; the former has demonstrated anti-TB action in in vitro and animal studies. The comparative effect of metformin vs the sulfonylureas on TB risk in patients with type 2 diabetes mellitus (T2DM) remains unclear. In this retrospective cohort study, patients without chronic kidney disease who received a T2DM diagnosis during 2003 to 2013 were identified from the Taiwan National Health Insurance Research Database. Participants with ≥ 2 years of follow-up were reviewed and observed for TB until December 2013. Patients receiving metformin ≥ 60 cumulative defined daily dose (cDDD) and sulfonylureas < 15 cDDD in the initial 2 years were defined as metformin majors; it was the inverse for sulfonylurea majors. The two groups were matched 1:1 by propensity score and compared for TB risk by multivariate Cox regression analysis. Among 40,179 patients with T2DM, 263 acquired TB (0.65%) over a mean follow-up of 6.1 years. In multivariate analysis, the initial 2-year dosage of metformin, but not that of the sulfonylureas, was an independent predictor of TB (60-cDDD increase (adjusted hazard ratio [HR], 0.931; 95% CI, 0.877-0.990) after adjustment by cofactors, including adapted diabetes complication severity index. Metformin majors had a significantly lower TB risk than that of sulfonylurea majors before and after matching (HR, 0.477; 95% CI, 0.268-0.850 and HR, 0.337; 95% CI, 0.169-0.673; matched pairs, n = 3,161). Compared with the reference group (initial 2-year metformin < 60 cDDD), metformin treatment showed a dose-dependent association with TB risk (60-219 cDDD; HR, 0.860; 95% CI, 0.637-1.161; 220-479 cDDD, HR, 0.706; 95% CI, 0.485-1.028; ≥ 480 cDDD, HR, 0.319; 95% CI, 0.118-0.863). Metformin use in the initial 2 years was associated with a decreased risk of TB, and metformin users had a reduced risk compared with their sulfonylurea comparators. Copyright © 2017 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.

Pharmacokinetics of the adrenocorticolytic compounds 3-methylsulphonyl-DDE and o,p'-DDD (mitotane) in Minipigs.

PubMed

Hermansson, Veronica; Cantillana, Tatiana; Hovander, Lotta; Bergman, Ake; Ljungvall, Karl; Magnusson, Ulf; Törneke, Karolina; Brandt, Ingvar

2008-02-01

The pharmacokinetics of the adrenocorticolytic drug candidate 3-Methylsulphonyl-DDE (3-MeSO2-DDE) and the anticancer drug o,p'-DDD (mitotane) were studied in Göttingen minipigs. The animals were given 3-MeSO2-DDE or o,p'-DDD as single oral doses (30 mg/kg). Concentrations in plasma and subcutaneous fat were measured by gas chromatography at different time points during 180 days. Maximal plasma concentrations appeared within 24 h for both compounds, but were about 2 times higher for 3-MeSO2DDE. o,p'-DDD plasma concentrations declined rapidly to low levels during 4 days. 3-MeSO2-DDE also decreased rapidly, but remained at high concentrations throughout the study. In fat, 3-MeSO2-DDE reached about 25-fold higher levels than o,p'-DDD at 30 days, and both substances were eliminated slowly from this tissue. 3-MeSO2-DDE liver concentrations were about 18-fold higher than those in plasma at 180 days. In contrast, o,p'-DDD liver and plasma levels were about equal at 180 days. o,p'-DDD had roughly 45 times larger CL/F than 3-MeSO2-DDE, confirming that the elimination of this compound was more rapid. Both compounds were characterised by their localisation and retention in fat tissue, and the individual size of the fat stores clearly determined the plasma concentrations. It is concluded that although 3-MeSO2-DDE is an interesting candidate for therapeutic use due to its potential characteristics to specifically target adrenocortical tumour cells the slow elimination of the compound might make it challenging to design appropriate dosage regimes.

Assessment of perioperative antimicrobial prophylaxis using ATC/DDD methodology.

PubMed

Bozkurt, Fatma; Kaya, Safak; Gulsun, Serda; Tekin, Recep; Deveci, Özcan; Dayan, Saim; Hoşoglu, Salih

2013-12-01

In the light of international experience and guidelines and in order to improve the quality of perioperative antimicrobial prophylaxis (PAP), various hospitals have set up their own multidisciplinary healthcare teams and have evaluated the density of PAP through close supervision and interventions. The aim of the present study was to compare the density, quality, and cost of PAP before and after an intervention implemented at our hospital in order to increase the quality of PAP. PAP was monitored using a form prepared in line with the international guidelines, which was completed by the infection control nurse under the supervision of the infectious diseases specialist. In order to reduce the frequent errors in our PAP procedures, an intervention was implemented, and the period before this intervention (January-April 2011) was compared with the post-intervention period 1 year later (January-April 2012). The density of PAP was calculated according to the Anatomical Therapeutic Chemical classification/defined daily dose (ATC/DDD) methodology. A total of 2398 patients received PAP during this period. The most frequently used antibiotic before and after the intervention was cefazolin. Its use further increased after the intervention (p<0.001). After the intervention, the ratio of the correct timing of the first antibiotic dose increased from 91.7% to 99.0% (p<0.001), while the excessively long administration of PAP was reduced from 77.0% to 44.7% (p<0.001). The ratio of full compliance with the guidelines increased from 15.5% to 40.2% (p<0.001) and the rate of surgical site infections dropped from 18.5% to 12.0%. The density of antibiotic use dropped from 305.7 DDD/100 procedures=3.1 DDD/procedure to 162.1 DDD/100 procedures=1.6 DDD/procedure. The quality of PAP may be improved through better compliance with healthcare guidelines, close supervision, and training activities. Also, surgical site infections and the cost of PAP may be reduced through more appropriate antibiotic use, thus contributing to the national healthcare budget. Copyright © 2013 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Opioid consumption before and after the establishment of a palliative medicine unit in an Egyptian cancer centre.

PubMed

Alsirafy, Samy A; Ibrahim, Noha Y; Abou-Elela, Enas N

2012-01-01

Opioid consumption before and after the establishment of a palliative medicine unit (PMU) in an Egyptian cancer centre was reviewed. A comparison of consumption during the year before the PMU was established to consumption during the third year after the PMU's establishment revealed that morphine consumption increased by 698 percent, fentanyl by 217 percent, and tramadol by 230 percent. Expressed in defined daily dose (DDD) and adjusted for 1,000 new cancer patients, consumption increased by 460 percent, from 4,678 DDD/1,000 new patients to 26,175 DDD/1,000 new patients. Expressed in grams of oral morphine equivalent (g OME), consumption increased by 644 percent, from 233 g OME/1,000 new patients to 1,731 g OME/1,000 new patients. The establishment of the PMU was associated with an increase in opioid consumption, especially morphine, which is an indicator of improvement in cancer pain control. The expression of opioid consumption in OME in addition to DDD may provide further information, especially when weak opioids are included in the analysis.

Impact of the introduction of mandatory generic substitution in South Africa: private sector sales of generic and originator medicines for chronic diseases.

PubMed

Gray, Andrew Lofts; Santa-Ana-Tellez, Yared; J Wirtz, Veronika

2016-12-01

To assess the impact of mandatory offer of generic substitution, introduced in South Africa in May 2003, on private sector sales of generic and originator medicines for chronic diseases. Private sector sales data (June 2001 to May 2005) were obtained from IMS Health for proton pump inhibitors (PPIs; ATC code A02BC), HMG-CoA reductase inhibitors (statins; C10AA), dihydropyridine calcium antagonists (C08CA), angiotensin-converting enzyme inhibitors (ACE-I; C09AA) and selective serotonin reuptake inhibitors (SSRIs; N06AB). Monthly sales were expressed as defined daily doses per 1000 insured population per month (DDD/TIM). Interrupted time-series models were used to estimate the changes in slope and level of medicines use after the policy change. ARIMA models were used to correct for autocorrelation and stationarity. Only the SSRIs saw a significant rise in level of generic utilisation (0.2 DDD/TIM; P < 0.001) and a fall in originator usage (-0.1 DDD/TIM; P < 0.001) after the policy change. Utilisation of generic PPIs fell (level 0.06 DDD/TIM, P = 0.048; slope 0.01 DDD/TIM, P = 0.043), but utilisation of originator products also grew (level 0.05 DDD/TIM, P < 0.001; slope 0.003, P = 0.001). Generic calcium antagonists and ACE-I showed an increase in slope (0.01 DDD/TIM, P = 0.016; 0.02 DDD/TIM, P < 0.001), while the originators showed a decrease in slope (-0.003 DDD/TIM, P = 0.046; -0.01 DDD/TIM, P < 0.001). There were insufficient data on generic statin use before the policy change to allow for analysis. The mandatory offer of generic substitution appeared to have had a quantifiable effect on utilisation patterns in the 2 years after May 2003. Managed care interventions that were already in place before the intervention may have blunted the extent of the changes seen in this period. Generic policies are an important enabling provision for cost-containment efforts. However, decisions taken outside of official policy may anticipate or differ from that policy, with important consequences. © 2016 John Wiley & Sons Ltd.

Antimicrobial consumption on Austrian dairy farms: an observational study of udder disease treatments based on veterinary medication records.

PubMed

Firth, Clair L; Käsbohrer, Annemarie; Schleicher, Corina; Fuchs, Klemens; Egger-Danner, Christa; Mayerhofer, Martin; Schobesberger, Hermann; Köfer, Josef; Obritzhauser, Walter

2017-01-01

Antimicrobial use in livestock production is an important contemporary issue, which is of public interest worldwide. Antimicrobials are not freely available to Austrian farmers and can only be administered to livestock by veterinarians, or by farmers who are trained members of the Animal Health Service. Since 2015, veterinarians have been required by law to report antimicrobials dispensed to farmers for use in food-producing animals. The study presented here went further than the statutory framework, and collected data on antimicrobials dispensed to farmers and those administered by veterinarians. Seventeen veterinary practices were enrolled in the study via convenience sampling. These veterinarians were asked to contact interested dairy farmers regarding participation in the study (respondent-driven sampling). Data were collected from veterinary practice software between 1st October 2015 and 30th September 2016. Electronic data (89.4%) were transferred via an online interface and paper records (10.6%) were entered by the authors. Antimicrobial treatments with respect to udder disease were analysed by number of defined daily doses per cow and year (nDDD vet /cow/year), based on the European Medicines Agency technical unit, Defined Daily Dose for animals (DDD vet ). Descriptive statistics and the Wilcoxon rank sum test were used to analyse the results. Antimicrobial use data from a total of 248 dairy farms were collected during the study, 232 of these farms treated cows with antibiotics; dry cow therapy was excluded from the current analysis. The mean number of DDD vet /cow/year for the antimicrobial treatment of all udder disease was 1.33 DDD vet /cow/year. Of these treatments, 0.73 DDD vet /cow/year were classed as highest priority critically important antimicrobials (HPCIAs), according to the World Health Organization (WHO) definition. The Wilcoxon rank sum test determined a statistically significant difference between the median number of DDD vet /cow/year for acute and chronic mastitis treatment ( W  = 10,734, p  < 0.001). The most commonly administered antimicrobial class for the treatment of acute mastitis was beta-lactams. Intramammary penicillin was used at a mean of 0.63 DDD vet /cow/year, followed by the third generation cephalosporin, cefoperazone, (a HPCIA) at 0.60 DDD vet /cow/year. Systemic antimicrobial treatments were used at a lower overall level than intramammary treatments for acute mastitis. This study demonstrated that Austrian dairy cows in the study population were treated with antimicrobial substances for udder diseases at a relatively low frequency, however, a substantial proportion of these treatments were with substances considered critically important for human health. While it is vital that sick cows are treated, reductions in the overall use of antimicrobials, and critically important substances in particular, are still possible.

Use of generic and essential medicines for prevention and treatment of cardiovascular diseases in Portugal.

PubMed

Gama, Helena; Torre, Carla; Guerreiro, José Pedro; Azevedo, Ana; Costa, Suzete; Lunet, Nuno

2017-06-29

The successful control of cardiovascular diseases at the lowest possible cost requires the use of the most effective and affordable medicines. We aimed to describe the trends in the ambulatory use of medicines for prevention and treatment of cardiovascular diseases [Anatomic Therapeutic Chemical classification system (ATC): C and B01A] in Portugal, between 2004 and 2012, and to estimate the potential for expenditure reduction through changes in patterns of use. We analysed sell-out data, expressed as defined daily doses (DDD) and pharmacy retail price (€), from a nationwide database. We estimated potential reduction in expenditures through the increase, up to 90% of the volume of DDD, in the use of generic and essential medicines; the latter were defined according to guidelines from Portugal and another European country. Overall consumption increased by approximately 50% from 2004 to 2012, reaching nearly 2400 million DDD, whereas expenditure decreased to 753 million € (-31.3% since 2006). Use of generics and essential medicines increased, representing 43.6 and 39.9% of DDD consumption in 2012, respectively. The 40 most used groups of medicines in 2012 accounted for just over 80% of overall consumption; among these, increase in use of generics and essential medicines would have contributed to a saving of 275 million €. Changes in patterns of consumption of medicines towards a more frequent use of generics, a preferential use of essential medicines and a more rational use of fixed-dose combinations may contribute to a more efficient use of health resources.

Current Status and Future Challenges in Risk-Based Radiation Engineering

NASA Technical Reports Server (NTRS)

Pellish, Jonathan A.

2017-01-01

This presentation covers the basis and challenges for radiation effects in electronic systems. The three main types of radiation effects in electronics are: 1) total ionizing dose (TID), 2) total non-ionizing dose (TNID) / displacement damage dose (DDD), and 3) single-event effect (SEE). Some content on relevant examples of effects, current concerns, and possible environmental model-driven solutions are also included.

A novel multiple-stage antimalarial agent that inhibits protein synthesis.

PubMed

Baragaña, Beatriz; Hallyburton, Irene; Lee, Marcus C S; Norcross, Neil R; Grimaldi, Raffaella; Otto, Thomas D; Proto, William R; Blagborough, Andrew M; Meister, Stephan; Wirjanata, Grennady; Ruecker, Andrea; Upton, Leanna M; Abraham, Tara S; Almeida, Mariana J; Pradhan, Anupam; Porzelle, Achim; Luksch, Torsten; Martínez, María Santos; Luksch, Torsten; Bolscher, Judith M; Woodland, Andrew; Norval, Suzanne; Zuccotto, Fabio; Thomas, John; Simeons, Frederick; Stojanovski, Laste; Osuna-Cabello, Maria; Brock, Paddy M; Churcher, Tom S; Sala, Katarzyna A; Zakutansky, Sara E; Jiménez-Díaz, María Belén; Sanz, Laura Maria; Riley, Jennifer; Basak, Rajshekhar; Campbell, Michael; Avery, Vicky M; Sauerwein, Robert W; Dechering, Koen J; Noviyanti, Rintis; Campo, Brice; Frearson, Julie A; Angulo-Barturen, Iñigo; Ferrer-Bazaga, Santiago; Gamo, Francisco Javier; Wyatt, Paul G; Leroy, Didier; Siegl, Peter; Delves, Michael J; Kyle, Dennis E; Wittlin, Sergio; Marfurt, Jutta; Price, Ric N; Sinden, Robert E; Winzeler, Elizabeth A; Charman, Susan A; Bebrevska, Lidiya; Gray, David W; Campbell, Simon; Fairlamb, Alan H; Willis, Paul A; Rayner, Julian C; Fidock, David A; Read, Kevin D; Gilbert, Ian H

2015-06-18

There is an urgent need for new drugs to treat malaria, with broad therapeutic potential and novel modes of action, to widen the scope of treatment and to overcome emerging drug resistance. Here we describe the discovery of DDD107498, a compound with a potent and novel spectrum of antimalarial activity against multiple life-cycle stages of the Plasmodium parasite, with good pharmacokinetic properties and an acceptable safety profile. DDD107498 demonstrates potential to address a variety of clinical needs, including single-dose treatment, transmission blocking and chemoprotection. DDD107498 was developed from a screening programme against blood-stage malaria parasites; its molecular target has been identified as translation elongation factor 2 (eEF2), which is responsible for the GTP-dependent translocation of the ribosome along messenger RNA, and is essential for protein synthesis. This discovery of eEF2 as a viable antimalarial drug target opens up new possibilities for drug discovery.

A novel multiple-stage antimalarial agent that inhibits protein synthesis

NASA Astrophysics Data System (ADS)

Baragaña, Beatriz; Hallyburton, Irene; Lee, Marcus C. S.; Norcross, Neil R.; Grimaldi, Raffaella; Otto, Thomas D.; Proto, William R.; Blagborough, Andrew M.; Meister, Stephan; Wirjanata, Grennady; Ruecker, Andrea; Upton, Leanna M.; Abraham, Tara S.; Almeida, Mariana J.; Pradhan, Anupam; Porzelle, Achim; Martínez, María Santos; Bolscher, Judith M.; Woodland, Andrew; Norval, Suzanne; Zuccotto, Fabio; Thomas, John; Simeons, Frederick; Stojanovski, Laste; Osuna-Cabello, Maria; Brock, Paddy M.; Churcher, Tom S.; Sala, Katarzyna A.; Zakutansky, Sara E.; Jiménez-Díaz, María Belén; Sanz, Laura Maria; Riley, Jennifer; Basak, Rajshekhar; Campbell, Michael; Avery, Vicky M.; Sauerwein, Robert W.; Dechering, Koen J.; Noviyanti, Rintis; Campo, Brice; Frearson, Julie A.; Angulo-Barturen, Iñigo; Ferrer-Bazaga, Santiago; Gamo, Francisco Javier; Wyatt, Paul G.; Leroy, Didier; Siegl, Peter; Delves, Michael J.; Kyle, Dennis E.; Wittlin, Sergio; Marfurt, Jutta; Price, Ric N.; Sinden, Robert E.; Winzeler, Elizabeth A.; Charman, Susan A.; Bebrevska, Lidiya; Gray, David W.; Campbell, Simon; Fairlamb, Alan H.; Willis, Paul A.; Rayner, Julian C.; Fidock, David A.; Read, Kevin D.; Gilbert, Ian H.

2015-06-01

There is an urgent need for new drugs to treat malaria, with broad therapeutic potential and novel modes of action, to widen the scope of treatment and to overcome emerging drug resistance. Here we describe the discovery of DDD107498, a compound with a potent and novel spectrum of antimalarial activity against multiple life-cycle stages of the Plasmodium parasite, with good pharmacokinetic properties and an acceptable safety profile. DDD107498 demonstrates potential to address a variety of clinical needs, including single-dose treatment, transmission blocking and chemoprotection. DDD107498 was developed from a screening programme against blood-stage malaria parasites; its molecular target has been identified as translation elongation factor 2 (eEF2), which is responsible for the GTP-dependent translocation of the ribosome along messenger RNA, and is essential for protein synthesis. This discovery of eEF2 as a viable antimalarial drug target opens up new possibilities for drug discovery.

Impact of Over-the-Counter Restrictions on Antibiotic Consumption in Brazil and Mexico

PubMed Central

Santa-Ana-Tellez, Yared; Mantel-Teeuwisse, Aukje K.; Dreser, Anahi; Leufkens, Hubert G. M.; Wirtz, Veronika J.

2013-01-01

Background In Latin American countries over-the-counter (OTC) dispensing of antibiotics is common. In 2010, both Mexico and Brazil implemented policies to enforce existing laws of restricting consumption of antibiotics only to patients presenting a prescription. The objective of the present study is therefore to evaluate the impact of OTC restrictions (2010) on antibiotics consumption in Brazil and Mexico. Methods and Findings Retail quarterly sales data in kilograms of oral and injectable antibiotics between January 2007 and June 2012 for Brazil and Mexico were obtained from IMS Health. The unit of analysis for antibiotics consumption was the defined daily dose per 1,000 inhabitants per day (DDD/TID) according to the WHO ATC classification system. Interrupted time series analysis was conducted using antihypertensives as reference group to account for changes occurring independently of the OTC restrictions directed at antibiotics. To reduce the effect of (a) seasonality and (b) autocorrelation, dummy variables and Prais-Winsten regression were used respectively. Between 2007 and 2012 total antibiotic usage increased in Brazil (from 5.7 to 8.5 DDD/TID, +49.3%) and decreased in Mexico (10.5 to 7.5 DDD/TID, −29.2%). Interrupted time series analysis showed a change in level of consumption of −1.35 DDD/TID (p<0.01) for Brazil and −1.17 DDD/TID (p<0.00) for Mexico. In Brazil the penicillins, sulfonamides and macrolides consumption had a decrease in level after the intervention of 0.64 DDD/TID (p = 0.02), 0.41 (p = 0.02) and 0.47 (p = 0.01) respectively. While in Mexico it was found that only penicillins and sulfonamides had significant changes in level of −0.86 DDD/TID (p<0.00) and −0.17 DDD/TID (p = 0.07). Conclusions Despite different overall usage patterns of antibiotics in Brazil and Mexico, the effect of the OTC restrictions on antibiotics usage was similar. In Brazil the trend of increased usage of antibiotics was tempered after the OTC restrictions; in Mexico the trend of decreased usage was boosted. PMID:24146761

Cardiovascular drugs consumption--comparison between two Croatian regions, City of Zagreb and Lika-Senj County.

PubMed

Jurković, Drazen; Stimac, Danijela; Bajramović, Dubravko; Tiljak, Hrvoje; Stevanović, Ranko

2014-06-01

The aim of this paper is to determine the differences in the outpatient consumption of cardiovascular drugs between Croatian regions: the City of Zagreb and Lika-Senj County. The data on the number of packages and the purchase price for each drug have been obtained from all pharmacies in Lika-Senj County and all pharmacies in the City of Zagreb. Defined daily doses/1000 inhabitants/day (DDD/1000/day) was calculated for every drug in accordance with its code name and Anatomical Therapeutic Chemical/Defined Daily Dose (ATC/DDD) index of the World Health Organization (WHO) for 2007. For drug combinations without defined daily doses, equivalent doses (ED) were used. The quality of drug prescribing within the group of cardiovascular drugs was assessed using the Drug Utilization (DU90%) method and the adherence of the DU90% segment to the guidelines for prescribing individual drug groups. The statistical significance of differences in results between the City of Zagreb and Lika-Senj County was tested using the chi-square test at the level of statistical significance p < 0.05. The comparison of the share of the five most often prescribed drug groups in Lika-Senj County has shown statistically significant differences when compared to the City of Zagreb (chi2 = 28.93, df = 4, p < 0.001). The total outpatient consumption of cardiovascular drugs in the City of Zagreb and Lika-Senj County differs significantly. The consumption, quality of prescribing drugs and cost/DDD in the City of Zagreb is higher than in Lika-Senj County; in the City of Zagreb, newer and more expensive drugs are prescribed to a higher extent.

Differences in utilisation of gastroprotective drugs between 2001 and 2005 in Australia and Nova Scotia, Canada.

PubMed

Tett, Susan E; Sketris, Ingrid; Cooke, Charmaine; van Zanten, Sander Veldhuyzen; Barozzi, Nadia

2013-07-01

This study aimed to compare use of histamine H2 receptor antagonists (H2RAs) and proton pump inhibitors (PPIs), 2001-2005, in the elderly and social security beneficiaries in Australia (AUS) and Nova Scotia, Canada (NS). Prescription dispensing data were collected for all subsidised H2RAs and PPIs. In AUS, dispensing data for concession beneficiaries were obtained from the Pharmaceutical Benefits Scheme database. In NS, data were sourced from the Pharmacare database. Relevant population data were used to convert to World Health Organisation Anatomic Therapeutic Chemical defined daily doses (2005) per 1000 beneficiaries per day (DDD/1000/day). Overall use of gastroprotective agents was similar and rising in NS and AUS (100-160 DDD/1000/day) over this 5-year time window. However, the proportion of this use accounted for by PPIs was far higher in AUS (over 85% by 2005) than in NS (23% rising to 35% over the 5 years). In AUS, PPI use rose from 50 to about 140 DDD/1000/day over the 5 years, whereas PPI use in NS rose slowly to less than 60 DDD/1000/day by 2005. H2RA use in NS was always high (over 100 DDD/1000/day), whereas in AUS, H2RA use fell from 54 to around 24 DDD/1000/day over this period. AUS had much higher use of PPIs than NS over 2001-2005. The proportion of PPIs in all gastroprotective agents rose in AUS to be nearly 90%. The differences in utilisation during this time window could lead to differences in health outcomes from either lower gastro-intestinal bleeding risk or higher long-term adverse effects of PPIs. Copyright © 2013 John Wiley & Sons, Ltd.

Recent increase in detection of alprazolam in Victorian heroin-related deaths.

PubMed

Rintoul, Angela C; Dobbin, Malcolm D H; Nielsen, Suzanne; Degenhardt, Louisa; Drummer, Olaf H

2013-03-04

To examine the rate of detection of alprazolam among cases of heroin-related death (HRD) in Victoria, including the relationship between alprazolam supply and HRDs. Population-based study of community alprazolam supply in Victoria and HRDs reported to the Victorian coroner from January 1990 to December 2010. Number of prescriptions for alprazolam supplied; defined daily dose (DDD) per 1000 population per 04 of alprazolam; number of cases of HRD in which alprazolam was detected through postmortem toxicological testing. Alprazolam supply increased by 1426%, from 0.42 DDD/1000/04 in 1990, to 6.41 in 2010. For every 1 unit increase in DDD/1000/04, the proportion of cases of HRD in which alprazolam was detected increased at an incidence rate ratio of 2.4 (95% CI, 2.1-2.8; P < 0.001). Alprazolam was detected among increasing proportions of HRDs, from 5.3% in 2005 to a peak of 35.3% in 2009. The increase in detection of alprazolam among cases of HRD, particularly since 2005, and the disproportionate increase in prescribing of the high-dose 2 mg formulation compared with other formulations suggest a need to examine alprazolam prescribing and to identify inappropriate prescribing and the circumstances of diversion from licit to illicit use.

Application of ATC/DDD methodology to evaluate perioperative antimicrobial prophylaxis.

PubMed

Akalin, Serife; Kutlu, Selda Sayin; Cirak, Bayram; Eskiçorapcı, Saadettin Yilmaz; Bagdatli, Dilek; Akkaya, Semih

2012-02-01

To evaluate quality of perioperative antibiotic prophylaxis (PAP) and to calculate the cost per procedure in a Turkish university hospital. A 352-bed teaching hospital in Denizli, Turkey. An prospective audit was performed between July and October 2010. All clean, clean-contaminated and contaminated elective surgical procedures in ten surgical wards were recorded. Antimicrobial use was calculated per procedure using the ATC-DDD system. The appropriateness of antibiotic use for each procedure was evaluated according to international guidelines on PAP. In addition, the cost per procedure was calculated. Overall, in 577 of the 625 (92.3%) of the studied procedures, PAP was used. PAP was indicated in 12.5% of the group where it was not used, and not indicated in 7.1% of the group where it was used. Unnecessarily prolonged antimicrobial prophylaxis was observed in 56.9% of the procedures, mean duration was 2.6 ± 2.7 days. The most frequently used antimicrobials were cefazolin (117.9 DDD/100-operation) and sulbactam/ampicillin (102.2 DDD/100-operation). The timing of the starting dose was appropriate in 545 procedures (94.5%). In the group that received PAP, only 80 (13.7%) of the procedures were found to be fully appropriate and correct. The density of antimicrobial use per operation was 2.8 DDD. The mean cost of the use of prophylactic antimicrobials 18.6 per procedure. The density of antimicrobial use in PAP was found to be very high in our hospital. Antibiotic overuse extended into the postoperative period.

Characterization of mitotane (o,p'-DDD)--cyclodextrin inclusion complexes: phase-solubility method and NMR.

PubMed

Alfonsi, R; Attivi, D; Astier, A; Socha, M; Morice, S; Gibaud, S

2013-05-01

Mitotane (o,p'-dichlorodimethyl dichloroethane [o,p'-DDD]) is used for the treatment of adrenocortical cancer and occasionally Cushing's syndrome. This drug is very poorly soluble in water, and following oral administration, approximately 60% of the dose is recovered in the feces unaltered. The preparation of a soluble formulation (i.e. by complexation with cyclodextrins) with improved bioavailability is the aim of this work. The inclusion of mitotane in methyl-ß-cyclodextrins was studied using both phase-solubility methods and NMR experiments. To elucidate the inclusion mechanism, o,p'-DDD was compared to its regioisomer (i.e. p,p'-DDD). It was demonstrated that two dimethyl-ß-cyclodextrins (DMßCD) can complex with the aromatic rings. From the phase-solubility diagrams, we observe that both cases are very different: K(1:1) is between 37 000 and 85 000 mol.l(-1), whereas K(1:2) is between 5.3 and 32 mol.l(-1). The NMR experiments confirmed the inclusion but it also gave an insight into the kinetics of the dissociation: the ortho-chloro moiety is in slow exchange on the NMR time scale, whereas the para-chloro moiety is in fast exchange rate. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

SU-F-T-144: Analytical Closed Form Approximation for Carbon Ion Bragg Curves in Water

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tuomanen, S; Moskvin, V; Farr, J

2016-06-15

Purpose: Semi-empirical modeling is a powerful computational method in radiation dosimetry. A set of approximations exist for proton ion depth dose distribution (DDD) in water. However, the modeling is more complicated for carbon ions due to fragmentation. This study addresses this by providing and evaluating a new methodology for DDD modeling of carbon ions in water. Methods: The FLUKA, Monte Carlo (MC) general-purpose transport code was used for simulation of carbon DDDs for energies of 100–400 MeV in water as reference data model benchmarking. Based on Thomas Bortfeld’s closed form equation approximating proton Bragg Curves as a basis, we derivedmore » the critical constants for a beam of Carbon ions by applying models of radiation transport by Lee et. al. and Geiger to our simulated Carbon curves. We hypothesized that including a new exponential (κ) residual distance parameter to Bortfeld’s fluence reduction relation would improve DDD modeling for carbon ions. We are introducing an additional term to be added to Bortfeld’s equation to describe fragmentation tail. This term accounts for the pre-peak dose from nuclear fragments (NF). In the post peak region, the NF transport will be treated as new beams utilizing the Glauber model for interaction cross sections and the Abrasion- Ablation fragmentation model. Results: The carbon beam specific constants in the developed model were determined to be : p= 1.75, β=0.008 cm-1, γ=0.6, α=0.0007 cm MeV, σmono=0.08, and the new exponential parameter κ=0.55. This produced a close match for the plateau part of the curve (max deviation 6.37%). Conclusion: The derived semi-empirical model provides an accurate approximation of the MC simulated clinical carbon DDDs. This is the first direct semi-empirical simulation for the dosimetry of therapeutic carbon ions. The accurate modeling of the NF tail in the carbon DDD will provide key insight into distal edge dose deposition formation.« less

Outpatient utilization of psychopharmaceuticals in the City of Zagreb 2001-2006.

PubMed

Stimac, Danijela; Culig, Josip

2009-03-01

A comprehensive insight into drug utilization as an economic and primarily a public health issue can only be acquired in the context of overall health state of the respective population. The objectives of the study were: 1) to determine the real outpatient utilization of psychopharmaceuticals in Zagreb, 2) to determine the psychopharmaceutical prescribing quality during the study period; and 3) to propose appropriate interventions in Zagreb on the basis of the results obtained. Data on drug utilization were obtained from all Zagreb pharmacies. The number of defined daily doses (DDD) and number of DDD per 1000 inhabitants per day (DDD/1000/day) were calculated from the number of particular drug packages. The Drug Utilization 90% (DU90%) method was used as a criterion of prescribing quality. Outpatient utilization of psychopharmaceuticals showed a declining pattern from 115.40 DDD/1000/day in 2001 to 93.15 DDD/1000/day in 2006. Anxiolytics accounted for the majority of this drug group utilization in the City of Zagreb, although the anxiolytic/antidepressant ratio decreased from 7.19 in 2001 to 3.86 in 2006. The utilization of selective serotonin reuptake inhibitors showed a 2.5-fold increase and accounted for 90% of overall antidepressant utilization. A 2.5-fold decrease was recorded in the utilization of antipsychotics, while the atypical/typical antipsychotic ratio changed from 1:2 in 2001 to 1.1:1 in 2006. Despite some improvement observed in the prescribing quality, the predominance of benzodiazepines in the utilization of psychopharmaceuticals points to the need of additional rationalization in the field.

Trends in the use of antiasthmatic medications in Morocco (1999-2010).

PubMed

Ghanname, Imane; Ahid, Samir; Berrada, Ghizlane; Belaiche, Abdelmjid; Hassar, Mohamed; Cherrah, Yahya

2013-12-01

Asthma is a big public health problem in Morocco. The drug therapy existing in Morocco is currently insufficient because of the low purchasing power and the low health insurance coverage available to the average citizen in Morocco. In this study we evaluated the consumption of antiasthmatics in Morocco during the period 1999-2010, the classes of used drugs and the generics' market share. We used sales data from the Moroccan subsidiaries of the IMS Health "Intercontinental Marketing Service". The consumption volume was converted to Defined Daily Doses (DDDs). During 1999-2010, antiasthmatics's consumption increased from 3.91 to 14.47 DDD per 1000 inhabitants per day. In 2010, the association Beta-2-mimetic-Glucocorticosteroids were the most consumed (8.53 DDD/1000 Inhabitants/day) followed by the short-acting inhaled Beta-2-mimetic (4 DDD/1000 Inhabitants/day) and inhaled Glucocorticosteroids alone accounted for 1.13 DDD/1000 Inhabitants/day. The largest consumption share in volume was held by the short-acting inhaled Beta-2-mimetic (42%) followed by the combination Beta-2-mimetic-Glucocorticosteroids (38%). Between 1999 and 2010, the market for generic antiasthmatics increased from 1.84 to 2.18 DDD/1000 Inhabitants/day. The ratio of the monthly average cost of treatment to the minimum wage in Morocco decreased from 10.8% in 1999 to 7.11% in 2010. Antiasthmatics' consumption in Morocco has undergone significant changes between 1999 and 2010. However, the availability of these drugs expressed as the Average Monthly Expenditure/Guaranteed Minimum Wage ratio improved. Despite this, the use of antiasmathics in Morocco remains low.

Price analysis of multiple sclerosis disease-modifying therapies marketed in the United States.

PubMed

Bin Sawad, Aseel; Seoane-Vazquez, Enrique; Rodriguez-Monguio, Rosa; Turkistani, Fatema

2016-11-01

This study assessed trends in the average wholesale price (AWP) at the market entry of disease-modifying therapies (DMTs) approved by Food and Drug Administration (FDA) in the period 1987-2014. DMT regulatory information was derived from the FDA website. The AWPs per unit at market entry data were derived from the Red Book (Truven Health Analytics Inc.). The AWP history for each DMT was collected from its date of approval to 31 December 2014. The FDA approved label defined daily dose (DDD) for adult patients was obtained from FDA approved labels. The AWP per DDD and the AWP/DDD per year of therapy were computed. Descriptive statistics, Wilcoxon tests, t-test, and multiple linear regression were performed. The statistical significance level was set at 0.05. The FDA approved 12 multiple sclerosis (MS) DMTs, including five new drug applications (NDAs) and seven biologic license applications (BLAs) as of 31 December 2014. The FDA granted orphan designation to five DMTs. There was one DMT approved by the FDA in the 1980s, three in the 1990s, three in 2000s, and five in the period 2010-2014. The market entry inflation-adjusted AWP per DDD was $10.23 for the first DMT (mitoxantrone hydrochloride) that was approved in the 1980s. The median market entry inflation-adjusted AWP per DDD was $12.41 (interquartile range [IQR] = 4.51) for DMTs approved in the 1990s, $71.26 (IQR = 58.35) in the 2000s, and $172.56 (IQR = 84.97) in the period 2010-2014. The median AWP per DDD was statistically significantly different (p = 0.011) for orphan (median = $41.82, IQR = 56.077) compared to non-orphan drugs (median = $171.32, IQR = 199.29). Year of market entry was positively associated with DMT prices at US market entry (p = 0.01). The AWP per DDD for DMTs at market entry increased substantially over time. The increase in DMTs prices exceeded the general consumer price index.

Effect of Statin Intensity on the Risk of Epilepsy After Ischaemic Stroke: Real-World Evidence from Population-Based Health Claims.

PubMed

Lin, Fang-Ju; Lin, Hung-Wei; Ho, Yunn-Fang

2018-04-01

Statins possess neuroprotective effects. However, real-world evidence supporting their utility in post-stroke epilepsy (PSE) prevention is limited. The association between statin use, including timing of prescribing (pre-stroke vs post-stroke), type (lipophilicity, intensity of therapy) and dose intensity, and risk of developing PSE were investigated by studying Taiwanese health claims (2003-2013). Patients with new-onset ischaemic stroke were identified. The main outcome was a diagnosis of epilepsy after ischaemic stroke. According to pre-stroke statin use, groups of current users, former users, and non-users were compared using ANOVA. An extended Cox regression model was utilized to estimate the hazard ratio (HR) of PSE, with post-stroke statin use and certain comedications as time-dependent variables. Serial sensitivity analyses were performed to ensure study robustness. Of the 20,858 ischaemic stroke patients, 954 (4.6%) developed PSE. Post-stroke statin use (adjusted HR (aHR) 0.55; 95% confidence interval 0.46-0.67, p < 0.001), but not pre-stroke statin use was associated with a significantly reduced risk of developing PSE. A dose-response correlation was also observed between PSE risk reduction and quartiles of the statin cumulative defined daily dose (cDDD) (aHR 0.84, 0.67, 0.53, and 0.50 for the lowest, second, third, and highest quartiles of cDDD, respectively). Risk predictors and protectors against PSE were also characterized. The post-stroke use of statins after ischaemic stroke was associated with PSE risk reduction in a cDDD-dependent manner. Further clinical studies on the potential applications of statins for PSE prophylaxis, particularly among at-risk patients, are warranted.

Drug usage by outpatients in Croatia during an 8-year period: Influence of changes in pricing policy.

PubMed

Vitezic, Dinko; Madjarevic, Tomislav; Gantumur, Monja; Buble, Tonci; Vitezic, Miomira; Kovacevic, Miljenko; Mrsic-Pelcic, Jasenka; Sestan, Branko

2012-07-01

The aim of our study was to investigate the changes in drug usage and financial expenditure according to legal changes in Croatia during the period 2001 - 2008, especially considering pricing policy. The data on outpatient drug usage during the studied period was obtained from the Croatian National Health Insurance (CNHI). CNHI maintains a database on drugs prescribed by primary health care physicians and dispensed by pharmacies. The data was calculated and presented in defined daily doses (DDD) per inhabitant per year for antibiotics and in DDD/1,000 inhabitants/day for other drugs. The data is also presented in Euro/DDD and the financial expenditures are presented in Euros. During the investigated period drug usage increased 81.33%, while financial expenditure increased 77.23%. While total DDD/1,000 increased ~ 10% every year, financial expenditure increased 10 - 20% annually until 2006, but since then there have been no significant changes. Pricing policy changes could influence drug financial expenditure considerably in the short-term, but it is also important to apply a combination of measures for drug expenditure control. Numerous interventions from authorities from different countries all over the world, prove that there is still no so called "gold standard" which could restrain growing usage and expenditure of drugs. Clinical pharmacologists and clinical pharmacists should be included in these processes.

Cytogenetic status of human lymphocytes after exposure to low concentrations of p,p'-DDT, and its metabolites (p,p'-DDE, and p,p'-DDD) in vitro.

PubMed

Gerić, Marko; Ceraj-Cerić, Nikolina; Gajski, Goran; Vasilić, Želimira; Capuder, Željka; Garaj-Vrhovac, Vera

2012-06-01

Despite that the use of DDT has been restricted for more than 40 years to malaria affected areas, low doses of this pesticide and its metabolites DDE and DDD can be found in the environment around the world. Although it has been shown that these pollutants induce cell and DNA damage, the mechanisms of their cytogenotoxic activity remains largely unknown. This study looks into their possible genotoxic effects, at doses that can be found in body fluids, on human lymphocytes using the cytokinesis-block micronucleus assay and the comet assay. After exposure for 1, 6, and 24 h compounds p,p'-DDT (0.1 μg mL(-1)), p,p'-DDE (4.1 μg mL(-1)), and p,p'-DDD (3.9 μg mL(-1)) showed increase in DNA damage. The most significant results were observed at exposure period of 24 h where number of micronucleated cells increased from control 2.5±0.71 to 23.5±3.54, 13.5±0.71, and 16.5±6.36 for DDT, DDE, and DDD, respectively. Similar effect was observed using comet test where the percentage of DNA in comets tail increased from control 1.81±0.16 to 17.24±0.55, 11.21±0.56 and 9.28±0.50 for each compound, respectively. At the same time Fpg-comet assay failed to report induction of oxidative DNA damage of these pollutants. Additionally, the type of cell death was determined using diffusion assay and necrosis dominated. Our findings suggest that even at low concentrations, these pesticides could induce cytogenetic damage to human peripheral blood lymphocytes and in that manner have the impact on human health as well. Copyright © 2012 Elsevier Ltd. All rights reserved.

Comparison of Psychotropic Drug Prescribing Quality between Zagreb, Croatia and Sarajevo, B&H.

PubMed

Polić-Vižintin, Marina; Štimac, Danijela; Čatić, Tarik; Šostar, Zvonimir; Zelić, Ana; Živković, Krešimir; Draganić, Pero

2014-12-01

The purpose of this paper was to compare outpatient consumption and quality of psychotropic drug prescribing between Croatia and Bosnia & Herzegovina 2006-2010. Data on drug utilization from Zagreb Municipal Pharmacy and Sarajevo Public Pharmacy were used to calculate the number of defined daily doses (DDD) and DDD per 1000 inhabitants per day (DDD/TID) using the WHO Anatomical-Therapeutic-Chemical methodology. Total utilization of psychopharmaceuticals increased in both cities; however, it was higher in Zagreb than in Sarajevo throughout the study period. The utilization of psycholeptics increased in Zagreb by 2.4% (from 74.5 to 76.3 DDD/TID) and in Sarajevo by 3.8% (from 62.4 to 64.8 DDD/TID). The utilization of anxiolytics decreased in Zagreb by 2.1% and in Sarajevo by even 18.7%. The utilization of antidepressants increased in both cities with predominance of SSRI over TCA utilization, greater in Sarajevo (96.6%) than in Zagreb (10.2%). The anxiolytic/antidepressant ratio decreased by 11.1% in Zagreb (from 2.87 to 2.55) and by 58.7% in Sarajevo (from 5.66 to 2.34). Outpatient utilization of antipsychotics increased significantly in Sarajevo, predominated by typical ones, whereas in Zagreb the utilization of antipsychotics was stable, predominated by atypical ones. In Croatia and Bosnia & Herzegovina, there was an obvious tendency to follow western trends in drug prescribing, as demonstrated by the increased use of antidepressants and reduced use of anxiolytics. Despite some improvement observed in the prescribing quality, high use of antipsychotics with dominance of typical antipsychotics in Sarajevo points to the need of prescribing guidelines for antipsychotics.

40 CFR Table 1 to Subpart Ddd of... - Applicability of General Provisions (40 CFR Part 63, Subpart A) to Subpart DDD of Part 63

Code of Federal Regulations, 2010 CFR

2010-07-01

... (40 CFR Part 63, Subpart A) to Subpart DDD of Part 63 1 Table 1 to Subpart DDD of Part 63 Protection... Hazardous Air Pollutants for Mineral Wool Production Pt. 63, Subpt. DDD, Table 1 Table 1 to Subpart DDD of Part 63—Applicability of General Provisions (40 CFR Part 63, Subpart A) to Subpart DDD of Part 63...

40 CFR Table 1 to Subpart Ddd of... - Applicability of General Provisions (40 CFR Part 63, Subpart A) to Subpart DDD of Part 63

Code of Federal Regulations, 2011 CFR

2011-07-01

... (40 CFR Part 63, Subpart A) to Subpart DDD of Part 63 1 Table 1 to Subpart DDD of Part 63 Protection... Hazardous Air Pollutants for Mineral Wool Production Pt. 63, Subpt. DDD, Table 1 Table 1 to Subpart DDD of Part 63—Applicability of General Provisions (40 CFR Part 63, Subpart A) to Subpart DDD of Part 63...

Further characterization of diabetes mellitus and body weight loss in males of the congenic mouse strain DDD.Cg-A(y.).

PubMed

Suto, Jun-ichi; Satou, Kunio

2015-02-01

The A(y) allele at the agouti locus causes obesity and promotes linear growth in mice. However, body weight gain stops between 16 and 17 weeks after birth, and then, body weight decreases gradually in DDD.Cg-A(y) male mice. Body weight loss is a consequence of diabetes mellitus, which is genetically controlled mainly by a quantitative trait locus (QTL) on chromosome 4. This study aimed to further characterize diabetes mellitus and body weight loss in DDD.Cg-A(y) males. The number of β-cells was markedly reduced, and plasma insulin levels were very low in the DDD.Cg-A(y) males. Using a backcross progeny of DDD × (B6 × DDD.Cg-A(y)) F1-A(y), we identified one significant QTL for plasma insulin levels on distal chromosome 4, which was coincidental with QTL for hyperglycemia and lower body weight. The DDD allele was associated with decreased plasma insulin levels. When the DDD.Cg-A(y) males were housed under three different housing conditions [group housing (4 or 5 DDD.Cg-A(y) and DDD males), individual housing (single DDD.Cg-A(y) male) and single male housing with females (single DDD.Cg-A(y) male with DDD.Cg-A(y) or DDD females)], diabetes mellitus and body weight loss were most severely expressed in individually housed mice. Thus, the severity of diabetes and body weight loss in the DDD.Cg-A(y) males was strongly influenced by the housing conditions. These results demonstrate that both genetic and nongenetic environmental factors are involved in the development of diabetes mellitus and body weight loss in the DDD.Cg-A(y) males.

Further characterization of diabetes mellitus and body weight loss in males of the congenic mouse strain DDD.Cg-Ay

PubMed Central

SUTO, Jun-ichi; SATOU, Kunio

2014-01-01

The Ay allele at the agouti locus causes obesity and promotes linear growth in mice. However, body weight gain stops between 16 and 17 weeks after birth, and then, body weight decreases gradually in DDD.Cg-Ay male mice. Body weight loss is a consequence of diabetes mellitus, which is genetically controlled mainly by a quantitative trait locus (QTL) on chromosome 4. This study aimed to further characterize diabetes mellitus and body weight loss in DDD.Cg-Ay males. The number of β-cells was markedly reduced, and plasma insulin levels were very low in the DDD.Cg-Ay males. Using a backcross progeny of DDD × (B6 × DDD.Cg-Ay) F1-Ay, we identified one significant QTL for plasma insulin levels on distal chromosome 4, which was coincidental with QTL for hyperglycemia and lower body weight. The DDD allele was associated with decreased plasma insulin levels. When the DDD.Cg-Ay males were housed under three different housing conditions [group housing (4 or 5 DDD.Cg-Ay and DDD males), individual housing (single DDD.Cg-Ay male) and single male housing with females (single DDD.Cg-Ay male with DDD.Cg-Ay or DDD females)], diabetes mellitus and body weight loss were most severely expressed in individually housed mice. Thus, the severity of diabetes and body weight loss in the DDD.Cg-Ay males was strongly influenced by the housing conditions. These results demonstrate that both genetic and nongenetic environmental factors are involved in the development of diabetes mellitus and body weight loss in the DDD.Cg-Ay males. PMID:25373882

77 FR 50613 - Didecyl Dimethyl Ammonium Carbonate and Didecyl Dimethyl Ammonium Bicarbonate; Exemption From the...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-08-22

... used as sanitizers on appliances, beverage bottling, counter tops, food packaging, refrigerators..., countertops, and in food/beverage processing facilities. The assessment calculated the Daily Dietary Dose (DDD... estimates from exposure to treated food packaging and beverage bottles are also below the Agency's LOC...

Poor guideline adherence in the initiation of antidepressant treatment in children and adolescents in the Netherlands: choice of antidepressant and dose.

PubMed

de Vries, Ymkje Anna; de Jonge, Peter; Kalverdijk, Luuk; Bos, Jens H J; Schuiling-Veninga, Catharina C M; Hak, Eelko

2016-11-01

The Dutch guideline for the treatment of depression in young people recommends initiating antidepressant treatment with fluoxetine, as the evidence for its efficacy is strongest and the risk of suicidality may be lower than with other antidepressants. Furthermore, low starting doses are recommended. We aimed to determine whether antidepressant prescriptions are in accord with guidelines. A cohort of young people aged between 6 and 17 at the time of antidepressant initiation was selected from IABD, a Dutch pharmacy prescription database. The percentage of prescriptions for each antidepressant was determined. Starting and maintenance doses were determined and compared with recommendations for citalopram, fluoxetine, fluvoxamine, and sertraline. During the study period, 2942 patients initiated antidepressant treatment. The proportion of these young people who were prescribed fluoxetine increased from 10.1 % in 1994-2003 to 19.7 % in 2010-2014. However, the most commonly prescribed antidepressants were paroxetine in 1994-2003 and citalopram in 2004-2014. The median starting and maintenance doses were ≤0.5 DDD/day for tricyclic antidepressants and 0.5-1 DDD/day for SSRIs and other antidepressants. Starting doses were guideline-concordant 58 % of the time for children, 31 % for preteens, and 16 % for teens. Sixty percent of teens were prescribed an adult starting dose. In conclusion, guideline adherence was poor. Physicians preferred citalopram over fluoxetine, in contrast to the recommendations. Furthermore, although children were prescribed a low starting dose relatively frequently, teens were often prescribed an adult starting dose. These results suggest that dedicated effort may be necessary to improve guideline adherence.

Near elimination of ventricular pacing in SafeR mode compared to DDD modes: a randomized study of 422 patients.

PubMed

Davy, Jean-Marc; Hoffmann, Ellen; Frey, Axel; Jocham, Kurt; Rossi, Stefano; Dupuis, Jean-Marc; Frabetti, Lorenzo; Ducloux, Pascale; Prades, Emmanuel; Jauvert, Gaël

2012-04-01

SafeR performance versus DDD/automatic mode conversion (DDD/AMC) and DDD with a 250-ms atrioventricular (AV) delay (DDD/LD) modes was assessed toward ventricular pacing (Vp) reduction. After a 1-month run-in phase, recipients of dual-chamber pacemakers without persistent AV block and persistent atrial fibrillation (AF) were randomly assigned to SafeR, DDD/AMC, or DDD/LD in a 1:1:1 design. The main endpoint was the percentage of Vp (%Vp) at 2 months and 1 year after randomization, ascertained from device memories. Secondary endpoints include %Vp at 1 year according to pacing indication and 1-year AF incidence based on automatic mode switch device stored episodes. Among 422 randomized patients (73.2±10.6 years, 50% men, sinus node dysfunction 47.4%, paroxysmal AV block 30.3%, bradycardia-tachycardia syndrome 21.8%), 141 were assigned to SafeR versus 146 to DDD/AMC and 135 to DDD/LD modes. Mean %Vp at 2 months was 3.4±12.6% in SafeR versus 33.6±34.7% and 14.0±26.0% in DDD/AMC and DDD/LD modes, respectively (P<0.0001 for both). At 1 year, mean %Vp in SafeR was 4.5±15.3% versus 37.9±34.4% and 16.7±28.0% in DDD/AMC and DDD/LD modes, respectively (P<0.0001 for both). The proportion of patients in whom Vp was completely eliminated was significantly higher in SafeR (69%) versus DDD/AMC (15%) and DDD/LD (45%) modes (P<0.0001 for both), regardless of pacing indication. The absolute risk of developing permanent AF or of remaining in AF for >30% of the time was 5.4% lower in SafeR than in the DDD pacing group (ns). In this selected patient population, SafeR markedly suppressed unnecessary Vp compared with DDD modes. ©2012, The Authors. Journal compilation ©2012 Wiley Periodicals, Inc.

Chiral effects in adrenocorticolytic action of o,p'-DDD (mitotane) in human adrenal cells.

PubMed

Asp, V; Cantillana, T; Bergman, A; Brandt, I

2010-03-01

Adrenocortical carcinoma (ACC) is a rare malignant disease with poor prognosis. The main pharmacological choice, o,p'-DDD (mitotane), produces severe adverse effects. Since o,p'-DDD is a chiral molecule and stereoisomers frequently possess different pharmacokinetic and/or pharmacodynamic properties, we isolated the two o,p'-DDD enantiomers, (R)-(+)-o,p'-DDD and (S)-(-)-o,p'-DDD, and determined their absolute structures. The effects of each enantiomer on cell viability and on cortisol and dehydroepiandrosterone (DHEA) secretion in the human adrenocortical cell line H295R were assessed. We also assayed the o,p'-DDD racemate and the m,p'- and p,p'-isomers. The results show small but statistically significant differences in activity of the o,p'-DDD enantiomers for all parameters tested. The three DDD isomers were equally potent in decreasing cell viability, but p,p'-DDD affected hormone secretion slightly less than the o,p'- and m,p'-isomers. The small chiral differences in direct effects on target cells alone do not warrant single enantiomer administration, but might reach importance in conjunction with possible stereochemical effects on pharmacokinetic processes in vivo.

Widespread increase of empirical carbapenem use in acute care hospitals in Catalonia, Spain.

PubMed

Grau, Santiago; Fondevilla, Esther; Echeverría-Esnal, Daniel; Alcorta, Amaia; Limon, Enric; Gudiol, Francesc

2018-04-24

The overall increase in the use of carbapenems could lead to the selection of carbapenem-resistant bacteria. The objectives of this study were to analyze carbapenem use from 2008 to 2015 and their prescription profile in 58 hospitals affiliated to the VINCat Programme (nosocomial infection vigilance system). Retrospective, longitudinal and descriptive study of carbapenem use. Consecutive case-series study, looking for carbapenem prescription characteristics, conducted in January 2016. Use was calculated in defined daily doses (DDD)/100 patient-days (PD); prescription profiles were assessed using a standardized survey. Carbapenem use increased 88.43%, from 3.37 DDD/100-PD to 6.35 DDD/100-PD (p<0.001). A total of 631 patients were included in the prescription analysis. Carbapenems were prescribed empirically in 76.2% of patients, mainly for urinary tract and intra-abdominal infections due to suspicion of polymicrobial mixed infection (27.4%) and severity (25.4%). A worrying increase in carbapenem use was found in Catalonia. Stewardship interventions are required to prevent carbapenem overuse. Copyright © 2018 Elsevier España, S.L.U. and Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica. All rights reserved.

Structural and Molecular Basis for the Novel Catalytic Mechanism and Evolution of DddP, an Abundant Peptidase-Like Bacterial Dimethylsulfoniopropionate Lyase: A New Enzyme from an Old Fold

NASA Astrophysics Data System (ADS)

Zhang, Y. Z.; Wang, P.; Chen, X. L.; Li, C. Y.; Gao, X.; Zhu, D.; Xie, B. B.; Qin, Q. L.; Zhang, X. Y.; Su, H. N.; Zhou, B. C.; Xun, L.

2015-12-01

The microbial cleavage of dimethylsulfoniopropionate (DMSP) generates volatile dimethyl sulfide (DMS) and is an important step in global sulfur and carbon cycles. DddP is a DMSP lyase in marine bacteria and the deduced dddP gene product is abundant in marine metagenomic data sets. However, DddP belongs to the M24 peptidase family according to sequence alignment. Peptidases hydrolyze C-N bonds but DddP is deduced to cleave C-S bonds. Mechanisms responsible for this striking functional shift are currently unknown. We determined the structures of DMSP lyase RlDddP (the DddP from Ruegeria lacuscaerulensis ITI_1157) bound to inhibitory 2-(N-morpholino) ethanesulfonic acid or PO43- and of two mutants of RlDddP bound to acrylate. Based on structural, mutational and biochemical analyses, we characterized a new ion-shift catalytic mechanism of RlDddP for DMSP cleavage. Further, we suggested the structural mechanism leading to the loss of peptidase activity and the subsequent development of DMSP lyase activity in DddP. This study sheds light on the catalytic mechanism and the divergent evolution of DddP, leading to a better understanding of marine bacterial DMSP catabolism and global DMS production.

Radiation Characterization of Commercial GaN Devices

NASA Technical Reports Server (NTRS)

Harris, Richard D.; Scheick, Leif Z.; Hoffman, James P.; Thrivikraman, Tushar; Jenabi, Masud; Gim, Yonggyu; Miyahira, Tetsuo

2011-01-01

Radiative feedback from primordial protostars and final mass of the first star Commercially available devices fabricated from GaN are beginning to appear from a number of different suppliers. Based on previous materials and prototype device studies, it is expected that these commercial devices will be quite tolerant to the types of radiation encountered in space. This expectation needs to be verified and the study described herein was undertaken for that purpose. All of the parts discussed in this report are readily available commercially. The parts chosen for study are all targeted for RF applications. Three different studies were performed: 1) a preliminary DDD/TID test of a variety of part types was performed by irradiating with 50 MeV protons, 2) a detailed DDD/TID study of one particular part type was performed by irradiating with 50 MeV protons, and 3) a SEB/SEGR test was performed on a variety of part types by irradiating with heavy ions. No significant degradation was observed in the tests performed in this study.

[Resistance of uropathogenic strains of Escherichia coli in pregnant women and other women in generative ages in comparison with antibiotics consumption in Zagreb].

PubMed

Culig, Josip; Mlinarić-Dzepina, Ana; Leppée, Marcel; Vranes, Jasmina

2010-02-01

To compare resistance of uropathogenic strains of Escherichia coli (UPEC) to antibiotics in women in generative ages and pregnant women during two year period (2004 and 2008) in Zagreb, and comparison of resistance and the consumption of antibiotics. The standard disk-diffusion method was used for sensitivity testing to 16 different antibiotics. Data on antibiotic utilization were used to calculate the number of defined daily doses (DDD) and DDD per 1000 inhabitants using Anatomical-Therapeutic-Chemical/DDD methodology. Data on antibiotic consumption during pregnancy were collected using a questionnaire filled in by 893 women after delivery. During 2004 resistance of UPEC to antimicrobial drugs was not different in pregnant and in non-pregnant women, with the exception of amoxicillin and nitrofurantoin, with statistically higher resistance in pregnant women (p < 0.01). Four years later the statistically higher resistance to norfloxacin was observed in non-pregnant women (p < 0.01). Comparing the resistance in 2004 and 2008, in the both groups of women a statistically significant decrease of resistance to cefalexin and nitrofurantoin was detected (p < 0.01). Outpatient utilization of antimicrobial drugs in Zagreb increased significantly, from 32 to 39 DDD/1000 inhabitants per day. The most used antibiotic was co-amoxiclav, and its utilization increased from 9.6 to 12.2 DDD/1000/day. Amoxicillin and co-amoxiclav were used during pregnancy by 9.6% interviewed women. The observed significant decrease of resistance to cefalexin makes that antibiotic the drug of choice for treatment of urinary tract infections in women in generative ages, and together with coamoxiclav can be administered in pregnancy. Constant monitoring of urinary tract pathogens resistance to antimicrobial agents ensures the effectiveness of empirical therapy, whose versatile use is limited due the potentially harmful effects of antimicrobial drugs on fetus.

Forecasting carbapenem resistance from antimicrobial consumption surveillance: Lessons learnt from an OXA-48-producing Klebsiella pneumoniae outbreak in a West London renal unit.

PubMed

Gharbi, M; Moore, L S P; Gilchrist, M; Thomas, C P; Bamford, K; Brannigan, E T; Holmes, A H

2015-08-01

This study aimed to forecast the incidence rate of carbapenem resistance and to assess the impact of an antimicrobial stewardship intervention using routine antimicrobial consumption surveillance data. Following an outbreak of OXA-48-producing Klebsiella pneumoniae (January 2008-April 2010) in a renal cohort in London, a forecasting ARIMA model was derived using meropenem consumption data [defined daily dose per 100 occupied bed-days (DDD/100OBD)] from 2005-2014 as a predictor of the incidence rate of OXA-48-producing organisms (number of new cases/year/100,000OBD). Interrupted times series assessed the impact of meropenem consumption restriction as part of the outbreak control. Meropenem consumption at lag -1 year (the preceding year), highly correlated with the incidence of OXA-48-producing organisms (r=0.71; P=0.005), was included as a predictor within the forecasting model. The number of cases/100,000OBD for 2014-2015 was estimated to be 4.96 (95% CI 2.53-7.39). Analysis of meropenem consumption pre- and post-intervention demonstrated an increase of 7.12 DDD/100OBD/year (95% CI 2.97-11.27; P<0.001) in the 4 years preceding the intervention, but a decrease thereafter. The change in slope was -9.11 DDD/100OBD/year (95% CI -13.82 to -4.39). Analysis of alternative antimicrobials showed a significant increase in amikacin consumption post-intervention from 0.54 to 3.41 DDD/100OBD/year (slope +0.72, 95% CI 0.29-1.15; P=0.01). Total antimicrobials significantly decreased from 176.21 to 126.24 DDD/100OBD/year (P=0.05). Surveillance of routinely collected antimicrobial consumption data may provide a key warning indicator to anticipate increased incidence of carbapenem-resistant organisms. Further validation using real-time data is needed. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.

Trends in antibiotic utilization in Vancouver associated with a community education program on antibiotic use.

PubMed

Fuertes, Elaine Isabelle; Henry, Bonnie; Marra, Fawziah; Wong, Hubert; Patrick, David M

2010-01-01

"Do Bugs Need Drugs" (DBND) is a community education program that was implemented in British Columbia (BC) in September 2005 to decrease inappropriate antibiotic use. This study conducted descriptive analyses of the association between DBND and changes in overall, pediatric, drug-specific, and indication-specific antibiotic utilization rates in Vancouver, BC. Utilization data on all oral solid and liquid antibiotics classified as "antibacterials for systemic use" were obtained from BC PharmaNet for the years 1996 to 2008. Utilization data were linked to physician billing data to allow indication-specific analyses. Following conversion to the defined daily dose (DDD), the Holt-Winters exponential smoothing method was used to project expected antibiotic use in the period after implementation based on use prior to implementation. Differences between expected and observed utilization rates were calculated. Overall antibiotic use has stabilized in recent years (16.2 DDD/1000 population/day in 2008). Fluoroquinolone use remains high (1.5 DDD/1000 population/day), as does the steadily increasing use of newer macrolides (1.1 to 2.7 DDD/1000 population/day between 1996 and 2008). Encouraging declines in overall and indication-specific prescription rates among children were observed. Following 3 years of DBND activities, antibiotic use was 5.8% lower than expected and the number of prescriptions dispensed to children was 10.6% lower than expected. This ecological study reports improvements in antibiotic use that occurred simultaneously to the delivery of the DBND program in Vancouver. However, we did not find a lowering of all targeted classes. Policy directives limiting the use of certain antibiotics may be required.

Seasonal Variation in Penicillin Use in Mexico and Brazil: Analysis of the Impact of Over-the-Counter Restrictions

PubMed Central

Santa-Ana-Tellez, Yared; Mantel-Teeuwisse, Aukje K.; Leufkens, Hubert G. M.

2014-01-01

During 2010, Mexico and Brazil implemented policies to enforce existing laws of restricting over-the-counter sales of antibiotics. We determined if the enforcement led to more appropriate antibiotic use by measuring changes in seasonal variation of penicillin use. We used retail quarterly sales data in defined daily doses per 1,000 inhabitant-days (DDD/TID) from IMS Health from the private sector in Mexico and Brazil from the first quarter of 2007 to the first quarter of 2013. This database contains information on volume of antibiotics sold in retail pharmacies using information from wholesalers. We used interrupted time-series models controlling for external factors with the use of antihypertensives with interaction terms to assess changes in trend, level, and variation in use between quarters for total penicillin use and by active substance. The most used penicillin was amoxicillin, followed by amoxicillin-clavulanic acid and ampicillin (minimal use in Brazil). Before the restrictions, the seasonal variation in penicillin use was 1.1 DDD/TID in Mexico and 0.8 DDD/TID in Brazil. In Mexico, we estimated a significant decrease in the seasonal variation of 0.4 DDD/TID after the restriction, mainly due to changes in seasonal variation of amoxicillin and ampicillin. In Brazil, the seasonal variation did not change significantly, overall and in the breakdown by individual active substances. For Mexico, inappropriate penicillin use may have diminished after the restrictions were enforced. For Brazil, increasing use and no change in seasonal variation suggest that further efforts are needed to reduce inappropriate penicillin use. PMID:25313222

Parallel Performance of Linear Solvers and Preconditioners

DTIC Science & Technology

2014-01-01

are produced by a discrete dislocation dynamics ( DDD ) simulation and change with each timestep of the DDD simulation as the dislocation structure...evolves. However, the coefficient—or stiffness matrix— remains constant during the DDD simulation and some expensive matrix factorizations only occur once...discrete dislocation dynamics ( DDD ) simulations. This can be achieved by coupling a DDD simulator for bulk material (Arsenlis et al., 2007) to a

A 5-year follow-up study of users of benzodiazepine: starting with diazepam versus oxazepam.

PubMed

Tvete, Ingunn Fride; Bjørner, Trine; Skomedal, Tor

2016-04-01

Drug dependency may develop during long-term benzodiazepine use, indicated, for example, by dose escalation. The first benzodiazepine chosen may affect the risk of dose escalation. To detect possible differences in benzodiazepine use between new users of diazepam and oxazepam over time. This 5-year prescription database study included 19 747 new benzodiazepine users, inhabitants of Norway, aged 30-60 years, with first redemption for diazepam or oxazepam. Individuals starting on diazepam versus oxazepam were analysed by logistic regression with sex, age, other drug redemptions, prescriber's specialty, household income, education level, type of work, and vocational rehabilitation support as background variables. Time to reach a daily average intake of ≥1 defined daily doses (DDD) over a 3-month period was analysed using a Cox proportional hazard regression model. New users of oxazepam had a higher risk for dose escalation compared with new users of diazepam. This was true even when accounting for differences in sociodemographic status and previous drug use (hazard ratio [HR] 1.33, 95% confidence interval = 1.17 to 1.51). Most doctors prescribed, according to recommendations, oxazepam to individuals they may have regarded as prone to and at risk of dependency. However, these individuals were at higher risk for dose escalation even when accounting for differences in sociodemographic status and previous drug use. Differences between the two user groups could be explained by different preferences for starting drug, DDD for oxazepam being possibly too low, and some unaccounted differences in illness. © British Journal of General Practice 2016.

Genetic background (DDD/Sgn versus C57BL/6J) strongly influences postnatal growth of male mice carrying the A(y) allele at the agouti locus: identification of quantitative trait loci associated with diabetes and body weight loss.

PubMed

Suto, Jun-ichi; Satou, Kunio

2013-05-04

Mice carrying the A(y) allele at the agouti locus become obese and are heavier than their non-A(y) littermates. However, this does not hold true for the genetic background of the DDD mouse strain. At 22 weeks of age, DDD.Cg-A(y) females are heavier than DDD females, whereas DDD.Cg-A(y) males are lighter than DDD males. This study aimed to determine the possible cause and identify the genes responsible for the lower body weight of DDD.Cg-A(y) males. Growth curves of DDD.Cg-A(y) mice were analyzed and compared with those of B6.Cg-A(y) mice from 5 to 25 weeks. In DDD.Cg-A(y) males, body weight gain stopped between 16 and 17 weeks and the body weight gradually decreased; thus, the lower body weight was a consequence of body weight loss. Quantitative trait locus (QTL) mapping was performed in backcrossed (BC) males of DDD × (B6 × DDD.Cg-A(y)) F(1)-A(y) mice. For the body weight at 25 weeks, significant QTLs were identified on chromosomes 1 and 4. The DDD allele was associated with a lower body weight at both loci. In particular, the QTL on chromosome 4 interacted with the A(y) allele. Furthermore, suggestive QTLs for plasma glucose and high molecular weight adiponectin levels were coincidentally mapped to chromosome 4. The DDD allele was associated with increased glucose and decreased adiponectin levels. When the body weight at 25 weeks and plasma glucose levels were considered as dependent and independent variables, respectively, BC A(y) males were classified into two groups according to statistical analysis using the partition method. Mice of one group had significantly higher glucose and lower adiponectin levels than those of the other group and exhibited body weight loss as observed with DDD-A(y) males. The lower body weight of DDD.Cg-A(y) male mice was a consequence of body weight loss. Diabetes mellitus has been suggested to be a possible contributory factor causing body weight loss. The QTL on distal chromosome 4 contained the major responsible genes. This QTL interacted with the Ay allele, implying the reason why body weight loss occurs in DDD.Cg-Ay but not in DDD males.

The organochlorine o,p'-DDD disrupts the adrenal steroidogenic signaling pathway in rainbow trout (Oncorhynchus mykiss).

PubMed

Lacroix, Martin; Hontela, Alice

2003-08-01

The mechanisms of action of o,p'-DDD on adrenal steroidogenesis were investigated in vitro in rainbow trout (Oncorhynchus mykiss). Acute exposures to o,p'-DDD inhibited ACTH-stimulated cortisol secretion while cell viability decreased significantly only at the highest concentration tested (200 microM o,p'-DDD). Stimulation of cortisol secretion with a cAMP analogue (dibutyryl-cAMP) was inhibited at a higher concentration than that needed to inhibit ACTH-stimulated cortisol synthesis in cells exposed to o,p'-DDD. Forskolin-stimulated cortisol secretion and cAMP production, and NaF-stimulated cAMP production were inhibited in a concentration-dependent manner by o,p'-DDD. In contrast, basal cortisol secretion was stimulated while basal cAMP production was unaffected by o,p'-DDD. Pregnenolone-stimulated cortisol secretion was enhanced by o,p'-DDD at a physiologically relevant pregnenolone concentration, while o,p'-DDD inhibited cortisol secretion when a pharmacological concentration of pregnenolone was used. Our results suggest that the cAMP generation step is a target in o,p'-DDD-mediated disruption of ACTH-stimulated adrenal steroidogenesis in rainbow trout but that other downstream targets such as steroidogenic enzymes responsible for cortisol synthesis might also be affected.

Usage patterns of 'over-the-counter' vs. prescription-strength nonsteroidal anti-inflammatory drugs in France.

PubMed

Duong, Mai; Salvo, Francesco; Pariente, Antoine; Abouelfath, Abdelilah; Lassalle, Regis; Droz, Cecile; Blin, Patrick; Moore, Nicholas

2014-05-01

Most risks of nonsteroidal anti-inflammatory drugs (NSAIDs) are pharmacological, dose and duration dependent. Usage patterns of prescription-only (POM) or 'over-the-counter (OTC)' NSAIDs may influence risks, but are not commonly described. The Echantillon Généraliste de Bénéficiaires database, the permanent 1/97 representative sample from the French national healthcare insurance systems, was queried over 2009-2010 to identify usage patterns, concomitant chronic diseases and cardiovascular medication in OTC and POM NSAID users. Over 2 years, 229 477 of 526 108 patients had at least one NSAID dispensation; 44 484 patients (19%) were dispensed only OTC NSAIDs (93% ibuprofen) and 121 208 (53%) only POM NSAIDs. The OTC users were younger (39.9 vs. 47.4 years old) and more often female (57 vs. 53%); 69% of OTC users and 49% of POM users had only one dispensation. A mean of 14.6 defined daily doses (DDD) were dispensed over 2 years for OTC vs. 53 for POM; 93% OTC vs. 60% POM patients bought ≤ 30 DDD over 2 years, and 1.5 vs. 12% bought ≥ 90 DDD. Chronic comorbidities were found in 19% of OTC users vs. 28% of POM users; 24 vs. 37% had at least one dispensation of a cardiovascular drug over the 2 years. Most of the use of NSAIDs appears to be short term, especially for OTC-type NSAIDs, such as ibuprofen. The validity of risk estimates for NSAIDs extrapolated from clinical trials or from observational studies not including OTC-type usage may need to be revised. © 2013 The British Pharmacological Society.

Genetic background (DDD/Sgn versus C57BL/6J) strongly influences postnatal growth of male mice carrying the Ay allele at the agouti locus: identification of quantitative trait loci associated with diabetes and body weight loss

PubMed Central

2013-01-01

Background Mice carrying the Ay allele at the agouti locus become obese and are heavier than their non-Ay littermates. However, this does not hold true for the genetic background of the DDD mouse strain. At 22 weeks of age, DDD.Cg-Ay females are heavier than DDD females, whereas DDD.Cg-Ay males are lighter than DDD males. This study aimed to determine the possible cause and identify the genes responsible for the lower body weight of DDD.Cg-Ay males. Results Growth curves of DDD.Cg-Ay mice were analyzed and compared with those of B6.Cg-Ay mice from 5 to 25 weeks. In DDD.Cg-Ay males, body weight gain stopped between 16 and 17 weeks and the body weight gradually decreased; thus, the lower body weight was a consequence of body weight loss. Quantitative trait locus (QTL) mapping was performed in backcrossed (BC) males of DDD × (B6 × DDD.Cg-Ay) F1-Ay mice. For the body weight at 25 weeks, significant QTLs were identified on chromosomes 1 and 4. The DDD allele was associated with a lower body weight at both loci. In particular, the QTL on chromosome 4 interacted with the Ay allele. Furthermore, suggestive QTLs for plasma glucose and high molecular weight adiponectin levels were coincidentally mapped to chromosome 4. The DDD allele was associated with increased glucose and decreased adiponectin levels. When the body weight at 25 weeks and plasma glucose levels were considered as dependent and independent variables, respectively, BC Ay males were classified into two groups according to statistical analysis using the partition method. Mice of one group had significantly higher glucose and lower adiponectin levels than those of the other group and exhibited body weight loss as observed with DDD-Ay males. Conclusions The lower body weight of DDD.Cg-Ay male mice was a consequence of body weight loss. Diabetes mellitus has been suggested to be a possible contributory factor causing body weight loss. The QTL on distal chromosome 4 contained the major responsible genes. This QTL interacted with the Ay allele, implying the reason why body weight loss occurs in DDD.Cg-Ay but not in DDD males. PMID:23641944

Implementation and impact of an audit and feedback antimicrobial stewardship intervention in the orthopaedics department of a tertiary-care hospital: a controlled interrupted time series study.

PubMed

Tavares, Margarida; Carvalho, Ana Cláudia; Almeida, José Pedro; Andrade, Paulo; São-Simão, Ricardo; Soares, Pedro; Alves, Carlos; Pinto, Rui; Fontanet, Arnaud; Watier, Laurence

2018-06-01

A prospective audit and feedback antimicrobial stewardship intervention conducted in the Orthopaedics Department of a university hospital in Portugal was evaluated by comparing an interrupted time series in the intervention group with a non-intervention (control) group. Monthly antibiotic use (except cefazolin) was measured as the World Health Organization's Anatomical Therapeutic Chemical defined daily doses (ATC-DDD) from January 2012 to September 2016, excluding the 6-month phase of intervention implementation starting on 1 January 2015. Compared with the control group, the intervention group had a monthly decrease in the use of fluoroquinolones by 2.3 DDD/1000 patient-days [95% confidence interval (CI) -3.97 to -0.63]. An increase in the use of penicillins by 103.3 DDD/1000 patient-days (95% CI 47.42 to 159.10) was associated with intervention implementation, followed by a decrease during the intervention period (slope = -5.2, 95% CI -8.56 to -1.82). In the challenging scenario of treatment of osteoarticular and prosthetic joint infections, an audit and feedback intervention reduced antibiotic exposure and spectrum. Copyright © 2018 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

Improving signal to noise in labeled biological specimens using energy-filtered TEM of sections with a drift correction strategy and a direct detection device.

PubMed

Ramachandra, Ranjan; Bouwer, James C; Mackey, Mason R; Bushong, Eric; Peltier, Steven T; Xuong, Nguyen-Huu; Ellisman, Mark H

2014-06-01

Energy filtered transmission electron microscopy techniques are regularly used to build elemental maps of spatially distributed nanoparticles in materials and biological specimens. When working with thick biological sections, electron energy loss spectroscopy techniques involving core-loss electrons often require exposures exceeding several minutes to provide sufficient signal to noise. Image quality with these long exposures is often compromised by specimen drift, which results in blurring and reduced resolution. To mitigate drift artifacts, a series of short exposure images can be acquired, aligned, and merged to form a single image. For samples where the target elements have extremely low signal yields, the use of charge coupled device (CCD)-based detectors for this purpose can be problematic. At short acquisition times, the images produced by CCDs can be noisy and may contain fixed pattern artifacts that impact subsequent correlative alignment. Here we report on the use of direct electron detection devices (DDD's) to increase the signal to noise as compared with CCD's. A 3× improvement in signal is reported with a DDD versus a comparably formatted CCD, with equivalent dose on each detector. With the fast rolling-readout design of the DDD, the duty cycle provides a major benefit, as there is no dead time between successive frames.

Comparing antibiotic consumption between two European countries: are packages an adequate surrogate for prescriptions?

PubMed

Watier, Laurence; Cavalié, Philippe; Coignard, Bruno; Brun-Buisson, Christian

2017-11-01

Defined daily doses (DDD) are the gold standard indicator for quantifying prescriptions. Since 2014, the European Centre for Disease Prevention and Control (ECDC) has also been using the number of packages per 1,000 inhabitants per day (ipd), as a surrogate for prescriptions, to report antibiotic consumption in the community and to perform comparisons between European Union (EU) countries participating in the European Surveillance of Antimicrobial Consumption Network (ESAC-Net). In 2015, consumption was reported to range across Europe from 1.0 to 4.7 packages per 1,000 ipd. Our analysis showed that consumption of antibiotics for systemic use per 1,000 ipd was on average 1.3 times greater in France than in Belgium when considering prescriptions in the numerator, 2.5 times greater when considering packages and 1.2 times greater when considering DDD. As long as the same metrics are used over time, antibiotic consumption data aggregated and disseminated by ECDC are useful for assessing temporal trends at the European level and within individual countries; these data may also be used for benchmarking across EU countries. While DDD - although imperfect - are the most widely accepted metric for this purpose, antibiotic packages do not appear suitable for comparisons between countries and may be misleading.

Comparing antibiotic consumption between two European countries: are packages an adequate surrogate for prescriptions?

PubMed Central

Watier, Laurence; Cavalié, Philippe; Coignard, Bruno; Brun-Buisson, Christian

2017-01-01

Defined daily doses (DDD) are the gold standard indicator for quantifying prescriptions. Since 2014, the European Centre for Disease Prevention and Control (ECDC) has also been using the number of packages per 1,000 inhabitants per day (ipd), as a surrogate for prescriptions, to report antibiotic consumption in the community and to perform comparisons between European Union (EU) countries participating in the European Surveillance of Antimicrobial Consumption Network (ESAC-Net). In 2015, consumption was reported to range across Europe from 1.0 to 4.7 packages per 1,000 ipd. Our analysis showed that consumption of antibiotics for systemic use per 1,000 ipd was on average 1.3 times greater in France than in Belgium when considering prescriptions in the numerator, 2.5 times greater when considering packages and 1.2 times greater when considering DDD. As long as the same metrics are used over time, antibiotic consumption data aggregated and disseminated by ECDC are useful for assessing temporal trends at the European level and within individual countries; these data may also be used for benchmarking across EU countries. While DDD - although imperfect - are the most widely accepted metric for this purpose, antibiotic packages do not appear suitable for comparisons between countries and may be misleading. PMID:29162212

Comparative effect of antipsychotics on risk of self-harm among patients with schizophrenia.

PubMed

Ma, C-H; Chang, S-S; Tsai, H-J; Gau, S S-F; Chen, I-M; Liao, S-C; Chien, Y-L; Hsieh, M H; Wu, C-S

2018-04-01

To investigate the association of different antipsychotic treatments with hospitalization due to self-harm among patients with schizophrenia. This retrospective cohort study was based on Taiwan's universal health insurance database. Patients aged 15-45 years with a newly diagnosed schizophrenic disorder in 2001-2012 were included. The study outcome was the first hospitalization due to self-harm or undetermined injury after the diagnosis of schizophrenic disorders. The exposure status of antipsychotics was modeled as a time-dependent variable. The analyses were stratified by antipsychotic dosage based on defined daily dose (DDD). Among 70 380 patients with a follow-up of 500 355 person-years, 2272 self-harm hospitalization episodes were identified. Compared with none or former use, current use of several second-generation antipsychotics with a dose of one DDD or above, including amisulpride, aripiprazole, clozapine, risperidone, and sulpiride, was associated with decreased risk of self-harm hospitalization, with clozapine showing the strongest effect (adjusted rate ratio = 0.26, 95% confidence interval 0.15-0.47). The protective effect on self-harm may vary across different antipsychotics. Further studies are needed to replicate the findings. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Molecularly Defined Nanostructures Based on a Novel AAA-DDD Triple Hydrogen-Bonding Motif.

PubMed

Papmeyer, Marcus; Vuilleumier, Clément A; Pavan, Giovanni M; Zhurov, Konstantin O; Severin, Kay

2016-01-26

A facile and flexible method for the synthesis of a new AAA-DDD triple hydrogen-bonding motif is described. Polytopic supramolecular building blocks with precisely oriented AAA and DDD groups are thus accessible in few steps. These building blocks were used for the assembly of large macrocycles featuring four AAA-DDD interactions and a macrobicyclic complex with a total of six AAA-DDD interactions. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Antimicrobial usage in ambulatory patients with respiratory infections in Taiwan, 2001.

PubMed

Ho, Monto; Hsiung, Chao Agnes; Yu, Hui-Tzu; Chi, Cheng-Liang; Yin, Hsiao-Chuan; Chang, Hong-Jen

2004-02-01

Excess use of antimicrobials by ambulatory patients is a determinant of antimicrobial resistance. This study investigated the types of illnesses for which antimicrobials were prescribed and the amounts prescribed with special emphasis on respiratory infections for the year in which the Bureau of National Health Insurance (BNHI) enforced a policy to restrict antimicrobials for upper respiratory infections. The number of ambulatory patients seen and the types of ambulatory facilities in Taiwan were also described. Raw data were obtained from the BNHI database on every 500 th visit in 2001. Medical diagnoses were categorized according to the ICD-9-CM system. Antimicrobial consumption was expressed in defined daily doses per 1000 population per day (DDD/1000/day). Among the population of 22.3 million in Taiwan, there were 285.8 million ambulatory patient visits (12.8 per person), including 108.9 million visits (4.9 per person) for respiratory infections, of which 62.7 million (2.8 per person) were for upper respiratory infections (URI). Antimicrobial consumption was 19.83 DDD/1000/day [standard error (SE), 0.00055], of which 9.97 DDD/1000/day (SE, 0.00047) were for respiratory infections and 4.03 DDD/1000/day (0.00055) were for URI. 23.6% of visits for URI entailed a prescription for antimicrobials. About two-thirds (66.5%) of ambulatory patients were seen in clinics, mostly private ones, and 67.6% of all antimicrobials were received there. Aminopenicillins and cephalosporins constituted 35.2% and 19.5%, respectively, of antimicrobials prescribed. Despite the new BNHI rule restricting antimicrobial usage for URI, Taiwan still has an excessive number of ambulatory patient visits, especially for respiratory infections and URI. The majority of antimicrobials used were for URI. They were mostly prescribed in private clinics rather than hospital outpatient departments.

Reducing Prescriptions of Long-Acting Benzodiazepine Drugs in Denmark: A Descriptive Analysis of Nationwide Prescriptions during a 10-Year Period.

PubMed

Eriksen, Sophie Isabel; Bjerrum, Lars

2015-06-01

Prolonged consumption of benzodiazepine drugs (BZD) and benzodiazepine receptor agonists (zolpidem, zaleplon, zopiclone; altogether Z drugs) is related to potential physiological and psychological dependence along with other adverse effects. This study aimed to analyse the prescribing of long-acting BZD (half-life >10 hr), compared to short-acting BZD in Denmark during a 10-year period. Descriptive analysis of total sales data from the Danish Register of Medicinal Product Statistics, to individuals in the primary healthcare sector, of all BZD and Z drugs in the period of 2003-2013. Prescription data derive from all community and hospital pharmacies in Denmark. The prescribing of long-acting BZD was reduced from 25.8 defined daily doses (DDD)/1000 inhabitants/day in 2003 to 8.8 DDD/1000 inhabitants/day in 2013, a relative reduction of 66%. The prescribing of short-acting BZD was reduced from 26.1 DDD/1000 inhabitants/day in 2003 to 16.4 DDD/1000 inhabitants/day in 2013, a relative reduction of 37%. Prescription data in this study did not include information about indications for initiating treatments. In addition, due to compliance problems, some of the prescribed drugs may not have been consumed according to the prescription. The observed reduction in BZD use was correlated to the introduction of new national guidelines on prescription of addictive drugs, but this study was not designed to detect a causal relationship. The prescribing of long-acting BZD decreased considerably more than the prescribing of short-acting BZD in the 10-year period. © 2014 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

Seasonal variation in penicillin use in Mexico and Brazil: analysis of the impact of over-the-counter restrictions.

PubMed

Santa-Ana-Tellez, Yared; Mantel-Teeuwisse, Aukje K; Leufkens, Hubert G M; Wirtz, Veronika J

2015-01-01

During 2010, Mexico and Brazil implemented policies to enforce existing laws of restricting over-the-counter sales of antibiotics. We determined if the enforcement led to more appropriate antibiotic use by measuring changes in seasonal variation of penicillin use. We used retail quarterly sales data in defined daily doses per 1,000 inhabitant-days (DDD/TID) from IMS Health from the private sector in Mexico and Brazil from the first quarter of 2007 to the first quarter of 2013. This database contains information on volume of antibiotics sold in retail pharmacies using information from wholesalers. We used interrupted time-series models controlling for external factors with the use of antihypertensives with interaction terms to assess changes in trend, level, and variation in use between quarters for total penicillin use and by active substance. The most used penicillin was amoxicillin, followed by amoxicillin-clavulanic acid and ampicillin (minimal use in Brazil). Before the restrictions, the seasonal variation in penicillin use was 1.1 DDD/TID in Mexico and 0.8 DDD/TID in Brazil. In Mexico, we estimated a significant decrease in the seasonal variation of 0.4 DDD/TID after the restriction, mainly due to changes in seasonal variation of amoxicillin and ampicillin. In Brazil, the seasonal variation did not change significantly, overall and in the breakdown by individual active substances. For Mexico, inappropriate penicillin use may have diminished after the restrictions were enforced. For Brazil, increasing use and no change in seasonal variation suggest that further efforts are needed to reduce inappropriate penicillin use. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Effects of closed-loop stimulation vs. DDD pacing on haemodynamic variations and occurrence of syncope induced by head-up tilt test in older patients with refractory cardioinhibitory vasovagal syncope: the Tilt test-Induced REsponse in Closed-loop Stimulation multicentre, prospective, single blind, randomized study.

PubMed

Palmisano, Pietro; Dell'Era, Gabriele; Russo, Vincenzo; Zaccaria, Maria; Mangia, Rolando; Bortnik, Miriam; De Vecchi, Federica; Giubertoni, Ailia; Patti, Fabiana; Magnani, Andrea; Nigro, Gerardo; Rago, Anna; Occhetta, Eraldo; Accogli, Michele

2018-05-01

Closed-loop stimulation (CLS) seemed promising in preventing the recurrence of vasovagal syncope (VVS) in patients with a cardioinhibitory response to head-up tilt test (HUTT) compared with conventional pacing. We hypothesized that the better results of this algorithm are due to its quick reaction in high-rate pacing delivered in the early phase of vasovagal reflex, which increase the cardiac output and the blood pressure preventing loss of consciousness. This prospective, randomized, single-blind, multicentre study was designed as an intra-patient comparison and enrolled 30 patients (age 62.2 ± 13.5 years, males 60.0%) with cardioinhibitory VVS, carrying a dual-chamber pacemaker incorporating CLS algorithm. Two HUTTs were performed one week apart: one during DDD-CLS 60-130/min pacing and the other during DDD 60/min pacing; patients were randomly and blindly assigned to two groups: in one the first HUTT was performed in DDD-CLS (n = 15), in the other in DDD (n = 15). Occurrence of syncope and haemodynamic variations induced by HUTT was recorded during the tests. Compared with DDD, DDD-CLS significantly reduced the occurrence of syncope induced by HUTT (30.0% vs. 76.7%; P < 0.001). In the patients who had syncope in both DDD and DDD-CLS mode, DDD-CLS significantly delayed the onset of syncope during HUTT (from 20.8 ± 3.9 to 24.8 ± 0.9 min; P = 0.032). The maximum fall in systolic blood pressure recorded during HUTT was significantly lower in DDD-CLS compared with DDD (43.2 ± 30.3 vs. 65.1 ± 25.8 mmHg; P = 0.004). In patients with cardioinhibitory VVS, CLS reduces the occurrence of syncope induced by HUTT, compared with DDD pacing. When CLS is not able to abort the vasovagal reflex, it seems to delay the onset of syncope.

Pharmacoepidemiological Data from Drug Dispensing Charities as a Measure of Health Patterns in a Population not Assisted by the Italian National Health Service.

PubMed

Bini, Silvia; Cerri, Cesare; Rigamonti, Antonello E; Bertazzi, Pietro A; Fiorini, Gianfrancesco; Cella, Silvano G

2016-08-19

We analysed drug dispensation by charitable organisations in a year time. Drugs were grouped according to the Anatomic Therapeutic Chemical classification and the amount dispensed was calculated with the system of the Daily Defined Dose (DDD) and expressed as DDD/1000 subjects/day. A number of 87,550 subjects were studied (13,308 Italians; 74,242 Immigrants). Though we noticed a great sesonal variability, the drugs most frequently dispensed were those for the respiratory, cardiovascular and gastrointestinal system and antibiotics, which is different from the rest of the Italian population and the immigrant population assisted by our National Health Service (NHS). We also found that chronic diseases are increasing in these subjects. We conclude that the subjects not receiving NHS assitance have, at least in part, different health patterns and requirements. This should be considered when planning tailored interventions.

The effect of dose and type of proton pump inhibitor use on risk of fractures and osteoporosis treatment in older Australian women: A prospective cohort study.

PubMed

van der Hoorn, Mariëlle M C; Tett, Susan E; de Vries, Oscar J; Dobson, Annette J; Peeters, G M E E Geeske

2015-12-01

Proton pump inhibitors (PPIs) are among the most prescribed medications worldwide, however, there is growing concern regarding potential negative effects on bone health. The aim was to examine the effect of dose and type of PPI use on subsequent use of osteoporosis medication and fractures in older Australian women. Data were included from 4432 participants (born 1921-26) in the 2002 survey of the Australian Longitudinal Study on Women's Health. Medication data were from the national pharmaceutical administrative database (2003-2012, inclusive). Fractures were sourced from linked hospital datasets available for four major States of Australia. Competing risk regression models used PPI exposure as a time-dependent covariate and either time to first osteoporosis medication prescription or fracture as the outcome, with death as a competing risk. Of the 2328 PPI users and 2104 PPI non-users, 827 (36%) and 550 (26%) became users of osteoporosis medication, respectively. PPI use was associated with an increased risk of subsequent use of osteoporosis medication (adjusted sub-hazard ratio [SHR]=1.28; 95% confidence interval [CI]=1.13-1.44) and subsequent fracture (SHR=1.29, CI=1.08-1.55). Analysis with PPI categorized according to defined daily dose (DDD), showed some evidence for a dose-response effect (osteoporosis medication: <400 DDD: SHR=1.23, CI=1.06-1.42 and ≥400 DDD: SHR=1.39, CI=1.17-1.65, compared with non-users; SHRs were in the same range for fractures). Esomeprazole was the most common PPI prescribed (22.9%). Analysis by type of PPI use showed an increased subsequent risk for: (1) use of osteoporosis medication for rabeprazole (SHR=1.51, CI=1.08-2.10) and esomeprazole (SHR=1.48, CI=1.17-1.88); and (2) fractures for rabeprazole (SHR=2.06, CI=1.37-3.10). Users of multiple types of PPI also had increased risks for use of osteoporosis medication and fractures. An appropriate benefit/risk assessment should be made when prescribing PPIs, especially for esomeprazole and rabeprazole, as osteoporosis and fracture risks were increased in this cohort of elderly females subsequent to PPI prescription. Copyright © 2015 Elsevier Inc. All rights reserved.

Celecoxib and sulfasalazine had negative association with coronary artery diseases in patients with ankylosing spondylitis

PubMed Central

Wu, Li-Chih; Leong, Pui-Ying; Yeo, Kai-Jieh; Li, Ting-Yu; Wang, Yu-Hsun; Chiou, Jeng-Yuan; Wei, James Cheng-Chung

2016-01-01

Abstract The aim of the study is to assess the effects of celecoxib and sulfasalazine on the risk of coronary artery disease (CAD) in patients with ankylosing spondylitis (AS). Using the claims data of Taiwan National Health Insurance (NHI) database, a nationally representative data that contain the medical records of 23 million Taiwan residents, we randomly selected 1 million cohort from the database, and then we enrolled only patients who were newly diagnosed with AS (n = 4829) between year 2001 and 2010, excluding patients who had CAD (ICD-9- CM codes: 410–414) before the diagnosis of AS (n = 4112). According to propensity score matched 1:2 on age, gender, AS duration, Charlson comorbidity index, hypertension, and hyperlipidemia, 236 and 472 patients were included in the case (AS with CAD) and control (AS without CAD) groups, respectively. We used the WHO defined daily dose (DDD) as a tool to assess the dosage of sulfasalazine and celecoxib exposure. Conditional logistic regression was used to estimate the crude and adjusted odds ratios (ORs) and 95% confidence interval (CI) for the risk of CAD associated with use of sulfasalazine and celecoxib. Among 4112 AS patients, 8.4% (346/4112) developed CAD. CAD in AS patients were positively associated with age of 35 to 65, Charlson comorbidities index (CCI), hypertension, and hyperlipidemia. There was no gender difference between case and control groups. After adjustment for age, gender, CCI, hypertension, and hyperlipidemia, sulfasalazine users with an average daily dose ≥ 0.5 DDD (0.5 gm/day) had negative association with CAD events as compared to sulfasalazine nonusers (OR 0.63; 95% CI, 0.40–0.99, P < 0.05). NSAIDs, including celecoxib, etoricoxib, but no naproxen and diclofenac were negatively associated with CAD. Celecoxib users, with an average daily dose > 1.5 DDD, were negatively associated with CAD events, compared to celecoxib nonusers (OR 0.34; 95% CI, 0.13–0.89; P < 0.05). In this 10-year population-based case-control study, 8.4% of AS patients developed CAD. Sulfasalazine usage at an average dose of ≥ 0.5 gm/day demonstrated negative association with CAD events in patients with AS. PMID:27603385

[Pharmacoeconomic indicators of cardiovascular drug utilization in the Republic of Croatia and city of Zagreb in 2008].

PubMed

Stimac, Danijela; Stambuk, Ivanka

2010-12-01

In comparison with original drugs, generic drugs have the same efficacy but considerably lower price and should therefore be preferred to original drugs on prescribing. The aim of the present study was to assess outpatient utilization and rationality of cardiovascular drug prescribing in the City of Zagreb and Republic of Croatia based on the generic to original drug prescribing ratio. Data on the financial indicators and number of cardiovascular drug packages issued in 2008 were obtained from the Croatian Institute of Health Insurance. These data were used to calculate the number of defined daily doses (DDD) and number of DDD per 1000 inhabitants per day (DDD/1000/day). The index of generic/original drug utilization was determined for Zagreb and Croatia as a measure for assessment of prescribing rationality; the significance of difference was determined by X2-test. The rate of prescribing original cardiovascular drugs was significantly higher in Zagreb as compared with Croatia as a whole. The index of prescribing generic versus original drugs was 1.20 (249/208 DDD/1000/day) in Zagreb and 1.65 (249/151 DDD/1000/day) in Croatia. Difference in the utilization of generic drugs between Zagreb and Croatia as determined by X2-test (the level of statistical significance was set at P<0.05) was statistically significant (P=0.021). The highest differences were recorded in the most widely prescribed drug groups, i.e. ACE inhibitors with the generic/original drug index of 1.38 in Zagreb and 2.02 in Croatia; and hypolipemics with the generic/original drug index of 0.96 in Zagreb and 1.34 in Croatia. According to financial indicators, the generic/original drug index was 1.44 in Croatia and only 0.96 in Zagreb. The significantly greater influence of pharmaceutical industry marketing in Zagreb entailed the significantly higher rate of original drug prescribing, which is associated with considerably greater drug expenses. Measures to stimulate prescribing generic drugs should be launched at the national level.

Effects of over-the-counter sales restriction of antibiotics on substitution with medicines for symptoms relief of cold in Mexico and Brazil: time series analysis.

PubMed

Santa-Ana-Tellez, Yared; Mantel-Teeuwisse, Aukje K; Leufkens, Hubert G M; Wirtz, Veronika J

2016-11-01

We evaluated changes in the use of non-steroidal anti-inflammatory drugs (NSAIDs), non-opioid analgesics and cough and cold medicines and its relation with the use of antibiotics after the over-the-counter (OTC) antibiotic sales restrictions in Mexico and Brazil. IMS Health provided retail quarterly data from the private sectors in Mexico and Brazil from the first quarter of 2007 to the first quarter of 2013. Data of each active substance of antibiotics, easily accessible medicines perceived as antibiotics substitutes (cough and cold medicines, analgesics and NSAIDs-the latter two being combined in the analyses), and medicines to control for external factors that can affect the medicines usage trend (antihypertensives) were converted from kilograms to defined daily doses per 1000 inhabitants days (DDD/TID). Interrupted time series were used to estimate changes in level of medicines use at the intervention point and slope after the regulation. The Gregory-Hansen cointegration test was used to explore the relation between the use of antibiotics and perceived substitutes. After the regulation in Mexico NSAIDs-analgesics usage level increased by 1.1 DDD/TID with a slope increase of 0.2 DDD/TID per quarter and the cough and cold medicines usage level increased by 0.4 DDD/TID. In Brazil NSAIDs-analgesics usage level increased by 1.9 DDD/TID, and cough and cold medicines did not change. In the two countries, NSAIDs-analgesics usage changes were related with antibiotic usage changes; in Mexico cough and cold medicines usage changes had a relation with the antibiotics usage changes. These results showed a substitution effect on the use of other medicines, especially NSAIDs and analgesics, after reinforcement of OTC antibiotics sales restrictions. These regulations aimed to improve the antibiotics use and as a consequence reduce antimicrobial resistance; however, this type of policies should be comprehensive and take into account the potential substitution effects on the use of other medicines. © The Author 2016. Published by Oxford University Press in association with The London School of Hygiene and Tropical Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Vertebral degenerative disc disease severity evaluation using random forest classification

NASA Astrophysics Data System (ADS)

Munoz, Hector E.; Yao, Jianhua; Burns, Joseph E.; Pham, Yasuyuki; Stieger, James; Summers, Ronald M.

2014-03-01

Degenerative disc disease (DDD) develops in the spine as vertebral discs degenerate and osseous excrescences or outgrowths naturally form to restabilize unstable segments of the spine. These osseous excrescences, or osteophytes, may progress or stabilize in size as the spine reaches a new equilibrium point. We have previously created a CAD system that detects DDD. This paper presents a new system to determine the severity of DDD of individual vertebral levels. This will be useful to monitor the progress of developing DDD, as rapid growth may indicate that there is a greater stabilization problem that should be addressed. The existing DDD CAD system extracts the spine from CT images and segments the cortical shell of individual levels with a dual-surface model. The cortical shell is unwrapped, and is analyzed to detect the hyperdense regions of DDD. Three radiologists scored the severity of DDD of each disc space of 46 CT scans. Radiologists' scores and features generated from CAD detections were used to train a random forest classifier. The classifier then assessed the severity of DDD at each vertebral disc level. The agreement between the computer severity score and the average radiologist's score had a quadratic weighted Cohen's kappa of 0.64.

Allelic Variants of Complement Genes Associated with Dense Deposit Disease

PubMed Central

Abrera-Abeleda, Maria Asuncion; Nishimura, Carla; Frees, Kathy; Jones, Michael; Maga, Tara; Katz, Louis M.; Zhang, Yuzhou

2011-01-01

The alternative pathway of the complement cascade plays a role in the pathogenesis of dense deposit disease (DDD). Deficiency of complement factor H and mutations in CFH associate with the development of DDD, but it is unknown whether allelic variants in other complement genes also associate with this disease. We studied patients with DDD and identified previously unreported sequence alterations in several genes in addition to allelic variants and haplotypes common to patients with DDD. We found that the likelihood of developing DDD increases with the presence of two or more risk alleles in CFH and C3. To determine the functional consequence of this finding, we measured the activity of the alternative pathway in serum samples from phenotypically normal controls genotyped for variants in CFH and C3. Alternative pathway activity was higher in the presence of variants associated with DDD. Taken together, these data confirm that DDD is a complex genetic disease and may provide targets for the development of disease-specific therapies. PMID:21784901

An AAA-DDD triply hydrogen-bonded complex easily accessible for supramolecular polymers.

PubMed

Han, Yi-Fei; Chen, Wen-Qiang; Wang, Hong-Bo; Yuan, Ying-Xue; Wu, Na-Na; Song, Xiang-Zhi; Yang, Lan

2014-12-15

For a complementary hydrogen-bonded complex, when every hydrogen-bond acceptor is on one side and every hydrogen-bond donor is on the other, all secondary interactions are attractive and the complex is highly stable. AAA-DDD (A=acceptor, D=donor) is considered to be the most stable among triply hydrogen-bonded sequences. The easily synthesized and further derivatized AAA-DDD system is very desirable for hydrogen-bonded functional materials. In this case, AAA and DDD, starting from 4-methoxybenzaldehyde, were synthesized with the Hantzsch pyridine synthesis and Friedländer annulation reaction. The association constant determined by fluorescence titration in chloroform at room temperature is 2.09×10(7)  M(-1) . The AAA and DDD components are not coplanar, but form a V shape in the solid state. Supramolecular polymers based on AAA-DDD triply hydrogen bonded have also been developed. This work may make AAA-DDD triply hydrogen-bonded sequences easily accessible for stimuli-responsive materials. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Maritime Operations in Disconnected, Intermittent, and Low-Bandwidth Environments

DTIC Science & Technology

2013-06-01

of a Dynamic Distributed Database ( DDD ) is a core element enabling the distributed operation of networks and applications, as described in this...document. The DDD is a database containing all the relevant information required to reconfigure the applications, routing, and other network services...optimize application configuration. Figure 5 gives a snapshot of entries in the DDD . In current testing, the DDD is replicated using Domino

Long-term follow-up of DDD and VDD pacing: a prospective non-randomized single-centre comparison of patients with symptomatic atrioventricular block.

PubMed

Marchandise, Sébastien; Scavée, Christophe; le Polain de Waroux, Jean-Benoit; de Meester, Christophe; Vanoverschelde, Jean-Louis; Debbas, Nadia

2012-04-01

This prospective non-randomized single-centre registry compared clinical outcome, pacing parameters, and long-term survival in patients receiving VDD or DDD pacemaker (PMs) for symptomatic atrioventricular (AV) block. Single-lead VDD (n= 166) and DDD (n= 254) PMs were implanted in 420 successive patients with isolated AV block between January 2001 and December 2009. At the end of the follow-up period [median 25 (1-141) months], there was no difference in the incidence of atrial fibrillation [11.2% in the VDD group; 11.4% in the DDD group (P= 0.95)], myocardial infarction [31.1% in the VDD group; 25.2% in the DDD group (P= 0.20)], or dilated cardiomyopathy [9.9% in the VDD group; 8.9% in the DDD group (P= 0.74)]. At last follow-up, 65.9% of the VDD PMs and 89.3% of the DDD PMs were still programmed in their original mode with good atrial sensing. Due to permanent atrial fibrillation, 7.9% patients out of the VDD group had been switched to VVIR mode and 8.7% patients out of the DDD group to VVIR or DDIR mode. The P-wave amplitude was poor (sensed P-wave <0.5 mV) in 19.1% of the VDD PM and 1.6% of the DDD PM (P< 0.001) and 7.1% of the VDD patients and 0.4% of the DDD patients had been switched to VVIR pacing mode due to P-wave undersensing and AV dissociation (P= 0.003). Symptomatic atrial undersensing requiring upgrading was similar in both groups. The overall survival, adjusted for age, was not significantly different in the VDD and the DDD group (log rank: 0.26). Moreover, Cox survival analysis excluded the pacing mode as a significant predictor of mortality [hazard ratio (HR) = 0.79, confidence interval (CI) (0.46-1.35), P= 0.39]. Comparing VDD and DDD pacing, a significantly larger number of VDD-paced patients developed poor atrial signal detection without clinical impact. However, atrial under sensing did not influence the incidence of atrial fibrillation, myocardial infarction, dilated cardiomyopathy, or mortality.

Surgical and Functional Outcomes After Multilevel Cervical Fusion for Degenerative Disc Disease Compared With Fusion for Radiculopathy: A Study of Workers' Compensation Population.

PubMed

Faour, Mhamad; Anderson, Joshua T; Haas, Arnold R; Percy, Rick; Woods, Stephen T; Ahn, Uri M; Ahn, Nicholas U

2017-05-01

Retrospective cohort comparative study. To evaluate presurgical and surgical factors that affect return to work (RTW) status after multilevel cervical fusion, and to compare outcomes after multilevel cervical fusion for degenerative disc disease (DDD) versus radiculopathy. Cervical fusion provides more than 90% of symptomatic relief for radiculopathy and myelopathy. However, cervical fusion for DDD without radiculopathy is considered controversial. In addition, multilevel fusion is associated with poorer surgical outcomes with increased levels fused. Data of cervical comorbidities was collected from Ohio Bureau of Workers' Compensation for subjects with work-related injuries. The study population included subjects who underwent multilevel cervical fusion. Patients with radiculopathy or DDD were identified. Multivariate logistic regression was performed to identify factors that affect RTW status. Surgical and functional outcomes were compared between groups. Stable RTW status within 3 years after multilevel cervical fusion was negatively affected by: fusion for DDD, age > 55 years, preoperative opioid use, initial psychological evaluation before surgery, injury-to-surgery > 2 years and instrumentation.DDD group had lower rate of achieving stable RTW status (P= 0.0001) and RTW within 1 year of surgery (P= 0.0003) compared with radiculopathy group. DDD patients were less likely to have a stable RTW status [odds ratio, OR = 0.63 (0.50-0.79)] or RTW within 1 year after surgery [OR = 0.65 (0.52-0.82)].DDD group had higher rate of opioid use (P= 0.001), and higher rate of disability after surgery (P= 0.002). Multiple detriments affect stable RTW status after multilevel cervical fusion including DDD. DDD without radiculopathy was associated with lower RTW rates, less likelihood to return to work, higher disability, and higher opioid use after surgery. Multilevel cervical fusion for DDD may be counterproductive. Future studies should investigate further treatment options of DDD, and optimize patient selection criteria for surgical intervention. 3.

Biochemical, Kinetic, and Spectroscopic Characterization of Ruegeria pomeroyi DddW—A Mononuclear Iron-Dependent DMSP Lyase

PubMed Central

Brummett, Adam E.; Schnicker, Nicholas J.; Crider, Alexander; Todd, Jonathan D.; Dey, Mishtu

2015-01-01

The osmolyte dimethylsulfoniopropionate (DMSP) is a key nutrient in marine environments and its catabolism by bacteria through enzymes known as DMSP lyases generates dimethylsulfide (DMS), a gas of importance in climate regulation, the sulfur cycle, and signaling to higher organisms. Despite the environmental significance of DMSP lyases, little is known about how they function at the mechanistic level. In this study we biochemically characterize DddW, a DMSP lyase from the model roseobacter Ruegeria pomeroyi DSS-3. DddW is a 16.9 kDa enzyme that contains a C-terminal cupin domain and liberates acrylate, a proton, and DMS from the DMSP substrate. Our studies show that as-purified DddW is a metalloenzyme, like the DddQ and DddP DMSP lyases, but contains an iron cofactor. The metal cofactor is essential for DddW DMSP lyase activity since addition of the metal chelator EDTA abolishes its enzymatic activity, as do substitution mutations of key metal-binding residues in the cupin motif (His81, His83, Glu87, and His121). Measurements of metal binding affinity and catalytic activity indicate that Fe(II) is most likely the preferred catalytic metal ion with a nanomolar binding affinity. Stoichiometry studies suggest DddW requires one Fe(II) per monomer. Electronic absorption and electron paramagnetic resonance (EPR) studies show an interaction between NO and Fe(II)-DddW, with NO binding to the EPR silent Fe(II) site giving rise to an EPR active species (g = 4.29, 3.95, 2.00). The change in the rhombicity of the EPR signal is observed in the presence of DMSP, indicating that substrate binds to the iron site without displacing bound NO. This work provides insight into the mechanism of DMSP cleavage catalyzed by DddW. PMID:25993446

DDD versus VVIR versus VVI mode in patients with indication to dual-chamber stimulation: a prospective, randomized, controlled, single-blind study.

PubMed

Moro, Eugenio; Caprioglio, Francesco; Berton, Giuseppe; Marcon, Carlo; Riva, Umberto; Corbucci, Giorgio; Delise, Pietro

2005-09-01

The aim of this study was to compare VVI, VVIR and DDD modes in patients with indication to dual-chamber stimulation, depending on left ventricular function. Two groups of patients were implanted with a DDD pacemaker: Group I with ejection fraction > 40% and Group II with ejection fraction < 40%. Patients with a history of atrial arrhythmia or retrograde conduction were excluded. At follow-up (1 month each) quality of life (QoL), patient preference and echo parameters were collected. At hospital discharge all patients were programmed in DDD for 1 month and then randomized to VVI or VVIR mode. At the end of the period in VVI or VVIR mode each patient underwent a control period in DDD and then was programmed in VVIR or VVI mode. Seventeen patients out of 23 preferred DDD mode and 6 did not perceive any subjective difference among DDD, VVI and VVIR modes (4/9 in Group I and 2/14 in Group II, p = 0.0017). QoL was significantly different between the two groups and at each follow-up showed the best values in DDD. The correlation between QoL and Tei index was 0.62 in Group I (p < 0.001) and 0.35 in Group II (p = 0.001). Neither ejection fraction nor fractional shortening showed any significant difference during the three phases of the study. Most patients preferred the DDD mode. The Tei index showed a good correlation with QoL and both QoL and Tei index significantly improved with DDD mode as compared to VVI and VVIR.

Quantitative trait loci that control body weight and obesity in an F2 intercross between C57BL/6J and DDD.Cg-Ay mice.

PubMed

Suto, Jun-ichi

2011-07-01

I have developed a congenic mouse strain for the A(y) allele at the agouti locus in an inbred DDD/Sgn strain, DDD.Cg-A(y). DDD.Cg-A(y) females are extremely obese and significantly heavier than B6.Cg-A(y) females. The objectives of this study were to determine the genetic basis of obesity in DDD.Cg-A(y) mice, and to determine whether or not their high body weight was due to the presence of DDD background-specific modifiers. I performed quantitative trait locus (QTL) analyses for body weight and body mass index in two types of F(2) mice [F2 A(y) (F(2) mice carrying the A(y) allele) and F(2) non-A(y) (F2 mice without the A(y) allele)] produced by crossing C57BL/6J females and DDD.Cg-A(y) males. The results of the QTL analysis of F(2) A(y) mice were very similar to those obtained for F(2) non-A(y) mice. It was unlikely that the high body weight of DDD.Cg-A(y) mice was due to the presence of specific modifiers. When both F(2) datasets were merged and analyzed, four significant body weight QTLs were identified on chromosomes 6, 9, and 17 (2 loci) and four significant obesity QTLs were identified on chromosomes 1, 6, 9, and 17. Although the presence of DDD background-specific modifiers was not confirmed, a multifactorial basis of obesity in DDD.Cg-A(y) females was thus revealed.

Impact of pacemaker mode in patients with atrioventricular conduction disturbance after trans-catheter aortic valve implantation.

PubMed

Takahashi, Masao; Badenco, Nicolas; Monteau, Jacques; Gandjbakhch, Estelle; Extramiana, Fabrice; Urena, Marina; Karam, Nicole; Marijon, Eloi; Algalarrondo, Vincent; Teiger, Emmanuel; Lellouche, Nicolas

2018-03-14

This study aimed to assess the impact of pacemaker mode programming on clinical outcomes in patients with high-degree atrioventricular conduction disturbance (AVCD) after transcatheter aortic valve implantation (TAVI). Although high-degree AVCD after TAVI can receive pacemaker, recovery of the AVCD is often observed. Specific pacemaker algorithms (AAI-DDD mode switch) are available which favor spontaneous atrioventricular conduction. Of 1,621 consecutive multi-center TAVI patients, 269 (16.4%) received pacemaker. We retrospectively included 91 patients with persistent high-degree AVCD at hospital discharge. Pacemaker dependency was defined as absence, inadequate intrinsic ventricular rhythm, or ventricular pacing time > 95% on pacemaker interrogation during follow-up. Comparison of heart failure hospitalization and death between conventional DDD (cDDD) and other modes was examined (AAI-DDD and VVI). During a mean follow-up duration of 13 months, the pacemaker dependency rate was 52.8%. Patients with cDDD mode (N = 36: 40.0%) had significantly more pacemaker dependency. Multivariate analysis showed that cDDD mode was independently associated with pacemaker dependency (odds ratio = 3.63, P = 0.03). Moreover, cDDD patients had a significant higher incidence of heart failure hospitalization (Hospitalization: cDDD vs. others = 45.4% vs. 18.2%, P = 0.03) and had a higher incidence of mortality (Death: cDDD vs. the others = 27.0% vs. 4.4%, P = 0.06). Up to half of patients implanted for high-degree AVCD after TAVI had conduction recovery. Patients with cDDD programming at hospital discharge had more pacemaker dependency and a worse cardiac prognosis. Thus, pacemaker mode should be systematically set to promote spontaneous atrioventricular conduction in patients with pacemaker implantation after TAVI. © 2018 Wiley Periodicals, Inc.

Comparative Study of Electrical Stimulation of the Heart with VDD and DDD Pacemakers as to the Evolution to Atrial Fibrillation

PubMed Central

de Campos, Nelson Leonardo Kerdahi Leite; de Andrade, Rubens Ramos; Fellicio, Marcello Laneza; Martins, Antônio Sergio; Garzesi, André Monti; Garcia, Leonardo Rufino; Takeda, Tassya Bueno

2017-01-01

Introduction The pacemaker implantation VDD is considered simpler, faster, less expensive and causes fewer complications compared to DDD. However, the VDD pacemaker has not been widely used in many centers, perhaps for fear of dysfunction of the sinus node and the reduction of atrial sensitivity by the pacemaker during follow-up after implantation. Objective To compare patients with DDD and VDD pacemakers regarding the evolution of chronic atrial fibrillation (AF) and length of stay outside this postoperative arrhythmia. Methods It was included 158 patients with dual chamber pacemakers, 48 DDD and 110 VDD. Follow-up period: between January 1, 1999 and December 31, 2015. The mean follow-up of patients with DDD was 5.35 years and the VDD, 4.74 years. The percentage of each group (DDD and VDD) which evolved to AF during follow-up was assessed. Also, it was made an actuarial study with the respective curves indicating the time free from AF for each group. Patients were classified according to the diagnosis that led to pacemaker implantation and the degree of heart failure. Results The percentage of patients who developed AF was higher in DDD group (10.42%) than in VDD group (6.36%), but without statistical significance. Patients with DDD and VDD remained free of AF for similar period. Conclusion Considering the results, the VDD pacemaker continues to be a good option to the DDD for routine use in cases properly indicated. PMID:29211212

Comparative Study of Electrical Stimulation of the Heart with VDD and DDD Pacemakers as to the Evolution to Atrial Fibrillation.

PubMed

Campos, Nelson Leonardo Kerdahi Leite de; Andrade, Rubens Ramos de; Fellicio, Marcello Laneza; Martins, Antônio Sergio; Garzesi, André Monti; Garcia, Leonardo Rufino; Takeda, Tassya Bueno

2017-01-01

The pacemaker implantation VDD is considered simpler, faster, less expensive and causes fewer complications compared to DDD. However, the VDD pacemaker has not been widely used in many centers, perhaps for fear of dysfunction of the sinus node and the reduction of atrial sensitivity by the pacemaker during follow-up after implantation. To compare patients with DDD and VDD pacemakers regarding the evolution of chronic atrial fibrillation (AF) and length of stay outside this postoperative arrhythmia. It was included 158 patients with dual chamber pacemakers, 48 DDD and 110 VDD. Follow-up period: between January 1, 1999 and December 31, 2015. The mean follow-up of patients with DDD was 5.35 years and the VDD, 4.74 years. The percentage of each group (DDD and VDD) which evolved to AF during follow-up was assessed. Also, it was made an actuarial study with the respective curves indicating the time free from AF for each group. Patients were classified according to the diagnosis that led to pacemaker implantation and the degree of heart failure. The percentage of patients who developed AF was higher in DDD group (10.42%) than in VDD group (6.36%), but without statistical significance. Patients with DDD and VDD remained free of AF for similar period. Considering the results, the VDD pacemaker continues to be a good option to the DDD for routine use in cases properly indicated.

Intradiscal thermal annuloplasty for the treatment of lumbar discogenic pain in patients with multilevel degenerative disc disease.

PubMed

Kapural, Leonardo; Mekhail, Nagy; Korunda, Zdenko; Basali, Ayman

2004-08-01

Symptomatic degenerative disc disease (DDD) may lead to significant deterioration of quality of life and increased disability. Intradiscal thermal annuloplasty (IDTA) is a minimally invasive treatment for painful DDD. We hypothesized that there may be an improvement in pain scores and the pain disability index (PDI) of patients who have multilevel DDD after IDTA. Patients 24-66 yr old, male and female with multilevel DDD (MDDD) and matched 1 or 2 level DDD (1,2-DDD) patients were enrolled in the study. Visual analog pain scale (VAS) score and PDI were observed for 12 mo. The 1,2-DDD patient group had a 2.5 +/- 2.4 VAS score at 12 mo after annuloplasty compared to 7.7 +/- 2 before the procedure. The MDDD VAS score was 4.9 +/- 2.9 at 12 mo compared to 7.4 +/- 1.8 before the procedure. Similar improvements in PDI were found. The pain relief and PDI were significantly better in patients with 1,2-DDD than in the MDDD group (P = 0.0037 and P = 0.041, respectively). We concluded that IDTA is an effective treatment of discogenic pain and that the number of discs affected by degeneration is an important determinant of the procedure outcome.

Early Intervention of Didang Decoction on MLCK Signaling Pathways in Vascular Endothelial Cells of Type 2 Diabetic Rats

PubMed Central

Song, Zhenqiang; Li, Jing; Li, Chunshen

2016-01-01

In the study, type 2 diabetic rat model was established using streptozotocin (STZ) combined with a high-fat diet, and the rats were divided into control and diabetic groups. Diabetic groups were further divided into nonintervening, simvastatin, Didang Decoction (DDD) early-phase intervening, DDD mid-phase intervening, and DDD late-phase intervening groups. The expression level of MLCK was detected using Western Blot analysis, and the levels of cyclic adenosine monophosphate (cAMP), protein kinase C (PKC), and protein kinase A (PKA) were examined using Real Time PCR. Under the electron microscope, the cells in the early-DDD-intervention group and the simvastatin group were significantly more continuous and compact than those in the diabetic group. Compared with the control group, the expression of cAMP-1 and PKA was decreased in all diabetic groups, whereas the expression of MLCK and PKC was increased in early- and mid-phase DDD-intervening groups (P < 0.05); compared with the late-phase DDD-intervening group, the expression of cAMP-1 and PKA was higher, but the level of MLCK and PKC was lower in early-phase DDD-intervening group (P < 0.05). In conclusion, the early use of DDD improves the permeability of vascular endothelial cells by regulating the MLCK signaling pathway. PMID:27703477

Higher systemic antibiotic consumption in a population of South Korea (2008 - 2009).

PubMed

Sohn, Hyun Soon; Oh, Ock Hee; Kwon, Jin-Won; Lee, Young Sook

2013-07-01

This study was conducted to investigate overall systemic antibiotic consumption levels and specific patterns using standardized Anatomical Therapeutic Chemical/Defined Daily Dose (ATC/DDD) methodology. National Health Insurance claims data during 2008 and 2009 was used. Antibiotic prescription data was classified using the ATC system and converted into DDD. Consumption figures were presented as the number of DDD per 1,000 inhabitants per day (DID). Detailed information on indications and seasonal variations, age and institutional determinants on antibiotic consumption were also explored. Total consumption was slightly increased from 24.3 to 25.2 DID in 2009 compared to 2008. The most frequently prescribed antibiotic was amoxicillin/clavulanic acid (5.1 and 5.2 DID, in 2008 and 2009, respectively), followed by cefaclor (3.0 and 3.3 DID) and amoxicillin (3.3 and 3.2 DID). Respiratory system diseases were the main causes of antimicrobial prescription (47.3%) and acute forms of bronchitis, tonsillitis and sinusitis were the most common diseases. There were typical seasonal fluctuations with heightened winter peaks. Consumption figures under 5 years of age (41.6 and 43.3 DID) were even higher than figures in aged 65 - 80 (36.2 and 39.1 DID). Antibiotic consumption in South Korea remained high compared with other OECD countries. Efforts to increase prudent antibiotic use, especially for upper respiratory system infections and for younger children, should be made to decrease antibiotic use.

Decreasing Clostridium difficile Infections by an Antimicrobial Stewardship Program That Reduces Moxifloxacin Use

PubMed Central

Equiluz-Bruck, Susanne; Fudel, Marta; Reiter, Ingun; Schmid, Andrea; Singer, Erna; Chott, Andreas

2014-01-01

Clostridium difficile infections (CDI) in hospitalized patients are known to be closely related to antibiotic exposure. Although several substances can cause CDI, the risk differs between individual agents. In Vienna and other eastern parts of Austria, CDI ribotype 027 is currently highly prevalent. This ribotype has the characteristic of intrinsic moxifloxacin resistance. Therefore, we hypothesized that moxifloxacin restriction can decrease the number of CDI cases in hospitalized patients. Our antibiotic stewardship (ABS) group applied an information campaign on CDI and formal restriction of moxifloxacin in Wilhelminenspital (Vienna, Austria), a 1,000- bed tertiary care hospital. The preintervention period (period 1) was January through May 2013, and the intervention period (period 2) was June through December 2013. We recorded the defined daily doses (DDD) of moxifloxacin and the number of CDI patients/month. Moxifloxacin use was reduced from a mean (± standard error of the mean [SEM]) of 1,038 ± 109 DDD per month (period 1) to 42 ± 10 DDD per month (period 2) (P = 0.0045). Total antibiotic use was not affected. The mean (±SEM) numbers of CDI cases in period 1 were 59 ± 3 per month and in period 2 were 32 ± 3 per month (46% reduction; P = 0.0044). Reducing moxifloxacin use in combination with providing structured information on CDI was associated with an immediate decrease in CDI rates in this large community teaching hospital. PMID:24936597

Utilization of Parenteral Morphine by Application of ATC/DDD Methodology: Retrospective Study in the Referral Teaching Hospital.

PubMed

Dragojevic-Simic, Viktorija; Rancic, Nemanja; Stamenkovic, Dusica; Simic, Radoje

2017-01-01

Few studies analyzed the pattern of opioid analgesic utilization in hospital settings. The aim of this study was to determine the consumption pattern of parenteral morphine in patients hospitalized in the Serbian referral teaching hospital and to correlate it with utilization at the national and international level. In retrospective study, the required data were extracted from medical records of surgical patients who received parenteral morphine in the 5-year period, from 2011 to 2015. We used the Anatomical Therapeutic Chemical Classification/Defined Daily Doses (DDD) international system for consumption evaluation. While the number of performed surgical procedures in our hospital steadily increased from 2011 to 2015, the number of inpatient bed-days decreased from 2012. However, the consumption of parenteral morphine varied and was not more than 0.867 DDD/100 bed-days in the observed period. Based on the available data, parenteral morphine consumption in our hospital was lower compared with international data. The low level of morphine use in the hospital was in accordance with national data, and compared with other countries, morphine consumption applied for medical indications in Serbia was low. Adequate legal provision to ensure the availability of opioids, better education and training of medical personnel, as well as multidisciplinary approach should enable more rational and individual pain management in the future, not only within the hospitals.

[Appropriateness of ketorolac use in a trauma hospital].

PubMed

Angeles González-Fernández, M

2009-06-01

To evaluate the suitability of ketorolac and non-steroidal anti-inflamatory drugs (NSAIDs) and other analgesic drugs currently used in the hospital. We have followed the steps to develop a PDCA cycle (plan, do, check, act) or quality improvement cycle. The quality problem was analysed using an Ishikawa diagram. We defined both qualitative quality indicators, those that measure prescription quality, and quantitative ones (defined daily dose, DDD/100BDs), which measure drug consumption, being the objectives to achieve. The study was conducted in all patients admitted to the hospital and who were admitted to orthopaedic and trauma surgery and plastic surgery departments with unit-dose dispensing systems. The strategy used was to give information to physicians through meetings and documentation. Finally, the results were analysed and compared with the initial objectives. The study was performed on 260 patients in the first study period and 292 in the second. Qualitative indicators: intravenous ketorolac use < or =2 days, increased in 25.5% (p<0.001); in patients > or =65 years old at dose < or =60 mg/day it increased 27.7% (p<0.05). Quantitative indicators: in the second study period, ketorolac use decreased (plastic surgery department: 61.8 DDD/100BDs to 14.8), whereas tramadol, ibuprofen and metamizole increased (plastic surgery department: 0 to 14.1 in tramadol, 8.7 to 48.6 in ibuprofen and 50.1 to 71 in metamizole). Appropriateness of ketorolac, NSAIDs and tramadol use has been achieved, thus improving patient safety. Strategies have been effective.

Diversity of bacterial dimethylsulfoniopropionate degradation genes in surface seawater of Arctic Kongsfjorden.

PubMed

Zeng, Yin-Xin; Qiao, Zong-Yun; Yu, Yong; Li, Hui-Rong; Luo, Wei

2016-09-08

Dimethylsulfoniopropionate (DMSP), which is the major source of organic sulfur in the world's oceans, plays a significant role in the global sulfur cycle. This compound is rapidly degraded by marine bacteria either by cleavage to dimethylsulfide (DMS) or demethylation to 3-methylmercaptopropionate (MMPA). The diversity of genes encoding bacterial demethylation (dmdA) and DMS production (dddL and dddP) were measured in Arctic Kongsfjorden. Both dmdA and dddL genes were detected in all stations along a transect from the outer to the inner fjord, while dddP gene was only found in the outer and middle parts of the fjord. The dmdA gene was completely confined to the Roseobacter clade, while the dddL gene was confined to the genus Sulfitobacter. Although the dddP gene pool was also dominated by homologs from the Roseobacter clade, there were a few dddP genes showing close relationships to both Alphaproteobacter and Gammaproteobacter. The results of this study suggest that the Roseobacter clade may play an important role in DMSP catabolism via both demethylation and cleavage pathways in surface waters of Kongsfjorden during summer.

Diversity of bacterial dimethylsulfoniopropionate degradation genes in surface seawater of Arctic Kongsfjorden

NASA Astrophysics Data System (ADS)

Zeng, Yin-Xin; Qiao, Zong-Yun; Yu, Yong; Li, Hui-Rong; Luo, Wei

2016-09-01

Dimethylsulfoniopropionate (DMSP), which is the major source of organic sulfur in the world’s oceans, plays a significant role in the global sulfur cycle. This compound is rapidly degraded by marine bacteria either by cleavage to dimethylsulfide (DMS) or demethylation to 3-methylmercaptopropionate (MMPA). The diversity of genes encoding bacterial demethylation (dmdA) and DMS production (dddL and dddP) were measured in Arctic Kongsfjorden. Both dmdA and dddL genes were detected in all stations along a transect from the outer to the inner fjord, while dddP gene was only found in the outer and middle parts of the fjord. The dmdA gene was completely confined to the Roseobacter clade, while the dddL gene was confined to the genus Sulfitobacter. Although the dddP gene pool was also dominated by homologs from the Roseobacter clade, there were a few dddP genes showing close relationships to both Alphaproteobacter and Gammaproteobacter. The results of this study suggest that the Roseobacter clade may play an important role in DMSP catabolism via both demethylation and cleavage pathways in surface waters of Kongsfjorden during summer.

[Measurement of antimicrobial consumption using DDD per 100 bed-days versus DDD per 100 discharges after the implementation of an antimicrobial stewardship program].

PubMed

Collado, Roberto; Losa, Juan Emilio; Álvaro, Elena Alba; Toro, Piedad; Moreno, Leonor; Pérez, Montserrat

2015-12-01

Monitoring antimicrobial consumption in hospitals is a necessary measure. The indicators commonly employed do not clearly reflect the antibiotic selection pressure. The objective of this study is to evaluate two different methods that analyze antimicrobial consumption based on DDD, per stay and per discharge, before and after the implementation an antimicrobial stewardship program. Comparative pre-post study of antimicrobial consumption with the implementation of an antimicrobial stewardship program using DDD per 100 bed-days and DDD per 100 discharges as indicators. Hospital bed days remained stable and discharges increased slightly along the period of study Antibiotic consumption in DDD per 100 bed-days decreased by 2.5% versus 3.8% when expressed as DDD per 100 discharges. Antifungal consumption decreased by more than 50%. When average hospital stay decreases, reductions in the consumption of antimicrobials with an antimicrobial stewardship program system occur at the expense of reducing the number of patients receiving treatment, while increases occur due to longer durations of treatment.

Flood forecasting with DDD-application of a parsimonious hydrological model in operational flood forecasting in Norway

NASA Astrophysics Data System (ADS)

Skaugen, Thomas; Haddeland, Ingjerd

2014-05-01

A new parameter-parsimonious rainfall-runoff model, DDD (Distance Distribution Dynamics) has been run operationally at the Norwegian Flood Forecasting Service for approximately a year. DDD has been calibrated for, altogether, 104 catchments throughout Norway, and provide runoff forecasts 8 days ahead on a daily temporal resolution driven by precipitation and temperature from the meteorological forecast models AROME (48 hrs) and EC (192 hrs). The current version of DDD differs from the standard model used for flood forecasting in Norway, the HBV model, in its description of the subsurface and runoff dynamics. In DDD, the capacity of the subsurface water reservoir M, is the only parameter to be calibrated whereas the runoff dynamics is completely parameterised from observed characteristics derived from GIS and runoff recession analysis. Water is conveyed through the soils to the river network by waves with celerities determined by the level of saturation in the catchment. The distributions of distances between points in the catchment to the nearest river reach and of the river network give, together with the celerities, distributions of travel times, and, consequently unit hydrographs. DDD has 6 parameters less to calibrate in the runoff module than the HBV model. Experiences using DDD show that especially the timing of flood peaks has improved considerably and in a comparison between DDD and HBV, when assessing timeseries of 64 years for 75 catchments, DDD had a higher hit rate and a lower false alarm rate than HBV. For flood peaks higher than the mean annual flood the median hit rate is 0.45 and 0.41 for the DDD and HBV models respectively. Corresponding number for the false alarm rate is 0.62 and 0.75 For floods over the five year return interval, the median hit rate is 0.29 and 0.28 for the DDD and HBV models, respectively with false alarm rates equal to 0.67 and 0.80. During 2014 the Norwegian flood forecasting service will run DDD operationally at a 3h temporal resolution. Running DDD at a 3h resolution will give a better prediction of flood peaks in small catchments, where the averaging over 24 hrs will lead to a underestimation of high events, and we can better describe the progress floods in larger catchments. Also, at a 3h temporal resolution we make better use of the meteorological forecasts that for long have been provided at a very detailed temporal resolution.

The Role of Twinning Deformation on the Hardening Response of Polycrystalline Magnesium from Discrete Dislocation Dynamics Simulations

DTIC Science & Technology

2015-01-01

polycrystalline magnesium (Mg) was studied using three-dimensional discrete dislocation dynamics ( DDD ). A systematic interaction model between dislocations...and f1012g tension twin boundaries (TBs) was proposed and introduced into the DDD framework. In addition, a nominal grain boundary (GB) model based...dynamics ( DDD ). A systematic interaction model between dislocations and f10 12g tension twin boundaries (TBs) was proposed and introduced into the DDD

Antibiotic consumption in non-teaching Lebanese hospitals: A cross-sectional study.

PubMed

Iskandar, Katia; Hanna, Pierre A; Salameh, Pascale; Raad, Etwal B

2016-01-01

The rising threat of antibiotic resistance is linked to patterns of antibiotic use in hospital settings where global efforts are undertaken to encourage reporting and benchmarking antibiotic consumption in an attempt to improve prescription regimens. In Lebanon, where data concerning the level of antibiotic consumption in hospitals is scarce, the aim of our paper is to track the intensity of antibiotic consumption in order to identify potential evidence of antibiotic misuse or abuse. The study is conducted in 2012 for a period of 12-month using data from pharmacy records in 27 non-teaching Lebanese hospitals according to the Anatomical, Therapeutic and chemical classification system and Defined Daily Dose (ATC/DDD) recommended by the World Health Organization and compiling data on ABC Calc software version 3.1. Results show that the average antibiotic consumption excluding pediatric cases is 72.56 Defined Daily Dose per 100 Bed-Days (DDD/100BD). Total broad spectrum antibiotic consumption is 12.14 DDD/100BD with no significant difference found between public and private hospitals (p>0.05 for all). The most commonly used antibiotics were Amoxycillin/Clavulanic acid, Ceftriaxone, Amoxycillin and Cefuroxime for parenteral use. Consumption of beta-lactams, Cephalosporins, Carbapenems, Monobactams and quinolones did not vary significantly by region, occupancy rate, number of beds including the number of intensive care unit beds. Our data findings provides baseline information on patterns of antibiotic consumption in Lebanon and the issue calls for concerted efforts to encourage data reporting on national basis and to correlate future findings with results of antibiotic susceptibility testing which can provide insights and tools needed to assess the public health consequences of antimicrobial misuse and to evaluate the impact of antibiotic resistance containment interventions. Copyright © 2016 King Saud Bin Abdulaziz University for Health Sciences. Published by Elsevier Ltd. All rights reserved.

Association between use of multiple psychoactive medicines and hospitalization for falls: retrospective analysis of a large healthcare claim database.

PubMed

Pratt, Nicole L; Ramsay, Emmae N; Kalisch Ellett, Lisa M; Nguyen, Tuan A; Barratt, John D; Roughead, Elizabeth E

2014-07-01

Little is known about the impact of taking multiple psychoactive medicines on the risk of hospitalization for falls. To identify the association between multiple psychoactive medicine use and hospitalization for falls. A retrospective cohort study was conducted between July 2011 and June 2012 in the Australian veteran population who had been dispensed at least one psychoactive medicine within the previous year. Psychoactive medicines with sedative properties included antipsychotics, anxiolytics, hypnotics, antidepressants, opioids, anti-epileptics, anti-Parkinson medicines and medicines for migraine. The associations between falls and the number of psychoactive medicines used or the number of doses were analysed in comparison with falls that occurred when no psychoactive medicine was used. The adjusted results showed a significantly increased risk of falls when patients were on one or more psychoactive medicines or were receiving 0.1-0.9 defined daily dose (DDD) or more per day. The incident rate ratios (IRRs) were 1.22 (95% confidence interval [CI] 1.08-1.38) for those on one psychoactive medicine, 1.70 (95% CI 1.45-1.99) for those on two, 1.96 (95% CI 1.58-2.43) for those on three or four, and 3.15 (95% CI 1.90-5.23) for those on five or more. A similar result was observed when the data were analysed by dose, with the highest risk being found for those taking three or more DDD per day (adjusted IRR 4.26, 95% CI 2.75-6.58). Increased numbers or increased doses of psychoactive medicines are associated with an increased risk of hospitalization for falls in older adults. Strategies to reduce the psychoactive medicine burden are likely to translate into significant health benefits.

Isolation of Brazilian marine fungi capable of growing on DDD pesticide.

PubMed

Ortega, Scarlet Nere; Nitschke, Marcia; Mouad, Ana Maria; Landgraf, Maria Diva; Rezende, Maria Olímpia Oliveira; Seleghim, Mirna Helena Regali; Sette, Lara Durães; Porto, André Luiz Meleiro

2011-02-01

The fungi Aspergillus sydowii Ce15, Aspergillus sydowii Ce19, Aspergillus sydowii Gc12, Bionectria sp. Ce5, Penicillium miczynskii Gc5, Penicillium raistrickii Ce16 and Trichoderma sp. Gc1, isolated from marine sponges Geodia corticostylifera and Chelonaplysylla erecta, were evaluated for their ability to grow in the presence of DDD pesticide. Increasing concentrations of DDD pesticide, i.e., 5.0 mg (1.56 × 10⁻¹² mmol), 10.0 mg (3.12 × 10⁻²) mmol) and 15.0 mg (4.68 × 10⁻² mmol) in solid and liquid culture media were tested. The fungi Trichoderma sp. Gc1 and Penicillium miczynskii Gc5 were able to grow in the presence of up to 15.0 mg of DDD, suggesting their potential for biodegradation. A 100% degradation of DDD was attained in liquid culture medium when Trichoderma sp. Gc1 was previously cultivated for 5 days and supplemented with 5.0 mg of DDD in the presence of hydrogen peroxide. However, the quantitative analysis showed that DDD was accumulated on mycelium and biodegradation level reached a maximum value of 58% after 14 days.

Impact of a clinical microbiology-intensive care consulting program in a cardiothoracic intensive care unit.

PubMed

Arena, Fabio; Scolletta, Sabino; Marchetti, Luca; Galano, Angelo; Maglioni, Enivarco; Giani, Tommaso; Corsi, Elisabetta; Lombardi, Silvia; Biagioli, Bonizella; Rossolini, Gian Maria

2015-09-01

A preintervention-postintervention study was carried out over a 4-year period to assess the impact of an antimicrobial stewardship intervention, based on clinical microbiologist ward rounds (clinical microbiology-intensive care partnership [CMICP]), at a cardiothoracic intensive care unit. Comparison of clinical data for 37 patients with diagnosis of bacteremia (18 from preintervention period, 19 from postintervention period) revealed that CMICP implementation resulted in (1) significant increase of appropriate empirical treatments (+34%, P = .029), compliance with guidelines (+28%, P = .019), and number of de-escalations (+42%, P = .032); and (2) decrease (average = 2.5 days) in time to optimization of antimicrobial therapy and levofloxacin (Δ 2009-2012 = -74 defined daily dose [DDD]/1,000 bed days) and teicoplanin (Δ 2009-2012 = -28 DDD/1,000 bed days) use. Copyright © 2015 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.

[Impact of regulatory measures in the trends of community consumption of antibiotics in Chile].

PubMed

Bavestrello, Luis; Cabello, Angela; Casanova, Dunny

2002-11-01

The indiscriminate use of antibiotics increases the appearance of bacterial resistance and forces the use of more expensive alternatives. The Chilean Ministry of Health is regulating the consumption of antibiotics since September 1999. These regulatory measures restricted the sale of antibiotics only when these were prescribed by an MD or an DS. To study the impact of these regulatory measures on antibiotics sales in pharmacies. A retrospective analysis of antibiotics sales in pharmacies from 1996 to 2000. The information was obtained from the International Marketing System (IMS Health), an auditing system of pharmacy sales. The consumption unit used was the Defined Daily Dose per 1000 inhabitants/day (DDD). There was an important reduction in DDD, after the introduction of regulatory measures, for amoxicillin, ampicillin, erythromycin, trimethoprim/sulpha, chroramphenicol, cloxacillin and phenoxymethylpenicillin. There was also a important fall in sales, expressed in dollars. The regulatory measures of the Ministry of Health, had an immediate and great impact on antibiotics sales in Chile.

Re-use of explanted DDD pacemakers as VDD- clinical utility and cost effectiveness.

PubMed

Namboodiri, K K N; Sharma, Y P; Bali, H K; Grover, A

2004-01-01

Re-use of DDD pulse generators explanted from patients died of unrelated causes is associated with an additional cost of two transvenous leads if implanted as DDD itself, and high rate of infection according to some studies. We studied the clinical and economical aspects of reutilization of explanted DDD pacemakers programmed to VDD mode. Out of 28 patients who received VDD pacemaker during the period, October 2000- September 2001 in the Department of Cardiology, PGIMER, Chandigarh, 5 poor patients were implanted with explanted DDD pulse generators programmed to VDD mode. Each implantation was planned and carried out according to a standard protocol. The age ranged from 45 to 75 (mean-61) years. The indications for pacing were complete heart block (4) and second degree AV block (1). The clinical profile, costs and complications, if any were noted and followed up at regular intervals. The results were compared with patients who received new DDD pulse generators during this period. The additional cost for the atrial lead was not required in these patients. None of these patients had any local site infection. Compared to the two-lead system, the single lead system provided more rapid implantation and minimized complications associated with placement of an atrial lead. The explanted DDD pacemaker can be safely reused as VDD mode with same efficacy in selected patient population. This is associated with lower cost and complications compared to reimplantation as DDD itself.

Impact of a new palliative care consultation team on opioid prescription in a University Hospital.

PubMed

Centeno, Carlos; Portela, María Angustias; Noguera, Antonio; Idoate, Antonio; Rubiales, Alvaro Sanz

2009-01-16

There are no validated measuring tools to gauge the effectiveness of a Hospital Palliative Care Consultation Team (PCCT). One way would be to consider its effect on the consumption of opioids expressed in total amounts and different formulations administered. We perform this study to evaluate the impact of a hospital PCCT on the trends of opioid prescription in a University Hospital. A seven year retrospective study on opioid prescription was carried out in the Clínica Universidad de Navarra. The period includes three years before and three years after the PCCT was implemented. Prescription was analysed calculating yearly the Defined Daily Dose (DDD) adjusted to 1000 hospital stays (DDD/1000HS). Indicators considered were the proportion of patients treated using opioids compared to the total estimated in need of treatment (rate of effectiveness) and the proportion of patients potentially requiring opioids but not treated who were incorporated into the treatment group (rate of improvement). From 2001 to 2007, total opioid prescription was low in non-oncology Departments (range: 69-110 DDD/1000HS) while parenteral morphine and fentanyl did not register any changes. In the same period of time, total opioid prescription increased in the Oncology Department from 240 to 558 DDD/1000HS. The rate of effectiveness in the three years prior to the implantation of the consultation team was 64% and in the three following years rose to 87%. The rate of improvement prior to the palliative care consultation team was 43% and in the three following years was 64%. A change in opioid prescription was registered after the implementation of the PCCT resulting in an increase in the prescription of parenteral morphine and methadone and a decrease in transdermal fentanyl. Implementation of a PCCT in a University Hospital is associated with a higher and more adequate use of opioids.

Impact of a new palliative care consultation team on opioid prescription in a University Hospital

PubMed Central

Centeno, Carlos; Portela, María Angustias; Noguera, Antonio; Idoate, Antonio; Rubiales, Álvaro Sanz

2009-01-01

Background There are no validated measuring tools to gauge the effectiveness of a Hospital Palliative Care Consultation Team (PCCT). One way would be to consider its effect on the consumption of opioids expressed in total amounts and different formulations administered. We perform this study to evaluate the impact of a hospital PCCT on the trends of opioid prescription in a University Hospital. Methods A seven year retrospective study on opioid prescription was carried out in the Clínica Universidad de Navarra. The period includes three years before and three years after the PCCT was implemented. Prescription was analysed calculating yearly the Defined Daily Dose (DDD) adjusted to 1000 hospital stays (DDD/1000HS). Indicators considered were the proportion of patients treated using opioids compared to the total estimated in need of treatment (rate of effectiveness) and the proportion of patients potentially requiring opioids but not treated who were incorporated into the treatment group (rate of improvement). Results From 2001 to 2007, total opioid prescription was low in non-oncology Departments (range: 69–110 DDD/1000HS) while parenteral morphine and fentanyl did not register any changes. In the same period of time, total opioid prescription increased in the Oncology Department from 240 to 558 DDD/1000HS. The rate of effectiveness in the three years prior to the implantation of the consultation team was 64% and in the three following years rose to 87%. The rate of improvement prior to the palliative care consultation team was 43% and in the three following years was 64%. A change in opioid prescription was registered after the implementation of the PCCT resulting in an increase in the prescription of parenteral morphine and methadone and a decrease in transdermal fentanyl. Conclusion Implementation of a PCCT in a University Hospital is associated with a higher and more adequate use of opioids. PMID:19149875

40 CFR 129.101 - DDT, DDD and DDE.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 40 Protection of Environment 22 2011-07-01 2011-07-01 false DDT, DDD and DDE. 129.101 Section 129.101 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) WATER PROGRAMS TOXIC POLLUTANT EFFLUENT STANDARDS Toxic Pollutant Effluent Standards and Prohibitions § 129.101 DDT, DDD and DDE...

High variability of TB, HIV, hepatitis C treatment and opioid substitution therapy among prisoners in Germany.

PubMed

Müller, Jana; Schmidt, Daniel; Kollan, Christian; Lehmann, Marc; Bremer, Viviane; Zimmermann, Ruth

2017-10-25

In Germany, medical care of prisoners is completely separated from extramural health care. The extent and quality of medical care among prisoners in Germany are therefore largely unknown. We performed a secondary data analysis of pharmacy sales data for tuberculosis (TB), HIV, hepatitis C (HCV) and opioid substitution treatment (OST) delivered to prisons in 11 federal states (FS) in Germany between 01/2012 and 03/2013. The aims of this study were to assess (i) the treatment availability for the selected diseases and OST in German prisons, (ii) the proportion of prisoners treated per FS and overall for TB, HIV, HCV and OST during the study period. Substances unique to or typically used for the treatment of each disease were defined as marker substances with defined daily doses (DDD). For each marker substance we assessed the cumulative number of DDD, the average daily number of DDD (DDD d ) and average treatment prevalence per day in percent (adTP). Accordingly, the DDD d represents one person treated per day and the adTP means the proportion of prisoners treated per day. We compared the adTP of the diseases with previously measured prevalences. We obtained data from pharmacies supplying prisons in 11 of 16 German FS. Of the included prisons, 41% were supplied with medicines for TB, 71% for HIV and 58% for HCV and OST. Twice as many delivered marker substances for TB were indicated for the continuation phase and chemoprevention than the intensive phase. The HIV adTP ranged from 0.06% to 0.94%, HCV adTP ranged from 0.03% to 0.59% and OST adTP ranged from 0% to 7.90%. The overall adTP for the respective treatment was 0.39% for HIV, 0.12% for HCV and 2.18% for OST. According to our findings treatment rates for TB were consistent with the expected TB prevalence, at least in Berlin. HIV treatment seems to be offered to an adequate proportion of estimated infected prisoners. In contrast, the HCV treatment prevalence was low. High variation among FS in provision of all treatments, particularly of OST, point to inconsistent treatment practices, although nationwide extramural treatment guidelines for Germany exist.

Lumbar Facet Joint Motion in Patients with Degenerative Disc Disease at Affected and Adjacent Levels

PubMed Central

Li, Weishi; Wang, Shaobai; Xia, Qun; Passias, Peter; Kozanek, Michal; Wood, Kirkham; Li, Guoan

2013-01-01

Study Design Controlled laboratory study. Objective To evaluate the effect of lumbar degenerative disc diseases (DDDs) on motion of the facet joints during functional weight-bearing activities. Summary of Background Data It has been suggested that DDD adversely affects the biomechanical behavior of the facet joints. Altered facet joint motion, in turn, has been thought to associate with various types of lumbar spine pathology including facet degeneration, neural impingement, and DDD progression. However, to date, no data have been reported on the motion patterns of the lumbar facet joint in DDD patients. Methods Ten symptomatic patients of DDD at L4–S1 were studied. Each participant underwent magnetic resonance images to obtain three-dimensional models of the lumbar vertebrae (L2–S1) and dual fluoroscopic imaging during three characteristic trunk motions: left-right torsion, left-right bending, and flexion-extension. In vivo positions of the vertebrae were reproduced by matching the three-dimensional models of the vertebrae to their outlines on the fluoroscopic images. The kinematics of the facet joints and the ranges of motion (ROMs) were compared with a group of healthy participants reported in a previous study. Results In facet joints of the DDD patients, there was no predominant axis of rotation and no difference in ROMs was found between the different levels. During left-right torsion, the ROMs were similar between the DDD patients and the healthy participants. During left-right bending, the rotation around mediolateral axis at L4–L5, in the DDD patients, was significantly larger than that of the healthy participants. During flexion-extension, the rotations around anterioposterior axis at L4–L5 and around craniocaudal axis at the adjacent level (L3–L4), in the DDD patients, were also significantly larger, whereas the rotation around mediolateral axis at both L2–L3 and L3–L4 levels in the DDD patients were significantly smaller than those of the healthy participants. Conclusion DDD alters the ROMs of the facet joints. The rotations can increase significantly not only at the DDD levels but also at their adjacent levels when compared to those of the healthy participants. The increase in rotations did not occur around the primary rotation axis of the torso motion but around the coupled axes. This hypermobility in coupled rotations might imply a biomechanical mechanism related to DDD. PMID:21270686

Reductive dechlorination of DDT to DDD by yeast

USGS Publications Warehouse

Kallman, Burton J.; Andrews, Austin K.

1963-01-01

Labeled DDD [ 1,1-dichlor-o-2,2-bis(p-chlorophenyl)-ethane] was formed from C14-labeled DDT in the presence of yeast. The formation of DDD from DDE [1,1-dichloro-2,2-bis (p-chlorophenyl)-ethylene] was not observed, indicating that a reductive dechlorination of DDT occurs.

The Structure of RdDddP from Roseobacter denitrificans Reveals That DMSP Lyases in the DddP-Family Are Metalloenzymes

PubMed Central

Hehemann, Jan-Hendrik; Law, Adrienne; Redecke, Lars; Boraston, Alisdair B.

2014-01-01

Marine microbes degrade dimethylsulfoniopropionate (DMSP), which is produced in large quantities by marine algae and plants, with DMSP lyases into acrylate and the gas dimethyl sulfide (DMS). Approximately 10% of the DMS vents from the sea into the atmosphere and this emission returns sulfur, which arrives in the sea through rivers and runoff, back to terrestrial systems via clouds and rain. Despite their key role in this sulfur cycle DMSP lyases are poorly understood at the molecular level. Here we report the first X-ray crystal structure of the putative DMSP lyase RdDddP from Roseobacter denitrificans, which belongs to the abundant DddP family. This structure, determined to 2.15 Å resolution, shows that RdDddP is a homodimeric metalloprotein with a binuclear center of two metal ions located 2.7 Å apart in the active site of the enzyme. Consistent with the crystallographic data, inductively coupled plasma mass spectrometry (ICP-MS) and total reflection X-ray fluorescence (TRXF) revealed the bound metal species to be primarily iron. A 3D structure guided analysis of environmental DddP lyase sequences elucidated the critical residues for metal binding are invariant, suggesting all proteins in the DddP family are metalloenzymes. PMID:25054772

Decreasing Clostridium difficile infections by an antimicrobial stewardship program that reduces moxifloxacin use.

PubMed

Wenisch, Judith Maria; Equiluz-Bruck, Susanne; Fudel, Marta; Reiter, Ingun; Schmid, Andrea; Singer, Erna; Chott, Andreas

2014-09-01

Clostridium difficile infections (CDI) in hospitalized patients are known to be closely related to antibiotic exposure. Although several substances can cause CDI, the risk differs between individual agents. In Vienna and other eastern parts of Austria, CDI ribotype 027 is currently highly prevalent. This ribotype has the characteristic of intrinsic moxifloxacin resistance. Therefore, we hypothesized that moxifloxacin restriction can decrease the number of CDI cases in hospitalized patients. Our antibiotic stewardship (ABS) group applied an information campaign on CDI and formal restriction of moxifloxacin in Wilhelminenspital (Vienna, Austria), a 1,000- bed tertiary care hospital. The preintervention period (period 1) was January through May 2013, and the intervention period (period 2) was June through December 2013. We recorded the defined daily doses (DDD) of moxifloxacin and the number of CDI patients/month. Moxifloxacin use was reduced from a mean (±standard error of the mean [SEM]) of 1,038±109 DDD per month (period 1) to 42±10 DDD per month (period 2) (P=0.0045). Total antibiotic use was not affected. The mean (±SEM) numbers of CDI cases in period 1 were 59±3 per month and in period 2 were 32±3 per month (46% reduction; P=0.0044). Reducing moxifloxacin use in combination with providing structured information on CDI was associated with an immediate decrease in CDI rates in this large community teaching hospital. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Carbapenem stewardship: positive impact on hospital ecology.

PubMed

Lima, Ana Lucia Lei Munhoz; Oliveira, Priscila Rosalba Domingos de; Paula, Adriana Pereira de; Dal-Paz, Karine; Almeida, João Nóbrega de; Félix, Cássia da Silva; Rossi, Flávia

2011-01-01

Excessive group 2 carbapenem use may result in decreased bacterial susceptibility. We evaluated the impact of a carbapenem stewardship program, restricting imipenem and meropenem use. Ertapenem was mandated for ESBL-producing Enterobacteriaceae infections in the absence of non-fermenting Gram-negative bacilli (GNB) from April 2006 to March 2008. Group 2 carbapenems were restricted for use against GNB infections susceptible only to carbapenems and suspected GNB infections in unstable patients. Cumulative susceptibility tests were done for nosocomial pathogens before and after restriction using Clinical and Laboratory Standards Institute (CLSI) guide-lines.Vitek System or conventional identification methods were performed and susceptibility testing done by disk diffusion according to CLSI.Antibiotic consumption (t-test) and susceptibilities (McNemar's test) were determined. The defined daily doses (DDD) of group 2 carbapenems declined from 61.1 to 48.7 DDD/1,000 patient-days two years after ertapenem introduction (p = 0.027). Mean ertapenem consumption after restriction was 31.5 DDD/1,000 patient-days. Following ertapenem introduction no significant susceptibility changes were noticed among Gram-positive cocci. The most prevalent GNB were P. aeruginosa, Klebsiella pneumoniae, and Acinetobacter spp. There was no change in P. aeruginosa susceptibility to carbapenems. Significantly improved P. aeruginosa and K. pneumoniae ciprofloxacin susceptibilities were observed, perhaps due to decreased group 2 carbapenem use. K. pneumoniae susceptibility to trimethoprim-sulfamethoxazole improved. Preferential use of ertapenem resulted in reduced group 2 carbapenem use, with a positive impact on P. aeruginosa and K. pneumoniae susceptibility.

Elucidating Turnover Pathways of Bioactive Small Molecules by Isotopomer Analysis: The Persistent Organic Pollutant DDT

PubMed Central

Ehlers, Ina; Betson, Tatiana R.; Vetter, Walter; Schleucher, Jürgen

2014-01-01

The persistent organic pollutant DDT (1,1,1-trichloro-2,2-bis(4-chlorophenyl)ethane) is still indispensable in the fight against malaria, although DDT and related compounds pose toxicological hazards. Technical DDT contains the dichloro congener DDD (1-chloro-4-[2,2-dichloro-1-(4-chlorophenyl)ethyl]benzene) as by-product, but DDD is also formed by reductive degradation of DDT in the environment. To differentiate between DDD formation pathways, we applied deuterium NMR spectroscopy to measure intramolecular deuterium distributions (2H isotopomer abundances) of DDT and DDD. DDD formed in the technical DDT synthesis was strongly deuterium-enriched at one intramolecular position, which we traced back to 2H/1H fractionation of a chlorination step in the technical synthesis. In contrast, DDD formed by reductive degradation was strongly depleted at the same position, which was due to the incorporation of 2H-depleted hydride equivalents during reductive degradation. Thus, intramolecular isotope distributions give mechanistic information on reaction pathways, and explain a puzzling difference in the whole-molecule 2H/1H ratio between DDT and DDD. In general, our results highlight that intramolecular isotope distributions are essential to interpret whole-molecule isotope ratios. Intramolecular isotope information allows distinguishing pathways of DDD formation, which is important to identify polluters or to assess DDT turnover in the environment. Because intramolecular isotope data directly reflect isotope fractionation of individual chemical reactions, they are broadly applicable to elucidate transformation pathways of small bioactive molecules in chemistry, physiology and environmental science. PMID:25350380

Right atrial pacing impairs cardiac function during resynchronization therapy: acute effects of DDD pacing compared to VDD pacing.

PubMed

Bernheim, Alain; Ammann, Peter; Sticherling, Christian; Burger, Peter; Schaer, Beat; Brunner-La Rocca, Hans Peter; Eckstein, Jens; Kiencke, Stephanie; Kaiser, Christoph; Linka, Andre; Buser, Peter; Pfisterer, Matthias; Osswald, Stefan

2005-05-03

We aimed to compare the hemodynamic effects of right-atrial-paced (DDD) and right-atrial-sensed (VDD) biventricular paced rhythm on cardiac resynchronization therapy (CRT). Cardiac resynchronization therapy improves hemodynamics in patients with severe heart failure and left ventricular (LV) dyssynchrony. However, the impact of active right atrial pacing on resynchronization therapy is unknown. Seventeen CRT patients were studied 10 months (range: 1 to 46 months) after implantation. At baseline, the programmed atrioventricular delay was optimized by timing LV contraction properly at the end of atrial contraction. In both modes the acute hemodynamic effects were assessed by multiple Doppler echocardiographic parameters. Compared to DDD pacing, VDD pacing resulted in much better improvement of intraventricular dyssynchrony assessed by the septal-to-posterior wall motion delay (VDD 106 +/- 83 ms vs. DDD 145 +/- 95 ms; p = 0.001), whereas the interventricular mechanical delay (difference between onset of pulmonary and aortic outflow) did not differ (VDD 20 +/- 21 ms vs. DDD 18 +/- 17 ms; p = NS). Furthermore, VDD pacing significantly prolonged the rate-corrected LV filling period (VDD 458 +/- 123 ms vs. DDD 371 +/- 94 ms; p = 0.0001) and improved the myocardial performance index (VDD 0.60 +/- 0.18 vs. DDD 0.71 +/- 0.23; p < 0.01). Our findings suggest that avoidance of right atrial pacing results in a higher degree of LV resynchronization, in a substantial prolongation of the LV filling period, and in an improved myocardial performance. Thus, the VDD mode seems to be superior to the DDD mode in CRT patients.

Beta2-adrenergic agonist use and the risk of multiple sclerosis: a total population-based case-control study.

PubMed

Tsai, Ching-Piao; Lin, Feng-Cheng; Lee, Charles Tzu-Chi

2014-10-01

The aim of this study was to investigate whether the use of fenoterol, a beta2-adrenergic agonist, was associated with multiple sclerosis (MS) risk by conducting a total population-based case-control study in Taiwan. A total of 578 patients with newly diagnosed MS who had a severely disabling disease (SDD) certificate between January 1, 2002 and December 1, 2008 comprised the case group. These cases were compared with 2890 gender-, age-, residence-, and insurance premium-matched controls. Fenoterol use was analyzed using a conditional logistic regression model that controlled for asthma, chronic obstructive pulmonary disease (COPD), salbutamol and steroid use. Compared with the group of people who did not use fenoterol, the adjusted odds ratios were 0.67 (95% confidence interval (CI) = 0.48-0.93, p = 0.016) for the group prescribed fenoterol below 2.25 cumulative defined daily dose (cDDD) and 0.49 (95% CI = 0.33-0.71, p < 0.001) for the group with a cumulative fenoterol use of more than 2.25 cDDD. The dose-response relationship was similar within the non-asthma patients. The associations were similar between males and females, but differences between age groups were observed. The results of this study suggest that fenoterol use may reduce the risk of MS. © The Author(s), 2014.

A field assessment of long-term laboratory sediment toxicity tests with the amphipod Hyalella azteca

USGS Publications Warehouse

Ingersoll, Christopher G.; Wang, Ning; Hayward, Jeannie M. R.; Jones, John R.; Jones, Susan B.; Ireland, D. Scott

2005-01-01

Response of the amphipod Hyalella azteca exposed to contaminated sediments for 10 to 42 d in laboratory toxicity tests was compared to responses observed in controlled three-month invertebrate colonization exposures conducted in a pond. Sediments evaluated included a sediment spiked with dichlorodiphenyldichloroethane (DDD) or dilutions of a field sediment collected from the Grand Calumet River (GCR) in Indiana (USA) (contaminated with organic compounds and metals). Consistent effects were observed at the highest exposure concentrations (400 ??g DDD/goc [DDD concentrations normalized to grams of organic carbon (goc) in sedimentl or 4% GCR sediment) on survival, length, and reproduction of amphipods in the laboratory and on abundance of invertebrates colonizing sediments in the field. Effect concentrations for DDD observed for 10-d length and 42-d reproduction of amphipods (e.g., chronic value [ChV] of 66 ??g DDD/goc and 25% inhibition concentration [IC25] of 68 ??g DDD/goc for reproduction) were similar to the lowest effect concentrations for DDD measured on invertebrates colonizing sediment the field. Effect concentrations for GCR sediment on 28-d survival and length and 42-d reproduction and length of amphipods (i.e., ChVs of 0.20-0.66% GCR sediment) provided more conservative effect concentrations compared to 10-d survival or length of amphipods in the laboratory or the response of invertebrates colonizing sediment in the field (e.g., ChVs of 2.2% GCR sediment). Results of this study indicate that use of chronic laboratory toxicity tests with H. azteca and benthic colonization studies should be used to provide conservative estimates of impacts on benthic communities exposed to contaminated sediments. Bioaccumulation of DDD by oligochaetes colonizing the DDD-spiked sediment was similar to results of laboratory sediment tests previously conducted with the oligochaete Lumbriculus variegates, confirming that laboratory exposures can be used to estimate bioaccumulation by oligochaetes exposed in the field. ?? 2005 SETAC.

Developmentally Disabled Persons in Family Settings: Report No. 2.

ERIC Educational Resources Information Center

Cox, Wendy M.; Wilson, Wendell L.

The second in a series of three reports, this document presents findings of clients of Washington's Division of Developmental Disabilities (DDD), ages 22-29, who were living with their families at age 18 but now live elsewhere (group B). Findings are based on telephone interviews with families of 224 DDD clients and analysis of DDD records. The…

Developmentally Disabled Persons in Family Settings: Report No. 3.

ERIC Educational Resources Information Center

Cox, Wendy M.; Wilson, Wendell L.

The final part of a three part study of developmentally disabled persons in Washington State, this document focuses on clients of the Division of Developmental Disabilities (DDD), ages 19 through 26, who appeared to be eligible for DDD services but were not enrolled with the DDD (group C). Telephone interviews were conducted with parents of 55…

DDD(R)-pacing, but not AAI(R)-pacing induces left ventricular desynchronization in patients with sick sinus syndrome: tissue-Doppler and 3D echocardiographic evaluation in a randomized controlled comparison.

PubMed

Albertsen, Andi Eie; Nielsen, Jens Cosedis; Poulsen, Steen Hvitfeldt; Mortensen, Peter Thomas; Pedersen, Anders Kirstein; Hansen, Peter Steen; Jensen, Henrik Kjaerulf; Egeblad, Henrik

2008-02-01

Increasing evidence from randomized trials and experimental studies indicates that right ventricular (RV) pacing may induce congestive heart failure. We studied regional left ventricular (LV) dyssynchrony and global LV function in 50 consecutive patients with sick sinus syndrome (SSS) randomized to either atrial pacing [AAI(R)] or dual chamber RV-pacing [DDD(R)]. Fifty consecutive patients were randomized to AAI(R) or DDD(R)-pacing. Tissue-Doppler imaging was used to quantify LV dyssynchrony in terms of number of segments with delayed longitudinal contraction (DLC). Left ventricular ejection fraction (LVEF) was measured using three-dimensional echocardiography. Dyssynchrony was more pronounced in the DDD(R)-group than in the AAI(R)-group at the 12 months follow-up (P < 0.05). This reflected a significant increase of dyssynchrony in the DDD(R)-group from baseline to the 12 months follow-up (1.3 +/- 1 to 2.1 +/- 1 segments displaying DLC per patient), P < 0.05. No change was observed in the AAI(R)-group (1.6 +/- 2 to 1.3 +/- 2 segments displaying DLC per patient, NS). No difference in LVEF, NYHA or NT-proBNP was observed between AAI(R)- and DDD(R)-mode after 12 months of pacing although LVEF decreased significantly in the DDD(R)-group from baseline (63.1 +/- 8%) to the 12 months follow-up (59.3 +/- 8%, P < 0.05), while LVEF remained unchanged in the AAI(R)-group (61.5 +/- 11% at baseline vs. 62.3 +/- 7% after 12 months, NS. In patients with SSS, DDD(R)-pacing but not AAI(R)-pacing induces significant LV desynchronization and reduction of LVEF.

Long-term outcome in patients receiving permanent pacemaker implantation for atrioventricular block: Comparison of VDD and DDD pacing.

PubMed

Liao, Jo-Nan; Chao, Tze-Fan; Tuan, Ta-Chuan; Kong, Chi-Woon; Chen, Shih-Ann

2016-08-01

A permanent pacemaker (PPM) with dual chamber pacing (DDD) offers atrioventricular synchronization for patients with atrioventricular block (AVB). Single lead atrial synchronous ventricular pacing mode (VDD) is an alternative, but there are concerns about its efficacy and risk of atrial undersensing. Whether VDD can be a good alternative in patients with AVB remains unknown. The aim of the present study was to compare the long-term risk of mortality of VDD with DDD pacing.A total of 207 patients undergoing PPM implantations for AVB with VDD mode were enrolled from 2000 to 2013. Another 828 age- and sex-matched patients undergoing DDD implantations during the same period of time were selected as the control group in a 1 to 4 ratio. The study endpoint was mortality.A total of 1035 patients (64.3% male) were followed up for 46.5 ± 43.2 months. The mean ages were 75.0 years for VDD, and 74.9 years for DDD. The Kaplan-Meier survival analysis showed no significant difference in long-term survival between the VDD and DDD groups (log-rank P = 0.313). After adjustment for baseline characteristics, the VDD and DDD groups had a similar long-term prognosis with an adjusted hazard ratio of 0.875 (P = 0.445). Further analyses for the risk of cardiovascular and noncardiovascular deaths also showed no significant differences between the 2 groups.The long-term prognosis of VDD mode is comparable to that of DDD mode. Single lead VDD can be considered as an alternative choice in patients with AVB without sinus nodal dysfunction.

Upgrading from VVI to DDD pacing Mode during elective replacement of pulse generator: a comparative clinical-functional analysis.

PubMed

Teno, Luiz Antonio Castilho; Costa, Roberto; Martinelli Filho, Martino; Castilho, Fabian Cecchi Teno; Ruiz, Ivan

2007-02-01

Evaluate the clinical and functional behavior of the ventricular and atrioventricular stimulation modes in the elective replacement of pulse generator in patients with chagasic cardiopathy and atrioventricular block. Twenty-seven patients under ventricular and atrioventricular stimulation were comparatively evaluated at the beginning of the study, and alternately in ventricular and atrioventricular modes in two 90-day phases, with regard to: the clinical behavior evaluated according to quality of life and functional class, and the functional behavior evaluated by transthoracic echocardiography and the six-minute walk test. The statistical analysis was performed with patients at baseline, and under ventricular and atrioventricular modes, using the chi-square test and the repeated measures analysis of variance, and taking into consideration a 0.05 level of significance. The mean quality-of-life scores were: functional capacity (VVI 71.3+/-18.2 , DDD 69.3+/-20.4); overall health status (VVI 68.1+/-21.8, DDD 69.4+/-19.4) and vitality (VVI 64.8+/-24.6 , DDD 67.6+/-25.5); on echocardiography: LVEF (VVI 52.5+/-12.8 , DDD 51.8+/-14.9), LVDD (VVI 53.0+/-7.7 , DDD 42.4+/-7.8), LA (VVI 38.6+/-5.4 DDD 38.5+/-5.1), and in the six-minute walk test: distance walked (VVI 463.4+/-84.7, DDD 462.6+/-63.4). There were four cases of complications, three of them associated with the change in stimulation mode. This study showed no differences between the two stimulation modes in the clinical behavior assessed by quality of life and functional class, and in the functional behavior, evaluated according to the ecochardiographic findings and the six-minute walk test.

Degradation of chlorinated pesticide DDT by litter-decomposing basidiomycetes.

PubMed

Suhara, Hiroto; Adachi, Ai; Kamei, Ichiro; Maekawa, Nitaro

2011-11-01

One hundred and two basidiomycete strains (93 species in 41 genera) that prefer a soil environment were examined for screening of 1,1,1-trichloro-2,2-bis(4-chlorophenyl)ethane (DDT) biodegradation. Three strains within two litter-decomposing genera, Agrocybe and Marasmiellus, were selected for their DDT biotransformation capacity. Eight metabolites; 1,1-dichloro-2,2-bis(4-chlorophenyl)ethane (DDD), two monohydroxy-DDTs, monohydroxy-DDD, 2,2-dichloro-1,1-bis(4-chlorophenyl)ethanol, putative 2,2-bis(4-chlorophenyl)ethanol and two unidentified compounds were detected from the culture with Marasmiellus sp. TUFC10101. A P450 inhibitor, 1-ABT, inhibited the formation of monohydroxy-DDTs and monohydroxy-DDD from DDT and DDD, respectively. These results indicated that oxidative pathway which was catalyzed by P450 monooxygenase exist beside reductive dechlorination of DDT. Monohydroxylation of the aromatic rings of DDT (and DDD) by fungal P450 is reported here for the first time.

Dechlorination of DDT, DDD and DDE in soil (slurry) phase using magnesium/palladium system.

PubMed

Gautam, Sumit Kumar; Suresh, Sumathi

2006-12-01

Mg0/Pd4+ was able to dechlorinate >99% of extractable DDT (initial concentration of 10 mg DDT kg(-1) of soil) and >90% of extractable DDT (initial concentration of 50 mg DDT kg(-1) of soil) in soil slurry. Mg0/Pd4+ was also found to be effective in dechlorinating of 50 mg kg(-1) DDD and DDE, in soil aged for varying time periods. GC-MS analyses revealed the formation of 1,1-diphenylethane as an end product from DDT, DDE and DDD. To the best of our knowledge this is the first report describing the application Mg0/Pd4+ system for remediation of DDT, DDD and DDE contaminated soil. We conclude that reductive dechlorination reaction catalyzed by Mg0/Pd4+ may be a promising system to remediate soil contaminated with DDT and its dechlorinated products such as DDD and DDE.

Documentation Driven Development for Complex Real-Time Systems

DTIC Science & Technology

2004-12-01

This paper presents a novel approach for development of complex real - time systems , called the documentation-driven development (DDD) approach. This... time systems . DDD will also support automated software generation based on a computational model and some relevant techniques. DDD includes two main...stakeholders to be easily involved in development processes and, therefore, significantly improve the agility of software development for complex real

Mathematical and Computational Aspects of Multiscale Materials Modeling, Mathematics-Numerical analysis, Section II.A.a.3.4, Conference and symposia organization II.A.2.a

DTIC Science & Technology

2015-02-04

dislocation dynamics models ( DDD ), continuum representations). Coupling of these models is difficult. Coupling of atomistics and DDD models has been...explored to some extent, but the coupling between DDD and continuum models of the evolution of large populations of dislocations is essentially unexplored

--No Title--

Science.gov Websites

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Does football cause an increase in degenerative disease of the lumbar spine?

PubMed

Gerbino, Peter G; d'Hemecourt, Pierre A

2002-02-01

Degenerative disease of the lumbar spine is exceedingly common. Whether any specific activity increases the likelihood of developing degenerative disc disease (DDD) or facet degeneration (FD) has enormous implications. Within the field of occupational medicine there are specific activities, occupations, and morphologic characteristics that have been related to low back pain. Several specific risk factors have been conclusively linked to low back pain, and in particular DDD and FD. Within the sport of American football, there has long been the feeling that many athletes have or will develop low back pain, DDD, and FD. Proving that certain risk factors present in football will predictably lead to an increase in LBP, DDD, and FD is more difficult. At this time, it can be said that football players, in general, increase their risk of developing low back pain, DDD, and FD as their years of involvement with their sport increase. Because specific spine injuries like fracture, disc herniation, and spondylolysis are more frequent in football players, the resulting DDD and FD are greater than that of the general population. The weightlifting and violent hyperextension that are part of American football are independent risk factors for degenerative spine disease.

A Precise Drunk Driving Detection Using Weighted Kernel Based on Electrocardiogram.

PubMed

Wu, Chung Kit; Tsang, Kim Fung; Chi, Hao Ran; Hung, Faan Hei

2016-05-09

Globally, 1.2 million people die and 50 million people are injured annually due to traffic accidents. These traffic accidents cost $500 billion dollars. Drunk drivers are found in 40% of the traffic crashes. Existing drunk driving detection (DDD) systems do not provide accurate detection and pre-warning concurrently. Electrocardiogram (ECG) is a proven biosignal that accurately and simultaneously reflects human's biological status. In this letter, a classifier for DDD based on ECG is investigated in an attempt to reduce traffic accidents caused by drunk drivers. At this point, it appears that there is no known research or literature found on ECG classifier for DDD. To identify drunk syndromes, the ECG signals from drunk drivers are studied and analyzed. As such, a precise ECG-based DDD (ECG-DDD) using a weighted kernel is developed. From the measurements, 10 key features of ECG signals were identified. To incorporate the important features, the feature vectors are weighted in the customization of kernel functions. Four commonly adopted kernel functions are studied. Results reveal that weighted feature vectors improve the accuracy by 11% compared to the computation using the prime kernel. Evaluation shows that ECG-DDD improved the accuracy by 8% to 18% compared to prevailing methods.

Long-term follow-up of DDD pacing mode.

PubMed

Ulman, Mateusz; Dębski, Maciej; Ząbek, Andrzej; Haberka, Kazimierz; Lelakowski, Jacek; Małecka, Barbara

2014-01-01

The aim of this study was to determine the long-term survival of DDD pacing and identify the main reasons for its loss. The study group consisted of 496 patients in whom a DDD pacing system was implanted between October 1984 and March 2002 and who were followed up until July 2010. The follow-up period was 152.1 ± 35.5 months. The patients' mean age at the time of implantation was 59.5 ± 12.5 years, and 53.5% were male; 58% had sick sinus syndrome (SSS), 26% had atrioventricular block (AVB), 15% had both of these indications simultaneously, and 1% had other indications. The incidence of lead malfunction, progression to chronic atrial fibrillation (AF), and the rate of infective complications was analysed. During the follow-up, 369 patients remained in DDD mode stimulation. DDD mode survival rate at one, five, ten and 15 years was, respectively, 96%, 86%, 77% and 72%. The most common reason for reprogramming out of DDD mode was the development of permanent AF in 65 (13.1%) patients. The occurrence of chronic AF was associated with a prior history of paroxysmal AF (p = 0.0001), SSS (p = 0.0215), and older age at time of implantation (p = 0.0068) compared to patients who remained in sinus rhythm. Lead malfunction caused loss of DDD mode pacing in 56 (11.3%) patients. Atrial leads were damaged in 37 patients, ventricular in 12 patients, and both leads in seven patients. The subclavian vein puncture was correlated with the mechanical damage of the atrial lead (p = 0.02935) compared to cephalic vein access. At the moment of complication, the patients with a dysfunctional lead were significantly younger than those who progressed to chronic AF(p = 0.0019). Infective complications which caused temporary loss of DDD pacing were observed in six patients: five had pocket infection and one had lead-dependent infective endocarditis. 1. Effective DDD pacing from the originally implanted system was noted in a high percentage (72%) of patients in long-term observation (15 years). 2. Progression to permanent AF is the most common reason for loss of DDD pacing;a history of paroxysmal AF and old age are the risk factors. 3. Subclavian vein puncture is associated with a higher rate of atrial lead damage.

A health insurance company-initiated practice support intervention for optimizing acid-suppressing drug prescriptions in primary care.

PubMed

Smeets, Hugo M; Hoes, Arno W; Zuithoff, Nicolaas P A; van Dijk, Paul C M; van der Lee, Arnold P M; de Wit, Niek J

2011-08-01

A health insurance-initiated programme to improve cost-effectiveness of acid-suppressing drugs (ASDs). To evaluate the effect of two different interventions of general practitioner support in reducing drug prescription. A sequential cluster randomized controlled trial with 90 participating general practitioners in a telephone support (TS) group or practice visit (PV) group. TS group received support in phase-1 (first 6 months), but served as control group in phase-2 (6-12 months period). PV group received no intervention in phase-1, serving as the control group for the TS group, but received support in phase-2. Prescription data were extracted from Agis Health Insurance Database. Outcomes were the proportion of responders to drug reduction and the number of defined daily dose (DDD). Differences in users and DDD were analysed using multilevel regression analysis. At baseline, 3424 patients used ASD chronically (211 DDDs, on average). The difference between TS and control groups among responders was 3.2% [95% confidence interval (CI): 0.8; 5.6] and relative risk was 1.26 (95% CI: 1.06; 1.51). The difference between PV and control groups was not relevant (0.4%, 95% CI: -1.99; 2.79 and relative risk: 1.01, 95% CI: 0.82; 1.20). The difference in DDD per patient was -3.0 (95% CI: -8.9; 2.9) and -5.82 (95% CI: -12.4; 0.73), respectively. This health insurance company-initiated intervention had a moderate effect on ASD prescription. In contrast to TS, PVs did not seem to reduce ASD prescription rates.

Non-steroidal anti-inflammatory drugs, Cyclooxygenase-2 inhibitors and paracetamol use in Queensland and in the whole of Australia.

PubMed

Barozzi, Nadia; Tett, Susan E

2008-09-24

Cross national drug utilization studies can provide information about different influences on physician prescribing. This is important for medicines with issues around safety and quality of use, like non selective non-steroidal anti-inflammatory drugs (ns-NSAIDs) and cyclo-oxygenase-2 (COX-2) inhibitors. To enable comparison of prescription medicine use across different jurisdictions with a range of population sizes, data first need to be compared within Australia to understand whether use in a smaller sub-population may be considered as representative of the total use within Australia. The aim of this study was to compare the utilization of non selective NSAID, COX-2 inhibitors and paracetamol between Queensland and Australia. Dispensing data were obtained for concession beneficiaries for Australia for ns-NSAIDs, COX-2 inhibitors and paracetamol subsidized by the PBS over the period 1997-2003. The same data were purchased for Queensland. Data were converted to Defined Daily Dose (DDD)/1000 beneficiaries/day (World Health Organization anatomical therapeutic chemical classification, 2005). Total NSAID and paracetamol consumption were similar in Australia and Queensland. Ns-NSAID use decreased sharply with the introduction of COX-2 inhibitors (from approximately 80 to 40 DDD/1000 beneficiaries/day). Paracetamol was constant (approximately 45 DDD/1000 beneficiaries/day). COX-2 inhibitors consumption was initially higher in Queensland than in the whole of Australia. Despite initial divergence in celecoxib use between Queensland and Australia, the use of ns-NSAIDs, COX-2 inhibitors and paracetamol overall, in concession beneficiaries, was comparable in Australia and Queensland.

Environment of Space Interactions with Space Systems

NASA Technical Reports Server (NTRS)

2004-01-01

The primary product of this research project was a computer program named SAVANT. This program uses the Displacement Damage Dose (DDD) method of calculating radiation damage to solar cells. This calculation method was developed at the Naval Research Laboratory, and uses fundamental physical properties of the solar cell materials to predict radiation damage to the solar cells. This means that fewer experimental measurements are required to characterize the radiation damage to the cells, which results in a substantial cost savings to qualify solar cells for orbital missions. In addition, the DDD method makes it easier to characterize cells that are already being used, but have not been fully tested using the older technique of characterizing radiation damage. The computer program combines an orbit generator with NASA's AP-8 and AE-8 models of trapped protons and electrons. This allows the user to specify an orbit, and the program will calculate how the spacecraft moves during the mission, and the radiation environment that it encounters. With the spectrum of the particles, the program calculates how they would slow down while traversing the coverglass, and provides a slowed-down spectrum.

Triptans use and overuse: A pharmacoepidemiology study from the French health insurance system database covering 4.1 million people.

PubMed

Braunstein, David; Donnet, Anne; Pradel, Vincent; Sciortino, Vincent; Allaria-Lapierre, Véronique; Lantéri-Minet, Michel; Micallef, Joëlle

2015-11-01

The objective of this study was to estimate and to characterize the actual patterns of triptan use and overuse in France using a drug reimbursement database. We included all people covered by the French General Health Insurance System (GHIS) from the Provence-Alpes-Côte-d'Azur (PACA) and Corsica administrative areas who had at least one dispensed dose of triptans between May 2010 and December 2011. All dispensed doses of triptans, migraine prophylactic treatment and psychotropic medications were extracted from the GHIS database. Triptan overuse was defined as triptan use >20 defined daily doses (DDD) per month on a regular basis for more than three consecutive months. Risk of overuse was assessed using logistic regression adjusted for gender and age. We included 99,540 patients who had at least one prescription of a triptan over the 20 months of the study. Among them, 2243 patients (2.3%) were identified as overusers and received 20.2% of the total DDD prescribed. Twelve percent of overusers and 6.9% of non-overusers were aged more than 65 years (OR: 1.81). Overusers did not have a greater number of prescribers and pharmacists than non-overusers. They were more frequently prescribed a prophylactic medication for migraine treatment (56.8% vs 35.9%, OR: 2.36), benzodiazepines (69.9% vs 54.7%, OR: 1.93) and antidepressants (49.4% vs 30.2%, OR: 2.33). This work suggests that triptan overuse may be due to insufficient prescriber awareness of appropriate prescribing. The off-label prescription of triptans among the elderly necessitates investigating their cardiovascular risk profile in this sub-group. © International Headache Society 2015.

Improvement, Verification, and Refinement of Spatially-Explicit Exposure Models in Risk Assessment - FishRand Spatially-Explicit Bioaccumulation Model Demonstration

DTIC Science & Technology

2015-08-01

21  Figure 4. Data-based proportion of DDD , DDE and DDT in total DDx in fish and sediment by... DDD dichlorodiphenyldichloroethane DDE dichlorodiphenyldichloroethylene DDT dichlorodiphenyltrichloroethane DoD Department of Defense ERM... DDD ) at the other site. The spatially-explicit model consistently predicts tissue concentrations that closely match both the average and the

Quantifying the use of the statin antilipemic drugs: comparisons and contrasts between Nova Scotia, Canada, and Queensland, Australia.

PubMed

Cooke, Charmaine; Nissen, Lisa; Sketris, Ingrid; Tett, Susan E

2005-04-01

Jurisdictions are developing public drug insurance systems to improve access to pharmaceuticals, cost-effective prescribing, and patient health and well-being. We compared 2 jurisdictions with different pharmaceutical policies to determine prescribing patterns for 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (ie, statins). The aim of this work was to investigate the feasibility of using available prescription administrative databases to compare the use of statins in Queensland, Australia, and in Nova Scotia, Canada. Data from the Nova Scotia Pharmacare Program and the Health Insurance Commission in Australia were used to obtain dispensing data. Utilization was compared for the 5-year period from 1997 through 2001, using the World Health Organization anatomic therapeutic chemical/defined daily dose (DDD) system. In the year 2001, there were 177,000 beneficiaries in the public drug plan in Nova Scotia (62% aged > or = 65 years old) and 960,000 concession beneficiaries (pensioners and social security recipients, 61 aged > or = 65 years) in Queensland. These 2 groups were comparable. The overall utilization of statin medications increased steadily in both areas over the study period, from 50 to 205 DDD/1000 beneficiaries per day. Comparison of the 2 growth lines showed no statistically significant differences in overall statin use despite differences in brand availabilities and policies about prescribing. In the year 2001, atorvastatin was the most commonly prescribed statin in both areas, comprising 46% of statin use in Nova Scotia and 51% in Queensland. Mean doses of each statin prescribed were slightly above the DDDs. Expenditure on statins per 1000 beneficiaries and per DDD were similar in each jurisdiction, being slightly higher in Nova Scotia. Despite differences in pharmaceutical reimbursement systems, use of the statins was similar in Nova Scotia and Queensland. The feasibility of the methodology was demonstrated. Future studies, including comparisons of drug utilization for other classes of drugs for which drug policies may be divergent (eg, different pricing structures or prior authorization requirements), or for which less evidence for appropriate use is available, may be useful.

Patterns of lumbar disc degeneration are different in degenerative disc disease and disc prolapse magnetic resonance imaging analysis of 224 patients.

PubMed

Kanna, Rishi M; Shetty, Ajoy Prasad; Rajasekaran, S

2014-02-01

Existing research on lumbar disc degeneration has remained inconclusive regarding its etiology, pathogenesis, symptomatology, prevention, and management. Degenerative disc disease (DDD) and disc prolapse (DP) are common diseases affecting the lumbar discs. Although they manifest clinically differently, existing studies on disc degeneration have included patients with both these features, leading to wide variations in observations. The possible relationship or disaffect between DDD and DP is not fully evaluated. To analyze the patterns of lumbar disc degeneration in patients with chronic back pain and DDD and those with acute DP. Prospective, magnetic resonance imaging-based radiological study. Two groups of patients (aged 20-50 years) were prospectively studied. Group 1 included patients requiring a single level microdiscectomy for acute DP. Group 2 included patients with chronic low back pain and DDD. Discs were assessed by magnetic resonance imaging through Pfirmann grading, Schmorl nodes, Modic changes, and the total end-plate damage score for all the five lumbar discs. Group 1 (DP) had 91 patients and group 2 (DDD) had 133 patients. DP and DDD patients differed significantly in the number, extent, and severity of degeneration. DDD patients had a significantly higher number of degenerated discs than DP patients (p<.000). The incidence of multilevel and pan-lumbar degeneration was also significantly higher in DDD group. The pattern of degeneration also differed in both the groups. DDD patients had predominant upper lumbar involvement, whereas DP patients had mainly lower lumbar degeneration. Modic changes were more common in DP patients, especially at the prolapsed level. Modic changes were present in 37% of prolapsed levels compared with 9.9% of normal discs (p<.00). The total end-plate damage score had a positive correlation with disc degeneration in both the groups. Further the mean total end-plate damage score at prolapsed level was also significantly higher. The results suggest that patients with disc prolapse, and those with back pain with DDD are clinically and radiologically different groups of patients with varying patterns, severity, and extent of disc degeneration. This is the first study in literature to compare and identify significant differences in these two commonly encountered patient groups. In patients with single-level DP, the majority of the other discs are nondegenerate, the lower lumbar spine is predominantly involved and the end-plate damage is higher. Patients with back pain and DDD have larger number of degenerate discs, early multilevel degeneration, and predominant upper lumbar degeneration. The knowledge that these two groups of patients are different clinically and radiologically is critical for our improved understanding of the disease and for future studies on disc degeneration and disc prolapse. Copyright © 2014 Elsevier Inc. All rights reserved.

A FFT-based formulation for efficient mechanical fields computation in isotropic and anisotropic periodic discrete dislocation dynamics

NASA Astrophysics Data System (ADS)

Bertin, N.; Upadhyay, M. V.; Pradalier, C.; Capolungo, L.

2015-09-01

In this paper, we propose a novel full-field approach based on the fast Fourier transform (FFT) technique to compute mechanical fields in periodic discrete dislocation dynamics (DDD) simulations for anisotropic materials: the DDD-FFT approach. By coupling the FFT-based approach to the discrete continuous model, the present approach benefits from the high computational efficiency of the FFT algorithm, while allowing for a discrete representation of dislocation lines. It is demonstrated that the computational time associated with the new DDD-FFT approach is significantly lower than that of current DDD approaches when large number of dislocation segments are involved for isotropic and anisotropic elasticity, respectively. Furthermore, for fine Fourier grids, the treatment of anisotropic elasticity comes at a similar computational cost to that of isotropic simulation. Thus, the proposed approach paves the way towards achieving scale transition from DDD to mesoscale plasticity, especially due to the method’s ability to incorporate inhomogeneous elasticity.

Discrete Dislocation Dynamics Simulations of Twin Size-Effects in Magnesium

DTIC Science & Technology

2015-01-01

deformation induced softening. Over the past two decades, discrete dislocation dynamics ( DDD ) has been one of the most efficient methods to capture...14] and intermittent behavior [15] of the FCC and BCC materials. More recently, DDD simulations of Mg investigated a number of important effects...plays an important and sometimes dominant role in the mechanical behavior of both single crystals and polycrystals. As a result, such DDD simulations

Quantitative trait loci that control body weight in DDD/Sgn and C57BL/6J inbred mice.

PubMed

Suto, Jun-Ichi; Kojima, Misaki

2017-02-01

Inbred DDD/Sgn mice are heavier than inbred C57BL/6J mice. In the present study, we performed quantitative trait loci (QTL) mapping for body weight using R/qtl in reciprocal F 2 male populations between the two strains. We identified four significant QTL on Chrs 1, 2, 5, and 17 (proximal region). The DDD/Sgn allele was associated with increased body weight at QTL on Chrs 1 and 5, and the DDD/Sgn allele was associated with decreased body weight at QTL on Chrs 2 and 17. A multiple regression analysis indicated that the detected QTL explain 30.94 % of the body weight variation. Because DDD/Sgn male mice have extremely high levels of circulating testosterone relative to other inbred mouse strains, we performed QTL mapping for plasma testosterone level to examine the effect of testosterone levels on body weight. We identified one suggestive QTL on Chr 5, which overlapped with body weight QTL. The DDD/Sgn allele was associated with increased testosterone level. Thus, we confirmed that there was a genetic basis for the changes in body weight and testosterone levels in male mice. These findings provide insights into the genetic mechanism by which body weight is controlled in male mice.

A clinical comparison between a new dual-chamber pacing mode-AAIsafeR and DDD mode.

PubMed

Xue-Jun, Ren; Zhihong, Han; Ye, Wang; Huifeng, Du; Jinrong, Zhang; Fang, Chen; Jihong, Guo

2010-02-01

The aim of this study was to compare the cross-follow-up results in DDD or AAISafeR mode and to describe the safety and effectiveness of this pacing mode. The Symphony 2450/2550 cardiac pacemakers were implanted in 30 patients with sick sinus syndrome between February 2006 and September 2006. They were randomized to the DDD mode or AAISafeR mode for 3 months and then crossed over to the alternate pacing modality for an additional 3 months. No AAISafeR-related adverse event was observed. All documented episodes of paroxysmal atrial ventricular block caused the immediate switch of the pacing mode from AAI to DDD. The cumulative percent ventricular pacing was significantly reduced in the AAISafeR mode compared with the DDD mode (0.9% [0%-3%] versus 51.3% [2%-91%] P = 0.001; 2.94% [0%-18%] versus 41.18% [0%-65%] P = 0.0001). After 3 months in DDD mode, left atrial diameter, left ventricular enddiastolic diameter, and left ventricular end-systolic diameter increased significantly and left ventricular ejection fraction decreased. However, no obvious changes appeared in 3 months of AAISafeR mode. Switches to DDD occurred during follow-up in 21 patients due to different-degree atrial ventricular block. The AAISafeR mode substantially reduces the amount of unnecessary right ventricular pacing in the bradycardia population and effectively prevents the deleterious effects on cardiac performance. An international randomized study will further ascertain the efficacy of this new pacing mode specifically in the prevention of heart failure hospitalization and atrial fibrillation.

DDD versus VVIR pacing in patients, ages 70 and over, with complete heart block.

PubMed

Ouali, Sana; Neffeti, Elyes; Ghoul, Karima; Hammas, Sami; Kacem, Slim; Gribaa, Rim; Remedi, Fahmi; Boughzela, Essia

2010-05-01

Dual-chamber pacing is believed to have an advantage over single-chamber ventricular pacing. The aim of the study was to determine whether elderly patients with implanted pacemaker for complete atrioventricular block gain significant benefit from dual-chamber (DDD) compared with single-chamber ventricular demand (VVIR). The study was designed as a double-blind randomized two-period crossover study-each pacing mode was maintained for 3 months. Thirty patients (eight men, mean age 76.5 +/- 4.3 years) with implanted PM were submitted to a standard protocol, which included an interview, functional class assessment, quality of life (QoL) questionnaires, 6-minute walk test, and transthoracic echocardiographic examinations. QoL was measured by the SF-36. All these parameters were obtained on DDD mode pacing and VVIR mode pacing. Paired data were compared. QoL was significantly different between the two groups and showed the best values in DDD. Overall, no patient preferred VVIR mode, 18 preferred DDD mode, and 12 expressed no preference. No differences in mean walking distances were observed between patients with single-chamber and dual-chamber pacing. VVI pacing elicited marked decrease in left ventricle ejection fraction and significant enlargement of the left atrium. DDD pacing resulted in significant increase of the peak systolic velocities in lateral mitral annulus and septal mitral annulus. Early diastolic velocities on both sides of mitral annulus did not change. In active elderly patients with complete heart block, DDD pacing is associated with improved quality of life and systolic ventricular function compared with VVI pacing.

Long-Term Outcome of Single-Chamber Atrial Pacing Compared with Dual-Chamber Pacing in Patients with Sinus-Node Dysfunction and Intact Atrioventricular Node Conduction

PubMed Central

Kim, Won Ho; Joung, Boyoung; Shim, Jaemin; Park, Jong Sung; Hwang, Eui-Seock; Pak, Hui-Nam; Kim, Sungsoon

2010-01-01

Purpose The optimal pacing mode with either single chamber atrial pacemaker (AAI or AAIR) or dual chamber pacemaker (DDD or DDDR) is still not clear in sinus-node dysfunction (SND) and intact atrioventricular (AV) conduction. Materials and Methods Patients who were implanted with permanent pacemaker using AAI(R) (n = 73) or DDD(R) (n = 113) were compared. Results The baseline characteristics were comparable between the two groups, with a mean follow-up duration of 69 months. The incidence of death did not show statistical difference. However, the incidence of hospitalization for congestive heart failure (CHF) was significantly lower in the AAI(R) group (0%) than the DDD(R) group (8.8%, p = 0.03). Also, atrial fibrillation (AF) was found in 2.8% in the AAI(R) group, which was statistically different from 15.2% of patients in the DDD(R) group (p = 0.01). Four patients (5.5%) with AAI(R) developed AV block, and subsequently switched to DDD(R) pacing. The risk of AF was lower in the patients implanted with AAI(R) than those with DDD(R) [hazard ratio (HR), 0.84; 95% confidence interval, 0.72 to 0.97, p = 0.02]. Conclusion In patients with SND and intact AV conduction, AAI(R) pacing can achieve a better clinical outcome in terms of occurrence of CHF and AF than DDD(R) pacing. These findings support AAI(R) pacing as the preferred pacing mode in patients with SND and intact AV conduction. PMID:20879047

A novel Death Defying Domain in Met entraps the active site of Caspase-3 and blocks apoptosis in hepatocytes

PubMed Central

Ma, Jihong; Zou, Chunbin; Guo, Lida; Seneviratne, Danushka S.; Tan, Xinping; Kwon, Yong-Kook; An, Jiyan; Bowser, Robert; DeFrances, Marie C.; Zarnegar, Reza

2013-01-01

Met, the transmembrane tyrosine kinase receptor for hepatocyte growth factor (HGF) is known to function as a potent anti-apoptotic mediator in normal and neoplastic cells. Herein we report that intracellular cytoplasmic tail of Met has evolved to harbor a tandem pair of Caspase-3 cleavage sites, which bait, trap and disable the active site of Caspase-3, thereby blocking the execution of apoptosis. We call this Caspase-3 cleavage motif the ‘Death Defying Domain’ (DDD). This site consists of the following sequence: DNAD-DEVD-T (where the hyphens denote caspase cleavage sites). Through functional and mechanistic studies, we show that upon DDD cleavage by Caspase-3, the resulting DEVD-T peptide acts as a competitive inhibitor and entraps the active site of Caspase-3 akin to DEVD-CHO, which is a potent, synthetic inhibitor of Caspase-3 activity. By gain and loss-of-function studies using restoration of DDD expression in DDD deficient hepatocytic cells, we found that both Caspase-3 sites in DDD are necessary for inhibition of Caspase-3 and promotion of cell survival. Employing mutagenesis studies, we show that DDD could operate independently of Met’s enzymatic activity as determined by using kinase-dead human Met mutant constructs. Studies of both human liver cancer tissues and cell lines uncovered that DDD cleavage and entrapment of Caspase-3 by DDD occur in vivo, further proving that this site has physiological and pathophysiological relevance. Conclusion Our findings show that Met can directly inhibit Caspase-3 via a novel mechanism and promote hepato-cyte survival. Results presented here will further our understanding of the mechanisms that control not only normal tissue homeostasis but also abnormal tissue growth such as cancer and degenerative diseases in which apoptotic caspases are at play. PMID:24122846

Effects of proton pump inhibitors on lung cancer precise radiotherapy-induced radiation pneumonitis.

PubMed

Su, QiaoLi; Wang, Duoning; Yuan, Bo; Liu, Feng; Lei, Yi; Li, Shuangqing

2014-11-01

The objective of this study was to explore the effects of proton pump inhibitors (PPIs) on the development and prognosis of lung cancer precise radiotherapy-induced radiation pneumonitis. Clinical materials of 84 lung cancer patients who had radiation pneumonitis after precise radiotherapy were retrospectively analyzed, and the patients were divided into PPI group and control group, according to whether or not PPIs were applied. The development and prognosis of patients and the effects of different doses of PPI on patient condition from two groups were compared. There were 57 PPI cases in PPI group and 27 cases in control group. Basic characteristics of patients were not statistically different between the two groups; however, white blood cell count, oxygenation indexes, blood gas pH, and lung imaging index were significantly different (p < 0.05), indicating that radiation pneumonitis tended to be more severe in PPI group. As regards effects of PPI on prognosis of two groups, remission rate of radiation pneumonia in PPI group was significantly less than that of the control group. Among 57 cases in PPI group, there were 31 patients applied with PPI ≤ 1DDD and 31 patients applied with PPI > 1DDD. In comparison of the various parameters of patients, 7 days after being applied with different doses of PPI, there were no significant differences between the parameters of radiation pneumonitis. PPIs should be cautiously utilized to avoid the effects of lung cancer radiotherapy-induced radiation pneumonia.

Use of acid-suppressive therapy before anti-reflux surgery in 2922 patients: a nationwide register-based study in Denmark.

PubMed

Lødrup, A; Pottegård, A; Hallas, J; Bytzer, P

2015-07-01

Guidelines recommend that patients with gastro-oesophageal reflux disease are adequately treated with acid-suppressive therapy before undergoing anti-reflux surgery. Little is known of the use of acid-suppressive drugs before anti-reflux surgery. To determine the use of proton pump inhibitors and H2 -receptor antagonists in the year before anti-reflux surgery. A nationwide retrospective study of all patients aged ≥18 undergoing first-time anti-reflux surgery in Denmark during 2000-2012 using data from three different sources: the Danish National Register of Patients, the Danish National Prescription Register, and the Danish Person Register. The study population thus included 2922 patients (median age: 48 years, 55.7% male). The annual proportion of patients redeeming ≥180 DDD of acid-suppressive therapy increased from 17.0% 5 years before anti-reflux surgery to 64.9% 1 year before. The probability for inadequate dosing 1 year before surgery (<180 DDD) was significantly increased for younger patients, patients operated in the period 2000-2003, patients who had not undergone pre-surgical manometry, pH- or impedance monitoring, and patients who had not redeemed prescriptions on NSAID or anti-platelet drugs. Compliance with medical therapy should be evaluated thoroughly before planning anti-reflux surgery, as a high proportion of patients receive inadequate dosing of acid-suppressive therapy prior to the operation. © 2015 John Wiley & Sons Ltd.

Long-term outcome in patients receiving permanent pacemaker implantation for atrioventricular block

PubMed Central

Liao, Jo-Nan; Chao, Tze-Fan; Tuan, Ta-Chuan; Kong, Chi-Woon; Chen, Shih-Ann

2016-01-01

Abstract A permanent pacemaker (PPM) with dual chamber pacing (DDD) offers atrioventricular synchronization for patients with atrioventricular block (AVB). Single lead atrial synchronous ventricular pacing mode (VDD) is an alternative, but there are concerns about its efficacy and risk of atrial undersensing. Whether VDD can be a good alternative in patients with AVB remains unknown. The aim of the present study was to compare the long-term risk of mortality of VDD with DDD pacing. A total of 207 patients undergoing PPM implantations for AVB with VDD mode were enrolled from 2000 to 2013. Another 828 age- and sex-matched patients undergoing DDD implantations during the same period of time were selected as the control group in a 1 to 4 ratio. The study endpoint was mortality. A total of 1035 patients (64.3% male) were followed up for 46.5 ± 43.2 months. The mean ages were 75.0 years for VDD, and 74.9 years for DDD. The Kaplan–Meier survival analysis showed no significant difference in long-term survival between the VDD and DDD groups (log-rank P = 0.313). After adjustment for baseline characteristics, the VDD and DDD groups had a similar long-term prognosis with an adjusted hazard ratio of 0.875 (P = 0.445). Further analyses for the risk of cardiovascular and noncardiovascular deaths also showed no significant differences between the 2 groups. The long-term prognosis of VDD mode is comparable to that of DDD mode. Single lead VDD can be considered as an alternative choice in patients with AVB without sinus nodal dysfunction. PMID:27583889

Biventricular pacing preserves left ventricular performance in patients with high-grade atrio-ventricular block: a randomized comparison with DDD(R) pacing in 50 consecutive patients.

PubMed

Albertsen, Andi E; Nielsen, Jens C; Poulsen, Steen H; Mortensen, Peter T; Pedersen, Anders K; Hansen, Peter S; Jensen, Henrik K; Egeblad, Henrik

2008-03-01

We aimed to investigate whether biventricular (BiV) pacing minimizes left ventricular (LV) dyssynchrony and preserves LV ejection fraction (LVEF) as compared with standard dual-chamber DDD(R) pacing in consecutive patients with high-grade atrio-ventricular (AV) block. Fifty patients were randomized to DDD(R) pacing or BiV pacing. LVEF was measured using three-dimensional echocardiography. Tissue-Doppler imaging was used to quantify LV dyssynchrony in terms of number of segments with delayed longitudinal contraction (DLC). LVEF was not different between groups after 12 months (P = 0.18). In the DDD(R) group LVEF decreased significantly from 59.7(57.4-61.4)% at baseline to 57.2(52.1-60.6)% at 12 months of follow-up (P = 0.03), whereas LVEF remained unchanged in the BiV group [58.9(47.1-61.7)% at baseline vs. 60.1(55.2-63.3)% after 12 months (P = 0.15)]. Dyssynchrony was more prominent in the DDD(R) group than in the BiV group at baseline (2.2 +/- 2.2 vs. 1.4 +/- 1.3 segments with DLC per patient, P = 0.10); and at 12 month follow-up (1.8 +/- 1.9 vs. 0.8 +/- 0.9 segments with DLC per patient, P = 0.02). NT-proBNP was unchanged in the DDD(R) group during follow-up (122 +/- 178 pmol/L vs. 91 +/- 166 pmol/L, NS) but decreased significantly in the BiV-group (from 198 +/- 505 pmol/L to 86 +/- 95 pmol/L after 12 months, P = 0.02). BiV pacing minimizes LV dyssynchrony, preserves LV function, and reduces NT-proBNP in contrast to DDD(R) pacing in patients with high-grade AV block.

Bioavailability to grains of rice of aged and fresh DDD and DDE in soils.

PubMed

Yao, Fenxia; Yu, Guifen; Bian, Yongrong; Yang, Xinglun; Wang, Fang; Jiang, Xin

2007-05-01

DDT had been widely used around the world before 1980s and is still under production and use for non-agricultural purposes in China. Because of their special physicochemical properties, p,p'-DDT and its main metabolites, p,p'-DDD and p,p'-DDE, accumulated and persisted in the environment, presenting potential menace on biota. A green-house study was conducted to determine the bioavailability of p,p'-DDD and p,p'-DDE to grains of rice and the influences of traditional Chinese farming practices on their bioaccumulation. Paddy rice and dry rice were grown in submerged paddy soils and non-submerged upland soils, respectively. Two types of soil, Hydragric Anthrosols (An) and Hydragric Acrisols (Ac), were employed. Bioaccumulation factors (BAFs) of DDE ranged from 0.67 for rice grown in non-submerged An to 0.84 in submerged An in the control group, whilst BAFs were all below 0.04 in experimental groups. BAFs of DDD varied from 1.39 for submerged An to 2.26 for submerged Ac in original soils. In contrast, BAFs were between 0.05 for non-submerged Ac and 0.08 for submerged An in DDD-contaminated soils. Flooding seemed to have two contradictory effects on the DDE/DDD accumulation by rice: on one hand, it made the pollutants more mobile and bioavailable; while on the other hand, it enhanced the degradation and binding of POPs. Adding rice straw to the soils protected DDE from being taken up yet promoted DDD accumulation by rice. Furthermore, the distinct inorganic component of the soils might also play an important role in the environmental activities of POPs.

Three-dimensional cell groups with disordered nuclei and cellular discohesion (3DDD) are associated with high sensitivity and specificity for cystoscopic urine cytopathological diagnosis of low-grade urothelial neoplasia.

PubMed

Mai, Kien T; Ball, Christopher G; Kos, Zuzana; Belanger, Eric C; Islam, Shahidul; Sekhon, Harman

2014-07-01

Cystoscopic urine obtained before the resection of low-grade urothelial carcinoma (LGUC), with adequate cytological sampling of the tumor, frequently revealed the presence of three-dimensional cell groups with disordered nuclei and cellular discohesion (3DDD). 936 cystoscopic urine specimens were categorized into five groups: Group 1 (80 specimens) with biopsy-proven LGUC within 6 months of cytologic examination, Group 2 (23 specimens) with biopsy proven LGUC within 6 to 36 months of cytologic examination, Group 3 (527 specimens) with a history of LGUC but no tumor for a period of greater than 3 years, Group 4 (300 specimens) with no association with LGUC, and Group 5 (6 specimens) with urinary lithiasis. Specimens with scant cellularity accounted for 20% of those in Group 1. For 3DDD in detecting LGUC in adequate cystoscopic urine, the sensitivity was 70%, specificity was 94%. Two- or three-dimensional cell groups with ordered nuclei and/or cellular non-discohesion were often seen in specimens from Groups 4 or 5. The 3DDD was present in a significant number of cases with concurrent negative cystoscopic findings but also positive LGUC in ensuing follow-up. In these cases, 3DDD with or without tumor identified at concurrent cystoscopy were found to be morphologically similar. Furthermore, the presence of 3DDD in 8% of Group 3 likely represents urothelial dysplasia that is not cystoscopically detectable. The high specificity and sensitivity of 3DDD is demonstrated. These findings are consistent with the decreased cell adhesion and disordered nuclear arrangement of low grade urothelial neoplasia. © 2013 Wiley Periodicals, Inc.

Comparison of DDD versus VVIR pacing modes in elderly patients with atrioventricular block.

PubMed

Kılıçaslan, Barış; Vatansever Ağca, Fahriye; Kılıçaslan, Esin Evren; Kınay, Ozan; Tigen, Kürşat; Cakır, Cayan; Nazlı, Cem; Ergene, Oktay

2012-06-01

Dual-chamber pacing is believed to have an advantage over single-chamber ventricular pacing. The aim of this study was to determine whether elderly patients who have implanted pacemakers for complete atrioventricular block gain significant benefits from dual-chamber (DDD) pacemakers compared with single chamber ventricular (VVIR) pacemakers. This study was designed as a randomized, two-period crossover study-each pacing mode was maintained for 1 month. Thirty patients (16 men, mean age 68.87 ± 6.89 years) with implanted DDD pacemakers were submitted to a standard protocol, which included an interview, pacemaker syndrome assessment, health related quality of life (HRQoL) questionnaires assessed by an SF-36 test, 6-minute walk test (6MWT), and transthoracic echocardiographic examinations. All of these parameters were obtained on both DDD and VVIR mode pacing. Paired data were compared. HRQoL scores were similar, and 6MWT results did not differ between the two groups. VVIR pacing elicited significant enlargement of the left atrium and impaired left ventricular diastolic functions as compared with DDD pacing. Two patients reported subclinical pacemaker syndrome, but this was not statistically significant. Our study revealed that in active elderly patients with complete heart block, DDD pacing and VVIR pacing yielded similar improvements in QoL and exercise performance. However, after a short follow-up period, we noted that VVIR pacing caused significant left atrial enlargement and impaired left ventricular diastolic functions.

Targeted drug discovery and development, from molecular signaling to the global market: an educational program at New York University, 5-year metrics

PubMed Central

Lee, Gloria; Plaksin, Joseph; Ramasamy, Ravichandran; Gold-von Simson, Gabrielle

2018-01-01

Drug discovery and development (DDD) is a collaborative, dynamic process of great interest to researchers, but an area where there is a lack of formal training. The Drug Development Educational Program (DDEP) at New York University was created in 2012 to stimulate an improved, multidisciplinary DDD workforce by educating early stage scientists as well as a variety of other like-minded students. The first course of the program emphasizes post-compounding aspects of DDD; the second course focuses on molecular signaling pathways. In five years, 196 students (candidates for PhD, MD, Master’s degree, and post-doctoral MD/PhD) from different schools (Medicine, Biomedical Sciences, Dentistry, Engineering, Business, and Education) completed the course(s). Pre/post surveys demonstrate knowledge gain across all course topics. 26 students were granted career development awards (73% women, 23% underrepresented minorities). Some graduates of their respective degree-granting/post-doctoral programs embarked on DDD related careers. This program serves as a framework for other academic institutions to develop compatible programs designed to train a more informed DDD workforce. PMID:29657854

Advances in Discrete Dislocation Dynamics Modeling of Size-Affected Plasticity

NASA Astrophysics Data System (ADS)

El-Awady, Jaafar A.; Fan, Haidong; Hussein, Ahmed M.

In dislocation-mediated plasticity of crystalline materials, discrete dislocation dynamics (DDD) methods have been widely used to predict the plastic deformation in a number of technologically important problems. These simulations have led to significant improvement in the understanding of the different mechanism that controls the mechanical properties of crystalline materials, which can greatly accelerate the future development of materials with superior properties. This chapter provides an overview of different practical applications of both two-dimensional and three-dimensional DDD simulations in the field of size-affected dislocation-mediated plasticity. The chapter is divided into two major tracks. First, DDD simulations focusing on aspects of modeling size-dependent plasticity in single crystals in uniaxial micro-compression/tension, microtorsion, microbending, and nanoindentation are discussed. Special attention is directed towards the role of cross-slip and dislocation nucleation on the overall response. Second, DDD simulations focusing on the role of interfaces, including grain and twin boundaries, on dislocation-mediated plasticity are discussed. Finally, a number of challenges that are withholding DDD simulations from reaching their full potential are discussed.

Complete dechlorination of DDE/DDD using magnesium/palladium system.

PubMed

Gautam, Sumit Kumar; Suresh, Sumathi

2007-04-01

Kinetic studies on the dechlorination of 1,1-dichloro-2,2 bis (4,-chlorophenyl) ethane (DDD) and 1,1,dichloro-2,2 bis (4,-chlorophenyl) ethylene (DDE) in 0.05% biosurfactant revealed that the reaction follows second-order kinetics. The rate of reaction was dependent on the presence of acid, initial concentrations of the target compound, and zerovalent magnesium/tetravalent palladium. Gas chromatography-mass spectrometry analyses of DDE dechlorination revealed the formation of a completely dechlorinated hydrocarbon skeleton, with diphenylethane as the end product, thereby implying the removal of all four chlorine atoms of DDE. In the case of DDD, we identified two partially dechlorinated intermediates [namely, 1,1-dichloro-2, 2 bis (phenyl) ethane and 1, chloro-2, 2 bis (phenyl) ethane] and diphenylethane as the end product. On the basis of products formed from DDD dehalogenation, we propose the removal of aryl chlorine atoms as a first step. Our investigation reveals that biosurfactant may be an attractive solubilizing agent for DDT and its residues. The magnesium/palladium system is a promising option because of its high reactivity and ability to achieve complete dechlorination of DDE and DDD.

Prescription opioid analgesics for pain management in Australia: 20 years of dispensing.

PubMed

Islam, M M; McRae, I S; Mazumdar, S; Taplin, S; McKetin, R

2016-08-01

Opioid prescribing/dispensing data can inform policy surrounding regulation by informing trends and types of opioid prescribed and geographic variations. In Australia so far only partial data on dispensing have been published, and data for states/territories remain unknown. Using a range of measures, this study examines 20-year (1992-2011) trends in prescription opioid analgesics in Australia - both nationally and for individual jurisdictions. Dispensing data were obtained from the Drug Utilisation Sub-Committee and the Pharmaceutical Benefits Scheme (PBS) websites. Trends in numbers of prescriptions and daily defined dose (DDD)/1000 people/day were examined over time and across states/territories. Seasonal variations in PBS/Repatriation Pharmaceutical Benefits Scheme (RPBS) items for nationwide dispensing were adjusted using a centred moving smoothing technique. In two decades, 165.32 million prescriptions for opioids were dispensed, with codeine and its derivatives the most prescribed formulation (50.1%) followed by tramadol (13.5%) and oxycodone derivatives (12.7%). In terms of DDD/1000 people/day, dispensing increased from 5.38 in 1992 to 14.46 in 2011. There are significant increasing trends for total, PBS/RPBS and under co-payment prescriptions (priced below patient co-payment). The DDD/1000 people/day for items dispensed through PBS/RPBS was highest in Tasmania. Prescription opioid dispensing increased substantially over the study period. With an ageing population, this trend is likely to continue in future. A growing concern about harms associated with opioid use warrants balanced control measures so that harms could be minimised without reducing effective pain treatment. Research examining utilisation in small geographic areas may help design spatially tailored interventions. A real-time drug-monitoring programme may reduce undue prescribing and dispensing. © 2016 Royal Australasian College of Physicians.

The Impact of Restricting Over-the-Counter Sales of Antimicrobial Drugs: Preliminary Analysis of National Data.

PubMed

Moura, Maria Luísa; Boszczowski, Icaro; Mortari, Naíma; Barrozo, Lígia Vizeu; Chiaravalloti Neto, Francisco; Lobo, Renata Desordi; Pedroso de Lima, Antonio Carlos; Levin, Anna S

2015-09-01

To describe the nationwide impact of a restrictive law on over-the-counter sales of antimicrobial drugs, implemented in Brazil in November 2010. Approximately 75% of the population receives healthcare from the public health system and receives free-of-charge medication if prescribed. Total sales in private pharmacies as compared with other channels of sales of oral antibiotics were evaluated in this observational study before and after the law (2008-2012). Defined daily dose per 1000 inhabitants per day (DDD/TID) was used as standard unit. In private pharmacies the effect of the restrictive law was statistically significant (P < 0.001) with an estimated decrease in DDD/TID of 1.87 (s.e. =  0.18). In addition, the trend of DDD/TID before the restrictive law was greater than after the intervention (P < 0.001). Before November 2010, the slope for the trend line was estimated as 0.08 (s.e. = 0.01) whereas after the law, the estimated slope was 0.03 (s.e. = 0.01). As for the nonprivate channels, no difference in sales was observed (P = 0.643). The impact in the South and Southeast (more developed) regions was higher than in the North, Northeast, and Mid-West. The state capitals had a 19% decrease, compared with 0.8% increase in the rest of the states. Before the law, the sales of antimicrobial drugs were steadily increasing. From November 2010, with the restrictive law, there was an abrupt drop in sales followed by an increase albeit at a significantly lower rate. The impact was higher in regions with better socio-economic status.

The use of melatonin in Swedish children and adolescents--a register-based study according to age, gender, and medication of ADHD.

PubMed

Furster, Catrin; Hallerbäck, Maria Unenge

2015-07-01

The use of melatonin is increasing among Swedish children and adolescents despite deficient knowledge of usage in these groups. The aim of this study was to investigate the use of melatonin in Swedish children and adolescents according to age, gender, dosage, treatment duration, and use of attention deficit hyperactivity disorder (ADHD) medication. Data from the Swedish Prescribed Drug Register was analyzed for children and adolescents 0-19 years old in Sweden during 2006-2013. The number of new users of melatonin in 2013 was 4296 and 3093 among boys and girls, respectively. Girls started treatment with melatonin in older ages compared to boys. Regular users of melatonin were most common among boys 10-14 years. The average defined daily dose (DDD) per regular user was decreasing from 2.4 DDD in 2006 to 1.7 DDD in 2012. Among girls and boys 5-9 years who were regular users in 2010, over 40 and 50%, respectively, were still regular users in 2013. In the age group 15-19 years, only about 10% were still regular users in 2013. In 2013, 65% of boys and 49% of girls, using melatonin regularly, also used medication for ADHD regularly. More Swedish boys than girls used melatonin regularly. The boys started treatment earlier and more often combined regular use of melatonin with regular use of medication for ADHD. This indicates that girls and boys partly are prescribed melatonin for different reasons. About half of the younger children stayed on melatonin treatment for several years, while 90% of adolescents (15-19 years) concluded their treatment.

Antimicrobial Stewardship Lessons From Mupirocin Use and Resistance in Methicillin-Resitant Staphylococcus Aureus.

PubMed

Peterson, Lance R; Samia, Noelle I; Skinner, Andrew M; Chopra, Amit; Smith, Becky

2017-01-01

The quantitative relationship between antimicrobial agent consumption and rise or fall of antibiotic resistance has rarely been studied. We began all admission surveillance testing for methicillin-resistant Staphylococcus aureus (MRSA) in August 2005 with subsequent contact isolation and decolonization using nasally applied mupirocin ointment for those colonized. In October 2012, we discontinued decolonization of medical (nonsurgical service) patients. We conducted a retrospective study from 2007 through 2014 of 445680 patients; 35235 were assessed because of mupirocin therapy and positive test results for MRSA. We collected data on those patients receiving 2% mupirocin ointment for decolonization to determine the defined daily doses (DDDs). A nonparametric regression technique was used to quantitate the effect of mupirocin consumption on drug resistance in MRSA. Using regressive modeling, we found that, when consumption was consistently >25 DDD/1000 patient-days, there was a statistically significant increase in mupirocin resistance with a correlating positive rate of change. When consumption was ≤25 DDD/1000 patient-days, there was a statistically significant decrease in mupirocin resistance with a correlating negative rate of change. The scatter plot of fitted versus observed mupirocin resistance values showed an R 2 value of 0.89-a high correlation between mupirocin use and resistance. Use of the antimicrobial agent mupirocin for decolonization had a threshold of approximately 25 DDD/1000 patient-days that separated a rise and fall of resistance within the acute-care setting. This has implications for how widely mupirocin can be used for decolonization, as well as for setting consumption thresholds when prescribing antimicrobials as part of stewardship programs. © The Author 2017. Published by Oxford University Press on behalf of Infectious Diseases Society of America.

The Impact of Restricting Over-the-Counter Sales of Antimicrobial Drugs

PubMed Central

Moura, Maria Luísa; Boszczowski, Icaro; Mortari, Naíma; Barrozo, Lígia Vizeu; Neto, Francisco Chiaravalloti; Lobo, Renata Desordi; Pedroso de Lima, Antonio Carlos; Levin, Anna S.

2015-01-01

Abstract To describe the nationwide impact of a restrictive law on over-the-counter sales of antimicrobial drugs, implemented in Brazil in November 2010. Approximately 75% of the population receives healthcare from the public health system and receives free-of-charge medication if prescribed. Total sales in private pharmacies as compared with other channels of sales of oral antibiotics were evaluated in this observational study before and after the law (2008–2012). Defined daily dose per 1000 inhabitants per day (DDD/TID) was used as standard unit. In private pharmacies the effect of the restrictive law was statistically significant (P < 0.001) with an estimated decrease in DDD/TID of 1.87 (s.e. =  0.18). In addition, the trend of DDD/TID before the restrictive law was greater than after the intervention (P < 0.001). Before November 2010, the slope for the trend line was estimated as 0.08 (s.e. = 0.01) whereas after the law, the estimated slope was 0.03 (s.e. = 0.01). As for the nonprivate channels, no difference in sales was observed (P = 0.643). The impact in the South and Southeast (more developed) regions was higher than in the North, Northeast, and Mid-West. The state capitals had a 19% decrease, compared with 0.8% increase in the rest of the states. Before the law, the sales of antimicrobial drugs were steadily increasing. From November 2010, with the restrictive law, there was an abrupt drop in sales followed by an increase albeit at a significantly lower rate. The impact was higher in regions with better socio-economic status. PMID:26402824

Vincristine, cisplatin, teniposide, and cyclophosphamide combination in the treatment of recurrent or metastatic adrenocortical cancer.

PubMed

Khan, Tanweera S; Sundin, Anders; Juhlin, Claes; Wilander, Erik; Oberg, Kjell; Eriksson, Barbro

2004-01-01

The efficacy and tolerability of a combination of vincristine, cisplatin, teniposide, and cyclophosphamide (OPEC) in 11 patients (median age, 45 yr) with recurrent and/or metastatic adrenocortical cancer (ACC) (seven functional and four nonfunctional) were evaluated. All patients received this regimen after the failure of streptozocin and o,p'-DDD (SO) combination therapy. The regimen comprised cyclophosphamide, 600 mg/m2, and vincristine, 1.5 mg/m2, maximum dose 2.0 mg (d 1); cisplatin, 100 mg/m2 (d 2) and teniposide, 150 mg/m2 (d 4). Cycles were repeated every 4 wk. One to eight cycles (median, six cycles) of OPEC were administered to each patient. The median duration of treatment was 6 mo. The overall 2-yr survival rate was 82% and the median survival since diagnosis was 44 mo while it was 21 mo since start of OPEC therapy. Responses were obtained in nine patients: partial response in two patients, and stable disease in seven patients. The median duration of response was 6.75 mo. A total of 60 cycles of chemotherapy were given to all patients; grade 1-2 toxicity occurred in 57 cycles, while grade 3 toxicity was observed only in two cycles, according to NCI's Common Toxicity Criteria. We conclude that the OPEC regimen may be considered in recurrent or metastatic ACC as a second-line medical treatment. However, the combination is accompanied by considerable side effects and dose modifications are necessary in order to be able to recommend the treatment. This regimen needs further evaluation compared with SO therapy preferably in a randomized multicenter trial.

DDE and DDD residues correlated with mortality of experimental birds

USGS Publications Warehouse

Stickel, William H.; Stickel, Lucille F.; Coon, Francis B.; Deichmann, William B.; Peñalver, Rafael A.; Radomski, Jack L.

1970-01-01

Nearly everywhere in nature are found DDE and DDD, which are metabolites of DDT, and they often become concentrated through food chains. DDD is also a commercial insecticide. large amounts of both are frequently found in birds, but the significance of these amounts has puzzled many owrkers. Studies at Clear Lake, California1 gave some data on DDD danger levels, but less is known of DDE, the member of the DDT group that is most frequent and most abundant in nature. Although DDE is toxic, relatively alrge residues are found in apparently healthy animals. As one step in untanglig the problem, it seemed important to determine the residue levels that indicate danger to life. earlier work with DDR and dieldrin has shown the value of this approach.2-5, 1 2

Microstructurally Based Cross-slip Mechanisms and Their Effects on Dislocation Microstructure Evolution in fcc Crystals

DTIC Science & Technology

2015-01-01

still necessary. One such model that could bridge this gap is discrete dis- location dynamics ( DDD ) simulations, in which both the time- and length-scale...limitations from atomic simulations are greatly reduced. Over the past two decades, two-dimen- sional (2D) and three-dimensional (3D) DDD methods have...dislocation ensem- bles according to physics-based rules [27–34]. The physics that can be incorporated in DDD simulations can range http://dx.doi.org

Biodegradation of 1,1,1-trichloro-2,2-bis(4-chlorophenyl) ethane (DDT) by using Serratia marcescens NCIM 2919.

PubMed

Grewal, Jasneet; Bhattacharya, Amrik; Kumar, Sumit; Singh, Dileep K; Khare, Sunil K

2016-12-01

A solvent tolerant bacterium Serratia marcescens NCIM 2919 has been evaluated for degradation of DDT (1,1,1-trichloro-2,2-bis (4-chlorophenyl) ethane). The bacterium was able to degrade up to 42% of initial 50 mg L -1 of DDT within 10 days of incubation. The highlight of the work was the elucidation of DDT degradation pathway in S. marcescens. A total of four intermediates metabolites viz. 2,2-bis (chlorophenyl)-1,1-dichloroethane (DDD), 2,2-bis (chlorophenyl)-1,1-dichloroethylene (DDE), 2,2-bis (chlorophenyl)-1-chloroethylene (DDMU), and 4-chlorobenzoic acid (4-CBA) were identified by GC-Mass and FTIR. 4-CBA was found to be the stable product of DDT degradation. Metabolites preceding 4-CBA were not toxic to strain as reveled through luxuriant growth in presence of varying concentrations of exogenous DDD and DDE. However, 4-CBA was observed to inhibit the growth of bacterium. The DDT degrading efficiency of S. marcescens NCIM 2919 hence could be used in combination with 4-CBA utilizing strains either as binary culture or consortia for mineralization of DDT. Application of S. marcescens NCIM 2919 to DDT contaminated soil, showed 74.7% reduction of initial 12.0 mg kg -1 of DDT after 18-days of treatment.

Multi-photon microscopy of tobacco-exposed organotypic skin models

NASA Astrophysics Data System (ADS)

Dao, Belinda; Yamazaki, Alissa; Sun, Chung Ho; Wang, Zifu; Pham, Nguyen; Oldham, Michael; Wong, Brian J. F.

2006-02-01

Cigarette smoking is the most preventable cause of death in the United States. Researchers have extensively studied smoking in regards to its association with cancer, cardiovascular, and pulmonary disease. In contrast, the impact of cigarette smoking on skin has received much less attention. To provide a better understanding of the effect of cigarette smoking on the human dermal layer, this study used multi-photon microscopy (MPM) to examine collagen in organotypic skin models exposed to cigarette smoke condensate (CSC). Adult and neonatal organotypic tissue-engineered artificial skin models (RAFTs) were constructed and exposed to varying concentrations of CSC. Imaging of the RAFTs was performed using MPM and second-harmonic generation signals (SHG), which allowed for collagen structure to be viewed and analyzed as well as for collagen density to be assessed from derived depth-dependent decay (DDD) values. RAFT contraction as related to exposure concentration was monitored as well. Results indicated a dose dependent between contraction rates and CSC concentration. Collagen structure showed more preservation of its original structure at a greater depth in RAFTs with higher concentrations of CSC. No clear trends could be drawn from analysis of derived DDD values.

Evaluation of an antibiotic intravenous to oral sequential therapy program.

PubMed

Pablos, Ana I; Escobar, Ismael; Albiñana, Sandra; Serrano, Olga; Ferrari, José M; Herreros de Tejada, Alberto

2005-01-01

This study was designed to analyse the drug consumption difference and economic impact of an antibiotic sequential therapy focused on quinolones. We studied the consumption of quinolones (ofloxacin/levofloxacin and ciprofloxacin) 6 months before and after the implementation of a sequential therapy program in hospitalised patients. It was calculated for each antibiotic, in its oral and intravenous forms, in defined daily dose (DDD/100 stays per day) and economical terms (drug acquisition cost). At the beginning of the program ofloxacin was replaced by levofloxacin and, since their clinical uses are similar, the consumption of both drugs was compared during the period. In economic terms, the consumption of intravenous quinolones decreased 60% whereas the consumption of oral quinolones increased 66%. In DDD/100 stays per day, intravenous forms consumption decreased 53% and oral forms consumption increased 36%. Focusing on quinolones, the implementation of a sequential therapy program based on promoting an early switch from intravenous to oral regimen has proved its capacity to alter the utilisation profile of these antibiotics. The program has permitted the hospital a global saving of 41420 dollars for these drugs during the period of time considered. Copyright (c) 2004 John Wiley & Sons, Ltd.

Potential savings from an evidence-based consumer-oriented public education campaign on prescription drugs.

PubMed

Donohue, Julie M; Fischer, Michael A; Huskamp, Haiden A; Weissman, Joel S

2008-10-01

To estimate potential savings associated with the Consumer Reports Best Buy Drugs program, a national educational program that provides consumers with price and effectiveness information on prescription drugs. National data on 2006 prescription sales and retail prices paid for angiotensin-converting enzyme inhibitors (ACEIs), β-blockers, calcium channel blockers, and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-coA) reductase inhibitors (statins). We converted national data on aggregate unit sales of drugs in the four classes to defined daily doses (DDD) and estimated a range of potential savings from generic and therapeutic substitution. We estimated that $2.76 billion, or 7.83 percent of sales, could be saved if use of the drugs recommended by the educational program was increased. The recommended drugs' prices were 15-65 percent lower per DDD than their therapeutic alternatives. The majority (57.4 percent) of potential savings would be achieved through therapeutic substitution. Substantial savings can be achieved through greater use of comparatively effective and lower cost drugs recommended by a national consumer education program. However, barriers to dissemination of consumer-oriented drug information must be addressed before savings can be realized. © Health Research and Educational Trust.

Potential Savings from an Evidence-Based Consumer-Oriented Public Education Campaign on Prescription Drugs

PubMed Central

Donohue, Julie M; Fischer, Michael A; Huskamp, Haiden A; Weissman, Joel S

2008-01-01

Objective To estimate potential savings associated with the Consumer Reports Best Buy Drugs program, a national educational program that provides consumers with price and effectiveness information on prescription drugs. Data Sources National data on 2006 prescription sales and retail prices paid for angiotensin-converting enzyme inhibitors (ACEIs), β-blockers, calcium channel blockers, and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-coA) reductase inhibitors (statins). Study Design We converted national data on aggregate unit sales of drugs in the four classes to defined daily doses (DDD) and estimated a range of potential savings from generic and therapeutic substitution. Principal Findings We estimated that $2.76 billion, or 7.83 percent of sales, could be saved if use of the drugs recommended by the educational program was increased. The recommended drugs’ prices were 15–65 percent lower per DDD than their therapeutic alternatives. The majority (57.4 percent) of potential savings would be achieved through therapeutic substitution. Conclusions Substantial savings can be achieved through greater use of comparatively effective and lower cost drugs recommended by a national consumer education program. However, barriers to dissemination of consumer-oriented drug information must be addressed before savings can be realized. PMID:18479406

A study on the quality of outpatient prescription of psychopharmaceuticals in the City of Zagreb 2006-2009.

PubMed

Zivković, Kresimir; Zelić-Kerep, Ana; Stimac, Danijela; Ozić, Sanja; Zivković, Nikica

2014-06-01

The lack of Croatian studies which could determine the justifiability of excessive psychopharmaceutical utilization was an encouragement to conduct this research. Furthermore, regarding the conduction of this study, it would be possible to determine whether the trend of drug utilization has increased, decreased or perhaps stabilized. The data on the outpatient utilization of psycholeptics and psychoanaleptics were collected from all Zagreb pharmacies, 2006-2009. Based on the collected data for all N05 and N06 groups of drugs, the defined daily doses (DDD) and DDD per thousand inhabitants per day (DDD/TID) have been calculated using the Anatomical-Therapeutic-Chemical classification (ATC) for 2006, 2007, 2008 and 2009. To indicate the quality of drug prescription the Drug Utilization 90% (DU 90%) method was used. Moreover, in order to determine a more precise quality of individual drug group prescriptions, the indicators have been calculated by determining the proportion of the total utilization of individual therapeutic and pharmacological therapeutic subgroups in DDD/TID a day. The utilization of anxiolytics (N05B) accounts for most of the psycholeptic utilization in the City of Zagreb throughout the entire study period. In the study period, the utilization of antidepressants has slightly increased, by 10.5%, taking the first and the last years of the period into account. In 2006, 5 benzodiazepines and the hypnotic zolpidem, as well as 5 selective serotonin reuptake inhibitors (SSRIs) and 1 third generation antipsychotic (olanzapin) were found in the DU 90% segment. In 2009, the DU 90% segment also comprised 5 benzodiazepines and the hypnotic zolpidem, as well as 6 SSRIs and 1 third generation antipsychotic (olanzapin). In the City of Zagreb, a general insight into the quality of psychopharmaceutical prescriptions indicates stability in comparison to earlier studies. The ratio index of the first generation antipsychotic utilization, compared to the third generation antipsychotics, shows an increase in the quality of prescription. Also, the ratio index of total tricyclic antidepressants (TCA) and SSRI utilization indicates improvement in quality of prescription. The ratio index of the entire outpatient utilization of anxiolytics and antidepressants expressed in DDD/TID unfortunately shows a very mild increase of prescription quality. Benzodiazepines accounted for more than 50% of the outpatient utilization of psychopharmaceuticals throughout the study period, which proves the need for precise guidelines as the most significant means of drug rationalization and utilization. It is necessary to identify priorities and problems in order to solve them successfully, by monitoring drug utilization and prescription on a national level. Results demonstrate that within the primary health care system, there is a need for constant education on rational prescription of this drug group.

Economic prescribing of corticosteroid nasal sprays in Germany: comparison of mometasone and budesonide nasal sprays on the basis of the DDD, the PDD and reference prices.

PubMed

Becker, Beril; Kruppert, Silvia; Kostev, Karel

2013-01-01

According to the German Social Security Code (SGB V), drugs should be prescribed on a cost-effective basis. An attempt is made to achieve this in Germany with the help of the DDD system and reference prices. Taking the example of the most frequently prescribed corticosteroid nasal sprays containing the active substances budesonide (BNS) or mometasone (MNS), we will show here that the DDD system is not necessarily suitable for tapping economic reserves. Despite the pharmacologic differences between the two substances, a uniformly defined daily dose (DDD) is assumed for both. Moreover, since 2006 they have formed a reference-price group of nasally administered medication with other active substances. Products were compared with regard to potential differences in patient populations and resulting treatment costs. The extent to which the two instruments are suitable for tapping economic reserves were estimated. We analyzed longitudinal diagnostic and prescription data in the IMS® Disease Analyzer Database from the period 2006 to July 2010. In total we analyzed data from 16,163 MNS and 4,218 BNS patients from GP practices plus 11,103 MNS and 2,521 BNS patients from ENT practices. The average quantity prescribed per patient differed in favor of MNS by -111.5 (for first prescriptions) to -260.1 puffs (after 730 days) in GP practices and by -137.3 to -488.3 puffs in ENT practices (p < 0.001). The mean calculated treatment cost per year from the point of view of the statutory health insurer was 20.40 € (GP practices) and 30.50 € (ENT practices) for MNS compared to 22.40 € (GP practices) and 32.10 € (ENT practices) for BNS. Based on the price level after the 2011 referenceprice adjustment, the treatment costs are 16.40 € (GP practices) and 24.20 € (ENT practices) for MNS versus 21.20 € (GP practices) and 32.30 € (ENT practices) for BNS. The volumes of MNS actually prescribed are significantly lower than those of BNS in the compared patient populations. Based on the actual consumption of the substances, there is no treatment-cost advantage for BNS in comparison to MNS from the statutory health insurer's point of view. By contrast, the reference-price adjustment results in a greater reduction of treatment costs for mometasone, so that in this case the statutory health insurer is able to tap economic reserves. Both the comparative parameters used for calculating the reference price and the DDD system are only conditionally suitable for tapping economic reserves for drugs.

Prenatal tolerance induction: relationship between cell dose, marrow T-cells, chimerism, and tolerance.

PubMed

Chen, Jeng-Chang; Chang, Ming-Ling; Huang, Shiu-Feng; Chang, Pei-Yeh; Muench, Marcus O; Fu, Ren-Huei; Ou, Liang-Shiou; Kuo, Ming-Ling

2008-01-01

It was reported that the dose of self-antigens can determine the consequence of deletional tolerance and donor T cells are critical for tolerance induction in mixed chimeras. This study aimed at assessing the effect of cell doses and marrow T cells on engraftment and tolerance induction after prenatal bone marrow transplantation. Intraperitoneal cell transplantation was performed in FVB/N (H-2K(q)) mice at gestational day 14 with escalating doses of adult C57BL/6 (H-2K(b)) marrows. Peripheral chimerism was examined postnatally by flow cytometry and tolerance was tested by skin transplantation. Transplantation of light-density marrow cells showed a dose response. High-level chimerism emerged with a threshold dose of 5.0 x 10(6) and host leukocytes could be nearly replaced at a dose of 7.5-10.0 x 10(6). High-dose transplants conferred a steady long-lasting donor-specific tolerance but were accompanied by >50% incidence of graft-versus-host disease. Depletion of marrow T cells lessened graft-versus-host disease to the detriment of engraftment. With low-level chimerism, tolerance was a graded phenomenon dependent upon the level of chimerism. Durable chimerism within 6 months required a threshold of > or = 2% chimerism at 1 month of age and predicted a 50% chance of long-term tolerance, whereas transient chimerism (<2%) only caused hyporesponsiveness to the donor. Tolerance induction did not succeed without peripheral chimerism even if a large amount of injected donor cells persisted in the peritoneum. Neither did an increase in cell doses or donor T-cell contents benefit skin graft survivals unless it had substantially improved peripheral chimerism. Thus, peripheral chimerism level can be a simple and straightforward test to predict the degree of prenatal immune tolerance.

Increased use of inhaled corticosteroids among young Danish adult asthmatics: an observational study.

PubMed

Davidsen, Jesper Rømhild; Søndergaard, Jens; Hallas, Jesper; Siersted, Hans Christian; Lykkegaard, Jesper; Andersen, Morten

2010-12-01

This population-based longitudinal study aimed to investigate trends in use of inhaled corticosteroids (ICS) and determinants of ICS use in young Danish adults with asthma. 106 757 users, aged 18-44 years, of anti-asthmatic drugs were identified in the Danish Register of Medical Product Statistics during 1997-2006. One year prevalences of ICS use were calculated in categories of gender, age, and annual consumption of inhaled beta-2-agonists (IBA) in defined daily doses (DDD) per year. Determinants of ICS use were estimated by logistic regression models. The one year prevalence of ICS use was constant, approximately 64%, during 1997-2000. An annual increase was observed from 67% in 2001 to 77% in 2006. This trend also existed when stratifying on gender, age and IBA use. Using 1997 as baseline, the adjusted odds ratios (ORs) of ICS use in 2000 was 0.98 (95% CI 0.96-1.01) compared to 1.12 (95% CI 1.09-1.15) in 2001, and 1.81 (95% CI 1.75-1.87) in 2006. Other determinants of high ICS use were female gender, young age, and high annual IBA consumption. Among those using at least 400 DDD of IBA per year (corresponding to 4.4 powder inhalations daily), nearly 20% had no ICS prescriptions in 2006. Treatment with ICS among young Danish adult asthmatics has increased since 2001. This apparent improvement was associated with the introduction of fixed dose combination inhalers with ICS and inhaled long-acting beta-2-agonists. However, there is still room for improvement. Copyright © 2010 Elsevier Ltd. All rights reserved.

Dense Deposit Disease

PubMed Central

Smith, Richard J.H; Harris, Claire L.; Pickering, Matthew C.

2011-01-01

Dense deposit disease (DDD) is an orphan disease that primarily affects children and young adults without sexual predilection. Studies of its pathophysiology have shown conclusively that it is caused by fluid-phase dysregulation of the alternative pathway of complement, however the role played by genetics and autoantibodies like C3 nephritic factors must be more thoroughly defined if we are to make an impact in the clinical management of this disease. There are currently no mechanism-directed therapies to offer affected patients, half of whom progress to end stage renal failure disease within 10 years of diagnosis. Transplant recipients face the dim prospect of disease recurrence in their allografts, half of which ultimately fail. More detailed genetic and complement studies of DDD patients may make it possible to identify protective factors prognostic for naïve kidney and transplant survival, or conversely risk factors associated with progression to renal failure and allograft loss. The pathophysiology of DDD suggests that a number of different treatments warrant consideration. As advances are made in these areas, there will be a need to increase healthcare provider awareness of DDD by making resources available to clinicians to optimize care for DDD patients. PMID:21601923

DDT, DDD, and DDE in soil of Xiangfen County, China: Residues, sources, spatial distribution, and health risks.

PubMed

Ma, Jin; Pan, Li-Bo; Yang, Xiao-Yang; Liu, Xiao-Ling; Tao, Shi-Yang; Zhao, Long; Qin, Xiao-Peng; Sun, Zai-Jin; Hou, Hong; Zhou, Yong-Zhang

2016-11-01

We collected and analyzed 128 surface soil samples from Xiangfen County for dichlorodiphenyltrichloroethane (DDT), dichlorodiphenyldichloroethane (DDD), and dichlorodiphenyldichloroethylene (DDE). Total DDT concentrations (DDTs; sum of p,p'-DDD, p,p'-DDE, and p,p'-DDT) ranged from ND to 427.81 ng g(-1) (dry weight, dw), with a mean of 40.26 ng g(-1) (dw). Among the three compounds, p,p'-DDD was the most dominant. The DDTs in Xiangfen County soils mainly originated from historical DDT use, but there were also new inputs likely related to dicofol use. The DDTs in Xiangfen County soils were mainly degraded under anaerobic conditions, and direct degradation to DDD was the main degradation route. Regions with relatively high concentrations of DDTs were mainly located in North and South Xiangfen County. In these regions, many soil samples contained p,p'-DDT as the predominant pollutant, suggestive of extensive new inputs of DDT. A health risk assessment revealed that there are no serious long-term health impacts of exposure to DDTs in soil, for adults or children. Copyright © 2016 Elsevier Ltd. All rights reserved.

40 CFR 52.29 - Visibility long-term strategies.

Code of Federal Regulations, 2010 CFR

2010-07-01

... listed where applicable in Subparts B through DDD of this part. The provisions of this section have been incorporated into the applicable implementation plan for various States, as provided in Subparts B through DDD...

40 CFR 52.29 - Visibility long-term strategies.

Code of Federal Regulations, 2011 CFR

2011-07-01

... listed where applicable in Subparts B through DDD of this part. The provisions of this section have been incorporated into the applicable implementation plan for various States, as provided in Subparts B through DDD...

Predictive factors of head and neck squamous cell carcinoma patient tolerance to high-dose cisplatin in concurrent chemoradiotherapy

PubMed Central

NAKANO, KENJI; SATO, YASUYOSHI; TOSHIYASU, TAKASHI; SATO, YUKIKO; INAGAKI, LINA; TOMOMATSU, JUNICHI; SASAKI, TORU; SHIMBASHI, WATARU; FUKUSHIMA, HIROFUMI; YONEKAWA, HIROYUKI; MITANI, HIROKI; KAWABATA, KAZUYOSHI; TAKAHASHI, SHUNJI

2016-01-01

Although high-dose cisplatin is the standard regimen of concurrent chemoradiotherapy (CCRT) for locally advanced head and neck squamous cell carcinoma (HNSCC), varying levels of patient tolerance towards cisplatin have been reported, and the predictive factors of cisplatin tolerance remain to be elucidated. The present study retrospectively reviewed newly diagnosed HNSCC patients who received CCRT. Cisplatin (80 mg/m2) was administered every 3 weeks. The proportion of high-dose cisplatin-tolerant patients (cumulative cisplatin dose, ≥200 mg/m2) was determined, and the predictive factors of cisplatin tolerance were analyzed in a logistic regression analysis. Between June 2006 and March 2013, a total of 159 patients were treated with CCRT. The median follow-up time was 36.7 months. A total of 73 patients (46%) tolerated a cumulative cisplatin dose ≥200 mg/m2; male gender [odds ratio (OR), 25.00; P=0.005] and high body surface area (BSA) (>1.80 m2; OR, 2.21; P=0.032) were significantly predictive of high-dose cisplatin tolerance. The high-dose cisplatin-tolerant patients had a significantly higher complete response (CR) rate (82 vs. 67%, P=0.045); however, there were no significant between-group differences in the 3-year OS (79.5 vs. 81.2%, P=0.59) or PFS (70.4 vs. 44.6%, P=0.076) by cisplatin tolerance. In clinical practice, approximately one-half of the patients tolerated high-dose cisplatin in CCRT. Male gender and high BSA could be predictive of cisplatin tolerance. PMID:26893880

Rituximab fails where eculizumab restores renal function in C3nef-related DDD.

PubMed

Rousset-Rouvière, Caroline; Cailliez, Mathilde; Garaix, Florentine; Bruno, Daniele; Laurent, Daniel; Tsimaratos, Michel

2014-06-01

Dense deposit disease (DDD), a C3 glomerulopathy (C3G), is a rare disease with unfavorable progression towards end-stage kidney disease. The pathogenesis of DDD is due to cytotoxic effects related to acquired or genetic dysregulation of the complement alternative pathway, which is at times accompanied by the production of C3 nephritic factor (C3NeF), an auto-antibody directed against the alternative C3 convertase. Available treatments include plasma exchange, CD20-targeted antibodies, and a terminal complement blockade via the anti-C5 monoclonal antibody eculizumab. We report here the case of an 8-year-old child with C3NeF and refractory DDD who presented with a nephritic syndrome. She tested positive for C3NeF activity; C3 was undetectable. Genetic analyses of the alternative complement pathway were normal. Methylprednisolone pulses and mycophenolate mofetil treatment resulted in complete recovery of renal function and a reduction in proteinuria. Corticosteroids were tapered and then withdrawn. Four months after corticosteroid discontinuation, hematuria and proteinuria recurred, and a renal biopsy confirmed an active DDD with a majority of extracapillary crescents. Despite an increase in immunosuppressive drugs, including methylprednisolone pulses and rituximab therapy, the patient suffered acute renal failure within 3 weeks, requiring dialysis. Eculizumab treatment resulted in a quick and impressive response. Hematuria very quickly resolved, kidney function improved, and no further dialysis was required. The patient received bimonthly eculizumab injections of 600 mg, allowing for normalization of renal function and reduction of proteinuria to <0.5 g per day. Since then, she continues to receive eculizumab. Complement regulation pathway-targeted therapy may be a specific and useful treatment for rapidly progressing DDD prior to the development of glomerulosclerosis. Our data provide evidence supporting the pivotal role of complement alternative pathway abnormalities in C3G with DDD.

1. Historic American Buildings Survey Frank O. Branzetti, Photographer July ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

1. Historic American Buildings Survey Frank O. Branzetti, Photographer July 9, 1940 (ddd) 6- MILE STONE, at 540 HANCOCK ST., QUINCY - Milestones H, I, CCC, DDD & EEE, Various Quincy locations, Quincy, Norfolk County, MA

Processing of Cryo-EM Movie Data.

PubMed

Ripstein, Z A; Rubinstein, J L

2016-01-01

Direct detector device (DDD) cameras dramatically enhance the capabilities of electron cryomicroscopy (cryo-EM) due to their improved detective quantum efficiency (DQE) relative to other detectors. DDDs use semiconductor technology that allows micrographs to be recorded as movies rather than integrated individual exposures. Movies from DDDs improve cryo-EM in another, more surprising, way. DDD movies revealed beam-induced specimen movement as a major source of image degradation and provide a way to partially correct the problem by aligning frames or regions of frames to account for this specimen movement. In this chapter, we use a self-consistent mathematical notation to explain, compare, and contrast several of the most popular existing algorithms for computationally correcting specimen movement in DDD movies. We conclude by discussing future developments in algorithms for processing DDD movies that would extend the capabilities of cryo-EM even further. © 2016 Elsevier Inc. All rights reserved.

Intradiscal injection of simvastatin results in radiologic, histologic, and genetic evidence of disc regeneration in a rat model of degenerative disc disease

PubMed Central

Than, Khoi D.; Rahman, Shayan U.; Wang, Lin; Khan, Adam; Kyere, Kwaku A.; Than, Tracey T.; Miyata, Yoshinari; Park, Yoon-Shin; La Marca, Frank; Kim, Hyungjin M.; Zhang, Huina; Park, Paul; Lin, Chia-Ying

2014-01-01

BACKGROUND CONTEXT A large percentage of back pain can be attributed to degeneration of the intervertebral disc (IVD). Bone morphogenetic protein-2 (BMP-2) is known to play an important role in chondrogenesis of the IVD. Simvastatin is known to up-regulate expression of BMP-2. Thus, we hypothesized that intradiscal injection of simvastatin in a rat model of degenerative disc disease (DDD) would result in retardation of DDD. PURPOSE To develop a novel conservative treatment for DDD and related discogenic back pain. STUDY DESIGN/SETTING Laboratory investigation. METHODS Disc injury was induced in 272 rats via 21-gauge needle puncture. After 6 weeks, injured discs were treated with simvastatin in a saline or hydrogel carrier. Rats were sacrificed at predetermined time points. Outcome measures assessed were radiologic, histologic, and genetic. Radiologically, the MRI index (number of pixels multiplied by corresponding image densities) was determined. Histologically, disc spaces were read by 3 blinded scorers employing a previously described histological grading scale. Genetically, nuclei pulposi were harvested and polymerase chain reaction was run to determine relative levels of aggrecan, collagen type II, and BMP-2 gene expression. This project was supported by Grant No. R01 AR056649 from NIAMS/NIH. There are no other financial conflicts of interest to report. RESULTS Radiologically, discs treated with 5 mg/mL simvastatin in hydrogel or saline demonstrated MRI indices that were normal through 8 weeks post-treatment, although this was more sustained when delivered in hydrogel. Histologically, discs treated with 5 mg/mL simvastatin in hydrogel demonstrated improved grades in comparison to discs treated at higher doses. Genetically, discs treated with 5 mg/mL of simvastatin in hydrogel demonstrated higher gene expression of aggrecan and collagen type II than control. CONCLUSIONS Degenerate discs treated with 5 mg/mL simvastatin in a hydrogel carrier demonstrated radiographic and histologic features resembling normal, non-injured IVDs. In addition, gene expression of aggrecan and collagen type II (important constituents of the IVD extracellular matrix) was up-regulated in treated discs. Injection of simvastatin into degenerate IVDs may result in retardation of disc degeneration and represents a promising investigational therapy for conservative treatment of DDD. PMID:24291703

Variation in Antiosteoporotic Drug Prescribing and Spending Across Spain. A Population-Based Ecological Cross-Sectional Study.

PubMed

Sanfélix-Gimeno, Gabriel; Librero-López, Julián; Modroño-Riaño, Gracia; Peiró, Salvador; Rodríguez-Bernal, Clara L

2018-01-01

Introduction: Evidence has shown that utilization of antiosteoporotic medications does not correspond with risk, and studies on other therapies have shown that adequacy of pharmaceutical prescribing might vary between regions. Nevertheless, very few studies have addressed the variability in osteoporotic drug consumption. We aimed to describe variations in pharmaceutical utilization and spending on osteoporotic drugs between Health Areas (HA) in Spain. Methods: Population-based cross-sectional ecological study of expenditure and utilization of the five therapeutic groups marketed for osteoporosis treatment in Spain in 2009. Small area variation analysis (SAVA) methods were used. The units of analysis were the 168 HA of 13 Spanish regions, including 7.2 million women aged 50 years and older. The main outcomes were the defined daily dose (DDD) per 1000 inhabitants and day (DDD/1000/Day) dispensed according to the pharmaceutical claims reimbursed, and the expenditure on antiosteoporotics at retail price per woman ≥50 years old and per year. Results: The average osteoporosis drug consumption was 116.8 DDD/1000W/Day, ranging from 78.5 to 158.7 DDD/1000W/Day between the HAs in the 5th and 95th percentiles. Seventy-five percent of the antiosteoporotics consumed was bisphosphonates, followed by raloxifene, strontium ranelate, calcitonins, and parathyroid hormones including teriparatide. Regarding variability by therapeutic groups, biphosphonates showed the lowest variation, while calcitonins and parathyroid hormones showed the highest variation. The annual expenditure on antiosteoporotics was €426.5 million, translating into an expenditure of €59.2 for each woman ≥50 years old and varying between €38.1 and €83.3 between HAs in the 5th and 95th percentiles. Biphosphonates, despite accounting for 79% of utilization, only represented 63% of total expenditure, while parathyroid hormones with only 1.6% of utilization accounted for 15% of the pharmaceutical spending. Conclusion: This study highlights a marked geographical variation in the prescription of antiosteoporotics, being more pronounced in the case of costly drugs such as parathyroid hormones. The differences in rates of prescribing explained almost all of the variance in drug spending, suggesting that the difference in prescription volume between territories, and not the price of the drugs, is the main source of variation in this setting. Data on geographical variation of prescription can help guide policy proposals for targeting areas with inadequate antiosteoporotic drug use.

The generation and functional characterization of induced pluripotent stem cells from human intervertebral disc nucleus pulposus cells.

PubMed

Zhu, Yanxia; Liang, Yuhong; Zhu, Hongxia; Lian, Cuihong; Wang, Liang; Wang, Yiwei; Gu, Hongsheng; Zhou, Guangqian; Yu, Xiaoping

2017-06-27

Disc degenerative disease (DDD) is believed to originate in the nucleus pulposus (NP) region therefore, it is important to obtain a greater number of active NP cells for the study and therapy of DDD. Human induced pluripotent stem cells (iPSCs) are a powerful tool for modeling the development of DDD in humans, and have the potential to be applied in regenerative medicine. NP cells were isolated from DDD patients following our improved method, and then the primary NP cells were reprogramed into iPSCs with Sendai virus vectors encoding 4 factors. Successful reprogramming of iPSCs was verified by the expression of surface markers and presence of teratoma. Differentiation of iPSCs into NP-like cells was performed in a culture plate or in hydrogel, whereby skin fibroblast derived-iPSCs were used as a control. Results demonstrated that iPSCs derived from NP cells displayed a normal karyotype, expressed pluripotency markers, and formed teratoma in nude mice. NP induction of iPSCs resulted in the expression of NP cell specific matrix proteins and related genes. Non-induced NP derived-iPSCs also showed some NP-like phenotype. Furthermore, NP-derived iPSCs differentiate much better in hydrogel than that in a culture plate. This is a novel method for the generation of iPSCs from NP cells of DDD patients, and we have successfully differentiated these iPSCs into NP-like cells in hydrogel. This method provides a novel treatment of DDD by using patient-specific NP cells in a relatively simple and straightforward manner.

Determination of the optimal atrioventricular interval in sick sinus syndrome during DDD pacing.

PubMed

Kato, Masaya; Dote, Keigo; Sasaki, Shota; Goto, Kenji; Takemoto, Hiroaki; Habara, Seiji; Hasegawa, Daiji; Matsuda, Osamu

2005-09-01

Although the AAI pacing mode has been shown to be electromechanically superior to the DDD pacing mode in sick sinus syndrome (SSS), there is evidence suggesting that during AAI pacing the presence of natural ventricular activation pattern is not enough for hemodynamic benefit to occur. Myocardial performance index (MPI) is a simply measurable Doppler-derived index of combined systolic and diastolic myocardial performance. The aim of this study was to investigate whether AAI pacing mode is electromechanically superior to the DDD mode in patients with SSS by using Doppler-derived MPI. Thirty-nine SSS patients with dual-chamber pacing devices were evaluated by using Doppler echocardiography in AAI mode and DDD mode. The optimal atrioventricular (AV) interval in DDD mode was determined and atrial stimulus-R interval was measured in AAI mode. The ratio of the atrial stimulus-R interval to the optimal AV interval was defined as relative AV interval (rAVI) and the ratio of MPI in AAI mode to that in DDD mode was defined as relative MPI (rMPI). The rMPI was significantly correlated with atrial stimulus-R interval and rAVI (r = 0.57, P = 0.0002, and r = 0.67, P < 0.0001, respectively). A cutoff point of 1.73 for rAVI provided optimum sensitivity and specificity for rMPI >1 based on the receiver operator curves. Even though the intrinsic AV conduction is moderately prolonged, some SSS patients with dual-chamber pacing devices benefit from the ventricular pacing with optimal AV interval. MPI is useful to determine the optimal pacing mode in acute experiment.

Derivation of mean dose tolerances for new fractionation schemes and treatment modalities

NASA Astrophysics Data System (ADS)

Perkó, Zoltán; Bortfeld, Thomas; Hong, Theodore; Wolfgang, John; Unkelbach, Jan

2018-02-01

Avoiding toxicities in radiotherapy requires the knowledge of tolerable organ doses. For new, experimental fractionation schemes (e.g. hypofractionation) these are typically derived from traditional schedules using the biologically effective dose (BED) model. In this report we investigate the difficulties of establishing mean dose tolerances that arise since the mean BED depends on the entire spatial dose distribution, rather than on the dose level alone. A formula has been derived to establish mean physical dose constraints such that they are mean BED equivalent to a reference treatment scheme. This formula constitutes a modified BED equation where the influence of the spatial dose distribution is summarized in a single parameter, the dose shape factor. To quantify effects we analyzed 24 liver cancer patients for whom both proton and photon IMRT treatment plans were available. The results show that the standard BED equation—neglecting the spatial dose distribution—can overestimate mean dose tolerances for hypofractionated treatments by up to 20%. The shape difference between photon and proton dose distributions can cause 30-40% differences in mean physical dose for plans having identical mean BEDs. Converting hypofractionated, 5/15-fraction proton doses to mean BED equivalent photon doses in traditional 35-fraction regimens resulted in up to 10 Gy higher doses than applying the standard BED formula. The dose shape effect should be accounted for to avoid overestimation of mean dose tolerances, particularly when estimating constraints for hypofractionated regimens. Additionally, tolerances established for one treatment modality cannot necessarily be applied to other modalities with drastically different dose distributions, such as proton therapy. Last, protons may only allow marginal (5-10%) dose escalation if a fraction-size adjusted organ mean dose is constraining instead of a physical dose.

45. AUXILIARY CHAMBER BETWEEN CHAMBER AND CONCRETE ENCLOSURE (LOCATION DDD), ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

45. AUXILIARY CHAMBER BETWEEN CHAMBER AND CONCRETE ENCLOSURE (LOCATION DDD), VIEW LOOKING EAST. LEAD ENCLOSED PIPING IS DRAIN FROM BOILER CHAMBER No. 1 - Shippingport Atomic Power Station, On Ohio River, 25 miles Northwest of Pittsburgh, Shippingport, Beaver County, PA

p,p\\'-Dichlorodiphenyl dichloroethane (DDD)

Integrated Risk Information System (IRIS)

p , p ' - Dichlorodiphenyl dichloroethane ( DDD ) ; CASRN 72 - 54 - 8 Human health assessment information on a chemical substance is included in the IRIS database only after a comprehensive review of toxicity data , as outlined in the IRIS assessment development process . Sections I ( Health Hazard

Dense Deposit Disease in Korean Children: A Multicenter Clinicopathologic Study

PubMed Central

Park, Se Jin; Kim, Yong-Jin; Ha, Tae-Sun; Lim, Beom Jin; Jeong, Hyeon Joo; Park, Yong Hoon; Lee, Dae Yeol; Kim, Pyung Kil; Kim, Kyo Sun; Chung, Woo Yeong

2012-01-01

The purpose of this study was to investigate the clinical, laboratory, and pathologic characteristics of dense deposit disease (DDD) in Korean children and to determine whether these characteristics differ between Korean and American children with DDD. In 2010, we sent a structured protocol about DDD to pediatric nephrologists throughout Korea. The data collected were compared with previously published data on 14 American children with DDD. Korean children had lower 24-hr urine protein excretion and higher serum albumin levels than American children. The light microscopic findings revealed that a higher percentage of Korean children had membranoproliferative glomerulonephritis patterns (Korean, 77.8%; American, 28.6%, P = 0.036), whereas a higher percentage of American children had crescents (Korean, 0%; American, 78.6%, P < 0.001). The findings from the electron microscopy revealed that Korean children were more likely to have segmental electron dense deposits in the lamina densa of the glomerular basement membrane (Korean, 100%; American, 28.6%, P = 0.002); mesangial deposit was more frequent in American children (Korean, 66.7%; American, 100%, P = 0.047). The histological findings revealed that Korean children with DDD were more likely to show membranoproliferative glomerulonephritis patterns than American children. The degree of proteinuria and hypoalbuminemia was milder in Korean children than American children. PMID:23091320

Comparison of semipermeable membrane device (SPMD) and large-volume solid-phase extraction techniques to measure water concentrations of 4,4'-DDT, 4,4'-DDE, and 4,4'-DDD in Lake Chelan, Washington.

PubMed

Ellis, Steven G; Booij, Kees; Kaputa, Mike

2008-07-01

Semipermeable membrane devices (SPMDs) spiked with the performance reference compound PCB29 were deployed 6.1 m above the sediments of Lake Chelan, Washington, for a period of 27 d, to estimate the dissolved concentrations of 4,4'-DDT, 4,4'-DDE, and 4,4'-DDD. Water concentrations were estimated using methods proposed in 2002 and newer equations published in 2006 to determine how the application of the newer equations affects historical SPMD data that used the older method. The estimated concentrations of DDD, DDE, and DDD calculated using the older method were 1.5-2.9 times higher than the newer method. SPMD estimates from both methods were also compared to dissolved and particulate DDT concentrations measured directly by processing large volumes of water through a large-volume solid-phase extraction device (Infiltrex 300). SPMD estimates of DDD+DDE+DDT (SigmaDDT) using the older and newer methods were lower than Infiltrex concentrations by factors of 1.1 and 2.3, respectively. All measurements of DDT were below the Washington State water quality standards for the protection of human health (0.59 ng l(-1)) and aquatic life (1.0 ng l(-1)).

DOE Office of Scientific and Technical Information (OSTI.GOV)

Perko, Z; Bortfeld, T; Hong, T

Purpose: The safe use of radiotherapy requires the knowledge of tolerable organ doses. For experimental fractionation schemes (e.g. hypofractionation) these are typically extrapolated from traditional fractionation schedules using the Biologically Effective Dose (BED) model. This work demonstrates that using the mean dose in the standard BED equation may overestimate tolerances, potentially leading to unsafe treatments. Instead, extrapolation of mean dose tolerances should take the spatial dose distribution into account. Methods: A formula has been derived to extrapolate mean physical dose constraints such that they are mean BED equivalent. This formula constitutes a modified BED equation where the influence of themore » spatial dose distribution is summarized in a single parameter, the dose shape factor. To quantify effects we analyzed 14 liver cancer patients previously treated with proton therapy in 5 or 15 fractions, for whom also photon IMRT plans were available. Results: Our work has two main implications. First, in typical clinical plans the dose distribution can have significant effects. When mean dose tolerances are extrapolated from standard fractionation towards hypofractionation they can be overestimated by 10–15%. Second, the shape difference between photon and proton dose distributions can cause 30–40% differences in mean physical dose for plans having the same mean BED. The combined effect when extrapolating proton doses to mean BED equivalent photon doses in traditional 35 fraction regimens resulted in up to 7–8 Gy higher doses than when applying the standard BED formula. This can potentially lead to unsafe treatments (in 1 of the 14 analyzed plans the liver mean dose was above its 32 Gy tolerance). Conclusion: The shape effect should be accounted for to avoid unsafe overestimation of mean dose tolerances, particularly when estimating constraints for hypofractionated regimens. In addition, tolerances established for a given treatment modality cannot necessarily be applied to other modalities with drastically different dose distributions.« less

40 CFR 63.1316 - PET and polystyrene affected sources-emissions control provisions.

Code of Federal Regulations, 2010 CFR

2010-07-01

... appropriate, and are not required to comply with the requirements specified in 40 CFR part 60, subpart DDD... requirements specified in 40 CFR part 60, subpart DDD. Compliance can be based on either organic HAP or TOC. (1...

40 CFR 63.1316 - PET and polystyrene affected sources-emissions control provisions.

Code of Federal Regulations, 2011 CFR

2011-07-01

... appropriate, and are not required to comply with the requirements specified in 40 CFR part 60, subpart DDD... requirements specified in 40 CFR part 60, subpart DDD. Compliance can be based on either organic HAP or TOC. (1...

DDE, DDT + dieldrin: Residues in American kestrels and relations to reproduction

USGS Publications Warehouse

Wiemeyer, Stanley N.; Porter, Ron; Hensler, G.L.; Maestrelli, J.R.

1986-01-01

Captive American kestrels (Falco sparverius) given long-term dietary dosages of DDT and dieldrin in combination, at low and high rates, were compared with controls to determine the effects of the toxicants on reproductive success and eggshell thickness. Additional kestrels were dosed with DDE to determine its effect on shell thickness. Tissues of birds that died or were sacrificed, and eggs, were analyzed for DDE, DDD, DDT, and dieldrin. Eight paired birds, mostly males, given a high dosage of DDT + dieldrin died of dieldrin poisoning. Three periods of heavy mortality involving only dosed birds, which occurred in summer 1966, fall 1967, and spring 1968, followed temperature declines and other stress factors. Organochlorine concentrations in tissues of sacrificed birds and eggs in all units of the DDT + dieldrin study were significantly different among treatments. Residue concentrations in tissues of birds on high dosage of DDT + dieldrin were about 3 times higher than those on low dosage, a difference similar to the relative magnitude of the dose rates. Concentrations of some toxicants, especially DDE, were significantly higher in tissues of males than females, although these differences were difficult to interpret because males generally were sacrificed later than females. Concentrations in tissues and eggs of dosed yearlings, placed on clean food 7 to 9 weeks before pairing, were often significantly lower than in those yearlings that remained on dosage. Concentrations of each toxicant were usually highly correlated (r > 0.85) among tissues, especially for DDE and dieldrin. Organochlorine concentrations in brains and eggs could be predicted from concentrations in carcasses. DDE and dieldrin concentrations in eggs were about one-half those in carcasses, DDD about one-seventh, and DDT 1.5 to 2 times higher in eggs than carcasses. Eggshells of DDT + dieldrin-dosed kestrels were 6-23% thinner than eggshells of corresponding controls in different groups and years. Organochlorine concentrations in eggs and tissues of females were poorly correlated with shell thickness. Of the four toxicants in eggs, DDE was significantly and most closely correlated with fledging success. Interpretation of direct comparisons between our DDT + dieldrin studies and most current field situations are difficult because contaminant profiles in our birds are unlike those in most field samples.

A critique of the molecular target-based drug discovery paradigm based on principles of metabolic control: advantages of pathway-based discovery.

PubMed

Hellerstein, Marc K

2008-01-01

Contemporary drug discovery and development (DDD) is dominated by a molecular target-based paradigm. Molecular targets that are potentially important in disease are physically characterized; chemical entities that interact with these targets are identified by ex vivo high-throughput screening assays, and optimized lead compounds enter testing as drugs. Contrary to highly publicized claims, the ascendance of this approach has in fact resulted in the lowest rate of new drug approvals in a generation. The primary explanation for low rates of new drugs is attrition, or the failure of candidates identified by molecular target-based methods to advance successfully through the DDD process. In this essay, I advance the thesis that this failure was predictable, based on modern principles of metabolic control that have emerged and been applied most forcefully in the field of metabolic engineering. These principles, such as the robustness of flux distributions, address connectivity relationships in complex metabolic networks and make it unlikely a priori that modulating most molecular targets will have predictable, beneficial functional outcomes. These same principles also suggest, however, that unexpected therapeutic actions will be common for agents that have any effect (i.e., that complexity can be exploited therapeutically). A potential operational solution (pathway-based DDD), based on observability rather than predictability, is described, focusing on emergent properties of key metabolic pathways in vivo. Recent examples of pathway-based DDD are described. In summary, the molecular target-based DDD paradigm is built on a naïve and misleading model of biologic control and is not heuristically adequate for advancing the mission of modern therapeutics. New approaches that take account of and are built on principles described by metabolic engineers are needed for the next generation of DDD.

Reduction in unnecessary ventricular pacing fails to affect hard clinical outcomes in patients with preserved left ventricular function: a meta-analysis.

PubMed

Shurrab, Mohammed; Healey, Jeff S; Haj-Yahia, Saleem; Kaoutskaia, Anna; Boriani, Giuseppe; Carrizo, Aldo; Botto, Gianluca; Newman, David; Padeletti, Luigi; Connolly, Stuart J; Crystal, Eugene

2017-02-01

Several pacing modalities across multiple manufacturers have been introduced to minimize unnecessary right ventricular pacing. We conducted a meta-analysis to assess whether ventricular pacing reduction modalities (VPRM) influence hard clinical outcomes in comparison to standard dual-chamber pacing (DDD). An electronic search was performed using Cochrane Central Register, PubMed, Embase, and Scopus. Only randomized controlled trials (RCT) were included in this analysis. Outcomes of interest included: frequency of ventricular pacing (VP), incident persistent/permanent atrial fibrillation (PerAF), all-cause hospitalization and all-cause mortality. Odds ratios (OR) were reported for dichotomous variables. Seven RCTs involving 4119 adult patients were identified. Ventricular pacing reduction modalities were employed in 2069 patients: (MVP, Medtronic Inc.) in 1423 and (SafeR, Sorin CRM, Clamart) in 646 patients. Baseline demographics and clinical characteristics were similar between VPRM and DDD groups. The mean follow-up period was 2.5 ± 0.9 years. Ventricular pacing reduction modalities showed uniform reduction in VP in comparison to DDD groups among all individual studies. The incidence of PerAF was similar between both groups {8 vs. 10%, OR 0.84 [95% confidence interval (CI) 0.57; 1.24], P = 0.38}. Ventricular pacing reduction modalities showed no significant differences in comparison to DDD for all-cause hospitalization or all-cause mortality [9 vs. 11%, OR 0.82 (95% CI 0.65; 1.03), P= 0.09; 6 vs. 6%, OR 0.97 (95% CI 0.74; 1.28), P = 0.84, respectively]. Novel VPRM measures effectively reduce VP in comparison to standard DDD. When actively programmed, VPRM did not improve clinical outcomes and were not superior to standard DDD programming in reducing incidence of PerAF, all-cause hospitalization, or all-cause mortality.

Molecular insight into bacterial cleavage of oceanic dimethylsulfoniopropionate into dimethyl sulfide

PubMed Central

Li, Chun-Yang; Wei, Tian-Di; Zhang, Sheng-Hui; Chen, Xiu-Lan; Gao, Xiang; Wang, Peng; Xie, Bin-Bin; Su, Hai-Nan; Qin, Qi-Long; Zhang, Xi-Ying; Yu, Juan; Zhang, Hong-Hai; Zhou, Bai-Cheng; Yang, Gui-Peng; Zhang, Yu-Zhong

2014-01-01

The microbial cleavage of dimethylsulfoniopropionate (DMSP) generates volatile DMS through the action of DMSP lyases and is important in the global sulfur and carbon cycles. When released into the atmosphere from the oceans, DMS is oxidized, forming cloud condensation nuclei that may influence weather and climate. Six different DMSP lyase genes are found in taxonomically diverse microorganisms, and dddQ is among the most abundant in marine metagenomes. Here, we examine the molecular mechanism of DMSP cleavage by the DMSP lyase, DddQ, from Ruegeria lacuscaerulensis ITI_1157. The structures of DddQ bound to an inhibitory molecule 2-(N-morpholino)ethanesulfonic acid and of DddQ inactivated by a Tyr131Ala mutation and bound to DMSP were solved. DddQ adopts a β-barrel fold structure and contains a Zn2+ ion and six highly conserved hydrophilic residues (Tyr120, His123, His125, Glu129, Tyr131, and His163) in the active site. Mutational and biochemical analyses indicate that these hydrophilic residues are essential to catalysis. In particular, Tyr131 undergoes a conformational change during catalysis, acting as a base to initiate the β-elimination reaction in DMSP lysis. Moreover, structural analyses and molecular dynamics simulations indicate that two loops over the substrate-binding pocket of DddQ can alternate between “open” and “closed” states, serving as a gate for DMSP entry. We also propose a molecular mechanism for DMS production through DMSP cleavage. Our study provides important insight into the mechanism involved in the conversion of DMSP into DMS, which should lead to a better understanding of this globally important biogeochemical reaction. PMID:24395783

Prognosis of intervertebral disc loss from diagnosis of degenerative disc disease

NASA Astrophysics Data System (ADS)

Li, S.; Lin, A.; Tay, K.; Romano, W.; Osman, Said

2015-03-01

Degenerative Disc Disease (DDD) is one of the most common causes of low back pain, and is a major factor in limiting the quality of life of an individual usually as they enter older stages of life, the disc degeneration reduces the shock absorption available which in turn causes pain. Disc loss is one of the central processes in the pathogenesis of DDD. In this study, we investigated whether the image texture features quantified from magnetic resonance imaging (MRI) could be appropriate markers for diagnosis of DDD and prognosis of inter-vertebral disc loss. The main objective is to use simple image based biomarkers to perform prognosis of spinal diseases using non-invasive procedures. Our results from 65 subjects proved the higher success rates of the combination marker compared to the individual markers and in the future, we will extend the study to other spine regions to allow prognosis and diagnosis of DDD for a wider region.

Residues of DDT in brains and bodies of birds that died on dosage and in survivors

USGS Publications Warehouse

Stickel, L.F.; Stickel, W.H.; Christensen, R.

1966-01-01

Residues of 1,1 ,l-trichloro-2,2-bis(p-chlorophenyl)-ethane (DDT) and 1,1 -dichloro-2.2-bis(p-chlorophenyl)-ethane (DDD) in brains of cowbirds (Molothrus ater) killed hy dietary dosage of DDT were similar in birds that died after various lengths of time on dosage and in birds that died of delayed effects after as much as 40 days on clean food, Residues of DDT and DDD, but not of 1,1 -dichloro-2.2-bis-(p-chlorophenyl)-ethylene (DDE), were much lower in survivors 112 days after dosage. The relative importance of DDT and DDD in brains could nlot he determined, but DDE appeared not to be critical. Residues in brains of cowbirds were similar to those reported for robins, sparrows, eagles, and white rats. Residues in livers and carcass remainders (with the possible exception of DDD in the liver) appeared unsuitable for diagnosing the cause of death.

AAA-DDD triple hydrogen bond complexes.

PubMed

Blight, Barry A; Camara-Campos, Amaya; Djurdjevic, Smilja; Kaller, Martin; Leigh, David A; McMillan, Fiona M; McNab, Hamish; Slawin, Alexandra M Z

2009-10-07

Experiment and theory both suggest that the AAA-DDD pattern of hydrogen bond acceptors (A) and donors (D) is the arrangement of three contiguous hydrogen bonding centers that results in the strongest association between two species. Murray and Zimmerman prepared the first example of such a system (complex 3*2) and determined the lower limit of its association constant (K(a)) in CDCl(3) to be 10(5) M(-1) by (1)H NMR spectroscopy (Murray, T. J. and Zimmerman, S. C. J. Am. Chem. Soc. 1992, 114, 4010-4011). The first cationic AAA-DDD pair (3*4(+)) was described by Bell and Anslyn (Bell, D. A. and Anslyn, E. A. Tetrahedron 1995, 51, 7161-7172), with a K(a) > 5 x 10(5) M(-1) in CH(2)Cl(2) as determined by UV-vis spectroscopy. We were recently able to quantify the strength of a neutral AAA-DDD arrangement using a more chemically stable AAA-DDD system, 6*2, which has an association constant of 2 x 10(7) M(-1) in CH(2)Cl(2) (Djurdjevic, S., Leigh, D. A., McNab, H., Parsons, S., Teobaldi, G. and Zerbetto, F. J. Am. Chem. Soc. 2007, 129, 476-477). Here we report on further AA(A) and DDD partners, together with the first precise measurement of the association constant of a cationic AAA-DDD species. Complex 6*10(+)[B(3,5-(CF(3))(2)C(6)H(3))(4)(-)] has a K(a) = 3 x 10(10) M(-1) at RT in CH(2)Cl(2), by far the most strongly bound triple hydrogen bonded system measured to date. The X-ray crystal structure of 6*10(+) with a BPh(4)(-) counteranion shows a planar array of three short (NH...N distances 1.95-2.15 A), parallel (but staggered rather than strictly linear; N-H...N angles 165.4-168.8 degrees), primary hydrogen bonds. These are apparently reinforced, as theory predicts, by close electrostatic interactions (NH-*-N distances 2.78-3.29 A) between each proton and the acceptor atoms of the adjacent primary hydrogen bonds.

Effects of adrenolytic mitotane on drug elimination pathways assessed in vitro.

PubMed

Theile, Dirk; Haefeli, Walter Emil; Weiss, Johanna

2015-08-01

Mitotane (1,1-dichloro-2-(o-chlorophenyl)-2-(p-chlorophenyl)ethane, o,p'-DDD) represents one of the most active drugs for the treatment of adrenocortical carcinoma. Its metabolites 1,1-(o,p'-dichlorodiphenyl) acetic acid (=o,p'-DDA) and 1,1-(o,p'-dichlorodiphenyl)-2,2 dichloroethene (=o,p'-DDE) partly contribute to its pharmacological effects. Because mitotane has a narrow therapeutic index and causes pharmacokinetic drug-drug interactions, knowledge about these compounds' effects on drug metabolizing and transporting proteins is crucial. Using quantitative real-time polymerase chain reaction, our study confirmed the strong inducing effects of o,p'-DDD on mRNA expression of cytochrome P450 3A4 (CYP3A4, 30-fold) and demonstrated that other enzymes and transporters are also induced (e.g., CYP1A2, 8.4-fold; ABCG2 (encoding breast resistance cancer protein, BCRP), 4.2-fold; ABCB1 (encoding P-glycoprotein, P-gp) 3.4-fold). P-gp induction was confirmed at the protein level. o,p'-DDE revealed a similar induction profile, however, with less potency and o,p'-DDA had only minor effects. Reporter gene assays clearly confirmed o,p'-DDD to be a PXR activator and for the first time demonstrated that o,p'-DDE and o,p'-DDA also activate PXR albeit with lower potency. Using isolated, recombinant CYP enzymes, o,p'-DDD and o,p'-DDE were shown to strongly inhibit CYP2C19 (IC50 = 0.05 and 0.09 µM). o,p'-DDA exhibited only minor inhibitory effects. In addition, o,p'-DDD, o,p'-DDE, and o,p'-DDA are demonstrated to be neither substrates nor inhibitors of BCRP or P-gp function. In summary, o,p'-DDD and o,p'-DDE might be potential perpetrators in pharmacokinetic drug-drug interactions through induction of drug-metabolizing enzymes or drug transporters and by potent inhibition of CYP2C19. In tumors over-expressing BCRP or P-gp, o,p'-DDD and its metabolites should retain their efficacy due to a lack of substrate characteristics.

NSAIDs utilization for musculoskeletal indications in elderly patients with cerebro/cardiovascular disease.

PubMed

Roberto, Giuseppe; Bartolini, Claudia; Rea, Federico; Onder, Graziano; Vitale, Cristiana; Trifirò, Gianluca; Kirchmayer, Ursula; Chinellato, Alessandro; Lucenteforte, Ersilia; Corrao, Giovanni; Mugelli, Alessandro; Lapi, Francesco; Gini, Rosa

2018-05-01

To describe NSAID utilization for musculoskeletal conditions in a large cohort of Italian elderly with cerebro/cardiovascular disease, a population in which NSAIDs should be generally avoided due to the prothrombotic potential. Administrative data from five Italian geographic areas were analyzed. Patients aged ≥ 65 with a cerebro/cardiovascular event recorded between 2008 and 2011 (cohort entry) were selected. Prescription NSAIDs reimbursed for musculoskeletal conditions and dispensed during 1 year follow-up were retrieved to describe (i) prevalence of use, (ii) average amount of defined daily doses of NSAIDs claimed by users per day of follow-up, and (iii) distribution of the received daily dose (RDD) among patients with ≥ 2 dispensings. Among new users, i.e., patients without NSAID dispensings during 2 years before cohort entry, the first dispensed NSAID molecule was observed. Overall, 511,989 patients were selected. Across the five geographic areas, prevalence of use ranged from 48 to 21% and average consumption ranged between 30 and 67 DDD/1000 users/day. Around 10% of patients in the overall cohort had a RDD > 1. Nimesulide (9.6%) and diclofenac (7.5%) had the highest prevalence of use. The most consumed NSAIDs were nimesulide and coxibs with 10.6 and 7.5 DDD/1000 users/day, respectively. Among new users recruited in 2011, 30% had diclofenac or a coxibs as the first prescription. NSAID use was common in the study cohort, particularly in central-southern areas. In contrast with current recommendations, coxibs and diclofenac were among the most prescribed active principles, even in new users. Interventions to promote appropriateness of use are warranted.

Risk-adjusted antibiotic consumption in 34 public acute hospitals in Ireland, 2006 to 2014

PubMed Central

Oza, Ajay; Donohue, Fionnuala; Johnson, Howard; Cunney, Robert

2016-01-01

As antibiotic consumption rates between hospitals can vary depending on the characteristics of the patients treated, risk-adjustment that compensates for the patient-based variation is required to assess the impact of any stewardship measures. The aim of this study was to investigate the usefulness of patient-based administrative data variables for adjusting aggregate hospital antibiotic consumption rates. Data on total inpatient antibiotics and six broad subclasses were sourced from 34 acute hospitals from 2006 to 2014. Aggregate annual patient administration data were divided into explanatory variables, including major diagnostic categories, for each hospital. Multivariable regression models were used to identify factors affecting antibiotic consumption. Coefficient of variation of the root mean squared errors (CV-RMSE) for the total antibiotic usage model was very good (11%), however, the value for two of the models was poor (> 30%). The overall inpatient antibiotic consumption increased from 82.5 defined daily doses (DDD)/100 bed-days used in 2006 to 89.2 DDD/100 bed-days used in 2014; the increase was not significant after risk-adjustment. During the same period, consumption of carbapenems increased significantly, while usage of fluoroquinolones decreased. In conclusion, patient-based administrative data variables are useful for adjusting hospital antibiotic consumption rates, although additional variables should also be employed. PMID:27541730

Who is Eligible for DDD Services? Report No. 5.24.

ERIC Educational Resources Information Center

Kohlenberg, Elizabeth; And Others

The effects of broadening the definition of eligibility for services from the Washington State Division of Developmental Disabilities (DDD) are analyzed. Five different definitions are discussed. The existing definition includes: (1) "statutory conditions," which includes persons who are mentally retarded or have difficulty carrying out…

Impact of pacing and high-pass filter settings on ventricular bipolar electrograms in implantable cardioverter defibrillator systems. - Implication of predictors for inappropriate therapy caused by oversensing of repolarization electrograms-.

PubMed

Maesato, Akira; Higa, Satoshi; Lin, Yenn-Jiang; Chinen, Ichiro; Ishigaki, Sugako; Yajima, Machiko; Masuzaki, Hiroaki; Chen, Shih-Ann

2011-01-01

Predictors of T wave oversensing with implantable cardioverter-defibrillator (ICD) systems remains to be clarified. Thirteen consecutive patients who underwent ICD implantations were included. The depolarization (R) and repolarization (T) of bipolar electrograms during baseline, AAI and DDD modes, and an isoproterenol (ISO) infusion were evaluated. The R wave amplitude during DDD was significantly lower as compared to that during the other conditions in all high-pass filter settings. In contrast, there was no significant difference in the T wave amplitude during the DDD as compared to the other conditions. With the DDD, there was a significantly higher incidence of a T/R ratio of greater than 0.25 as compared to that with the other conditions. T wave amplitude in Brugada syndrome was significantly higher than that in non-Brugada syndrome. The existence of Brugada syndrome and T/R ratio during the AAI with a high-pass filter setting of 10/20 Hz was an excellent predictor of T wave oversensing in the follow-up period. DDD had a significant impact on the R wave amplitude reduction and the T/R ratio during AAI can be predictors of T wave oversensing. These findings have important implications for inappropriate shocks due to T wave oversensing.

Coupled DDD-FEM modeling on the mechanical behavior of microlayered metallic multilayer film at elevated temperature

NASA Astrophysics Data System (ADS)

Huang, Minsheng; Li, Zhenhuan

2015-12-01

To investigate the mechanical behavior of the microlayered metallic thin films (MMMFs) at elevated temperature, an enhanced discrete-continuous model (DCM), which couples rather than superposes the two-dimensional climb/glide-enabled discrete dislocation dynamics (2D-DDD) with the linearly elastic finite element method (FEM), is developed in this study. In the present coupling scheme, two especial treatments are made. One is to solve how the plastic strain captured by the DDD module is transferred properly to the FEM module as an eigen-strain; the other is to answer how the stress field computationally obtained by the FEM module is transferred accurately to the DDD module to drive those discrete dislocations moving correctly. With these two especial treatments, the interactions between adjacent dislocations and between dislocation pile-ups and inter-phase boundaries (IBs), which are crucial to the strengthening effect in MMMFs, are carefully taken into account. After verified by comparing the computationally predicted results with the theoretical solutions for a dislocation residing in a homogeneous material and nearby a bi-material interface, this 2D-DDD/FEM coupling scheme is used to model the tensile mechanical behaviors of MMMFs at elevated temperature. The strengthening mechanism of MMMFs and the layer thickness effect are studied in detail, with special attentions to the influence of dislocation climb on them.

Psychotropic drugs and risk of motor vehicle accidents: a population-based case-control study

PubMed Central

Chang, Chia-Ming; Wu, Erin Chia-Hsuan; Chen, Chuan-Yu; Wu, Kuan-Yi; Liang, Hsin-Yi; Chau, Yeuk-Lun; Wu, Chi-Shin; Lin, Keh-Ming; Tsai, Hui-Ju

2013-01-01

Aim To examine comprehensively the relationship between exposure to four classes of psychotropic drugs including antipsychotics, antidepressants, benzodiazepines (BZDs) and Z-drugs, and motor vehicle accidents (MVAs). Method The authors conducted a matched case-control study of 5183 subjects with MVAs and 31 093 matched controls, identified from the claims records of outpatient service visits during the period from 2000 to 2009. Inclusion criteria were defined as subjects aged equal to or more than 18 years and involved in MVAs. Conditional logistic regressions with covariates adjustment (including urbanity, psychiatric and non-psychiatric outpatient visits and Charlson comorbidity score) were applied to examine the effect of four classes of psychotropic drugs on MVAs. Results Significant increased risk of MVAs was found in subjects taking antidepressants within 1 month (adjusted odds ratio (AOR) 1.73, 95% confidence interval (CI) 1.34, 2.22), 1 week (AOR 1.71, 95% CI 1.29, 2.26), and 1 day (AOR 1.70, 95% CI 1.26, 2.29) before MVAs occurred. Similar results were observed in subjects taking benzodiazepines (BZDs) (AOR 1.56, 95% CI 1.38, 1.75 for 1 month; AOR 1.64, 95% CI 1.43, 1.88 for 1 week, and AOR 1.62, 95% CI 1.39, 1.88 for 1 day) and Z-drugs (AOR 1.42, 95% CI 1.14, 1.76 for 1 month, AOR 1.37, 95% CI 1.06, 1.75 for 1 week, AOR 1.34, 95% CI 1.03, 1.75 for 1 day), but not antipsychotics. Moreover, significant dose effects of antidepressants (equal to or more than 0.6–1.0 DDD), BZDs (equal to or more than 0.1–0.5 DDD) and Z-drugs (more than 1 DDD) were observed, respectively, on the risk of experiencing an MVA. Conclusion Taken together, subjects taking antidepressants, BZDs and Z-drugs, separately, should be particularly cautioned for their increasing risk of MVAs. PMID:22971090

Drug exposure in register-based research—An expert-opinion based evaluation of methods

PubMed Central

Taipale, Heidi; Koponen, Marjaana; Tolppanen, Anna-Maija; Hartikainen, Sirpa; Ahonen, Riitta; Tiihonen, Jari

2017-01-01

Background In register-based pharmacoepidemiological studies, construction of drug exposure periods from drug purchases is a major methodological challenge. Various methods have been applied but their validity is rarely evaluated. Our objective was to conduct an expert-opinion based evaluation of the correctness of drug use periods produced by different methods. Methods Drug use periods were calculated with three fixed methods: time windows, assumption of one Defined Daily Dose (DDD) per day and one tablet per day, and with PRE2DUP that is based on modelling of individual drug purchasing behavior. Expert-opinion based evaluation was conducted with 200 randomly selected purchase histories of warfarin, bisoprolol, simvastatin, risperidone and mirtazapine in the MEDALZ-2005 cohort (28,093 persons with Alzheimer’s disease). Two experts reviewed purchase histories and judged which methods had joined correct purchases and gave correct duration for each of 1000 drug exposure periods. Results The evaluated correctness of drug use periods was 70–94% for PRE2DUP, and depending on grace periods and time window lengths 0–73% for tablet methods, 0–41% for DDD methods and 0–11% for time window methods. The highest rate of evaluated correct solutions for each method class were observed for 1 tablet per day with 180 days grace period (TAB_1_180, 43–73%), and 1 DDD per day with 180 days grace period (1–41%). Time window methods produced at maximum only 11% correct solutions. The best performing fixed method TAB_1_180 reached highest correctness for simvastatin 73% (95% CI 65–81%) whereas 89% (95% CI 84–94%) of PRE2DUP periods were judged as correct. Conclusions This study shows inaccuracy of fixed methods and the urgent need for new data-driven methods. In the expert-opinion based evaluation, the lowest error rates were observed with data-driven method PRE2DUP. PMID:28886089

Cost-Effectiveness of Surgical Versus Conservative Treatment for Thoracolumbar Burst Fractures.

PubMed

Aras, Efe Levent; Bunger, Cody; Hansen, Ebbe Stender; Søgaard, Rikke

2016-02-01

Historical, register-based cohort study following 85 patients in the course of a time frame extending from 2 years before to 2 years after trauma occurrence. To investigate the cost-effectiveness of surgery versus conservative management for thoracolumbar burst fractures. Despite the prevalence of thoracolumbar burst fractures, consensus has still not been reached in terms of their clinical management and whereas from a health policy point of view, efficient use of resources is equally important, literature pertaining to this aspect is limited. Consecutive patients who were admitted to a university clinic between 2004 and 2008 because of CT-verified AO type A3 fractures (T11-L2), age 18 to 65 years Patients with neurological compromise, osteoporosis, or malignancy were not included. The cost parameter defined primary and secondary health-care use (2010 &OV0556;) and the effect parameter was based on three alternative measures of pain medication: morphine milligram and defined daily doses (DDD) of narcotic and nonnarcotic analgesics. For cost-effectiveness analysis, we employed a difference-in-difference approach, including control for treatment selection (age, sex, and fracture type). Nonparametric bootstrapping was used to estimate conventional 95% confidence intervals of mean estimates. When taking into consideration all health-care consumption, surgical management was observed to cost an additional &OV0556;10,734 (4215; 15,144) as compared with conservative management. The differences on morphine at 527(-3031; 6,016) milligram, narcotic analgesics at -8(-176; 127) DDD, and nonnarcotic analgesics at -3(-72; 58) DDD were all insignificant The probability for surgery being cost-effective did not exceed 50% for any value of willingness to pay for effect. Surgical management does not seem to be a cost-effective strategy as compared with conservative management for traumatic thoracolumbar burst fractures without neurological deficits. In addition, higher-volume studies examining the clinical effect of alternative management strategies would be valuable. 3.

Communication Strategy: Proper Structure Necessary but not Sufficient

DTIC Science & Technology

2010-12-01

Information, (1998), http://www.ncbi.nlm.nih.gov/ bookshelf /br.fcgi?book=nap6200&part=a20006484ddd00073 (accessed November 12, 2010). “The multidimensional...Biotechnology Information (1998). http://www.ncbi.nlm.nih.gov/ bookshelf /br.fcgi?book=nap6200&part=a20006484ddd000 73 (accessed November 12, 2010

Communication Strategy: Proper Structure Necessary But Not Sufficient

DTIC Science & Technology

2010-01-01

Information, (1998), http://www.ncbi.nlm.nih.gov/ bookshelf /br.fcgi?book=nap6200&part=a20006484ddd00073 (accessed November 12, 2010). “The multidimensional...Biotechnology Information (1998). http://www.ncbi.nlm.nih.gov/ bookshelf /br.fcgi?book=nap6200&part=a20006484ddd000 73 (accessed November 12, 2010

Issue Brief on Diversity

ERIC Educational Resources Information Center

Division on Developmental Disabilities, Council for Exceptional Children (NJ1), 2013

2013-01-01

During the past year, the Diversity Committee of the Division of Developmental Disabilities (DDD) Board worked with the Board and the Issues Committee Chair to develop an issue brief addressing diversity, its impact on the membership and the wider community that is served by the work of DDD, resulting in recommendations that will influence policy…

Calculation of Glucose Dose for Intraperitoneal Glucose Tolerance Tests in Lean and Obese Mice.

PubMed

Jørgensen, Mikkel S; Tornqvist, Kristina S; Hvid, Henning

2017-01-01

Glucose tolerance tests are used frequently in nonclinical research with laboratory animals, for example during characterization of obese phenotypes. Despite published standard operating procedures for glucose tolerance tests in rodents, how glucose doses should be calculated when obese and lean animals are compared is not well documented. Typically the glucose dose is calculated as 2 g/kg body weight, regardless of body composition. With this approach, obese mice receive larger glucose doses than do lean animals, potentially leading to overestimation of glucose intolerance in obese animals. In this study, we performed intraperitoneal glucose tolerance tests in mice with diet-induced obesity and their lean controls, with glucose doses based on either the total body weight or the lean body mass of the animals. To determine glucose tolerance, we determined the blood glucose AUC during the glucose tolerance test. We found that the blood glucose AUC was increased significantly in obese mice compared with lean mice by 75% on average when glucose was dosed according to the lean body mass and by 87% when the glucose dose was calculated according to total body weight. Therefore, mice with diet-induced obesity were approximately equally glucose intolerant between the 2 dose-calculation protocols. However, we recommend calculating the glucose dose according to the lean body mass of the mice, because doing so eliminates the concern regarding overdosing of obese animals.

Tolerance to the anticonvulsant effect of morphine in mice: blockage by ultra-low dose naltrexone.

PubMed

Roshanpour, Maryam; Ghasemi, Mehdi; Riazi, Kiarash; Rafiei-Tabatabaei, Neda; Ghahremani, Mohammad Hossein; Dehpour, Ahmad Reza

2009-02-01

The present study evaluated the development of tolerance to the anticonvulsant effect of morphine in a mouse model of clonic seizures induced by pentylenetetrazole, and whether ultra-low doses of the opioid receptor antagonist naltrexone which selectively block G(s) opioid receptors were capable of preventing the observed tolerance. The results showed that the morphine anticonvulsant effect could be subject to tolerance after repeated administration. Both the development and expression of tolerance were inhibited by ultra-low doses of naltrexone, suggesting the possible involvement of G(s)-coupled opioid receptors in the development of tolerance to the anticonvulsant effect of morphine.

Absolute configuration determination through the unique intramolecular excitonic coupling in the circular dichroisms of o,p'-DDT and o,p'-DDD. A combined experimental and theoretical study.

PubMed

Tanaka, Hiroki; Inoue, Yoshihisa; Nakano, Takeshi; Mori, Tadashi

2017-04-12

Circular dichroisms (CDs) of the o,p'-isomers of 1,1,1-trichloro- and 1,1-dichloro-2,2-bis(chlorophenyl)ethanes (DDT and DDD) were investigated experimentally and theoretically. A series of strong Cotton effect peaks in a characteristic negative-negative-positive-negative, or its mirror-imaged, pattern were observed in the CD spectra of these persistent organic pollutants. The theoretical CD spectra at the SAC-CI/B95(d) and RI-CC2/def2-TZVPP levels well reproduced the experimental ones, enabling us to unambiguously assign the absolute configuration of (+)-DDT and (-)-DDD as S.

Maximum tolerated dose evaluation of the AMPA modulator Org 26576 in healthy volunteers and depressed patients: a summary and method analysis of bridging research in support of phase II dose selection.

PubMed

Nations, Kari R; Bursi, Roberta; Dogterom, Peter; Ereshefsky, Larry; Gertsik, Lev; Mant, Tim; Schipper, Jacques

2012-09-01

A key challenge to dose selection in early central nervous system (CNS) clinical drug development is that patient tolerability profiles often differ from those of healthy volunteers (HVs), yet HVs are the modal population for determining doses to be investigated in phase II trials. Without clear tolerability data from the target patient population, first efficacy trials may include doses that are either too high or too low, creating undue risk for study participants and the development program overall. Bridging trials address this challenge by carefully investigating safety and tolerability in the target population prior to full-scale proof-of-concept trials. Org 26576 is an alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor positive allosteric modulator that acts by modulating ionotropic AMPA-type glutamate receptors to enhance glutamatergic neurotransmission. In preparation for phase II efficacy trials in major depressive disorder (MDD), two separate phase I trials were conducted to evaluate safety, tolerability, and pharmacokinetics in HVs and in the target patient population. Both trials were randomized and placebo controlled, and included multiple rising-dose cohorts (HV range 100-400 mg bid; MDD range 100-600 mg bid). HVs (n = 36) and patients with MDD (n = 54) were dosed under similarly controlled conditions in an inpatient facility, HVs for up to 14 days and MDD patients for up to 28 days. Safety, tolerability, and pharmacokinetics were assessed frequently. Despite comparable pharmacokinetic profiles, the maximum tolerated dose (MTD) in depressed patients was 450 mg bid, twice the MTD established in HVs. No clinically relevant safety issues associated with Org 26576 were noted. This article presents safety, tolerability, and pharmacokinetic data from two different populations examined under similar dosing conditions. The important implications of such bridging work in phase II dose selection are discussed, as are study design and data interpretation challenges.

Cross Slip of Dislocation Loops in GaN Under Shear

DTIC Science & Technology

2014-03-01

methodology 2.1 Discrete dislocation dynamic ( DDD ) simula- tions In this work, we employ a modified version of the ParaDiS code [15, 16]. First a...plane. 4 Conclusions The cross slip mechanisms of different dislocation loops have been studied via DDD simulations using the type <a> active

Institutional profile: the national Swedish academic drug discovery & development platform at SciLifeLab

PubMed Central

Arvidsson, Per I; Sandberg, Kristian; Sakariassen, Kjell S

2017-01-01

The Science for Life Laboratory Drug Discovery and Development Platform (SciLifeLab DDD) was established in Stockholm and Uppsala, Sweden, in 2014. It is one of ten platforms of the Swedish national SciLifeLab which support projects run by Swedish academic researchers with large-scale technologies for molecular biosciences with a focus on health and environment. SciLifeLab was created by the coordinated effort of four universities in Stockholm and Uppsala: Stockholm University, Karolinska Institutet, KTH Royal Institute of Technology and Uppsala University, and has recently expanded to other Swedish university locations. The primary goal of the SciLifeLab DDD is to support selected academic discovery and development research projects with tools and resources to discover novel lead therapeutics, either molecules or human antibodies. Intellectual property developed with the help of SciLifeLab DDD is wholly owned by the academic research group. The bulk of SciLifeLab DDD's research and service activities are funded from the Swedish state, with only consumables paid by the academic research group through individual grants. PMID:28670468

Glomeruli of Dense Deposit Disease contain components of the alternative and terminal complement pathway

PubMed Central

Sethi, Sanjeev; Gamez, Jeffrey D.; Vrana, Julie A.; Theis, Jason D.; Bergen, H. Robert; Zipfel, Peter F.; Dogan, Ahmet; Smith, Richard J. H.

2009-01-01

Dense Deposit Disease (DDD), or membranoproliferative glomerulonephritis type II, is a rare renal disease characterized by dense deposits in the mesangium and along the glomerular basement membranes that can be seen by electron microscopy. Although these deposits contain complement factor C3, as determined by immunofluorescence microscopy, their precise composition remains unknown. To address this question, we used mass spectrometry to identify the proteins in laser microdissected glomeruli isolated from paraffin-embedded tissue of eight confirmed cases of DDD. Compared to glomeruli from five control patients, we found that all of the glomeruli from patients with DDD contain components of the alternative pathway and terminal complement complex. Factor C9 was uniformly present as well as the two fluid-phase regulators of terminal complement complex clusterin and vitronectin. In contrast, in nine patients with immune complex–mediated membranoproliferative glomerulonephritis, glomerular samples contained mainly immunoglobulins and complement factors C3 and C4. Our study shows that in addition to fluid-phase dysregulation of the alternative pathway, soluble components of the terminal complement complex contribute to glomerular lesions found in DDD. PMID:19177158

Institutional profile: the national Swedish academic drug discovery & development platform at SciLifeLab.

PubMed

Arvidsson, Per I; Sandberg, Kristian; Sakariassen, Kjell S

2017-06-01

The Science for Life Laboratory Drug Discovery and Development Platform (SciLifeLab DDD) was established in Stockholm and Uppsala, Sweden, in 2014. It is one of ten platforms of the Swedish national SciLifeLab which support projects run by Swedish academic researchers with large-scale technologies for molecular biosciences with a focus on health and environment. SciLifeLab was created by the coordinated effort of four universities in Stockholm and Uppsala: Stockholm University, Karolinska Institutet, KTH Royal Institute of Technology and Uppsala University, and has recently expanded to other Swedish university locations. The primary goal of the SciLifeLab DDD is to support selected academic discovery and development research projects with tools and resources to discover novel lead therapeutics, either molecules or human antibodies. Intellectual property developed with the help of SciLifeLab DDD is wholly owned by the academic research group. The bulk of SciLifeLab DDD's research and service activities are funded from the Swedish state, with only consumables paid by the academic research group through individual grants.

Outpatient utilization of psychopharmaceuticals: comparison between the cities of Zagreb and Sarajevo (2006-2009).

PubMed

Catić, Tarik; Stimac, Danijela; Zivković, Krešimir; Zelić, Ana

2012-08-01

To determine the real outpatient utilization of psychiatric drugs in Zagreb (Croatia) and Sarajevo (Bosnia and Herzegovina) and to compare the outpatient utilization of psychiatric drugs between this two cities. Data on the outpatient utilization of psycholpetics and psychoanaleptics (N05 and N06) in both cities were received from pharmacies and collected during 2006-2009. Based on the data obtained, a number of DDD and DDD per 1000 inhabitants perday (DDD/1000/day) has been calculated. The data in Zagreb were received from all pharmacies in Zagreb, whereas only 50% of pharmacies in Sarajevo participated, thus an extrapolation of data for Sarajevo was required and accomplished. All drugs were classified according to the ATC system. Based on the data obtained, a number of DDD and DDD/1000/day was calculated for all N05 and N06 drugs. Overall utilization trend was similar between the cities Sarajevo and Zagreb and followed trends in other neighbouring countries. Total consumption of psycholeptics and psychoanaleptics in Sarajevo was 22.6% (on average) lower than in Zagreb, during the 4-year period. During the 2006-2009 period the total consumption of psychopharmaceuticals showed increasing trend with peak in 2008 with similar trend between Zagreb and Sarajevo. It is necessary to implement systematic approach to drug utilization monitoring in Sarajevo and Bosnia and Herzegovina in general in order to improve prescribing quality as it is done in Croatia.

Long-term clinical effects of ventricular pacing reduction with a changeover mode to minimize ventricular pacing in a general pacemaker population

PubMed Central

Stockburger, Martin; Boveda, Serge; Moreno, Javier; Da Costa, Antoine; Hatala, Robert; Brachmann, Johannes; Butter, Christian; Garcia Seara, Javier; Rolando, Mara; Defaye, Pascal

2015-01-01

Aim Right ventricular pacing (VP) has been hypothesized to increase the risk in heart failure (HF) and atrial fibrillation (AF). The ANSWER study evaluated, whether an AAI-DDD changeover mode to minimize VP (SafeR) improves outcome compared with DDD in a general dual-chamber pacemaker population. Methods and results ANSWER was a randomized controlled multicentre trial assessing SafeR vs. standard DDD in sinus node disease (SND) or AV block (AVB) patients. After a 1-month run-in period, they were randomized (1 : 1) and followed for 3 years. Pre-specified co-primary end-points were VP and the composite of hospitalization for HF, AF, or cardioversion. Pre-specified secondary end-points were cardiac death or HF hospitalizations and cardiovascular hospitalizations. ANSWER enrolled 650 patients (52.0% SND, 48% AVB) at 43 European centres and randomized in SafeR (n = 314) or DDD (n = 318). The SafeR mode showed a significant decrease in VP compared with DDD (11.5 vs. 93.6%, P < 0.0001 at 3 years). Deaths and syncope did not differ between randomization arms. No significant difference between groups [HR = 0.78; 95% CI (0.48–1.25); P = 0.30] was found in the time to event of the co-primary composite of hospitalization for HF, AF, or cardioversion, nor in the individual components. SafeR showed a 51% risk reduction (RR) in experiencing cardiac death or HF hospitalization [HR = 0.49; 95% CI (0.27–0.90); P = 0.02] and 30% RR in experiencing cardiovascular hospitalizations [HR = 0.70; 95% CI (0.49–1.00); P = 0.05]. Conclusion SafeR safely and significantly reduced VP in a general pacemaker population though had no effect on hospitalization for HF, AF, or cardioversion, when compared with DDD. PMID:25179761

DDT Analysis of Wetland Sediments in Upper Escambia Bay, Florida

NASA Astrophysics Data System (ADS)

Hopko, M. N.; Wright, J.; Liebens, J.; Vaughan, P.

2017-12-01

Dichlorodiphenyltrichloroethane (DDT) was a commonly used pesticide from World War II through the 1960's. DDT is generally used to control mosquito populations and as an agricultural insecticide. The pesticide and its degradation products (DDD and DDE) can bioaccumulate within ecosystems having negative implications for animal and human health. Consequently, DDT usage was banned in the United States in 1973. In a contaminant study performed in Escambia Bay, Florida, in 2009, DDT was present in 25% of study sites, most of which were located in the upper bay wetlands. Concentrations were well above the Florida Department of Environmental Protection's (FDEP) Probable Effect Level (PEL) and ratios of DDT and its metabolites indicated a recent introduction to the system. A follow-up study performed in 2016 found no DDT, but did show DDE at several sites. The current study repeated sampling in May 2017 at sites from the 2009 and 2016 studies. Sediment samples were collected in triplicate using a ponar sampler and DDT, DDD and DDE were extracted using EPA methods 3540c and 3620c. Extracts were analyzed using a gas chromatograph with electron capture detection (GC-ECD) as per EPA method 8081c. Sediment was also analyzed for organic carbon and particle size using an elemental NC analyzer and a laser diffraction particle sizer. Results show the presence of breakdown products DDE and DDD at multiple sites, but no detectable levels of DDT at any site. Sampling sites with high levels of DDT contamination in 2009 show only breakdown products in both 2016 and 2017. Particle size has little influence on DDD or DDE concentrations but OC is a controlling factor as indicated for contaminated sites by Pearson correlations between OC and DDE and DDD of 0.82 and 0.92, respectively. The presence of only DDD and/or DDE in the 2016 and 2017 studies indicates that the parent, DDT, has not been re-introduced into the watershed since 2009 but is degrading in the environment.

78 FR 24426 - Orthopaedic and Rehabilitation Devices Panel of the Medical Devices Advisory Committee; Notice of...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-04-25

... application for the Kineflex/C Cervical Artificial Disc sponsored by SpinalMotion. The Kineflex/C is a metal-on-metal (cobalt chrome molybdenum alloy) cervical total disc replacement device. The Kineflex/C is... degenerative disc disease (DDD) where DDD is defined as discogenic back pain with degeneration of the disc as...

Ignition of Nanocomposite Thermites by Electric Spark and Shock Wave

DTIC Science & Technology

2014-04-30

Acknowledgments The research described here was based on work supported by the US Army Research Office under awards W911NG-13-0217 ( DDD ) and W911NF-12-1...0161 (ELD), and the US Defense Threat Reduc- tion Agency (DTRA) under award HDTRA1-12-1-0011 ( DDD ). William L. Shaw acknowledges support from the

Synthesis of C13- and N15-Labeled DNAN

DTIC Science & Technology

2014-07-24

Multiplicities are described as singlet (s), doublet (d), triplet (t), quartet (q), doublet of doublets (dd), doublet of doublet of doublets ( ddd ), multiplet...dd, 4.8Hz, 2.6Hz, 1H), 8.40 ( ddd , 8.8Hz, 2.6Hz, 1.8Hz, 1H), and 7.81 (d, 8.8Hz, 1H) ppm. 13C NMR (CDCl3): δ 147.8 (dd, 18Hz, 3Hz), 146.3 (dd, 17Hz...Dinitroanisole mp: 86-88 °C 1H NMR (CDCl3): δ 8.77 (m, 4.8Hz, 2.6Hz, 1H), 8.46 ( ddd , 9.2Hz, 2.6Hz, 1.8Hz, 1H), 7.23 (d, 9.2Hz, 1H), and 4.10 (s, 3H

The Effect of Reported Head Injury on Team Performance and Partner Evaluation

DTIC Science & Technology

2015-02-17

4 Measures……………………………………………………………………………… 5 DDD Task…….…………………………………………………………………. 5 Evaluation survey……………………………………………………………….. 5...6 The effects of injury condition on DDD performance and evaluation......................... 7 Discussion...tables 1. Overall team DDD score and evaluation subscales as a function of injury condition….. 7 2. Correlations among the measured variables

Selective serotonin reuptake inhibitors and the risk of hepatocellular carcinoma in hepatitis B virus-infected patients

PubMed Central

Chang, Chia-Ming; Hsieh, Ming-Shun; Yang, Tsung-Chieh; Hsieh, Vivian Chia-Rong; Chiang, Jen-Huai; Huang, Hsien-Hao; How, Chorng-Kuang; Hu, Sung-Yuan; Yen, David Hung-Tsang

2017-01-01

Background This study aimed to investigate the association between the use of selective serotonin reuptake inhibitors (SSRIs) and the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B virus (HBV) infection. Methods We conducted a population-based cohort study by using claims data from the Taiwan National Health Insurance Research Database (NHIRD). The study cohort comprised 1380 newly diagnosed HBV-infected patients with SSRI use who were frequency matched by age, sex, liver cirrhosis, and index year with HBV-infected patients without SSRI use in the comparison cohort. Each patient case was followed from 2000 to 2012 to identify incident HCC cases. Cox proportional hazards regression was performed to evaluate the association between SSRI use and HCC risk. The further sensitivity analysis used case-control study design. A total of 9070 HCC subjects retrieved from NHIRD, and equal non-HCC subjects were analyzed after matching for age and sex. Results We identified 9 and 24 HCC cases in the study and comparison cohorts during the follow-up period of 7056 and 6845 person-years, respectively. The incidence rate of HCC was 1.28 and 3.51 per 1000 person-years for SSRI and non-SSRI users, respectively. After adjusting for potential confounders, the adjusted hazard ratio (HR) for SSRI use was 0.28 (95% confidence interval [CI], 0.12–0.64; p = 0.0027). For SSRI users with a cumulative defined daily dose (cDDD) of 28–89, 90–364, and ≥365, the adjusted HRs were 0.51, 0.22, and 0.12, respectively, (95% CI, 0.21–1.25, 0.05–0.94, and 0.02–0.90, respectively) compared with non-SSRI users (<28 cDDD). The sensitivity analysis showed that the SSRI presented with a dose-response protective effect for HCC in the multivariate analysis. Conclusion SSRIs use may possibly reduce the risk of HCC in HBV-infected patients in a dose-responsive manner. PMID:29238221

Ecological Assessment of Clinicians' Antipsychotic Prescription Habits in Psychiatric Inpatients: A Novel Web- and Mobile Phone-Based Prototype for a Dynamic Clinical Decision Support System.

PubMed

Berrouiguet, Sofian; Barrigón, Maria Luisa; Brandt, Sara A; Nitzburg, George C; Ovejero, Santiago; Alvarez-Garcia, Raquel; Carballo, Juan; Walter, Michel; Billot, Romain; Lenca, Philippe; Delgado-Gomez, David; Ropars, Juliette; de la Calle Gonzalez, Ivan; Courtet, Philippe; Baca-García, Enrique

2017-01-26

Electronic prescribing devices with clinical decision support systems (CDSSs) hold the potential to significantly improve pharmacological treatment management. The aim of our study was to develop a novel Web- and mobile phone-based application to provide a dynamic CDSS by monitoring and analyzing practitioners' antipsychotic prescription habits and simultaneously linking these data to inpatients' symptom changes. We recruited 353 psychiatric inpatients whose symptom levels and prescribed medications were inputted into the MEmind application. We standardized all medications in the MEmind database using the Anatomical Therapeutic Chemical (ATC) classification system and the defined daily dose (DDD). For each patient, MEmind calculated an average for the daily dose prescribed for antipsychotics (using the N05A ATC code), prescribed daily dose (PDD), and the PDD to DDD ratio. MEmind results found that antipsychotics were used by 61.5% (217/353) of inpatients, with the largest proportion being patients with schizophrenia spectrum disorders (33.4%, 118/353). Of the 217 patients, 137 (63.2%, 137/217) were administered pharmacological monotherapy and 80 (36.8%, 80/217) were administered polytherapy. Antipsychotics were used mostly in schizophrenia spectrum and related psychotic disorders, but they were also prescribed in other nonpsychotic diagnoses. Notably, we observed polypharmacy going against current antipsychotics guidelines. MEmind data indicated that antipsychotic polypharmacy and off-label use in inpatient units is commonly practiced. MEmind holds the potential to create a dynamic CDSS that provides real-time tracking of prescription practices and symptom change. Such feedback can help practitioners determine a maximally therapeutic drug treatment while avoiding unproductive overprescription and off-label use. ©Sofian Berrouiguet, Maria Luisa Barrigón, Sara A Brandt, George C Nitzburg, Santiago Ovejero, Raquel Alvarez-Garcia, Juan Carballo, Michel Walter, Romain Billot, Philippe Lenca, David Delgado-Gomez, Juliette Ropars, Ivan de la Calle Gonzalez, Philippe Courtet, Enrique Baca-García. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 26.01.2017.

Irradiation with low-dose gamma ray enhances tolerance to heat stress in Arabidopsis seedlings.

PubMed

Zhang, Liang; Zheng, Fengxia; Qi, Wencai; Wang, Tianqi; Ma, Lingyu; Qiu, Zongbo; Li, Jingyuan

2016-06-01

Gamma irradiation at low doses can stimulate the tolerance to environmental stress in plants. However, the knowledge regarding the mechanisms underlying the enhanced tolerance induced by low-dose gamma irradiation is far from fully understood. In this study, to investigate the physiological and molecular mechanisms of heat stress alleviated by low-dose gamma irradiation, the Arabidopsis seeds were exposed to a range of doses before subjected to heat treatment. Our results showed that 50-Gy gamma irradiation maximally promoted seedling growth in response to heat stress. The production rate of superoxide radical and contents of hydrogen peroxide and malondialdehyde in the seedlings irradiated with 50-Gy dose under heat stress were significantly lower than those of controls. The activities of antioxidant enzymes, glutathione (GSH) content and proline level in the gamma-irradiated seedlings were significantly increased compared with the controls. Furthermore, transcriptional expression analysis of selected genes revealed that some components related to heat tolerance were stimulated by low-dose gamma irradiation under heat shock. Our results suggest that low-dose gamma irradiation can modulate the physiological responses as well as gene expression related to heat tolerance, thus alleviating the stress damage in Arabidopsis seedlings. Copyright © 2016 Elsevier Inc. All rights reserved.

Discontinuation of dialysis with eculizumab therapy in a pediatric patient with dense deposit disease.

PubMed

Tran, Cheryl L; Sethi, Sanjeev; Murray, David; Cramer, Carl H; Sas, David J; Willrich, Maria; Smith, Richard J; Fervenza, Fernando C

2016-04-01

Dense deposit disease (DDD) is a rare glomerular disease caused by an uncontrolled activation of the alternative complement pathway leading to end-stage renal disease in 50 % of patients. As such, DDD has been classified within the spectrum of complement component 3 (C3) glomerulopathies due to its pathogenesis from alternative pathway dysregulation. Conventional immunosuppressive therapies have no proven effectiveness. Eculizumab, a terminal complement inhibitor, has been reported to mitigate disease in some cases. We report on the efficacy of eculizumab in a pediatric patient who failed to respond to cyclophosphamide, corticosteroids, and plasma exchange. Complement biomarker profiling was remarkable for low serum C3, low properdin, and elevated soluble C5b-9. Consistent with these findings, the alternative pathway functional assay was abnormally low, indicative of alternative pathway activity, although neither C3-nephritic factors nor Factor H autoantibodies were detected. Eculizumab therapy was associated with significant improvement in proteinuria and renal function allowing discontinuation of hemodialysis (HD). Repeat C3 and soluble C5b-9 levels normalized, showing that terminal complement pathway activity was successfully blocked while the patient was receiving eculizumab therapy. Repeat testing for alternative pathway activation allowed for a successful decrease in eculizumab dosing. The case reported here demonstrates the successful recovery of renal function in a pediatric patient on HD following the use of eculizumab.

Safety of the Wearable Cardioverter Defibrillator (WCD) in Patients with Implanted Pacemakers.

PubMed

Schmitt, Joern; Abaci, Guezine; Johnson, Victoria; Erkapic, Damir; Gemein, Christopher; Chasan, Ritvan; Weipert, Kay; Hamm, Christian W; Klein, Helmut U

2017-03-01

The wearable cardioverter defibrillator (WCD) is an important approach for better risk stratification, applied to patients considered to be at high risk of sudden arrhythmic death. Patients with implanted pacemakers may also become candidates for use of the WCD. However, there is a potential risk that pacemaker signals may mislead the WCD detection algorithm and cause inappropriate WCD shock delivery. The aim of the study was to test the impact of different types of pacing, various right ventricular (RV) lead positions, and pacing modes for potential misleading of the WCD detection algorithm. Sixty patients with implanted pacemakers received the WCD for a short time and each pacing mode (AAI, VVI, and DDD) was tested for at least 30 seconds in unipolar and bipolar pacing configuration. In case of triggering the WCD detection algorithm and starting the sequence of arrhythmia alarms, shock delivery was prevented by pushing of the response buttons. In six of 60 patients (10%), continuous unipolar pacing in DDD mode triggered the WCD detection algorithm. In no patient, triggering occurred with bipolar DDD pacing, unipolar and bipolar AAI, and VVI pacing. Triggering was independent of pacing amplitude, RV pacing lead position, and pulse generator implantation site. Unipolar DDD pacing bears a high risk of false triggering of the WCD detection algorithm. Other types of unipolar pacing and all bipolar pacing modes do not seem to mislead the WCD detection algorithm. Therefore, patients with no reprogrammable unipolar DDD pacing should not become candidates for the WCD. © 2016 Wiley Periodicals, Inc.

Biological Treatment Approaches for Degenerative Disk Disease: A Literature Review of In Vivo Animal and Clinical Data

PubMed Central

Moriguchi, Yu; Alimi, Marjan; Khair, Thamina; Manolarakis, George; Berlin, Connor; Bonassar, Lawrence J.; Härtl, Roger

2016-01-01

Study Design  Literature review. Objective  Degenerative disk disease (DDD) has a negative impact on quality of life and is a major cause of morbidity worldwide. There has been a growing interest in the biological repair of DDD by both researchers and clinicians alike. To generate an overview of the recent progress in reparative strategies for the treatment of DDD highlighting their promises and limitations, a comprehensive review of the current literature was performed elucidating data from in vivo animal and clinical studies. Methods  Articles and abstracts available in electronic databases of PubMed, Web of Science, and Google Scholar as of December 2014 were reviewed. Additionally, data from unpublished, ongoing clinical trials was retrieved from clinicaltrials.gov and available abstracts from research forums. Data was extracted from the most recent in vivo animal or clinical studies involving any of the following: (1) treatment with biomolecules, cells, or tissue-engineered constructs and (2) annulus fibrosus repair. Results  Seventy-five articles met the inclusion criteria for review. Among these, 17 studies involved humans; 37, small quadrupeds; and 21, large quadrupeds. Findings from all treatments employed demonstrated improvement either in regenerative capacity or in pain attenuation, with the exception of one clinical study. Conclusion  Published clinical studies on cell therapy have reported encouraging results in the treatment of DDD and resultant back pain. We expect new data to emerge in the near future as treatments for DDD continue to evolve in parallel to our greater understanding of disk health and pathology. PMID:27433434

Determination of DDT and metabolites in surface water and sediment using LLE, SPE, ACE and SE.

PubMed

Sibali, Linda L; Okonkwo, Jonathan O; Zvinowanda, Caliphs

2009-12-01

Surface water and sediment samples collected from Jukskei River in South Africa, were subjected to different extraction techniques, liquid-liquid (LLE), solid-phase extraction (SPE), activated carbon extraction (ACE) and soxhlet extraction (SE) for sediment. The samples were extracted with dichloromethane, cleaned in a silica gel column and the extracts quantified using a Varian 3800 GC-ECD. The percentage recovery test for 2,4'DDT, DDE and DDD and 4,4'DDT, DDE and DDD in water ranged from 80%-96% and 76%-95% (LLE); 56%-76% and 56%-70% (SPE) and 75%-84% (ACE), respectively; while that recoveries for sediment samples varied from 65%-95% for 2,4'DDT, DDE and DDD and 80%-91% for 4,4'DDT, DDE and DDD. The high recoveries exhibited by ACE compared very well with LLE and SE. This was not the case with SPE which exhibited the lowest value of recoveries for both 2,4 and 4,4'DDD, DDE and DDT standard samples. The mean concentrations of DDT and metabolites ranged from nd-1.10 μg/L, nd-0.80 μg/L, nd-1.21 μg/L and 1.92 μg/L for LLE, SPE, ACE and SE, respectively. The total DDT (2,4' and 4,4'-DDT) in water and sediment samples ranged from 1.20-3.25 μg/L and 1.82-5.24 μg/L, respectively. The low concentrations of the DDT metabolites obtained in the present study may suggest a recent contamination of the river by DDT.

The effect of different atrioventricular delays on left atrium and left atrial appendage function in patients with DDD pacemaker.

PubMed

Kanadaşı, Mehmet; Caylı, Murat; Sahin, Durmuş Yıldıray; Sen, Ömer; Koç, Mevlüt; Usal, Ayhan; Batur, Mustafa Kemal; Demirtaş, Mustafa

2011-07-01

Although it has been known that optimization of atrioventricular delay (AVD) has favorable effect on the left ventricular functions in patients with DDD pacemaker, the effect of different AVDs on left atrium (LA) and left atrial appendage (LAA) functions has not been exactly evaluated. The aim of the present study was to assess the effect of different AVDs on LA and LAA functions in DDD pacemaker implanted patients with atrioventricular block. Forty-eight patients with DDD pacemaker were enrolled into the study. Patients were divided into two groups according to the echocardiographic diastolic function: Group I (normal diastolic function) and Group II (diastolic dysfunction). LAA emptying velocity on pulsed wave Doppler and LAA late systolic wave velocity by using tissue Doppler were recorded. Patients were paced for five successive continuous pacing periods of 10 minutes duration using five selective AVDs (80-250 ms). Significant effect on LA and LAA functions has not been observed by the setting of AVD in Group I. However, when the AVD was gradually shortened form 150 ms to 80 ms, LA and LAA functions gradually decreased in Group II patients. When AVD increased to 200 ms, LA and LAA functions were improved. Further increase in AVD resulted in decreased LA and LAA functions. Setting of AVD has not significant effect on the LA and LAA functions in patients with normal diastolic function, but moderate prolongation of AVD in physiological limits improved LA and LAA functions in DDD pacemaker implanted patients with diastolic dysfunction. © 2011, Wiley Periodicals, Inc.

Enantioselective induction of cytotoxicity by o,p'-DDD in PC12 cells: implications of chirality in risk assessment of POPs metabolites.

PubMed

Wang, Cui; Li, Zhuoyu; Zhang, Quan; Zhao, Meirong; Liu, Weiping

2013-04-16

The increased release of chiral persistent organic pollutants (POPs) into the environment has resulted in more attention to the role of enantioselectivity in the fate and ecotoxicological effects of these compounds. Although the enantioselectivity of chiral POPs has been considered in previous studies, little effort has been expended to discern the enantiospecific effects of chiral POPs metabolites, which may impede comprehensive risk assessments of these chemicals. In the present study, o,p'-DDD, the chiral metabolite of o,p'-DDT, was used as a model chiral metabolite. First, a preferential chiral separation at 100% ethanol was employed to obtain a pure enantiomer. The enantioselective cytotoxicity of o,p'-DDD in rat cells (PC12) was evaluated by detecting activation of the cellular apoptosis and oxidative stress systems and microarray analysis. We have documented for the first time that R-(+)-o,p'-DDD increases apoptosis by selectively disturbing the oxidative system (enzymes and molecules) and regulating the transcription of Aven, Bid, Cideb and Tp53. By comparing the data from the present study to data derived from the parent compound, we concluded that the R-enantiomer is the more detrimental stereostructure for both o,p'-DDT and o,p'-DDD. This observed stereostructural effect is in line with the structure-activity relationship formulated at other structural levels. Biological activities of the chiral metabolites are likely to occur in the same absolute configuration between chiral POPs and their metabolites provided that they have the similar stereostructures.

Modeling of abnormal mechanical properties of nickel-based single crystal superalloy by three-dimensional discrete dislocation dynamics

NASA Astrophysics Data System (ADS)

Yang, Hui; Li, Zhenhuan; Huang, Minsheng

2014-12-01

Unlike common single crystals, the nickel-based single crystal superalloy shows surprisingly anomalous flow strength (i.e. with the increase of temperature, the yield strength first increases to a peak value and then decreases) and tension-compression (TC) asymmetry. A comprehensive three-dimensional discrete dislocation dynamics (3D-DDD) procedure was developed to model these abnormal mechanical properties. For this purpose, a series of complicated dynamic evolution details of Kear-Wilsdorf (KW) locks, which are closely related to the flow strength anomaly and TC asymmetry, were incorporated into this 3D-DDD framework. Moreover, the activation of the cubic slip system, which is the origin of the decrease in yield strength with increasing temperature at relatively high temperatures, was especially taken into account by introducing a competition criterion between the unlocking of the KW locks and the activation of the cubic slip system. To test our framework, a series of 3D-DDD simulations were performed on a representative volume cell model with a cuboidal Ni3Al precipitate phase embedded in a nickel matrix. Results show that the present 3D-DDD procedure can successfully capture the dynamic evolution of KW locks, the flow strength anomaly and TC asymmetry. Then, the underlying dislocation mechanisms leading to these abnormal mechanical responses were investigated and discussed in detail. Finally, a cyclic deformation of the nickel-based single crystal superalloy was modeled by using the present DDD model, with a special focus on the influence of KW locks on the Bauschinger effect and cyclic softening.

Compendium of Current Single Event Effects for Candidate Spacecraft Electronics for NASA

NASA Technical Reports Server (NTRS)

O'Bryan, Martha V.; Label, Kenneth A.; Chen, Dakai; Campola, Michael J.; Casey, Megan C.; Lauenstein, Jean-Marie; Pellish, Jonathan A.; Ladbury, Raymond L.; Berg, Melanie D.

2015-01-01

NASA spacecraft are subjected to a harsh space environment that includes exposure to various types of ionizing radiation. The performance of electronic devices in a space radiation environment are often limited by their susceptibility to single event effects (SEE). Ground-based testing is used to evaluate candidate spacecraft electronics to determine risk to spaceflight applications. Interpreting the results of radiation testing of complex devices is and adequate understanding of the test condition is critical. Studies discussed herein were undertaken to establish the application-specific sensitivities of candidate spacecraft and emerging electronic devices to single-event upset (SEU), single-event latchup (SEL), single-event gate rupture (SEGR), single-event burnout (SEB), and single-event transient (SET). For total ionizing dose (TID) and displacement damage dose (DDD) results, see a companion paper submitted to the 2015 Institute of Electrical and Electronics Engineers (IEEE) Nuclear and Space Radiation Effects Conference (NSREC) Radiation Effects Data Workshop (REDW) entitled "compendium of Current Total Ionizing Dose and Displacement Damage for Candidate Spacecraft Electronics for NASA by M. Campola, et al.

Surface Wave Dynamics in the Coastal Zone

DTIC Science & Technology

2013-09-30

summarized in Figure 1. Scatter index # DDD 󈨙 0.73 Mad󈨐 Ting󈧅+ T&M󈧆 S&Hol󈨙 S&How󈨝 Lipp󈨤+ vdW󈧍 FA󈧐 R&S󈧇/07 Slopes J&B󈧋...Battjes & Janssen [1978] TG󈨗 = Thornton & Guza [1983] Bald󈨦 = Baldock et al. [1998] DDD 󈨙 = Dally et al. [1985] J&B󈧋 = Janssen & Battjes

Occurrences and fate of DDT principal isomers/metabolites, DDA, and o,p'-DDD enantiomers in fish, sediment and water at a DDT-impacted Superfund site.

PubMed

Garrison, A W; Cyterski, M; Roberts, K D; Burdette, D; Williamson, J; Avants, J K

2014-11-01

In the 1950s and 60s, discharges from a DDT manufacturing plant contaminated a tributary system of the Tennessee River near Huntsville, Alabama, USA. Regulatory action resulted in declaring the area a Superfund site which required remediation and extensive monitoring. Monitoring data collected from 1988, after remediation, through 2011 showed annual decreases approximating first-order decay in concentrations of total DDT and its six principal congeners (p,p'-DDT, o,p'-DDT, p,p'-DDD, o,p'-DDD, p,p'-DDE and o,p'-DDE) in filets from three species of fish. As of 2013, these concentrations met the regulatory requirements of 5 mg/kg or less total DDT for each fish tested. The enantiomer fractions (EF) of chiral o,p'-DDD in smallmouth buffalo and channel catfish were always below 0.5, indicating preferential decay of the (+)-enantiomer of this congener; this EF did not change significantly over 15 years. The often-neglected DDT metabolite p,p'-DDA was found at a concentration of about 20 μg/l in the ecosystem water. Published by Elsevier Ltd.

Differential effect of DDT, DDE, and DDD on COX-2 expression in the human trophoblast derived HTR-8/SVneo cells.

PubMed

Dominguez-Lopez, Pablo; Diaz-Cueto, Laura; Olivares, Aleida; Ulloa-Aguirre, Alfredo; Arechavaleta-Velasco, Fabian

2012-11-01

The purpose of this study was to investigate the effect of 1,1,1-trichloro-2,2-bis-(chlorophenyl)ethane (DDT), 1,1-bis-(chlorophenyl)-2,2-dichloroethene (DDE), and 1,1-dichloro-2,2-bis(chlorophenyl)ethane (DDD) isomers on COX-2 expression in a human trophoblast-derived cell line. Cultured HTR-8/SVneo trophoblast cells were exposed to DDT isomers and its metabolites for 24 h, and COX-2 mRNA and protein expression were assessed by RT-PCR, Western blotting, and ELISA. Prostaglandin E₂ production was also measured by ELISA. Both COX-2 mRNA and protein were detected under control (unexposed) conditions in the HTR-8/SVneo cell line. COX-2 protein expression and prostaglandin E₂ production but not COX-2 mRNA levels increased only after DDE and DDD isomers exposure. It is concluded that DDE and DDD exposure induce the expression of COX-2 protein, leading to increased prostaglandin E2 production. Interestingly, the regulation of COX-2 by these organochlorines pesticides appears to be at the translational level. © 2012 Wiley Periodicals, Inc.

Tolerance doses of cutaneous and mucosal tissues in ring-necked parakeets (Psittacula krameri) for external beam megavoltage radiation.

PubMed

Barron, Heather W; Roberts, Royce E; Latimer, Kenneth S; Hernandez-Divers, Stephen; Northrup, Nicole C

2009-03-01

Currently used dosages for external-beam megavoltage radiation therapy in birds have been extrapolated from mammalian patients and often appear to provide inadequate doses of radiation for effective tumor control. To determine the tolerance doses of cutaneous and mucosal tissues of normal birds in order to provide more effective radiation treatment for tumors that have been shown to be radiation responsive in other species, ingluvial mucosa and the skin over the ingluvies of 9 ring-necked parakeets (Psittacula krameri) were irradiated in 4-Gy fractions to a total dose of either 48, 60, or 72 Gy using an isocentric cobalt-60 teletherapy unit. Minimal radiation-induced epidermal changes were present in the high-dose group histologically. Neither dose-related acute nor chronic radiation effects could be detected in any group grossly in cutaneous or mucosal tissue over a 9-month period. Radiation doses of 72 Gy in 4-Gy fractions were well tolerated in the small number of ring-necked parakeets in this initial tolerance dose study.

The "tract" of history in the treatment of lumbar degenerative disc disease.

PubMed

Chedid, Khalil J; Chedid, Mokbel K

2004-01-15

In this paper past, present, and future treatments of degenerative disc disease (DDD) of the lumbar spine are outlined in a straight forward manner. This is done to review previous knowledge of the disease, define current treatment procedures, and discuss future perspectives. An analysis of a subject of this magnitude dictates that one describes as accurate a history as possible: an anatomical/historical "tract" with emphasis on all possible deviations. Although spinal disorders have been recognized for a long time, the view of DDD as a particular disease entity is a more recent development. In this paper, the authors attempt to outline the history of DDD of the lumbar spine in an unbiased and scientific fashion. Physiological, diagnostic, and therapeutic implications will all be addressed in this study.

Effects of ionizing radiation on embryos of the tardigrade Milnesium cf. tardigradum at different stages of development.

PubMed

Beltrán-Pardo, Eliana; Jönsson, K Ingemar; Wojcik, Andrzej; Haghdoost, Siamak; Harms-Ringdahl, Mats; Bermúdez-Cruz, Rosa M; Bernal Villegas, Jaime E

2013-01-01

Tardigrades represent one of the most desiccation and radiation tolerant animals on Earth, and several studies have documented their tolerance in the adult stage. Studies on tolerance during embryological stages are rare, but differential effects of desiccation and freezing on different developmental stages have been reported, as well as dose-dependent effect of gamma irradiation on tardigrade embryos. Here, we report a study evaluating the tolerance of eggs from the eutardigrade Milnesium cf. tardigradum to three doses of gamma radiation (50, 200 and 500 Gy) at the early, middle, and late stage of development. We found that embryos of the middle and late developmental stages were tolerant to all doses, while eggs in the early developmental stage were tolerant only to a dose of 50 Gy, and showed a declining survival with higher dose. We also observed a delay in development of irradiated eggs, suggesting that periods of DNA repair might have taken place after irradiation induced damage. The delay was independent of dose for eggs irradiated in the middle and late stage, possibly indicating a fixed developmental schedule for repair after induced damage. These results show that the tolerance to radiation in tardigrade eggs changes in the course of their development. The mechanisms behind this pattern are unknown, but may relate to changes in mitotic activities over the embryogenesis and/or to activation of response mechanisms to damaged DNA in the course of development.

Effects of Ionizing Radiation on Embryos of the Tardigrade Milnesium cf. tardigradum at Different Stages of Development

PubMed Central

Beltrán-Pardo, Eliana; Jönsson, K. Ingemar; Wojcik, Andrzej; Haghdoost, Siamak; Harms-Ringdahl, Mats; Bermúdez-Cruz, Rosa M.; Bernal Villegas, Jaime E.

2013-01-01

Tardigrades represent one of the most desiccation and radiation tolerant animals on Earth, and several studies have documented their tolerance in the adult stage. Studies on tolerance during embryological stages are rare, but differential effects of desiccation and freezing on different developmental stages have been reported, as well as dose-dependent effect of gamma irradiation on tardigrade embryos. Here, we report a study evaluating the tolerance of eggs from the eutardigrade Milnesium cf. tardigradum to three doses of gamma radiation (50, 200 and 500 Gy) at the early, middle, and late stage of development. We found that embryos of the middle and late developmental stages were tolerant to all doses, while eggs in the early developmental stage were tolerant only to a dose of 50 Gy, and showed a declining survival with higher dose. We also observed a delay in development of irradiated eggs, suggesting that periods of DNA repair might have taken place after irradiation induced damage. The delay was independent of dose for eggs irradiated in the middle and late stage, possibly indicating a fixed developmental schedule for repair after induced damage. These results show that the tolerance to radiation in tardigrade eggs changes in the course of their development. The mechanisms behind this pattern are unknown, but may relate to changes in mitotic activities over the embryogenesis and/or to activation of response mechanisms to damaged DNA in the course of development. PMID:24039737

Comparative CYP-dependent binding of the adrenocortical toxicants 3-methylsulfonyl-DDE and o,p'-DDD in Y-1 adrenal cells.

PubMed

Hermansson, Veronica; Asp, Vendela; Bergman, Ake; Bergström, Ulrika; Brandt, Ingvar

2007-11-01

The environmental pollutant 3-MeSO(2)-DDE [2-(3-methylsulfonyl-4-chlorophenyl)-2-(4-chlorophenyl)-1,1-dichloroethene] is an adrenocortical toxicant in mice, specifically in the glucocorticoid-producing zona fasciculata, due to a cytochrome P450 11B1 (CYP11B1)-catalysed bioactivation and formation of covalently bound protein adducts. o,p'-DDD [2-(2-chlorophenyl)-2-(4-chlorophenyl)-1,1-dichloroethane] is toxic and inhibits steroidogenesis in the human adrenal cortex after bioactivation by unidentified CYPs, but does not exert any toxic effects on the mouse adrenal. As a step towards determining in vitro/in vivo relationships for the CYP-catalysed binding and toxicity of 3-MeSO(2)-DDE and o,p'-DDD, we have investigated the irreversible protein binding of these two toxicants in the murine adrenocortical cell line Y-1. The irreversible binding of 3-MeSO(2)-DDE previously demonstrated in vivo was successfully reproduced and could be inhibited by the CYP-inhibitors etomidate, ketoconazole and metyrapone. Surprisingly, o,p'-DDD reached similar levels of binding as 3-MeSO(2)-DDE. The binding of o,p'-DDD was sensitive to etomidate and ketoconazole, but not to metyrapone. Moreover, GSH depletion increased the binding of 3-MeSO(2)-DDE, but not of o,p'-DDD, indicating an important role of GSH conjugation in the detoxification of the 3-MeSO(2)-DDE-derived reactive metabolite. In addition, the specificity of CYP11B1 in activating 3-MeSO(2)-DDE was investigated using structurally analogous compounds. None of the analogues produced histopathological lesions in the mouse adrenal in vivo following a single i.p. injection of 100 mg/kg body weight, but two of the compounds were able to decrease the irreversible binding of 3-MeSO(2)-DDE to Y-1 cells. These results indicate that the bioactivation of 3-MeSO(2)-DDE by CYP11B1 is highly structure-dependent. In conclusion, both 3-MeSO(2)-DDE and o,p'-DDD bind irreversibly to Y-1 cells despite differences in binding and adrenotoxicity in mice in vivo. This reveals a notable in vitro/in vivo discrepancy, the contributing factors of which remain unexplained. We consider the Y-1 cell line as appropriate for studies of the cellular mechanisms behind the adrenocortical toxicity of these substances.

Defining the Complement Biomarker Profile of C3 Glomerulopathy

PubMed Central

Zhang, Yuzhou; Nester, Carla M.; Martin, Bertha; Skjoedt, Mikkel-Ole; Meyer, Nicole C.; Shao, Dingwu; Borsa, Nicolò; Palarasah, Yaseelan

2014-01-01

Background and objectives C3 glomerulopathy (C3G) applies to a group of renal diseases defined by a specific renal biopsy finding: a dominant pattern of C3 fragment deposition on immunofluorescence. The primary pathogenic mechanism involves abnormal control of the alternative complement pathway, although a full description of the disease spectrum remains to be determined. This study sought to validate and define the association of complement dysregulation with C3G and to determine whether specific complement pathway abnormalities could inform disease definition. Design, setting, participants, & measurements This study included 34 patients with C3G (17 with C3 glomerulonephritis [C3GN] and 17 with dense deposit disease [DDD]) diagnosed between 2008 and 2013 selected from the C3G Registry. Control samples (n=100) were recruited from regional blood drives. Nineteen complement biomarkers were assayed on all samples. Results were compared between C3G disease categories and with normal controls. Results Assessment of the alternative complement pathway showed that compared with controls, patients with C3G had lower levels of serum C3 (P<0.001 for both DDD and C3GN) and factor B (P<0.001 for both DDD and C3GN) as well as higher levels of complement breakdown products including C3d (P<0.001 for both DDD and C3GN) and Bb (P<0.001 for both DDD and C3GN). A comparison of terminal complement pathway proteins showed that although C5 levels were significantly suppressed (P<0.001 for both DDD and C3GN) its breakdown product C5a was significantly higher only in patients with C3GN (P<0.05). Of the other terminal pathway components (C6–C9), the only significant difference was in C7 levels between patients with C3GN and controls (P<0.01). Soluble C5b-9 was elevated in both diseases but only the difference between patients with C3GN and controls reached statistical significance (P<0.001). Levels of C3 nephritic factor activity were qualitatively higher in patients with DDD compared with patients with C3GN. Conclusions Complement biomarkers are significantly abnormal in patients with C3G compared with controls. These data substantiate the link between complement dysregulation and C3G and identify C3G interdisease differences. PMID:25341722

SODIUM BICARBONATE FACILITATES LOW-DOSE ORAL TOLERANCE TO PEANUT IN MICE

EPA Science Inventory

Rationale: Oral tolerance specifically inhibits production of allergic IgE antibody and is therefore a potential method for suppressing food allergy. We have previously demonstrated that a single oral dose of one mg is sufficient to induce oral tolerance to egg white but not pean...

Solid phase synthesis of phosphorothioate oligonucleotides utilizing diethyldithiocarbonate disulfide (DDD) as an efficient sulfur transfer reagent.

PubMed

Cheruvallath, Zacharia S; Kumar, R Krishna; Rentel, Claus; Cole, Douglas L; Ravikumar, Vasulinga T

2003-04-01

Diethyldithiodicarbonate (DDD), a cheap and easily prepared compound, is found to be a rapid and efficient sulfurizing reagent in solid phase synthesis of phosphorothioate oligodeoxyribonucleotides via the phosphoramidite approach. Product yield and quality based on IP-LC-MS compares well with high quality oligonucleotides synthesized using phenylacetyl disulfide (PADS) which is being used for manufacture of our antisense drugs.

Fusion-nonfusion hybrid construct versus anterior cervical hybrid decompression and fusion: a comparative study for 3-level cervical degenerative disc diseases.

PubMed

Ding, Fan; Jia, Zhiwei; Wu, Yaohong; Li, Chao; He, Qing; Ruan, Dike

2014-11-01

A retrospective analysis. This study aimed to compare the safety and efficacy between the fusion-nonfusion hybrid construct (HC: anterior cervical corpectomy and fusion plus artificial disc replacement, ACCF plus cADR) and anterior cervical hybrid decompression and fusion (ACHDF: anterior cervical corpectomy and fusion plus discectomy and fusion, ACCF plus ACDF) for 3-level cervical degenerative disc diseases (cDDD). The optimal anterior technique for 3-level cDDD remains uncertain. Long-segment fusion substantially induced biomechanical changes at adjacent levels, which may lead to symptomatic adjacent segment degeneration. Hybrid surgery consisting of ACDF and cADR has been reported with good results for 2-level cDDD. In this context, ACCF combining with cADR may be an alternative to ACHDF for 3-level cDDD. Between 2009 and 2012, 28 patients with 3-level cDDD who underwent HC (n=13) and ACHDF (15) were retrospectively reviewed. Clinical assessments were based on Neck Disability Index, Japanese Orthopedic Association disability scale, visual analogue scale, Japanese Orthopedic Association recovery rate, and Odom criteria. Radiological analysis included range of motion of C2-C7 and adjacent segments and cervical lordosis. Perioperative parameters, radiological adjacent-level changes, and the complications were also assessed. HC showed better Neck Disability Index improvement at 12 and 24 months, as well as Japanese Orthopedic Association and visual analogue scale improvement at 24 months postoperatively (P<0.05). HC had better outcome according to Odom criteria but not significantly (P>0.05). The range of motion of C2-C7 and adjacent segments was less compromised in HC (P<0.05). Both 2 groups showed significant lordosis recovery postoperatively (P<0.05), but no difference was found between groups (P>0.05). The incidence of adjacent-level degenerative changes and complications was higher in ACHDF but not significantly (P>0.05). HC may be an alternative to ACHDF for 3-level cDDD due to the equivalent or superior early clinical outcomes, less compromised C2-C7 range of motion, and less impact at adjacent levels. 3.

Predicting in ungauged basins using a parsimonious rainfall-runoff model

NASA Astrophysics Data System (ADS)

Skaugen, Thomas; Olav Peerebom, Ivar; Nilsson, Anna

2015-04-01

Prediction in ungauged basins is a demanding, but necessary test for hydrological model structures. Ideally, the relationship between model parameters and catchment characteristics (CC) should be hydrologically justifiable. Many studies, however, report on failure to obtain significant correlations between model parameters and CCs. Under the hypothesis that the lack of correlations stems from non-identifiability of model parameters caused by overparameterization, the relatively new parameter parsimonious DDD (Distance Distribution Dynamics) model was tested for predictions in ungauged basins in Norway. In DDD, the capacity of the subsurface water reservoir M is the only parameter to be calibrated whereas the runoff dynamics is completely parameterised from observed characteristics derived from GIS and runoff recession analysis. Water is conveyed through the soils to the river network by waves with celerities determined by the level of saturation in the catchment. The distributions of distances between points in the catchment to the nearest river reach and of the river network give, together with the celerities, distributions of travel times, and, consequently unit hydrographs. DDD has 6 parameters less to calibrate in the runoff module than, for example, the well-known Swedish HBV model. In this study, multiple regression equations relating CCs and model parameters were trained from 84 calibrated catchments located all over Norway and all model parameters showed significant correlations with catchment characteristics. The significant correlation coefficients (with p- value < 0.05) ranged from 0.22-0.55. The suitability of DDD for predictions in ungauged basins was tested for 17 catchments not used to estimate the multiple regression equations. For 10 of the 17 catchments, deviations in Nash-Suthcliffe Efficiency (NSE) criteria between the calibrated and regionalised model were less than 0.1. The median NSE for the regionalised DDD for the 17 catchments, for two different time series was 0.66 and 0.72. Deviations in NSE between calibrated and regionalised models are well explained by the deviations between calibrated and regressed parameters describing spatial snow distribution and snowmelt, respectively. This latter result indicates the topic for further improvements in the model structure of DDD.

Retrospective analysis of reasons for failure of DDD pacemaker implantation in patients operated on between 1993 and 2005.

PubMed

Lelakowski, Jacek; Majewski, Jacek; Małecka, Barbara; Bednarek, Jacek; Stypuła, Paweł; Szeglowski, Marcin

2007-01-01

During implantation of a DDD pacemaker the following difficulties may be encountered: venous anomalies (the absence of vessels of adequate calibre or difficulty in subclavian vein puncture), arrhythmias during implantation (episodes of atrial flutter/fibrillation while the atrial leads are being positioned), lack of mechanical stability of the electrode in the heart chamber and inability to achieve an acceptable pacing and sensing threshold during implantation. The purpose of the study was to analyse retrospectively the reasons for DDD pacemaker failure in patients operated on between 1993 and 2005. We reviewed retrospectively all implantation data from 1988 to 2005 to identify patients with primary failure of DDD pacemaker implantation. Further analysis included patients who had received a DDD pacemaker between 1993 and 2005, when this type of pacemaker made up between 9 and 40% of all pacemaker implantations. We implanted 7469 pacemakers, including 1958 (26.2%) dual-chamber pacemakers, in 783 patients with atrioventricular block (AVB), 392 with sick sinus syndrome (SSS), 450 with AVB +/- SSS and 333 with tachy-brady syndrome (TBS). The mean age of the patients was 65.5 +/- 17.3 years. DDD pacing was unsuccessful in 108 (1.4%) patients, including 32 with AVB, 22 with SSS, 16 with SSS +/- AVB and 38 with TBS. The mean age of these patients was 78.5 +/- 19.4 years. The reasons for failed implantation were venous anomalies in 12%, an arrhythmia episode in 27.8%, a high pacing threshold in the atrium in 17.6%, low atrial potential amplitude in 25.9% and lack of mechanical stability of the electrode in 16.7% of patients. The difficulties were encountered in elderly patients (p < 0.01), most frequently in patients with SSS and TBS (71). Between 2004 and 2005 venous anomalies and a high pacing threshold were the main causes of failure. Currently the main difficulties encountered during pacemaker implantation are venous anomalies and a high pacing threshold. Arrhythmia episodes, low atrial potential amplitude and lack of mechanical stability are of minor importance. Elderly patients with sick sinus syndrome and tachy-brady syndrome have the highest failure rate. (Cardiol J 2007; 14: 155-159).

Treatment discontinuation and tolerability as a function of dose and titration of duloxetine in the treatment of major depressive disorder.

PubMed

Harada, Eiji; Shirakawa, Osamu; Satoi, Yoichi; Marangell, Lauren B; Escobar, Rodrigo

2016-01-01

We sought to better understand how dose and titration with duloxetine treatment may impact tolerability and treatment discontinuation in patients with major depressive disorder. We investigated Phase III duloxetine trials. Group 1 was a single placebo-controlled study with a 20 mg initial dose and a slow titration to 40 and 60 mg. Group 2 was a single study with a 40 mg initial dose and final "active" doses of 40 and 60 mg (5 mg control group), with 1-week titration. Group 3 consisted of eight placebo-controlled studies with starting doses of 40, 60, and 80 mg/day with minimal titration (final dose 40-120 mg/day). Tolerability was measured by rate of discontinuation due to adverse events (DCAE). The DCAE in Group 1 were 3.6% in the 60 mg group, 3.3% in the 40 mg group, and 3.2% in the placebo group. In Group 2, the DCAE were 15.0% in the 60 mg group, 8.1% in the 40 mg group, and 4.9% in the 5 mg group. In Group 3, the DCAE were 9.7% and 4.2% in the duloxetine and placebo groups, respectively. This study suggests that starting dose and titration may have impacted tolerability and treatment discontinuation. A lower starting dose of duloxetine and slower titration may contribute to improving treatment tolerability for patients with major depressive disorder.

Maximum tolerated dose of nalmefene in patients receiving epidural fentanyl and dilute bupivacaine for postoperative analgesia.

PubMed

Dougherty, T B; Porche, V H; Thall, P F

2000-04-01

This study investigated the ability of the modified continual reassessment method (MCRM) to determine the maximum tolerated dose of the opioid antagonist nalmefene, which does not reverse analgesia in an acceptable number of postoperative patients receiving epidural fentanyl in 0.075% bupivacaine. In the postanesthetic care unit, patients received a single intravenous dose of 0.25, 0.50, 0.75, or 1.00 microg/kg nalmefene. Reversal of analgesia was defined as an increase in pain score of two or more integers above baseline on a visual analog scale from 0 through 10 after nalmefene administration. Patients were treated in cohorts of one, starting with the lowest dose. The maximum tolerated dose of nalmefene was defined as that dose, among the four studied, with a final mean probability of reversal of anesthesia (PROA) closest to 0.20 (ie., a 20% chance of causing reversal). The modified continual reassessment method is an iterative Bayesian statistical procedure that, in this study, selected the dose for each successive cohort as that having a mean PROA closest to the preselected target PROA of 0.20. The modified continual reassessment method repeatedly updated the PROA of each dose level as successive patients were observed for presence or absence of ROA. After 25 patients, the maximum tolerated dose of nalmefene was selected as 0.50 microg/kg (final mean PROA = 0.18). The 1.00-microg/kg dose was never tried because its projected PROA was far above 0.20. The modified continual reassessment method facilitated determination of the maximum tolerated dose ofnalmefene . Operating characteristics of the modified continual reassessment method suggest it may be an effective statistical tool for dose-finding in trials of selected analgesic or anesthetic agents.

SU-C-16A-05: OAR Dose Tolerance Recommendations for Prostate and Cervical HDR Brachytherapy: Dose Versus Volume Metrics

DOE Office of Scientific and Technical Information (OSTI.GOV)

Geneser, S; Cunha, J; Pouliot, J

Purpose: HDR brachytherapy consensus dose tolerance recommendations for organs at risk (OARs) remain widely debated. Prospective trials reporting metrics must be sufficiently data-dense to assess adverse affects and identify optimally predictive tolerances. We explore the tradeoffs between reporting dose-metrics versus volume-metrics and the potential impact on trial outcome analysis and tolerance recommendations. Methods: We analyzed 26 prostate patients receiving 15 Gy HDR single-fraction brachytherapy boost to 45 Gy external beam radiation therapy and 28 cervical patients receiving 28 Gy HDR brachytherapy monotherapy in 4 fractions using 2 implants. For each OAR structure, a robust linear regression fit was performed formore » the dose-metrics as a function of the volume-metrics. The plan quality information provided by recommended dose-metric and volume-metric values were compared. Results: For prostate rectal dose, D2cc and V75 lie close to the regression line, indicating they are similarly informative. Two outliers for prostate urethral dose are substantially different from the remaining cohort in terms of D0.1cc and V75, but not D1cc, suggesting the choice of reporting dose metric is essential. For prostate bladder and cervical bladder, rectum, and bowel, dose outliers are more apparent via V75 than recommended dose-metrics. This suggests that for prostate bladder dose and all cervical OAR doses, the recommended volume-metrics may be better predictors of clinical outcome than dose-metrics. Conclusion: For plan acceptance criteria, dose and volume-metrics are reciprocally equivalent. However, reporting dosemetrics or volume-metrics alone provides substantially different information. Our results suggest that volume-metrics may be more sensitive to differences in planned dose, and if one metric must be chosen, volumemetrics are preferable. However, reporting discrete DVH points severely limits the ability to identify planning tolerances most predictive of adverse effects. Thus, we recommend that full OAR DVH reporting be required for future prospective trials.« less

Real-time display of flow-pressure-volume loops.

PubMed

Morozoff, P E; Evans, R W

1992-01-01

Graphic display of respiratory waveforms can be valuable for monitoring the progress of ventilated patients. A system has been developed that can display flow-pressure-volume loops as derived from a patient's respiratory circuit in real time. It can also display, store, print, and retrieve ventilatory waveforms. Five loops can be displayed at once: current, previous, reference, "ideal," and previously saved. Two components, the data-display device (DDD) and the data-collection device (DCD), comprise the system. An IBM 286/386 computer with a graphics card (VGA) and bidirectional parallel port is used for the DDD; an eight-bit microprocessor card and an A/D convertor card make up the DCD. A real-time multitasking operating system was written to control the DDD, while the DCD operates from in-line assembly code. The DCD samples the pressure and flow sensors at 100 Hz and looks for a complete flow waveform pattern based on flow slope. These waveforms are then passed to the DDD via the mutual parallel port. Within the DDD a process integrates the flow to create a volume signal and performs a multilinear regression on the pressure, flow, and volume data to calculate the elastance, resistance, pressure offset, and coefficient of determination. Elastance, resistance, and offset are used to calculate Pr and Pc where: Pr[k] = P[k]-offset-(elastance.V[k]) and Pc[k] = P[k]-offset-(resistance.F[k]). Volume vs. Pc and flow vs. Pr can be displayed in real time. Patient data from previous clinical tests were loaded into the device to verify the software calculations. An analog waveform generator was used to simulate flow and pressure waveforms that validated the system.(ABSTRACT TRUNCATED AT 250 WORDS)

An Overview of Starfish: A Table-Centric Tool for Interactive Synthesis

NASA Technical Reports Server (NTRS)

Tsow, Alex

2008-01-01

Engineering is an interactive process that requires intelligent interaction at many levels. My thesis [1] advances an engineering discipline for high-level synthesis and architectural decomposition that integrates perspicuous representation, designer interaction, and mathematical rigor. Starfish, the software prototype for the design method, implements a table-centric transformation system for reorganizing control-dominated system expressions into high-level architectures. Based on the digital design derivation (DDD) system a designer-guided synthesis technique that applies correctness preserving transformations to synchronous data flow specifications expressed as co- recursive stream equations Starfish enhances user interaction and extends the reachable design space by incorporating four innovations: behavior tables, serialization tables, data refinement, and operator retiming. Behavior tables express systems of co-recursive stream equations as a table of guarded signal updates. Developers and users of the DDD system used manually constructed behavior tables to help them decide which transformations to apply and how to specify them. These design exercises produced several formally constructed hardware implementations: the FM9001 microprocessor, an SECD machine for evaluating LISP, and the SchemEngine, garbage collected machine for interpreting a byte-code representation of compiled Scheme programs. Bose and Tuna, two of DDD s developers, have subsequently commercialized the design derivation methodology at Derivation Systems, Inc. (DSI). DSI has formally derived and validated PCI bus interfaces and a Java byte-code processor; they further executed a contract to prototype SPIDER-NASA's ultra-reliable communications bus. To date, most derivations from DDD and DRS have targeted hardware due to its synchronous design paradigm. However, Starfish expressions are independent of the synchronization mechanism; there is no commitment to hardware or globally broadcast clocks. Though software back-ends for design derivation are limited to the DDD stream-interpreter, targeting synchronous or real-time software is not substantively different from targeting hardware.

Biotransformation of dichlorodiphenyltrichloroethane in the benthic polychaete, Nereis succinea: quantitative estimation by analyzing the partitioning of chemicals between gut fluid and lipid.

PubMed

Wang, Fei; Pei, Yuan-yuan; You, Jing

2015-02-01

Biotransformation plays an important role in the bioaccumulation and toxicity of a chemical in biota. Dichlorodiphenyltrichloroethane (DDT) commonly co-occurs with its metabolites (dichlorodiphenyldichloroethane [DDD] and dichlorodiphenyldichloroethylene [DDE]), in the environment; thus it is a challenge to accurately quantify the biotransformation rates of DDT and distinguish the sources of the accumulated metabolites in an organism. The present study describes a method developed to quantitatively analyze the biotransformation of p,p'-DDT in the benthic polychaete, Nereis succinea. The lugworms were exposed to sediments spiked with DDT at various concentrations for 28 d. Degradation of DDT to DDD and DDE occurred in sediments during the aging period, and approximately two-thirds of the DDT remained in the sediment. To calculate the biotransformation rates, residues of individual compounds measured in the bioaccumulation testing (after biotransformation) were compared with residues predicted by analyzing the partitioning of the parent and metabolite compounds between gut fluid and tissue lipid (before biotransformation). The results suggest that sediment ingestion rates decreased when DDT concentrations in sediment increased. Extensive biotransformation of DDT occurred in N. succinea, with 86% of DDT being metabolized to DDD and <2% being transformed to DDE. Of the DDD that accumulated in the lugworms, approximately 70% was the result of DDT biotransformation, and the remaining 30% was from direct uptake of sediment-associated DDD. In addition, the biotransformation was not dependent on bulk sediment concentrations, but rather on bioaccessible concentrations of the chemicals in sediment, which were quantified by gut fluid extraction. The newly established method improved the accuracy of prediction of the bioaccumulation and toxicity of DDTs. © 2014 SETAC.

Quantitative trait loci that control plasma lipid levels in an F2 intercross between C57BL/6J and DDD.Cg-A(y) inbred mouse strains.

PubMed

Suto, Jun-ichi

2012-04-01

The objectives of this study were to characterize plasma lipid phenotypes and dissect the genetic basis of plasma lipid levels in an obese DDD.Cg-A(y) mouse strain. Plasma triglyceride (TG) levels were significantly higher in the DDD.Cg-A(y) strain than in the B6.Cg-A(y) strain. In contrast, plasma total-cholesterol (CHO) levels did not substantially differ between the two strains. As a rule, the A(y) allele significantly increased TG levels, but did not increase CHO levels. Quantitative trait locus (QTL) analyses for plasma TG and CHO levels were performed in two types of F(2) female mice [F(2)A(y) (F(2) mice carrying the A(y) allele) and F(2) non- A(y) mice (F(2) mice without the A(y) allele)] produced by crossing C57BL/6J females and DDD.Cg-A(y) males. Single QTL scan identified one significant QTL for TG levels on chromosome 1, and two significant QTLs for CHO levels on chromosomes 1 and 8. When the marker nearest to the QTL on chromosome 1 was used as covariates, four additional significant QTLs for CHO levels were identified on chromosomes 5, 6, and 17 (two loci). In contrast, consideration of the agouti locus genotype as covariates did not detect additional QTLs. DDD.Cg-A(y) showed a low CHO level, although it had Apoa2(b), which was a CHO-increasing allele at the Apoa2 locus. This may have been partly due to the presence of multiple QTLs, which were associated with decreased CHO levels, on chromosome 8.

Use of the p,p'-DDD: p,p'-DDE concentration ratio to trace contaminant migration from a hazardous waste site.

PubMed

Pinkney, Alfred E; McGowan, Peter C

2006-09-01

For approximately 50 years, beginning in the 1920s, hazardous wastes were disposed in an 11-hectare area of the Marine Corps Base (MCB) Quantico, Virginia, USA known as the Old Landfill. Polychlorinated biphenyls (PCBs) and DDT compounds were the primary contaminants of concern. These contaminants migrated into the sediments of a 78-hectare area of the Potomac River, the Quantico Embayment. Fish tissue contamination resulted in the MCB posting signs along the embayment shoreline warning fishermen to avoid consumption. In this paper, we interpret total PCB (t-PCBs) and total DDT (t-DDT, sum of six DDT, DDD, and DDE isomers) data from monitoring studies. We use the ratio of p,p'-DDD to p,p'-DDE concentrations as a tracer to distinguish site-related from regional contamination. The median DDD/DDE ratio in Quantico Embayment sediments (3.5) was significantly higher than the median ratio (0.71) in sediments from nearby Powells Creek, used as a reference area. In general, t-PCBs and t-DDT concentrations were significantly higher in killifish (Fundulus diaphanus) and carp (Cyprinus carpio) from the Quantico Embayment compared with Powells Creek. For both species, Quantico Embayment fish had mean or median DDD/DDE ratios greater than one. Median ratios were significantly higher in Quantico Embayment (4.6) than Powells Creek (0.28) whole body carp. In contrast, t-PCBs and t-DDT in channel catfish (Ictalurus punctatus) fillets were similar in Quantico Embayment and Powells Creek collections, with median ratios of 0.34 and 0.26, respectively. Differences between species may be attributable to movement (carp and killifish being more localized) and feeding patterns (carp ingesting sediment while feeding). We recommend that environmental scientists use this ratio when investigating sites with DDT contamination.

Organochlorine pesticide residues in bed sediments of the San Joaquin River and its tributary streams, California

USGS Publications Warehouse

Gilliom, R.J.; Clifton, D.G.

1987-01-01

The distribution and concentrations of organochlorine pesticide residues in bed sediments were assessed from samples collected at 24 sites in the San Joaquin River and its tributaries in the San Joaquin Valley, California. Sampling was designed to collect the finest grained bed sediments present in the vicinity of each site. One or more of the 14 pesticides analyzed were detected at every site. Pesticides detected at one or more sites were chlordane, DDD, DDE, DDT, dieldrin, endosulfan, mirex, and toxaphene. Pesticides not detected were endrin, heptachlor, heptachlor epoxide, lindane, methoxychlor, and perthane. The most frequently detected pesticides were DDD (83% of sites), DDE (all sites), DDT (33% of sites), and dieldrin (58% of sites). Maximum concentrations of these pesticides, which were correlated with each other and with the amount of organic carbon in the sample, were DDD, 260 micrograms/kg; DDE, 430 micrograms/kg; DDT, 420 micrograms/kg; and dieldrin, 8.9 micrograms/kg. Six small tributary streams that drain agricultural areas west of the San Joaquin River had the highest concentrations. Water concentrations and loads were estimated for each pesticide from its concentration in bed sediments, the concentration of suspended sediment, and streamflow. Estimated loadings of DDD, DDE, DDT, and dieldrin from tributaries to the San Joaquin River indicate that most of the loading to the river at the time of the study was probably from the westside tributaries. Estimated water concentrations exceeded the aquatic life criterion for the sum of DDD, DDE, and DDt of 0.001 microgram/L at nine of the 24 sites sampled. Five of the nine sites are westside tributaries and one is the San Joaquin River near Vernalis. (Author 's abstract)

[Atrial fibrillation before and after pacemaker implantation (WI and DDD) in patients with complete atrioventricular block].

PubMed

Matusik, Paweł; Woznica, Natalia; Lelakowsk, Jacek

2010-05-01

Atrial fibrillation (AF) is a frequent problem of patients with pacemakers, and depends not only on disease but also on stimulation method. The aim of the study was to estimate the prevalence of AF before and after pacemaker implantation as well as to assess the influence of VVI and DDD cardiac pacing on onset of AF in patients with complete atrioventricularblock (AVB). We included 155 patients controlled between 2000 and 2008 in Pacemaker Clinic because of AVB III degree, treated with VVI or DDD pacemaker implantation. Information about the health status of the patients was gathered from medical documentation and analysis of clinical ambulatory electrocardiograms. The study group comprised of 68 women and 87 men, mean age 68.7 +/- 13.9 years during implantation. 69% of patients had VVI pacemaker. There were 72.3% of patients with sinus rhythm before pacemaker implantation. During follow-up 4 +/- 2.8 years in 19.6% cases onset of atrial fibrillation de novo was diagnosed (in 31.3% in VVI mode vs. 2.2% in DDD mode; p = 0.00014). Mean time to AF since implantation was approximately 2.5 years. In VVI group (21 persons) amounted 32.1 months, while in 1 patient with DDD pacemaker 18 months. Between group with AF after implantation and with sinus rhythm preserved there was no statistically significant difference in age or gender (p = 0.89512 and p = 0.1253, respectively). Prevalence of atrial fibrillation after pacemaker implantation increased to 40%. Atrial fibrillation is frequent in patients before and after pacemaker implantation, especially in patients stimulated in VVI mode. Major possibility of atrial fibrillation onset after pacemaker implantation should result in more attention during routine ECG examination.

[Accumulation and degradation of organochorine pesticides in shellfish culture environment in Xiamen sea area].

PubMed

Zhong, Shuo-liang; Dong, Li-ming

2011-09-01

By using GC-ECD, the concentrations of organochlorine pesticides hexachlorocyclohexane (HCH) and dichlorodiphenyltrichloroethane (DDT) in the shellfish culture environment (sea water, sediments, and culture-shellfishes) in Xiamen sea area were analyzed, and the accumulation and degradation patterns of the HCH and DDT were preliminarily approached. In the sea area, there existed remarkable differences in the accumulation and degradation of HCH and DDT among different shellfish culture environments, being mostly associated with the habitation environment and physiological life habits of shellfish. The accumulated HCH isomers (Rx > 1) were mainly beta-HCH, delta-HCH, and gamma-HCH, whereas the degraded HCH isomers (Rx < 1) were mainly alpha-HCH. The ratio of alpha-HCH to gamma-HCH was less than or equal to 1.0, suggesting that the HCH was come from industrial HCH and lindane, most of the HCH had remained in the culture environment for a longer time, and a small amount of lindane was imported. The DDT in the sea water was aerobically degraded, its main degradation product was DDE, and the ratios of (DDD+DDE) to DDTs (p,p-DDE+p,p-DDD+o,p-DDT+p,p-DDT) was less than 0.5, whereas the DDT in sediments and shellfishes was anaerobically degraded, its main degradation product was DDD, and the ratios of (DDD+DDE) to DDTs was greater than 0.5, suggesting that there was a small amount of DDT newly imported in the sea water, and most DDT in sediments and shellfishes were already degraded and transformed into DDD and DDE. There were definite differences in the degradation rates of HCH isomers in the culture environment, suggesting the conformational change of HCH in its transformation processes in the shellfish culture ecosystem.

Cardiac pacing for severe childhood neurally mediated syncope with reflex anoxic seizures

PubMed Central

McLeod, K; Wilson, N; Hewitt, J; Norrie, J; Stephenson, J

1999-01-01

OBJECTIVE—To determine whether permanent cardiac pacing could prevent syncope and seizures in children with frequent severe neurally mediated syncope, and if so whether dual chamber pacing was superior to single chamber ventricular pacing.
METHODS—Dual chamber pacemakers were implanted into 12 children (eight male, four female) aged 2-14 years (median 2.8 years) with frequent episodes of reflex anoxic seizures and a recorded prolonged asystole during an attack. The pacemaker was programmed to sensing only (ODO), single chamber ventricular pacing with hysteresis (VVI), and dual chamber pacing with rate drop response (DDD) for four month periods, with each patient allocated to one of the six possible sequences of these modes, according to chronological order of pacemaker implantation. The parent and patient were blinded to the pacemaker mode and asked to record all episodes of syncope or presyncope ("near miss" events). The doctor analysing the results was blinded to the patient and pacemaker mode.
RESULTS—One patient was withdrawn from the study after the pacemaker was removed because of infection. In the remaining children, both dual chamber and single chamber pacing significantly reduced the number of syncopal episodes compared with sensing only (p = 0.0078 for both). VVI was as effective as DDD for preventing syncope, but DDD was superior to VVI in reducing near miss events (p = 0.016).
CONCLUSIONS—Permanent pacing is an effective treatment for children with severe neurally mediated syncope and reflex anoxic seizures. VVI is as effective as DDD in preventing syncope and seizures, but DDD is superior in preventing overall symptoms.


Keywords: syncope; reflex anoxic seizures; pacing; paediatric cardiology PMID:10573501

Dose Equivalents for Antipsychotic Drugs: The DDD Method.

PubMed

Leucht, Stefan; Samara, Myrto; Heres, Stephan; Davis, John M

2016-07-01

Dose equivalents of antipsychotics are an important but difficult to define concept, because all methods have weaknesses and strongholds. We calculated dose equivalents based on defined daily doses (DDDs) presented by the World Health Organisation's Collaborative Center for Drug Statistics Methodology. Doses equivalent to 1mg olanzapine, 1mg risperidone, 1mg haloperidol, and 100mg chlorpromazine were presented and compared with the results of 3 other methods to define dose equivalence (the "minimum effective dose method," the "classical mean dose method," and an international consensus statement). We presented dose equivalents for 57 first-generation and second-generation antipsychotic drugs, available as oral, parenteral, or depot formulations. Overall, the identified equivalent doses were comparable with those of the other methods, but there were also outliers. The major strength of this method to define dose response is that DDDs are available for most drugs, including old antipsychotics, that they are based on a variety of sources, and that DDDs are an internationally accepted measure. The major limitations are that the information used to estimate DDDS is likely to differ between the drugs. Moreover, this information is not publicly available, so that it cannot be reviewed. The WHO stresses that DDDs are mainly a standardized measure of drug consumption, and their use as a measure of dose equivalence can therefore be misleading. We, therefore, recommend that if alternative, more "scientific" dose equivalence methods are available for a drug they should be preferred to DDDs. Moreover, our summary can be a useful resource for pharmacovigilance studies. © The Author 2016. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Substituent effects in double-helical hydrogen-bonded AAA-DDD complexes.

PubMed

Wang, Hong-Bo; Mudraboyina, Bhanu P; Wisner, James A

2012-01-27

Two series of DDD and AAA hydrogen-bond arrays were synthesized that form triply-hydrogen-bonded double-helical complexes when combined in CDCl(3) solution. Derivatization of the DDD arrays with electron-withdrawing groups increases the complex association constants by up to a factor of 30 in those arrays examined. Derivatization of the AAA arrays with electron donating substituents reveals a similar magnitude effect on the complex stabilities. The effect of substitution on both types of arrays are modeled quite satisfactorily (R(2) > 0.96 in all cases) as free energy relationships with respect to the sums of their Hammett substituent constants. In all, the complex stabilities can be manipulated over more than three orders of magnitude (>20 kJ mol(-1)) using this type of modification. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Orchid flowers tolerance to gamma-radiation

NASA Astrophysics Data System (ADS)

Kikuchi, Olivia Kimiko

2000-03-01

Cut flowers are fresh goods that may be treated with fumigants such as methyl bromide to meet the needs of the quarantine requirements of importing countries. Irradiation is a non-chemical alternative to substitute the methyl bromide treatment of fresh products. In this research, different cut orchids were irradiated to examine their tolerance to gamma-rays. A 200 Gy dose did inhibit the Dendrobium palenopsis buds from opening, but did not cause visible damage to opened flowers. Doses of 800 and 1000 Gy were damaging because they provoked the flowers to drop from the stem. Cattleya irradiated with 750 Gy did not show any damage, and were therefore eligible for the radiation treatment. Cymbidium tolerated up to 300 Gy and above this dose dropped prematurely. On the other hand, Oncydium did not tolerate doses above 150 Gy.

A phase 1 dose-escalation study: safety, tolerability, and pharmacokinetics of FBS0701, a novel oral iron chelator for the treatment of transfusional iron overload.

PubMed

Rienhoff, Hugh Young; Viprakasit, Vip; Tay, Lay; Harmatz, Paul; Vichinsky, Elliott; Chirnomas, Deborah; Kwiatkowski, Janet L; Tapper, Amy; Kramer, William; Porter, John B; Neufeld, Ellis J

2011-04-01

There is still a clinical need for a well-tolerated and safe iron chelator for the treatment of transfusional iron overload. We describe the pharmacokinetic properties and safety data after 7 days of dosing of FBS0701, a novel oral, once-daily iron chelator. This phase 1b dose-escalation study to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of FBS0701, a novel oral iron chelator for the treatment of transfusional iron overload, was conducted in 16 adult patients with iron overloaded consequent to transfusions. FBS0701 was given daily for 7 days at doses up to 32 mg/kg and was well tolerated at all dose levels. Pharmacokinetics showed dose-proportionality. The maxium plasma concentration (C(max)) was reached within 60-90 minutes of dosing and the drug was rapidly distributed at the predicted therapeutic doses. The plasma elimination half-life (t(1/2)) was approximately 19 hours. There were no serious adverse events associated with the drug. Conclusions On the basis of these safety and pharmacokinetic data, FBS0701 warrants further clinical evaluation in patients with transfusional iron overload. (Clinicaltrials.gov identifier: NCT01186419).

An ethical assessment model for digital disease detection technologies.

PubMed

Denecke, Kerstin

2017-09-20

Digital epidemiology, also referred to as digital disease detection (DDD), successfully provided methods and strategies for using information technology to support infectious disease monitoring and surveillance or understand attitudes and concerns about infectious diseases. However, Internet-based research and social media usage in epidemiology and healthcare pose new technical, functional and formal challenges. The focus of this paper is on the ethical issues to be considered when integrating digital epidemiology with existing practices. Taking existing ethical guidelines and the results from the EU project M-Eco and SORMAS as starting point, we develop an ethical assessment model aiming at providing support in identifying relevant ethical concerns in future DDD projects. The assessment model has four dimensions: user, application area, data source and methodology. The model supports in becoming aware, identifying and describing the ethical dimensions of DDD technology or use case and in identifying the ethical issues on the technology use from different perspectives. It can be applied in an interdisciplinary meeting to collect different viewpoints on a DDD system even before the implementation starts and aims at triggering discussions and finding solutions for risks that might not be acceptable even in the development phase. From the answers, ethical issues concerning confidence, privacy, data and patient security or justice may be judged and weighted.

Construction Strategy and Progress of Whole Intervertebral Disc Tissue Engineering.

PubMed

Yang, Qiang; Xu, Hai-wei; Hurday, Sookesh; Xu, Bao-shan

2016-02-01

Degenerative disc disease (DDD) is the major cause of low back pain, which usually leads to work absenteeism, medical visits and hospitalization. Because the current conservative procedures and surgical approaches to treatment of DDD only aim to relieve the symptoms of disease but not to regenerate the diseased disc, their long-term efficiency is limited. With the rapid developments in medical science, tissue engineering techniques have progressed markedly in recent years, providing a novel regenerative strategy for managing intervertebral disc disease. However, there are as yet no ideal methods for constructing tissue-engineered intervertebral discs. This paper reviews published reports pertaining to intervertebral disc tissue engineering and summarizes data concerning the seed cells and scaffold materials for tissue-engineered intervertebral discs, construction of tissue-engineered whole intervertebral discs, relevant animal experiments and effects of mechanics on the construction of tissue-engineered intervertebral disc and outlines the existing problems and future directions. Although the perfect regenerative strategy for treating DDD has not yet been developed, great progress has been achieved in the construction of tissue-engineered intervertebral discs. It is believed that ongoing research on intervertebral disc tissue engineering will result in revolutionary progress in the treatment of DDD. © 2016 Chinese Orthopaedic Association and John Wiley & Sons Australia, Ltd.

Oligosaccharide composition is similar in drusen and dense deposits in membranoproliferative glomerulonephritis type II.

PubMed

D'souza, Yvonne B; Jones, Carolyn J P; Short, Colin D; Roberts, Ian S D; Bonshek, Richard E

2009-04-01

Drusen are a feature of age-related macular degeneration (AMD). Lesions similar in appearance to drusen are also found in the fundi of patients with membranoproliferative glomerulonephritis type II (dense deposit disease, DDD). The lamina densa of the glomerular basement membrane, in DDD, is transformed into an electron-dense structure by deposition of microscopically homogeneous material. Our study sought to compare the saccharide composition of drusen and dense deposits in the formalin-fixed, paraffin-embedded tissue from the eye and kidney. Six eye specimens were obtained from patients diagnosed with AMD but another eye was obtained from a patient with partial lipodystrophy, who died after renal failure presumably because of DDD. The kidney specimens were from three biopsy-proven cases of DDD. Glycosylation patterns were measured by the binding of 19 biotinylated lectins before and after neuraminidase pre-treatment. High mannose, bi/tri-antennary non-bisected and bisected complex N-glycan, N-acetyl glucosamine, galactose, and sialic acid residues were found in both drusen and dense deposits. Treatment with neuraminidase exposed subterminal galactose in both sites and sparse N-acetyl galactosamine residues in drusen alone. Our study found similar pathologic oligosaccharide structures in the eye and kidney, suggesting that drusen may be a common end result of retinal and glomerular disease.

The H3 antagonist ABT-288 is tolerated at significantly higher exposures in subjects with schizophrenia than in healthy volunteers.

PubMed

Othman, Ahmed A; Haig, George; Florian, Hana; Locke, Charles; Gertsik, Lev; Dutta, Sandeep

2014-06-01

ABT-288 is a potent and selective H3 receptor antagonist with procognitive effects in several preclinical models. In previous studies, 3 mg once daily was the maximal tolerated dose in healthy volunteers. This study characterized the safety, tolerability and pharmacokinetics of ABT-288 in stable subjects with schizophrenia. This was a randomized, double-blind, placebo-controlled, dose-escalating study of ABT-288 (10 dose levels, from 1 to 60 mg once daily for 14 days) in stable subjects with schizophrenia treated with an atypical antipsychotic. In each dose group, five to seven and two to three participants were assigned to ABT-288 and placebo, respectively. Of the 67 participants enrolled, nine participants (on ABT-288) were prematurely discontinued, in seven of these due to adverse events. ABT-288 was generally safe and tolerated at doses up to 45 mg once daily. The most common adverse events, in decreasing frequency (from 31 to 5%), were abnormal dreams, headache, insomnia, dizziness, somnolence, dysgeusia, dry mouth, psychotic disorder, parosmia and tachycardia. Adverse events causing early termination were psychotic events (four) and increased creatine phosphokinase, pyrexia and insomnia (one each). The half-life of ABT-288 ranged from 28 to 51 h, and steady state was achieved by day 12 of dosing. At comparable multiple doses, ABT-288 exposure in subjects with schizophrenia was 45% lower than that previously observed in healthy subjects. At trough, ABT-288 cerebrospinal fluid concentrations were 40% of the total plasma concentrations. ABT-288 was tolerated at a 15-fold higher dose and 12-fold higher exposures in subjects with schizophrenia than previously observed in healthy volunteers. The greater ABT-288 tolerability was not due to limited brain uptake. © 2013 The British Pharmacological Society.

Tolerance to repeated nicotine administration on performance, subjective, and physiological responses in nonsmokers.

PubMed

Heishman, S J; Henningfield, J E

2000-10-01

When administered acutely to nonsmokers, nicotine's effects on performance are inconsistent, perhaps because of suboptimal dosing or initial dysphoria that could interfere with performance. The purpose of this study was to determine if a range of nicotine doses administered for 8 days to nonsmokers would enhance psychomotor and cognitive abilities and to document the development of nicotine tolerance or sensitization. Twelve male volunteers, who reported ever smoking five cigarettes or less, participated in 8 consecutive experimental days in which they were administered four doses of nicotine polacrilex gum each day in this order: 0, 2, 4, and 8 mg. Performance, subjective, and physiological measures were assessed before and after each dose. Plasma nicotine concentration ranged from 6.9 to 11.5 ng/ml following the 8 mg dose. Nicotine increased rate of responding and decreased response time on working memory (digit recall); however, accuracy was impaired. Nicotine also decreased accuracy on visual scanning and attention (two-letter search), and the 8 mg dose impaired gross motor coordination (circular lights). Tolerance did not develop to the performance impairing effects of nicotine. Nicotine produced dose-related increases in ratings of dysphoria and negative mood, including tension, anxiety, nervousness, turning of stomach, and sedation. Tolerance developed to some, but not all, of these aversive effects. Tolerance also was not observed to the increased cardiovascular measures. Although tolerance developed to some of the aversive effects of nicotine, performance enhancement was not observed. These data do not support the hypothesis that nicotine-induced performance enhancement contributes to the reinforcing effects of tobacco use during the early stages of dependence development.

A Phase I Study of the Safety and Pharmacokinetics of Higher-Dose Icotinib in Patients With Advanced Non-Small Cell Lung Cancer

PubMed Central

Liu, Jian; Wu, Lihua; Wu, Guolan; Hu, Xingjiang; Zhou, Huili; Chen, Junchun; Zhu, Meixiang; Xu, Wei; Tan, Fenlai; Ding, Lieming; Wang, Yinxiang

2016-01-01

Lessons Learned This phase I study evaluated the maximum tolerated dose, dose-limiting toxicities, safety, pharmacokinetics, and efficacy of icotinib with a starting dose of 250 mg in pretreated, advanced non-small cell lung cancer patients. We observed a maximum tolerated dose of 500 mg with a favorable pharmacokinetics profile and antitumor activity. These findings provide clinicians with evidence for application of higher-dose icotinib. Background. Icotinib, an oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, has shown favorable tolerability and antitumor activity at 100–200 mg in previous studies without reaching the maximum tolerated dose (MTD). In July 2011, icotinib was approved by the China Food and Drug Administration at a dose of 125 mg three times daily for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) after failure of at least one platinum-based chemotherapy regimen. This study investigated the MTD, tolerability, and pharmacokinetics of higher-dose icotinib in patients with advanced NSCLC. Methods. Twenty-six patients with advanced NSCLC were treated at doses of 250–625 mg three times daily The EGFR mutation test was not mandatory in this study. Results. Twenty-four (92.3%) of 26 patients experienced at least one adverse event (AE); rash (61.5%), diarrhea (23.1%), and oral ulceration (11.5%) were most frequent AEs. Dose-limiting toxicities were seen in 2 of 6 patients in the 625-mg group, and the MTD was established at 500 mg. Icotinib was rapidly absorbed and eliminated. The amount of time that the drug was present at the maximum concentration in serum (Tmax) ranged from 1 to 3 hours (1.5–4 hours) after multiple doses. The t1/2 was similar after single- and multiple-dose administration (7.11 and 6.39 hours, respectively). A nonlinear relationship was observed between dose and drug exposure. Responses were seen in 6 (23.1%) patients, and 8 (30.8%) patients had stable disease. Conclusion. This study demonstrated that higher-dose icotinib was well-tolerated, with a MTD of 500 mg. Favorable antitumor activity and pharmacokinetic profile were observed in patients with heavily pretreated, advanced NSCLC. PMID:27789778

A Phase I Study of the Safety and Pharmacokinetics of Higher-Dose Icotinib in Patients With Advanced Non-Small Cell Lung Cancer.

PubMed

Liu, Jian; Wu, Lihua; Wu, Guolan; Hu, Xingjiang; Zhou, Huili; Chen, Junchun; Zhu, Meixiang; Xu, Wei; Tan, Fenlai; Ding, Lieming; Wang, Yinxiang; Shentu, Jianzhong

2016-11-01

This phase I study evaluated the maximum tolerated dose, dose-limiting toxicities, safety, pharmacokinetics, and efficacy of icotinib with a starting dose of 250 mg in pretreated, advanced non-small cell lung cancer patients. We observed a maximum tolerated dose of 500 mg with a favorable pharmacokinetics profile and antitumor activity.These findings provide clinicians with evidence for application of higher-dose icotinib. Icotinib, an oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, has shown favorable tolerability and antitumor activity at 100-200 mg in previous studies without reaching the maximum tolerated dose (MTD). In July 2011, icotinib was approved by the China Food and Drug Administration at a dose of 125 mg three times daily for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) after failure of at least one platinum-based chemotherapy regimen. This study investigated the MTD, tolerability, and pharmacokinetics of higher-dose icotinib in patients with advanced NSCLC. Twenty-six patients with advanced NSCLC were treated at doses of 250-625 mg three times daily The EGFR mutation test was not mandatory in this study. Twenty-four (92.3%) of 26 patients experienced at least one adverse event (AE); rash (61.5%), diarrhea (23.1%), and oral ulceration (11.5%) were most frequent AEs. Dose-limiting toxicities were seen in 2 of 6 patients in the 625-mg group, and the MTD was established at 500 mg. Icotinib was rapidly absorbed and eliminated. The amount of time that the drug was present at the maximum concentration in serum (T max ) ranged from 1 to 3 hours (1.5-4 hours) after multiple doses. The t 1/2 was similar after single- and multiple-dose administration (7.11 and 6.39 hours, respectively). A nonlinear relationship was observed between dose and drug exposure. Responses were seen in 6 (23.1%) patients, and 8 (30.8%) patients had stable disease. This study demonstrated that higher-dose icotinib was well-tolerated, with a MTD of 500 mg. Favorable antitumor activity and pharmacokinetic profile were observed in patients with heavily pretreated, advanced NSCLC. ©AlphaMed Press; the data published online to support this summary is the property of the authors.

Melatonin for Sleep in Children with Autism: A Controlled Trial Examining Dose, Tolerability, and Outcomes

ERIC Educational Resources Information Center

Malow, Beth; Adkins, Karen W.; McGrew, Susan G.; Wang, Lily; Goldman, Suzanne E.; Fawkes, Diane; Burnette, Courtney

2012-01-01

Supplemental melatonin has shown promise in treating sleep onset insomnia in children with autism spectrum disorders (ASD). Twenty-four children, free of psychotropic medications, completed an open-label dose-escalation study to assess dose-response, tolerability, safety, feasibility of collecting actigraphy data, and ability of outcome measures…

Dissipative Particle Dynamics at Isoenthalpic Conditions Using Shardlow-Like Splitting Algorithms

DTIC Science & Technology

2013-09-01

dd 11 d d ,...,1d 11 2 d 2 1 d dd dlnd ,...,1d1 dddd ddd ij 2 2 2...t W p t m ij i f C iji i i i i dd dlnd d1dd ddd                      pFp r p r  Ni ,...,1 , (10) while the fluctuation...pp rr v r p dd ddd             (11a) 6 j ji i i- j i- ji- j i- j mech,i j i i j mech,i j mech,i j j i 1 u 2 2m 2m u u d d d

Association of catechol-O-methyltransferase genetic variants with outcome in patients undergoing surgical treatment for lumbar degenerative disc disease.

PubMed

Dai, Feng; Belfer, Inna; Schwartz, Carolyn E; Banco, Robert; Martha, Julia F; Tighioughart, Hocine; Tromanhauser, Scott G; Jenis, Louis G; Kim, David H

2010-11-01

Surgical treatment for lumbar degenerative disc disease (DDD) has been associated with highly variable results in terms of postoperative pain relief and functional improvement. Many experts believe that DDD should be considered a chronic pain disorder as opposed to a degenerative disease. Genetic variation of the catechol-O-methyltransferase (COMT) gene has been associated with variation in human pain sensitivity and response to analgesics in previous studies. To determine whether genetic variation of COMT is associated with clinical outcome after surgical treatment for DDD. Prospective genetic association study. Sixty-nine patients undergoing surgical treatment for lumbar DDD. Diagnosis was based on documentation of chronic disabling low back pain (LBP) present for a minimum of 6 months and unresponsive to supervised nonoperative treatment, including activity modification, medication, physical therapy, and/or injection therapy. Plain radiographs and magnetic resonance imaging revealed intervertebral disc desiccation, tears, and/or collapse without focal herniation, nerve root compression, stenosis, spondylolisthesis, spondylolysis, or alternative diagnoses. Oswestry Disability Index (ODI) and visual analog score (VAS) for LBP. Surgical treatment included 65 instrumented fusions and four disc arthroplasty procedures. All patients completed preoperative and 1-year postoperative ODI questionnaires. DNA was extracted from a sample of venous blood, and genotype analysis was performed for five common COMT single nucleotide polymorphisms (SNPs). Potential genetic association between these COMT SNPs and the primary outcome variable, 1-year change in ODI, was investigated using both single-marker and haplotype association analyses. Association with VAS scores for LBP was analyzed as a secondary outcome variable. Single-marker analysis revealed that the COMT SNP rs4633 was significantly associated with greater improvement in ODI score 1 year after surgery (p=.03), with individuals homozygous for the less common "T" allele demonstrating the largest improvement in ODI. Haplotype analysis of four COMT SNPs, rs6269, rs4633, rs4818, and rs4680, also identified a common haplotype "ATCA" (haplotype frequency of 39.3% in the study population) associated with greater improvement in ODI (p=.046). The greatest mean improvement in ODI was observed in patients homozygous for the "ATCA"COMT haplotype. A nonsignificant trend was observed between SNP rs4633 and greater improvement in VAS score for LBP. This is the first study to report an association between surgical treatment success in DDD patients and genetic variation in the putative pain sensitivity gene COMT. These findings require replication in other DDD populations but suggest that genetic testing for pain-relevant genetic markers such as COMT may provide useful clinical information in terms of predicting outcome after surgery for patients diagnosed with DDD. Copyright © 2010 Elsevier Inc. All rights reserved.

Reimbursement of hormonal contraceptives and the frequency of induced abortion among teenagers in Sweden.

PubMed

Sydsjö, Adam; Sydsjö, Gunilla; Bladh, Marie; Josefsson, Ann

2014-05-29

Reduction in costs of hormonal contraceptives is often proposed to reduce rates of induced abortion among young women. This study investigates the relationship between rates of induced abortion and reimbursement of dispensed hormonal contraceptives among young women in Sweden. Comparisons are made with the Nordic countries Finland, Norway and Denmark. Official statistics on induced abortion and numbers of prescribed and dispensed hormonal contraceptives presented as "Defined Daily Dose/thousand women" (DDD/T) aged 15-19 years were compiled and related to levels of reimbursement in all Swedish counties by using public official data. The Swedish numbers of induced abortion were compared to those of Finland, Norway and Denmark. The main outcome measure was rates of induced abortion and DDD/T. No correlation was observed between rates of abortion and reimbursement among Swedish counties. Nor was any correlation found between sales of hormonal contraceptives and the rates of abortion. In a Nordic perspective, Finland and Denmark, which have no reimbursement at all, and Norway all have lower rates of induced abortion than Sweden. Reimbursement does not seem to be enough in order to reduce rates of induced abortion. Evidently, other factors such as attitudes, education, religion, tradition or cultural differences in each of Swedish counties as well as in the Nordic countries may be of importance. A more innovative approach is needed in order to facilitate safe sex and to protect young women from unwanted pregnancies.

Reimbursement of hormonal contraceptives and the frequency of induced abortion among teenagers in Sweden

PubMed Central

2014-01-01

Background Reduction in costs of hormonal contraceptives is often proposed to reduce rates of induced abortion among young women. This study investigates the relationship between rates of induced abortion and reimbursement of dispensed hormonal contraceptives among young women in Sweden. Comparisons are made with the Nordic countries Finland, Norway and Denmark. Methods Official statistics on induced abortion and numbers of prescribed and dispensed hormonal contraceptives presented as “Defined Daily Dose/thousand women” (DDD/T) aged 15-19 years were compiled and related to levels of reimbursement in all Swedish counties by using public official data. The Swedish numbers of induced abortion were compared to those of Finland, Norway and Denmark. The main outcome measure was rates of induced abortion and DDD/T. Results No correlation was observed between rates of abortion and reimbursement among Swedish counties. Nor was any correlation found between sales of hormonal contraceptives and the rates of abortion. In a Nordic perspective, Finland and Denmark, which have no reimbursement at all, and Norway all have lower rates of induced abortion than Sweden. Conclusions Reimbursement does not seem to be enough in order to reduce rates of induced abortion. Evidently, other factors such as attitudes, education, religion, tradition or cultural differences in each of Swedish counties as well as in the Nordic countries may be of importance. A more innovative approach is needed in order to facilitate safe sex and to protect young women from unwanted pregnancies. PMID:24884539

Impact of pharmacist intervention on antibiotic use and prophylactic antibiotic use in urology clean operations.

PubMed

Zhou, Y; Ma, L-Y; Zhao, X; Tian, S-H; Sun, L-Y; Cui, Y-M

2015-08-01

The use of prophylactic antibiotics in clean operations was routine in China before 2011. Along with the appeal for using antibiotics rationally by WHO in 2011, China launched a national special rectification scheme on clinical use of antibiotics from April that year. The scheme, aimed at achieving rational use of antibiotics, made pharmacists part of the responsible medical team. Our objective was to describe the impacts of pharmacist intervention on the use of antibiotics, particularly in urology clean operations. Pharmacists participated in antibiotic stewardship programmes of the hospital and urological clinical work and conducted real-time interventions at the same time from 2011 to 2013. Data on the use of antibiotics between 2010 and 2013 in urology were collected. Comparison of the 2013 data with those of 2010 showed that antibiotic use density [AUD= DDDs*100/(The number of patients who were treated the same period*Average days in hospital). DDDs = Total drug consumption (g)/DDD. DDD is the Defined Daily Dose] decreased by 57·8(58·8%); average antibiotic cost decreased by 246·94 dollars; the cost of antibiotics as a percentage of total drug cost decreased by 27·7%; the rate of use of antibiotics decreased from 100% to 7·3%. The study illustrates how an antibiotic stewardship programme with pharmacist participation including real-time interventions can promote improved antibiotic-prescribing and significantly decrease costs. © 2015 John Wiley & Sons Ltd.

The Australian rise of esomeprazole-was expenditure on samples a contributor?

PubMed

Kyle, Gregory J; Nissen, Lisa M; Tett, Susan E

2009-01-01

Administrative data from the Australian Pharmaceutical Benefits Scheme (PBS) showed rapid growth of esomeprazole dispensing when it was launched. Australia has universal prescription medicine coverage (the PBS), which included esomeprazole from August 2002. Free samples of new medicines are commonly provided to doctors. To determine if a relationship exists between marketing expenditure on samples and the dispensing rate for esomeprazole in Australia between June 2002 and September 2006. Quarterly sample expenditures at product/brand level for proton pump inhibitors (PPIs) for Australian general practitioners were obtained for July 2002 to September 2006. Corresponding PBS dispensing data were obtained for all PPIs and converted to defined daily dose (DDD)/1000 population/day. Spending on samples was calculated as dollars per dispensed prescription and plotted against time on the Australian market. Total PPI usage increased from 34.2 to 50.8 DDD/1000 population/day over the study period. Expenditure on samples per dispensed prescription was higher when a PPI was new on the market and diminished over 5-6 years to a relatively constant level. The rapid decline in this ratio was demonstrated by a case study following esomeprazole from launch in Australia for almost 5 years clearly demonstrating the initial investment to drive sales. A relationship appears to exist between expenditure on esomeprazole samples and its usage in Australia. A high initial investment was followed by a rapid reduction in cost per prescription dispensed, predominantly due to growth in market share. This trend was consistent with other PPIs.

Opioid analgesic use in Australia and The Netherlands: a cross-country comparison.

PubMed

Wagemaakers, Francisca N; Hollingworth, Samantha A; Kreijkamp-Kaspers, Sanne; Tee, Ernest H L; Leendertse, Anne J; van Driel, Mieke L

2017-08-01

Background Increasing use of opioid analgesics (OA) has been reported worldwide. Objective To compare the use of OA in two countries in order to better understand these trends. Setting Outpatient settings in Australia and The Netherlands. Method We analysed publicly available government data on outpatient OA dispensing over 15 years (2000-2014). We compared dispensing trends for specific OA and explored medical (national clinical guidelines), contextual and policy-related factors to explain differences in use between the two countries. Main outcome measure OA prescribing in Australia and The Netherlands, absolute volume of use, preferred types of opioids and changes over time. Results The average annual increase in OA prescribing was 10% in Australia and 8% in The Netherlands between 2000 and 2014. In 2014, the total use of OA was 10.0 daily defined doses (DDD)/1000 population/day in Australia and 9.4 DDD/1000 population/day in The Netherlands. In Australia, the most commonly prescribed opioids were oxycodone and tramadol, compared to fentanyl and tramadol in The Netherlands. We found differences in prescribing guidelines, culture of prescribing and regulatory frameworks that could explain some of the observed differences. Conclusion OA prescribing has increased remarkably in both countries between 2000 and 2014 but the types of prescribed OA vary. Differences in national evidence-based guidelines influenced the types of OA used. Prescribing culture as well as regulatory policies and costs, may also contribute to the different patterns of OA use.

Ezetimibe: Use, costs, and adverse events in Australia.

PubMed

Hollingworth, Samantha A; Ostino, Remo; David, Michael C; Martin, Jennifer H; Tett, Susan E

2017-02-01

To analyze the subsidized use and reported adverse events of ezetimibe, used to lower cholesterol, in Australia over the 11 years following its inclusion on the Pharmaceutical Benefits Scheme (PBS) in 2004. Pharmacoepidemiological analysis of dispensed prescriptions from Medicare Australia. Adverse event data were obtained from the Therapeutic Goods Administration. Use was measured by the defined daily dose (DDD) per 1000 population per day for each calendar year. Adverse events were counted by organ class system. Total ezetimibe use rose to 8.46 DDD/1000 population/d in the 11 years to 2015. Ezetimibe as a sole active ingredient was the most commonly dispensed formulation followed by the two combination products containing ezetimibe and 40 mg or 80 mg simvastatin. The average yearly increase in utilization was 19% with a 24% annual increase in costs to government (2006-2015) to $169.0 million in 2015. There were substantial differences in ezetimibe use between states, with no relationship to deaths from ischaemic heart disease (IHD) in each jurisdiction. The major reported adverse events were musculoskeletal and connective tissue disorders and gastrointestinal disorders. Ezetimibe use has increased rapidly in Australia since receiving public subsidy. Although the indications for subsidy are very restricted, there appears to have been widespread use, not explained by differential geographical IHD death rates. Latest guidelines still question the value of ezetimibe, so further discussion about whether the public spending on this medication for any potential improvement in population health outcomes is justified. © 2016 John Wiley & Sons Ltd.

Dose Effect of Rhenium (I)-diselenoether as Anticancer Drug in Resistant Breast Tumor-bearing Mice After Repeated Administrations.

PubMed

Collery, Philippe; Santoni, François; Ciccolini, Joseph; Tran, Thi Ngoc Nga; Mohsen, Ahmed; Desmaele, Didier

2016-11-01

Rhenium (I)-diselenoether has shown promising antiproliferative efficacy in both in vitro and in vivo models. However, the maximal tolerated dose and dose-effect relationships have not been fully addressed for this compound. Here, we evaluated the tolerance and efficacy of three dose-levels (namely 10, 40 and 100 mg/kg) intraperitoneally administered daily over 28 days in mice bearing the resistant MDA-MB231 breast cancer cell line. The upper dose was found to be toxic and was reduced to 60 mg/kg. The 10 mg/kg dose well tolerated, whereas 40 mg/kg was associated with 10% mortality (LD 10 ). Both 10 and 40 mg/kg dosing achieved a significantly similar regression of tumor growth compared with untreated animals. This study suggests that 10 mg/kg daily is the recommended dose for rhenium (I) diselenoether. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

An accelerated dose escalation with a grass pollen allergoid is safe and well-tolerated: a randomized open label phase II trial.

PubMed

Chaker, A M; Al-Kadah, B; Luther, U; Neumann, U; Wagenmann, M

2015-01-01

The number of injections in the dose escalation of subcutaneous immunotherapy (SCIT) is small for some currently used hypoallergenic allergoids, but can still be inconvenient to patients and can impair compliance. The aim of this trial was to compare safety and tolerability of an accelerated to the conventional dose escalation scheme of a grass pollen allergoid. In an open label phase II trial, 122 patients were 1:1 randomized for SCIT using a grass pollen allergoid with an accelerated dose escalation comprising only 4 weekly injections (Group I) or a conventional dose escalation including 7 weekly injections (Group II). Safety determination included the occurrence of local and systemic adverse events. Tolerability was assessed by patients and physicians. Treatment-related adverse events were observed in 22 (36.1 %) patients in Group I and 15 (24.6 %) in Group II. Local reactions were reported by 18 patients in Group I and 11 in Group II. Five Grade 1 systemic reactions (WAO classification) were observed in Group I and 2 in Group II. Grade 2 reactions occurred 3 times in Group I and 2 times in Group II. Tolerability was rated as "good" or "very good" by 53 (86.9 %) patients in Group I and 59 (100 %) in Group II by investigators. Forty-eight patients in Group I (80.0 %) and 54 in Group II (91.5 %) rated tolerability as "good" or "very good". The dose escalation of a grass pollen allergoid can be accelerated with safety and tolerability profiles comparable to the conventional dose escalation.

Ultra-low dose naltrexone attenuates chronic morphine-induced gliosis in rats.

PubMed

Mattioli, Theresa-Alexandra M; Milne, Brian; Cahill, Catherine M

2010-04-16

The development of analgesic tolerance following chronic morphine administration can be a significant clinical problem. Preclinical studies demonstrate that chronic morphine administration induces spinal gliosis and that inhibition of gliosis prevents the development of analgesic tolerance to opioids. Many studies have also demonstrated that ultra-low doses of naltrexone inhibit the development of spinal morphine antinociceptive tolerance and clinical studies demonstrate that it has opioid sparing effects. In this study we demonstrate that ultra-low dose naltrexone attenuates glial activation, which may contribute to its effects on attenuating tolerance. Spinal cord sections from rats administered chronic morphine showed significantly increased immuno-labelling of astrocytes and microglia compared to saline controls, consistent with activation. 3-D images of astrocytes from animals administered chronic morphine had significantly larger volumes compared to saline controls. Co-injection of ultra-low dose naltrexone attenuated this increase in volume, but the mean volume differed from saline-treated and naltrexone-treated controls. Astrocyte and microglial immuno-labelling was attenuated in rats co-administered ultra-low dose naltrexone compared to morphine-treated rats and did not differ from controls. Glial activation, as characterized by immunohistochemical labelling and cell size, was positively correlated with the extent of tolerance developed. Morphine-induced glial activation was not due to cell proliferation as there was no difference observed in the total number of glial cells following chronic morphine treatment compared to controls. Furthermore, using 5-bromo-2-deoxyuridine, no increase in spinal cord cell proliferation was observed following chronic morphine administration. Taken together, we demonstrate a positive correlation between the prevention of analgesic tolerance and the inhibition of spinal gliosis by treatment with ultra-low dose naltrexone. This research provides further validation for using ultra-low dose opioid receptor antagonists in the treatment of various pain syndromes.

Effects of multiple ascending doses of the glucagon receptor antagonist PF-06291874 in patients with type 2 diabetes mellitus.

PubMed

Kazierad, D J; Bergman, A; Tan, B; Erion, D M; Somayaji, V; Lee, D S; Rolph, T

2016-08-01

To assess the pharmacokinetics, pharmacodynamics, safety and tolerability of multiple ascending doses of the glucagon receptor antagonist PF-06291874 in patients with type 2 diabetes mellitus (T2DM). Patients were randomized to oral PF-06291874 or placebo on a background of either metformin (Part A, Cohorts 1-5: 5-150 mg once daily), or metformin and sulphonylurea (Part B, Cohorts 1-2: 15 or 30 mg once daily) for 14-28 days. A mixed-meal tolerance test (MMTT) was administered on days -1 (baseline), 14 and 28. Assessments were conducted with regard to pharmacokinetics, various pharmacodynamic variables, safety and tolerability. Circulating amino acid concentrations were also measured. PF-06291874 exposure was approximately dose-proportional with a half-life of ∼19.7-22.7 h. Day 14 fasting plasma glucose and mean daily glucose values were reduced from baseline in a dose-dependent manner, with placebo-corrected decreases of 34.3 and 42.4 mg/dl, respectively, at the 150 mg dose. After the MMTT, dose-dependent increases in glucagon and total glucagon-like peptide-1 (GLP-1) were observed, although no meaningful changes were noted in insulin, C-peptide or active GLP-1 levels. Small dose-dependent increases in LDL cholesterol were observed, along with reversible increases in serum aminotransferases that were largely within the laboratory reference range. An increase in circulating gluconeogenic amino acids was also observed on days 2 and 14. All dose levels of PF-06291874 were well tolerated. PF-06291874 was well tolerated, has a pharmacokinetic profile suitable for once-daily dosing, and results in reductions in glucose with minimal risk of hypoglycaemia. © 2016 John Wiley & Sons Ltd.

Instrumented posterior lumbar interbody fusion (PLIF) with interbody fusion device (Cage) in degenerative disc disease (DDD): 3 years outcome.

PubMed

Ahsan, M K; Hossain, M A; Sakeb, N; Khan, S I; Zaman, N

2013-10-01

This prospective interventional study carried out at Bangabandhu Sheikh Mujib Medical University and a private hospital in Dhaka, Bangladesh during the period from October 2003 to September 2011. Surgical treatment of degenerative disc disease (DDD) should aim to re-expand the interbody space and stabilize until fusion is complete. The present study conducted to find out the efficacy of using interbody fusion device (Cage) to achieve interbody space re-expansion and fusion in surgical management of DDD. We have performed the interventional study on 53 patients, 42 female and 11 male, with age between 40 to 67 years. All the patients were followed up for 36 to 60 months (average 48 months). Forty seven patients were with spondylolisthesis and 06 with desiccated disc. All subjects were evaluated with regard to immediate and long term complications, radiological fusion and interbody space re-expansion and maintenance. The clinical outcome (pain and disability) was scored by standard pre and postoperative questionnaires. Intrusion, extrusion and migration of the interbody fusion cage were also assessed. Forty seven patients were considered to have satisfactory outcome in at least 36 months follow up. Pseudoarthrosis developed in 04 cases and 06 patients developed complications. In this series posterior lumbar interbody fusion (PLIF) with interbody cage and instrumentation in DDD showed significant fusion rate and maintenance of interbody space. Satisfactory outcome observed in 88.68% cases.

Clinical features and outcomes of 98 children and adults with dense deposit disease

PubMed Central

Moon, Mikyung; Lanning, Lynne D.; McCarthy, Ann Marie; Smith, Richard J. H.

2015-01-01

Background Dense deposit disease (DDD) is an ultra-rare renal disease. Methods In the study reported here, 98 patients and their families participated in a descriptive patient-centered survey using an online research format. Reports were completed by patients (38%) or their parents (62%). Age at diagnosis ranged from 1.9 to 38.9 years (mean 14 years). Results The majority of patients presented with proteinuria and hematuria; 50% had hypertension and edema. Steroids were commonly prescribed, although their use was not evidence-based. One-half of the patients with DDD for 10 years progressed to end-stage renal disease (ESRD), with young females having the greatest risk for renal failure. Of first allografts, 45% failed within 5 years, most frequently due to recurrent disease (70%). Type 1 diabetes (T1D) was present in over 16% of families, which represents a 116-fold increase in incidence compared with the general population (p<0.001). Conclusions Based on these findings, we suggest that initiatives are needed to explore the high incidence of T1D in family members of DDD patients and the greater risk for progression to ESRD in young females with DDD. These efforts must be supported by sufficient numbers of patients to establish evidence-based practice guidelines for disease management. An international collaborative research survey should be implemented to encourage broad access and participation. PMID:22105967

Morphine tolerance as a function of ratio schedule: response requirement or unit price?

PubMed

Hughes, Christine E; Sigmon, Stacey C; Pitts, Raymond C; Dykstra, Linda A

2005-05-01

Key pecking by 3 pigeons was maintained by a multiple fixed-ratio 10, fixed-ratio 30, fixed-ratio 90 schedule of food presentation. Components differed with respect to amount of reinforcement, such that the unit price was 10 responses per 1-s access to food. Acute administration of morphine, l-methadone, and cocaine dose-dependently decreased overall response rates in each of the components. When a rate decreasing dose of morphine was administered daily, tolerance, as measured by an increase in the dose that reduced response rates to 50% of control (i.e., the ED50 value), developed in each of the components; however, the degree of tolerance was smallest in the fixed-ratio 90 component (i.e., the ED50 value increased the least). When the l-methadone dose-effect curve was redetermined during the chronic morphine phase, the degree of cross-tolerance conferred to l-methadone was similar across components, suggesting that behavioral variables may not influence the degree of cross-tolerance between opioids. During the chronic phase, the cocaine dose-effect curve shifted to the right for 2 pigeons and to the left for 1 pigeon, which is consistent with predictions based on the lack of pharmacological similarity between morphine and cocaine. When the morphine, l-methadone, and cocaine dose-effect curves were redetermined after chronic morphine administration ended, the morphine and l-methadone ED50s replicated those obtained prior to chronic morphine administration. The morphine data suggest that the fixed-ratio value (i.e., the absolute output) determines the degree of tolerance and not the unit price.

Reversal of oxycodone and hydrocodone tolerance by diazepam.

PubMed

Gonek, Maciej; Akbarali, Hamid I; Henderson, Graeme; Dewey, William L

2017-11-01

The Centers for Disease Control has declared opioid abuse to be an epidemic. Overdose deaths are largely assumed to be the result of excessive opioid consumption. In many of these cases, however, opioid abusers are often polydrug abusers. Benzodiazepines are one of the most commonly co-abused substances and pose a significant risk to opioid users. In 2016, the FDA required boxed warnings - the FDA's strongest warning - for prescription opioid analgesics and benzodiazepines about the serious risks associated with using these medications at the same time. The point of our studies was to evaluate the interactions between these two classes of drugs. We investigated whether diazepam adds to the depressant effects of opioids or do they alter the levels of tolerance to opioids. In the present study, we have found that the antinociceptive tolerance that developed to repeated administration of oxycodone was reversed by an acute dose of diazepam. Antinociceptive tolerance to hydrocodone was also reversed by acute injection of diazepam; however, a fourfold higher dose of diazepam was required when compared to reversal of oxycodone-induced tolerance. These doses of diazepam did not potentiate the acute antinociceptive effect of either opioid. The same dose of diazepam that reversed oxycodone antinociceptive tolerance also reversed oxycodone locomotor tolerance while having no potentiating effects. These studies show that diazepam does not potentiate the acute effect of prescription opioids but reverses the tolerance developed after chronic administration of the drugs. Copyright © 2017 Elsevier B.V. All rights reserved.

The Dichotic Digits difference Test (DDdT): Development, Normative Data, and Test-Retest Reliability Studies Part 1.

PubMed

Cameron, Sharon; Glyde, Helen; Dillon, Harvey; Whitfield, Jessica; Seymour, John

2016-06-01

The dichotic digits test is one of the most widely used assessment tools for central auditory processing disorder. However, questions remain concerning the impact of cognitive factors on test results. To develop the Dichotic Digits difference Test (DDdT), an assessment tool that could differentiate children with cognitive deficits from children with genuine dichotic deficits based on differential test results. The DDdT consists of four subtests: dichotic free recall (FR), dichotic directed left ear (DLE), dichotic directed right ear (DRE), and diotic. Scores for six conditions are calculated (FR left ear [LE], FR right ear [RE], and FR total, as well as DLE, DRE, and diotic). Scores for four difference measures are also calculated: dichotic advantage, right-ear advantage (REA) FR, REA directed, and attention advantage. Experiment 1 involved development of the DDdT, including error rate analysis. Experiment 2 involved collection of normative and test-retest reliability data. Twenty adults (aged 25 yr 10 mo to 50 yr 7 mo, mean 36 yr 4 mo) took part in the development study; 62 normal-hearing, typically developing, primary-school children (aged 7 yr 1 mo to 11 yr 11 mo, mean 9 yr 4 mo) and 10 adults (aged 25 yr 0 mo to 51 yr 6 mo, mean 34 yr 10 mo) took part in the normative and test-retest reliability study. In Experiment 1, error rate analysis was conducted on the 36 digit-pair combinations of the DDdT. Normative data collected in Experiment 2 were arcsine transformed to achieve a distribution that was closer to a normal distribution and z-scores calculated. Pearson product-moment correlations were used to determine the strength of relationships between DDdT conditions. The development study revealed no significant differences in the adult population between test and retest on any DDdT condition. Error rates on 36 digit pairs ranged from 1.5% to 16.7%. The most and the least error-prone digits were removed before commencement of the normative data study, leaving 25 unique digit pairs. Average z-scores calculated from the arcsine-transformed data collected from the 62 children who took part in the normative data study revealed that FR dichotic processing (LE, RE, and total) was highly correlated with diotic processing (r ranging from 0.5 to 0.6; p < 0.0001). Significant improvements in performance on retest occurred for the FR LE, RE, total, and diotic conditions (p ranging from 0.05 to 0.0004), the conditions that would be expected to improve with practice if the participant's response strategies are better the second time around. The addition of a diotic control task-that shares many response demands with the usual dichotic tasks-opens up the possibility of differentiating children who perform below expectations because of poor dichotic processing skills from those who perform poorly because of impaired attention, memory, or other cognitive abilities. The high correlation between dichotic and diotic performance suggests that factors other than dichotic performance play a substantial role in a child's ability to perform a dichotic listening task. This hypothesis is investigated further in the cognitive correlation study that follows in the companion paper (DDdT Study Part 2; Cameron et al, 2016). American Academy of Audiology.

Reducing calibration parameters to increase insight in catchment organization and similarity

NASA Astrophysics Data System (ADS)

Skaugen, Thomas; Onof, Christian

2013-04-01

Ideally, hydrological models should be built from equations parameterised from observed catchment characteristics and data. This state of affairs may never be reached, but a governing principle in hydrological modelling should be to keep the number of calibration parameters to a minimum. A reduced number of parameters to be calibrated, while maintaining the accuracy and detail required by modern hydrological models, will reduce parameter and model structure uncertainty and improve model diagnostics. The dynamics of runoff for small catchments are derived from the distribution of distances from points in the catchments to the nearest stream in a catchment. This distribution is unique for each catchment and can be determined from a geographical information system (GIS). The distribution of distances, will, when a celerity of (subsurface) flow is introduced, provide a distribution of travel times, or a unit hydrograph (UH). For spatially varying levels of saturation deficit we have different celerities and, hence, different UHs. Runoff is derived from the super-positioning of the different UHs. This study shows how celerities can be estimated if we assume that recession events represent the superpositioned UH for different levels of saturation deficit. The performance of the DDD (Distance Distribution Dynamics) model is compared to that of the Swedish HBV model and is found to perform equally well for eight Norwegian catchments although the number of parameters to be calibrated in the module concerning soil moisture and runoff dynamics is reduced from 7 in the HBV model to 1 in the DDD model. It is also shown that the DDD model has a more realistic representation of the subsurface hydrology. The transparency of the DDD model makes model diagnostics more easy and experience with DDD shows that differences in model performance may be related to differences in catchment characteristics. More specifically, it appears that the hydrological dynamics of bogs have to be taken especially into account when modelling Norwegian catchments.

The systolic index: a noninvasive approach for the assessment of cardiac function: implications for patients with DDD and CRT devices.

PubMed

Chirife, Raul; Ruiz, G Aurora; Gayet, Enrique; Muratore, Claudio; Mazzetti, Héctor; Pellegrini, Alejandro; Tentori, M Cristina

2013-10-01

Our objective was to evaluate the systolic index (SI), the ratio between rate-corrected left ventricular ejection time (LVETc), and a preejection period surrogate (PEPsu), to assess cardiac function in patients with DDD and cardiac resynchronization therapy (CRT) pacemakers. LVETc and PEPsu were automatically measured from electrocardiogram and finger photoplethismography. Atrioventricular (AV) and mode switch (CRT to DDD) were used as hemodynamic challenges. Performance of SI, beat-by-beat systolic blood pressure (SBP), and Doppler aortic velocity/time integral (AoVTI) were compared in 36 patients, and SI's detection of CRT to DDD mode switch in nine patients, responders to CRT. AVs were changed from 30 ms to 250 ms (20 ms steps) at constant paced heart rate, alternating with a reference AV (RefAV), to reduce hemodynamic drift. The coefficient of variation (standard deviation/mean) of SI, SBP, and AoVTI during all RefAVs were used as error marker. The percentage detection of hemodynamic changes during AV transitions was a marker of sensitivity. Fifty-five patients (males 62%, age 69.6 ± 17) were studied. SI detected 441 of 544 transitions (81%) versus 361 (66%) of SBP (P = 0.005). Error during RefAVs was smaller for SI (3.4%) as compared to AoVTI (7.8%, P = 0.015) and to SBP (5.7%, P = 0.005). SIs correlated with AoVTI (R from 0.71 to 0.98, all P < 0.001). SI detected all CRT to DDD changes (P < 0.001). The noninvasive SI obtained with a simple, observer-independent hemodynamic assessment procedure has higher accuracy than SBP and AoVTI and better sensitivity than SBP. It detects mechanical resynchronization in CRT and allows programming a suitable AV delay. ©2013, The Authors. Journal compilation ©2013 Wiley Periodicals, Inc.

Survival After Rate-Responsive Programming in Patients With Cardiac Resynchronization Therapy-Defibrillator Implants Is Associated With a Novel Parameter: The Heart Rate Score.

PubMed

Olshansky, Brian; Richards, Mark; Sharma, Arjun; Wold, Nicholas; Jones, Paul; Perschbacher, David; Wilkoff, Bruce L

2016-08-01

Rate-responsive pacing (DDDR) versus nonrate-responsive pacing (DDD) has shown no survival benefit for patients undergoing cardiac resynchronization therapy defibrillator (CRT-D) implants. The heart rate score (HRSc), an indicator of heart rate variation, may predict survival. We hypothesized that high-risk HRSc CRT-D patients will have improved survival with DDDR versus DDD alone. All CRT-D patients in LATITUDE remote monitoring (2006-2011), programmed DDD, had HRSc calculated at first data upload after implant (median 1.4 months). Patients subsequently reprogrammed to DDDR 7.6 median months later were compared with a propensity-matched DDD group and followed for 21.4 median months by remote monitoring. Data were adjusted for age, sex, lower rate limit, percent atrial pacing, percent biventricular pacing, and implant year. The social security death index was used to identify deaths. Remote monitoring provided programming and histogram data. DDDR programming in CRT-D patients was associated with improved survival (adjusted hazard ratio =0.77; P<0.001). However, only those with baseline HRSc ≥70% (2308/6164) had improved HRSc with DDDR (from 88±9% to 78±15%; P<0.001) and improved survival (hazard ratio =0.74; P<0.001). Patients with a high baseline HRSc and significant improvement over time were more likely to survive (hazard ratio =0.63; P=0.006). For patients with HRSc <70%, DDDR reprogramming increased the HRSc from 46±11% to 50±15% (P<0.001); survival did not change. The HRSc did not change with DDD pacing over time. In CRT-D patients with HRSc ≥70%, DDDR reprogramming improved the HRSc and was associated with survival. Patients with lower HRSc had no change in survival with DDDR programming. © 2016 American Heart Association, Inc.

Return to Work After Diskogenic Fusion in Workers' Compensation Subjects.

PubMed

Anderson, Joshua T; Haas, Arnold R; Percy, Rick; Woods, Stephen T; Ahn, Uri M; Ahn, Nicholas U

2015-12-01

Lumbar fusion for degenerative disk disease (DDD) is associated with variable clinical outcomes. Patients with workers' compensation claims often have worse fusion outcomes than the general population. Few studies have evaluated the risk factors for poor outcomes within this clinically distinct population. The goal of this study was to identify preoperative predictors of return to work status after fusion for DDD in a workers' compensation setting. The authors used International Classification of Diseases, Ninth Revision (ICD-9), diagnosis and Current Procedural Terminology (CPT) procedural codes to identify 1037 subjects from the Ohio Bureau of Workers' Compensation database who underwent fusion for DDD between 1993 and 2013. Of these subjects, 23.2% (n=241) made a sustained return to work within 2 years after fusion. To identify preoperative predictors of postoperative return to work status, the authors used multivariate logistic regression analysis, adjusting for many important covariates. These included prolonged time out of work (P<.001; odds ratio [OR], 0.24), psychiatric history (P<.001; OR, 0.14), prolonged use of opioid analgesics (P<.001; OR, 0.46), male sex (P=.014; OR, 0.65), and legal representation (P=.042; OR, 0.67). The return to work rates associated with these risk factors were 10.4%, 2.0%, 11.9%, 21.1%, and 20.7%, respectively. Of the study subjects, 76.8% (n=796) did not return to work and had considerably worse postoperative outcomes, highlighted by chronic opioid dependence and high rates of failed back syndrome, additional surgery, and new psychiatric comorbidity. The low return to work rates and other generally poor outcomes reported in this study may indicate a more limited role for lumbar fusion among patients with DDD who have workers' compensation claims. More studies are needed to determine whether fusion for DDD can improve function and quality of life in these patients. Copyright 2015, SLACK Incorporated.

Safety and tolerability of the γ-secretase inhibitor avagacestat in a phase 2 study of mild to moderate Alzheimer disease.

PubMed

Coric, Vladimir; van Dyck, Christopher H; Salloway, Stephen; Andreasen, Niels; Brody, Mark; Richter, Ralph W; Soininen, Hilkka; Thein, Stephen; Shiovitz, Thomas; Pilcher, Gary; Colby, Susan; Rollin, Linda; Dockens, Randy; Pachai, Chahin; Portelius, Erik; Andreasson, Ulf; Blennow, Kaj; Soares, Holly; Albright, Charles; Feldman, Howard H; Berman, Robert M

2012-11-01

To assess the safety, tolerability, and pharmacokinetic and pharmacodynamic effects of the -secretase inhibitor avagacestat in patients with mild to moderate Alzheimer disease (AD). Randomized, double-blind, placebo-controlled,24-week phase 2 study. Global, multicenter trial. A total of 209 outpatients with mild to moderate AD were randomized into the double-blind treatment phase. The median age of the patients was 75 years,58.9% were APOE ε4 carriers, and baseline measures of disease severity were similar among groups. Avagacestat, 25, 50, 100, or 125 mg daily,or placebo administered orally daily. Safety and tolerability of avagacestat. Discontinuation rates for the 25-mg and 50-mg doses of avagacestat were comparable with placebo but were higher in the 100-mg and 125-mg dose groups.Trends for worsening cognition, as measured by change from baseline Alzheimer Disease Assessment Scale cognitive subscale score, were observed in the 100-mg and125-mg dose groups. Treatment-emergent serious adverse events were similar across placebo and treatment groups. The most common reason for discontinuation was adverse events, predominantly gastrointestinal anddermatologic. Other adverse events occurring more frequentlyin patients undergoing treatment included reversibleglycosuria (without associated serum glucose changes), nonmelanoma skin cancer, and asymptomaticmagnetic resonance imaging findings. Exploratory cerebrospinal fluid amyloid isoforms and tau biomarker analysis demonstrated dose-dependent but not statistically significant reductions in a small subset of patients. Avagacestat dosed at 25 and 50 mg daily was relatively well tolerated and had low discontinuation rates. The 100-mg and 125-mg dose arms were poorly tolerated with trends for cognitive worsening. Exploratory cerebrospinal fluid biomarker substudies provide preliminary support for -secretase target engagement,but additional studies are warranted to better characterize pharmacodynamic effects at the 25- and 50-mg doses.This study establishes an acceptable safety and tolerability dose range for future avagacestat studies in AD. clinicaltrials.gov Identifier: NCT00810147

A Comparison of Four Indices for Combining Distance and Dose Differences

DOE Office of Scientific and Technical Information (OSTI.GOV)

Thomas, Simon J., E-mail: simon.thomas@addenbrookes.nhs.uk; Cowley, Ian R.

2012-04-01

Purpose: When one is comparing two dose distributions, a number of methods have been published to combine dose difference and distance to agreement into a single measure. Some have been defined as pass/fail indices and some as numeric indices. We show that the pass/fail indices can all be used to derive numeric indices, and we compare the results of using these indices to evaluate one-dimensional (1D) and three-dimensional (3D) dose distributions, with the aim of selecting the most appropriate index for use in different circumstances. Methods and Materials: The indices compared are the gamma index, the kappa index, the indexmore » in International Commission on Radiation Units and Measurements Report 83, and a box index. Comparisons are made for 1D and 3D distributions. The 1D distribution is chosen to have a variety of dose gradients. The 3D distribution is taken from a clinical treatment plan. The effect of offsetting distributions by known distances and doses is studied. Results: The International Commission on Radiation Units and Measurements Report 83 index causes large discontinuities unless the dose gradient cutoff is set to equal the ratio of the dose tolerance to the distance tolerance. If it is so set, it returns identical results to the kappa index. Where the gradient is very high or very low, all the indices studied in this article give similar results for the same tolerance values. For moderate gradients, they differ, with the box index being the least strict, followed by the gamma index, and with the kappa index being the most strict. Conclusions: If the clinical tolerances are much greater than the uncertainties of the measuring system, the kappa index should be used, with tolerance values determined by the clinical tolerances. In cases where the uncertainties of the measuring system dominate, the box index will be best able to determine errors in the delivery system.« less

Safety, tolerability and pharmacokinetics of the histamine H3 receptor antagonist, ABT-288, in healthy young adults and elderly volunteers

PubMed Central

Othman, Ahmed A; Haig, George; Florian, Hana; Locke, Charles; Zhang, Jun; Dutta, Sandeep

2013-01-01

Aim The objective of this work was to characterize the safety, tolerability and pharmacokinetics of ABT-288, a highly selective histamine H3 receptor antagonist, in healthy young adults and elderly subjects following single and multiple dosing in a phase 1 setting. Methods Single doses (0.1, 0.3, 1, 3, 10, 20 and 40 mg ABT-288) and multiple doses (0.5, 1.5, 3 and 6 mg ABT-288 once-daily for 14 days) were evaluated in young adults and multiple doses (0.5, 1.5, 3 and 5 mg ABT-288 once-daily for 12 days) were evaluated in elderly subjects using randomized, double-blind, placebo-controlled, dose-escalating study designs. The effect of food on ABT-288 pharmacokinetics (5 mg single dose) was evaluated using an open label, randomized, crossover design. Results ABT-288 safety, tolerability and pharmacokinetics were comparable in young and elderly subjects. Single doses up to 40 mg and multiple doses up to 3 mg once-daily were generally safe and well tolerated. The most frequently reported adverse events were hot flush, headache, abnormal dreams, insomnia, nausea and dizziness. ABT-288 exposure (AUC) was dose-proportional over the evaluated dose ranges. The mean elimination half-life ranged from 40 to 61 h across dose groups. Steady state was achieved by day 10 of once-daily dosing with 3.4- to 4.2-fold accumulation. Food did not have a clinically meaningful effect on ABT-288 exposure. Conclusions Based on the above results, 1 and 3 mg once-daily doses of ABT-288 were advanced to phase 2 evaluation in Alzheimer's patients. PMID:23016924

Safety, tolerability and pharmacokinetics of the histamine H3 receptor antagonist, ABT-288, in healthy young adults and elderly volunteers.

PubMed

Othman, Ahmed A; Haig, George; Florian, Hana; Locke, Charles; Zhang, Jun; Dutta, Sandeep

2013-05-01

The objective of this work was to characterize the safety, tolerability and pharmacokinetics of ABT-288, a highly selective histamine H3 receptor antagonist, in healthy young adults and elderly subjects following single and multiple dosing in a phase 1 setting. Single doses (0.1, 0.3, 1, 3, 10, 20 and 40 mg ABT-288) and multiple doses (0.5, 1.5, 3 and 6 mg ABT-288 once-daily for 14 days) were evaluated in young adults and multiple doses (0.5, 1.5, 3 and 5 mg ABT-288 once-daily for 12 days) were evaluated in elderly subjects using randomized, double-blind, placebo-controlled, dose-escalating study designs. The effect of food on ABT-288 pharmacokinetics (5 mg single dose) was evaluated using an open label, randomized, crossover design. ABT-288 safety, tolerability and pharmacokinetics were comparable in young and elderly subjects. Single doses up to 40 mg and multiple doses up to 3 mg once-daily were generally safe and well tolerated. The most frequently reported adverse events were hot flush, headache, abnormal dreams, insomnia, nausea and dizziness. ABT-288 exposure (AUC) was dose-proportional over the evaluated dose ranges. The mean elimination half-life ranged from 40 to 61 h across dose groups. Steady state was achieved by day 10 of once-daily dosing with 3.4- to 4.2-fold accumulation. Food did not have a clinically meaningful effect on ABT-288 exposure. Based on the above results, 1 and 3 mg once-daily doses of ABT-288 were advanced to phase 2 evaluation in Alzheimer's patients. © 2012 Abbott Laboratories. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.

Orientation influence on grain size-effects in ultrafine-grained magnesium

DOE PAGES

Fan, Haidong; Aubry, Sylvie; Arsenlis, A.; ...

2014-11-08

The mechanical behavior of ultrafine-grained magnesium was studied by discrete dislocation dynamics (DDD) simulations. Our results show basal slip yields a strong size effect, while prismatic and pyramidal slips produce a weak one. We developed a new size-strength model that considers dislocation transmission across grain boundaries. Good agreement between this model, current DDD simulations and previous experiments is observed. These results reveal that the grain size effect depends on 3 factors: Peierls stress, dislocation source strength and grain boundary strength.

Maritime Mobile Force Protection (MMFP) Program

DTIC Science & Technology

2010-05-28

to draw or write on the screen.  Thin design has a starting weight of 4.65lbs.  Capture handwriting : scrawl onscreen with the included dockable...Will say “Past CPA” if CPA has already occurred. Range at CPA DDD Yards Range at Closest Point of Approach to HVU Closing Speed DDD knots Speed of...closing to HVU, if greater than or equal to zero. Will say “Opening” if the closing speed is less than zero. Data Source Radar, AIS, Correlated Source

Readily functionalized AAA-DDD triply hydrogen-bonded motifs.

PubMed

Tong, Feng; Linares-Mendez, Iamnica J; Han, Yi-Fei; Wisner, James A; Wang, Hong-Bo

2018-04-25

Herein we present a new, readily functionalized AAA-DDD hydrogen bond array. A novel AAA monomeric unit (3a-b) was obtained from a two-step synthetic procedure starting with 2-aminonicotinaldehyde via microwave radiation (overall yield of 52-66%). 1H NMR and fluorescence spectroscopy confirmed the complexation event with a calculated association constant of 1.57 × 107 M-1. Likewise, the usefulness of this triple hydrogen bond motif in supramolecular polymerization was demonstrated through viscosity measurements in a crosslinked supramolecular alternating copolymer.

Ascending-dose study of noribogaine in healthy volunteers: pharmacokinetics, pharmacodynamics, safety, and tolerability.

PubMed

Glue, Paul; Lockhart, Michelle; Lam, Fred; Hung, Noelyn; Hung, Cheung-Tak; Friedhoff, Lawrence

2015-02-01

Noribogaine is the active metabolite of the naturally occurring psychoactive substance ibogaine, and may help suppress withdrawal symptoms in opioid-dependent subjects. The objectives of this Phase I study were to assess the safety, tolerability, pharmacokinetic, and pharmacodynamic profiles of noribogaine. In this ascending single-dose, placebo-controlled, randomized, double-blind, parallel-group study in 36 healthy drug-free male volunteers, 4 cohorts (n = 9) received oral doses of 3, 10, 30, or 60 mg or matching placebo, with intensive safety and pharmacokinetic assessments out to 216 hours, along with pharmacodynamic assessments sensitive to the effects of mu-opioid agonists. Noribogaine was rapidly absorbed, with peak concentrations occurring 2-3 hours after oral dosing, and showed dose-linear increases of area under the concentration-time curve (AUC) and Cmax between 3 and 60 mg. The drug was slowly eliminated, with mean half-life estimates of 28-49 hours across dose groups. Apparent volume of distribution was high (mean 1417-3086 L across dose groups). No safety or tolerability issues were identified in any cohort. No mu-opioid agonist pharmacodynamic effects were noted in pupillometry or cold-pressor testing. Single oral doses of noribogaine 3-60 mg were safe and well tolerated in healthy volunteers. © 2014, The American College of Clinical Pharmacology.

Development of a Web-Based Clinical Decision Support System for Drug Prescription: Non-Interventional Naturalistic Description of the Antipsychotic Prescription Patterns in 4345 Outpatients and Future Applications.

PubMed

Berrouiguet, Sofian; Barrigón, Maria Luisa; Brandt, Sara A; Ovejero-García, Santiago; Álvarez-García, Raquel; Carballo, Juan Jose; Lenca, Philippe; Courtet, Philippe; Baca-García, Enrique

2016-01-01

The emergence of electronic prescribing devices with clinical decision support systems (CDSS) is able to significantly improve management pharmacological treatments. We developed a web application available on smartphones in order to help clinicians monitor prescription and further propose CDSS. A web application (www.MEmind.net) was developed to assess patients and collect data regarding gender, age, diagnosis and treatment. We analyzed antipsychotic prescriptions in 4345 patients attended in five Psychiatric Community Mental Health Centers from June 2014 to October 2014. The web-application reported average daily dose prescribed for antipsychotics, prescribed daily dose (PDD), and the PDD to defined daily dose (DDD) ratio. The MEmind web-application reported that antipsychotics were used in 1116 patients out of the total sample, mostly in 486 (44%) patients with schizophrenia related disorders but also in other diagnoses. Second generation antipsychotics (quetiapine, aripiprazole and long-acting paliperidone) were preferably employed. Low doses were more frequently used than high doses. Long acting paliperidone and ziprasidone however, were the only two antipsychotics used at excessive dosing. Antipsychotic polypharmacy was used in 287 (26%) patients with classic depot drugs, clotiapine, amisulpride and clozapine. In this study we describe the first step of the development of a web application that is able to make polypharmacy, high dose usage and off label usage of antipsychotics visible to clinicians. Current development of the MEmind web application may help to improve prescription security via momentary feedback of prescription and clinical decision support system.

Development of a Web-Based Clinical Decision Support System for Drug Prescription: Non-Interventional Naturalistic Description of the Antipsychotic Prescription Patterns in 4345 Outpatients and Future Applications

PubMed Central

Berrouiguet, Sofian; Barrigón, Maria Luisa; Brandt, Sara A.; Ovejero-García, Santiago; Álvarez-García, Raquel; Carballo, Juan Jose; Lenca, Philippe; Courtet, Philippe; Baca-García, Enrique

2016-01-01

Purpose The emergence of electronic prescribing devices with clinical decision support systems (CDSS) is able to significantly improve management pharmacological treatments. We developed a web application available on smartphones in order to help clinicians monitor prescription and further propose CDSS. Method A web application (www.MEmind.net) was developed to assess patients and collect data regarding gender, age, diagnosis and treatment. We analyzed antipsychotic prescriptions in 4345 patients attended in five Psychiatric Community Mental Health Centers from June 2014 to October 2014. The web-application reported average daily dose prescribed for antipsychotics, prescribed daily dose (PDD), and the PDD to defined daily dose (DDD) ratio. Results The MEmind web-application reported that antipsychotics were used in 1116 patients out of the total sample, mostly in 486 (44%) patients with schizophrenia related disorders but also in other diagnoses. Second generation antipsychotics (quetiapine, aripiprazole and long-acting paliperidone) were preferably employed. Low doses were more frequently used than high doses. Long acting paliperidone and ziprasidone however, were the only two antipsychotics used at excessive dosing. Antipsychotic polypharmacy was used in 287 (26%) patients with classic depot drugs, clotiapine, amisulpride and clozapine. Conclusions In this study we describe the first step of the development of a web application that is able to make polypharmacy, high dose usage and off label usage of antipsychotics visible to clinicians. Current development of the MEmind web application may help to improve prescription security via momentary feedback of prescription and clinical decision support system. PMID:27764107

Inability of populations of Callosobruchus maculatus to develop tolerance to exposures of acute gamma irradiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Brower, J.H.

1974-03-01

The reproductive capacity and resistance to an acute dose of gamma irradiation were determined for populations of Callosobruchus maculatus treated with substerilizing doses of irradiation each generation for 30 generations. Reproductive capacity was decreased by an ancestral history of irradiation, the reduction being positively correlated with both the size of dose per generation and the number of ancestral generations treated. Irradiation of the selected populations with an acute dose revealed no increase in tolerance, even after 30 generations. In general, the greater the amount of accumulated ancestral exposure to irradiation, the greater the sensitivity to further irradiation. The ability tomore » develop a tolerance to ionizing irradiation may not be a general phenomenon in insects. (auth)« less

Arthroplasty for cervical spondylotic myelopathy: similar results to patients with only radiculopathy at 3 years' follow-up.

PubMed

Fay, Li-Yu; Huang, Wen-Cheng; Wu, Jau-Ching; Chang, Hsuan-Kan; Tsai, Tzu-Yun; Ko, Chin-Chu; Tu, Tsung-Hsi; Wu, Ching-Lan; Cheng, Henrich

2014-09-01

Cervical arthroplasty has been accepted as a viable option for surgical management of cervical spondylosis or degenerative disc disease (DDD). The best candidates for cervical arthroplasty are young patients who have radiculopathy caused by herniated disc with competent facet joints. However, it remains uncertain whether arthroplasty is equally effective for patients who have cervical myelopathy caused by DDD. The aim of this study was to compare the outcomes of arthroplasty for patients with cervical spondylotic myelopathy (CSM) and patients with radiculopathy without CSM. A total of 151 consecutive cases involving patients with CSM or radiculopathy caused by DDD and who underwent one- or two-level cervical arthroplasty were included in this study. Clinical outcome evaluations and radiographic studies were reviewed. Clinical outcome measurements included the Visual Analog Scale (VAS) of neck and arm pain, Japanese Orthopaedic Association (JOA) scores, and the Neck Disability Index (NDI) in every patient. For patients with CSM, Nurick scores were recorded for evaluation of cervical myelopathy. Radiographic studies included lateral dynamic radiographs and CT for detection of the formation of heterotopic ossification . Of the 151 consecutive patients with cervical DDD, 125 (82.8%; 72 patients in the myelopathy group and 53 in the radiculopathy group) had at least 24 months of clinical and radiographic follow-up. The mean duration of follow-up in these patients was 36.4 months (range 24-56 months). There was no difference in sex distribution between the 2 groups. However, the mean age of the patients in the myelopathy group was approximately 6 years greater than that of the radiculopathy group (53.1 vs 47.2 years, p < 0.001). The mean operation time, mean estimated blood loss, and the percentage of patients prescribed perioperative analgesic agents were similar in both groups (p = 0.754, 0.652, and 0.113, respectively). There were significant improvements in VAS neck and arm pain, JOA scores, and NDI in both groups. Nurick scores in the myelopathy group also improved significantly after surgery. In radiographic evaluations, 92.5% of patients in the radiculopathy group and 95.8% of those in the radiculopathy group retained spinal motion (no significant difference). Evaluation of CT scans showed heterotopic ossification in 34 patients (47.2%) in the myelopathy group and 25 patients (47.1%) in the radiculopathy group (p = 0.995). At a mean of over 3 years postoperatively, no secondary surgery was reported in either group. The severity of myelopathy improves after cervical arthroplasty in patients with CSM caused by DDD. At 3-year follow-up, the clinical and radiographic outcomes of cervical arthroplasty in DDD patients with CSM are similar to those patients who have only cervical radiculopathy. Therefore, cervical arthroplasty is a viable option for patients with CSM caused by DDD who require anterior surgery. However, comparison with the standard surgical treatment of anterior cervical discectomy and fusion is necessary to corroborate the outcomes of arthroplasty for CSM.

Pharmacokinetics, safety and tolerability of mipomersen in healthy Japanese volunteers and comparison with Western subjects.

PubMed

Li, Zhaoyang; Hard, Marjie L; Andersen, Grit; Pabst, Günther; Wagener, Gilbert; Singh, Tejdip; Chin, Wai; Culm-Merdek, Kerry; Boltje, Ingrid; von Moltke, Lisa L

2014-04-01

To characterize the safety, tolerability, pharmacokinetics (PK) and dose proportionality of mipomersen after single subcutaneous (SC) administration to Japanese healthy subjects; and to compare the PK profiles of Japanese and Western subjects. 20 healthy first-generation Japanese male subjects were enrolled into one of three treatment cohorts (50, 100 and 200 mg SC) in a dose-escalation design. Within each cohort, subjects were randomized in a 4 : 1 ratio to receive mipomersen or placebo. Mipomersen was absorbed rapidly after SC administration; median tmax varied between 2 and 3 hours. After reaching peak levels, plasma concentrations of mipomersen decayed multiphasically with an initial distribution t1/2 in several hours and a terminal t1/2 of 261 - 393 hours. Mean Cmax increased in a dose-linear manner while all mean AUC from time 0 to different cut points increased slightly more than dose proportionally. Although mean terminal t1/2 varied in the dose range tested, it did not show dose-dependence. The PK profiles of mipomersen in Japanese subjects are similar to those observed in Western subjects. A single SC dose of 50 mg, 100 mg and 200 mg mipomersen was well tolerated by male Japanese subjects. Single SC doses of 50 - 200 mg were safe and well tolerated when administered to Japanese subjects. Comparison of PK between Japanese and Western subjects does not support any need for dose adjustment in Japanese population in future clinical development.

Clinical pharmacokinetics of Icotinib, an anti-cancer drug: evaluation of dose proportionality, food effect, and tolerability in healthy subjects.

PubMed

Liu, Dongyang; Jiang, Ji; Zhang, Li; Tan, Fenlai; Wang, Yingxiang; Zhang, Don; Hu, Pei

2014-04-01

Icotinib, an oral epidermal growth factor receptor tyrosine kinase inhibitor, has proved effectiveness in xenografted nude mice. Purpose of the present studies was to investigate tolerability and pharmacokinetics of Icotinib in healthy subjects for the first time, including dose proportionality, food effect, and tolerability. Two studies were conducted in total of 22 healthy subjects: a randomized, two-Latin-square crossover, dose proportional study (n = 12) and a randomized two-way crossover food-effect study (n = 10). Plasma concentration of Icotinib reached peak at a median Tmax of 0.75-3.5 h after single dose and then declined with a mean t1/2β of 6.02-7.83 h. Over the dose range of 100-600 mg, AUC values were proportional to dose and Cmax showed a slight saturation when dose increases. Only 0.2 % of the dose was excreted through kidney in unchanged Icotinib. After dosing 400 mg of Icotinib with high-fat and high-calorie meal, mean Cmax and AUC were significantly increased by 59 and 79 %, respectively. Three subjects experienced four adverse events (rash, increase in AST and ALT, and external injury). Rash and increased levels of AST and ALT were considered as drug-related. No serious adverse events were reported. The current work demonstrated that Icotinib was well tolerated in healthy male subjects (n = 22) over the dose range of 100-600 mg with or without food. Icotinib exposure, expressed in AUC, was proportionally increased with dose over the above dose range. Food intake significantly increased the absorption and exposure of Icotinib in healthy subjects.

Yohimbine use for physical enhancement and its potential toxicity.

PubMed

Cimolai, Nevio; Cimolai, Tomas

2011-12-01

Yohimbine is a naturally sourced pharmacological agent, which produces hyperadrenergic physiological effects. In excess doses, it may typically cause agitation, anxiety, hypertension, and tachycardia. There is no conclusive evidence for this drug to be of benefit in bodybuilding, exercise tolerance, physical performance, or desirable alterations of body mass. Although tolerated generally well in low doses, the potential for dose-dependent toxicity should be recognized.

The First Report of KRT5 Mutation Underlying Acantholytic Dowling-Degos Disease with Mottled Hypopigmentation in an Indian Family

PubMed Central

Verma, Shyam; Pasternack, Sandra M.; Rütten, Arno; Ruzicka, Thomas; Betz, Regina C.; Hanneken, Sandra

2014-01-01

Galli Galli disease (GGD) is the name given to a rare form of acantholytic Dowling-Degos disease. (DDD), the latter itself being a rare condition. We believe we are describing for the first time in Indian dermatologic literature a case of GGD in a family where 25 persons have DDD and have been able to document a KRT5 mutation in four members of the family. Whereas reticulate pigmentation is a hallmark of DDD there are rare reports of mottled pigmentation with multiple asymptomatic hypopigmented macules scattered diffusely along with the pigmentation. All the cases described here show a mottled pigmentation comprising hypo and hyperpigmented asymptomatic macules. After the clinical diagnosis was made by one of the authors (SV) in India, the German authors repeated histological examination and successfully demonstrated a heterozygous nonsense mutation, c.C10T (p.Gln4X), in exon 1 of the KRT5 gene, from various centers in Munich, Bonn, Dusseldorf and Friedrichschafen in Germany. PMID:25284854

[Generic drugs and the consumption trends of antihypertensives in Morocco].

PubMed

Berrada El Azizi, Ghizlane; Ahid, Samir; Ghanname, Imane; Ghannam, Imane; Belaiche, Abdelmajid; Hassar, Mohammed; Cherrah, Yahia

2013-01-01

To evaluate the evolution of consumption of antihypertensive drugs generic among 1991-2010, to assess the impacts after the institution of Mandatory Health Insurance and the marketing of generic drugs. We used sales data from the Moroccan subsidiary of IMS Health Intercontinental Marketing Service. Consumption of generic antihypertensive drugs increased from 0.08 to 10.65 DDD/1 000 inhabitants/day between 1991 and 2010. In 2010, generic of the calcium channel blockers (CCBs) represented 4.08 DDD/1 000 inhabitants/day (82.09%), followed by angiotensin converting enzyme inhibitors (ACEI) by 2.40 DDD/1 000 inhabitants/day (48.29%). The generics market of CCBs is the most dominant and represented in 2010, 79.21% in volume and 62.58% in value. In developing countries like Morocco, the generic drug is a key element for access to treatment especially for the poor population. © 2013 Société Française de Pharmacologie et de Thérapeutique.

A hierarchical dislocation-grain boundary interaction model based on 3D discrete dislocation dynamics and molecular dynamics

NASA Astrophysics Data System (ADS)

Gao, Yuan; Zhuang, Zhuo; You, XiaoChuan

2011-04-01

We develop a new hierarchical dislocation-grain boundary (GB) interaction model to predict the mechanical behavior of polycrystalline metals at micro and submicro scales by coupling 3D Discrete Dislocation Dynamics (DDD) simulation with the Molecular Dynamics (MD) simulation. At the microscales, the DDD simulations are responsible for capturing the evolution of dislocation structures; at the nanoscales, the MD simulations are responsible for obtaining the GB energy and ISF energy which are then transferred hierarchically to the DDD level. In the present model, four kinds of dislocation-GB interactions, i.e. transmission, absorption, re-emission and reflection, are all considered. By this methodology, the compression of a Cu micro-sized bi-crystal pillar is studied. We investigate the characteristic mechanical behavior of the bi-crystal compared with that of the single-crystal. Moreover, the comparison between the present penetrable model of GB and the conventional impenetrable model also shows the accuracy and efficiency of the present model.

Single-dose lubiprostone along with split-dose PEG solution without dietary restrictions for bowel cleansing prior to colonoscopy: a randomized, double-blind, placebo-controlled trial.

PubMed

Stengel, Joel Z; Jones, David P

2008-09-01

Proper colonic cleansing prior to colonoscopy is paramount to ensuring complete mucosal visualization and polyp identification. In a double-blind fashion, we compared single-dose lubiprostone (24 microg) versus placebo pretreatment prior to a split-dose polyethylene glycol electrolyte (PEG-E) bowel preparation without dietary restriction to determine the efficacy, safety, and patient tolerability. Two hundred patients referred for outpatient colorectal cancer screening were randomized to receive a single-dose of unlabeled lubiprostone (24 microg) or placebo prior to a split-dose PEG-E bowel preparation without dietary restriction. The patients were surveyed prior to the colonoscopy on the tolerability of the bowel preparation, and any adverse events were recorded. The cleanliness of the colon was graded by the endoscopist during the procedure utilizing the Ottawa bowel preparation scale. One hundred ninety-one patients completed the study (95%). Split-dose PEG-E with lubiprostone pretreatment was found to be more effective at bowel cleansing in each segment of the colon when compared with split-dose PEG-E with placebo (P < 0.001). Patients enrolled in the lubiprostone treatment arm rated the overall experience as more tolerable (P 0.003) and complained of less abdominal bloating (P 0.049). No differences were observed between the groups for treatment-emergent side effects or adverse events (P > 0.05). Single-dose lubiprostone prior to split-dose PEG-E without dietary restriction significantly improves colonic mucosa visualization during colonoscopy and is well tolerated by patients.

75 FR 53586 - Bifenazate; Pesticide Tolerances

Federal Register 2010, 2011, 2012, 2013, 2014

2010-09-01

... characterized and were seen at dose(s) that produce evidence of overt systemic toxicity. These effects included... system, and these findings may be due to secondary effect of overt systemic toxicity. Further, there is... Adequate enforcement methodology is available to enforce the tolerance expression. High-performance liquid...

An extended 3D discrete-continuous model and its application on single- and bi-crystal micropillars

NASA Astrophysics Data System (ADS)

Huang, Minsheng; Liang, Shuang; Li, Zhenhuan

2017-04-01

A 3D discrete-continuous model (3D DCM), which couples the 3D discrete dislocation dynamics (3D DDD) and finite element method (FEM), is extended in this study. New schemes for two key information transfers between DDD and FEM, i.e. plastic-strain distribution from DDD to FEM and stress transfer from FEM to DDD, are suggested. The plastic strain induced by moving dislocation segments is distributed to an elementary spheroid (ellipsoid or sphere) via a specific new distribution function. The influence of various interfaces (such as free surfaces and grain boundaries (GBs)) on the plastic-strain distribution is specially considered. By these treatments, the deformation fields can be solved accurately even for dislocations on slip planes severely inclined to the FE mesh, with no spurious stress concentration points produced. In addition, a stress correction by singular and non-singular theoretical solutions within a cut-off sphere is introduced to calculate the stress on the dislocations accurately. By these schemes, the present DCM becomes less sensitive to the FE mesh and more numerically efficient, which can also consider the interaction between neighboring dislocations appropriately even though they reside in the same FE mesh. Furthermore, the present DCM has been employed to model the compression of single-crystal and bi-crystal micropillars with rigid and dislocation-absorbed GBs. The influence of internal GB on the jerky stress-strain response and deformation mode is studied in detail to shed more light on these important micro-plastic problems.

Organochlorine pesticide residues in bed sediments of the San Joaquin River, California

USGS Publications Warehouse

Gilliom, Robert J.; Clifton, Daphne G.

1990-01-01

Bed sediments of the San Joaquin River and its tributaries were sampled during October 7–11, 1985, and analyzed for organochiorine pesticide residues in order to determine their areal distribution and to evaluate and prioritize needs for further study. Residues of DDD, DDE, DDT, and dieldrin are widespread in the fine-grained bed sediments of the San Joaquin River and its tributaries despite little or no use of these pesticides for more than 15 years. The San Joaquin River has among the highest bed-sediment concentrations of DDD, DDE, DDT, and dieldrin residues of major rivers in the United States. Concentrations of all four pesticides were correlated with each other and with the amount of organic carbon and fine-grained particles in the bed sediments. The highest concentrations occurred in bed sediments of westside tributary streams. Potential tributary loads of DDD, DDE, DDT, and dieldrin to the San Joaquin River were computed from bed-sediment concentrations and data on streamfiow and suspended-sediment concentration in order to identify the general magnitude of differences between streams and to determine study priorities. The estimated loads indicate that the most important sources of residues during the study period were Salt Slough because of a high load of fine sediment, and Newman Wasteway, Orestimba Creek, and Hospital Creek because of high bed-sediment concentrations. Generally, the highest estimated loads of DDD, DDE, DDT, and dieldrin were in Orestimba and Hospital Creeks.

The two faces of hydrogen-bond strength on triple AAA-DDD arrays.

PubMed

Lopez, Alfredo Henrique Duarte; Caramori, Giovanni Finoto; Coimbra, Daniel Fernando; Parreira, Renato Luis Tame; da Silva, Éder Henrique

2013-12-02

Systems that are connected through multiple hydrogen bonds are the cornerstone of molecular recognition processes in biology, and they are increasingly being employed in supramolecular chemistry, specifically in molecular self-assembly processes. For this reason, the effects of different substituents (NO2, CN, F, Cl, Br, OCH3 and NH2) on the electronic structure, and consequently on the magnitude of hydrogen bonds in triple AAA-DDD arrays (A=acceptor, D=donor) were evaluated in the light of topological [electron localization function (ELF) and quantum theory of atoms in molecules (QTAIM)], energetic [Su-Li energy-decomposition analysis (EDA) and natural bond orbital analysis (NBO)], and geometrical analysis. The results based on local H-bond descriptors (geometries, QTAIM, ELF, and NBO) indicate that substitutions with electron-withdrawing groups on the AAA module tend to strengthen, whereas electron-donating substituents tend to weaken the covalent character of the AAA-DDD intermolecular H-bonds, and also indicate that the magnitude of the effect is dependent on the position of substitution. In contrast, Su-Li EDA results show an opposite behavior when compared to local H-bond descriptors, indicating that electron-donating substituents tend to increase the magnitude of H-bonds in AAA-DDD arrays, and thus suggesting that the use of local H-bond descriptors describes the nature of H bonds only partially, not providing enough insight about the strength of such H bonds. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Black Carbon Facilitated Dechlorination of DDT and its Metabolites by Sulfide.

PubMed

Ding, Kai; Xu, Wenqing

2016-12-06

1,1-trichloro-2,2-di(4-chlorophenyl)ethane (DDT) and its metabolites 1,1-dichloro-2,2-bis(4-chlorophenyl)ethane (DDD) and 1,1-dichloro-2,2-bis(4-chlorophenyl)ethylene (DDE), are often detected in soils and sediments containing high concentrations of black carbon. Sulfide (∼5 mM) from biological sulfate reduction often coexists with black carbon and serves as both a strong reductant and a nucleophile for the abiotic transformation of contaminants. In this study, we found that the abiotic transformation of DDT, DDD, and DDE (collectively referred to as DDX) require both sulfide and black carbon. 89.3 ± 1.8% of DDT, 63.2 ± 1.9% of DDD, and 50.9 ± 1.6% of DDE were degraded by sulfide (5 mM) in the presence of graphite powder (21 g/L) after 28 days at pH 7. Chloride was a product of DDX degradation. To better understand the reaction pathways, electrochemical cells and batch reactor experiments with sulfide-pretreated graphite powder were used to differentiate the involvement of black carbon materials in DDX transformation by sulfide. Our results suggest that DDT and DDD are transformed by surface intermediates formed from the reaction between sulfide and black carbon, while DDE degradation involves reductive dechlorination. This research lays the groundwork for developing an alternative in situ remediation technique for rapidly decontaminating soils and sediments to lower toxic products under environmentally relevant conditions.

Safety, tolerability, and pharmacokinetics of sumatriptan suppositories following single and multiple doses in healthy volunteers.

PubMed

Kunka, R L; Hussey, E K; Shaw, S; Warner, P; Aubert, B; Richard, I; Fowler, P A; Pakes, G E

1997-06-01

A suppository formulation of the 5HT1 agonist sumatriptan could prove an important therapeutic option in migraine patients who dislike or poorly tolerate injectable therapy and where oral tablet administration is unsuitable because of severe migraine-related vomiting. Two independent double-blind, randomized clinical studies were conducted to evaluate the safety, tolerability and pharmacokinetics of sumatriptan suppositories following ascending single doses (four different dose levels) and multiple doses. In the four-period, crossover, single-dose study, 24 healthy male subjects were randomized to receive a suppository containing 12.5, 25, 50, or 100 mg on separate occasions 3-14 days apart. The suppositories were generally well tolerated; transient asthenia, drowsiness, and headache were the most frequently reported adverse events, and these were not dose-related. Peak plasma concentrations (Cmax) of sumatriptan were proportional to dose from 25 to 100 mg; area under the plasma concentration-time curve (AUC infinity) values were proportional to dose except at the highest doses, when they were greater than those predicted from lower doses. For all doses, the tmax of sumatriptan occurred within 2.5 h, and the t1/2 was approximately 2 h. In the two-period, placebo-controlled, crossover, repeat-dose study, 12 healthy adult male subjects were randomized to receive either a 50-mg sumatriptan suppository or placebo suppository, administered rectally twice a day, for 11 doses (5 1/2 days). Adverse events were no more frequent with sumatriptan than with placebo, and stool guaiac, rectal examinations, and physical examinations remained normal. No significant differences were noted between Day 1 and Day 6 values in the AUC, Cmax, time of peak serum concentration (tmax), elimination half-life (t 1/2), fraction of the dose excreted in the urine (fe), or renal clearance (Clr) of sumatriptan or its pharmacologically inactive indole acetic acid metabolite. Serum metabolite concentrations were two to three-fold higher than corresponding sumatriptan concentrations. No clinically significant accumulation of sumatriptan or its metabolite occurred. Overall, these studies show that sumatriptan administration via a suppository formulation is well tolerated, allows rapid absorption of sumatriptan, results in sumatriptan Cmax values that are proportional to dose from 25 to 100 mg, and is not associated with accumulation of sumatriptan or its metabolite.

Feasibility of dual-chamber (DDD) pacing via a single-pass (VDD) pacing lead employing a floating atrial ring (dipole): case series, future considerations, and refinements.

PubMed

Kassotis, John; Voigt, Louis; Mongwa, Mbu; Reddy, C V R

2005-01-01

The objective of this study was to assess the feasibility of DDD pacing from a standard single-pass VDD pacemaker system. Over the past 2 decades significant advances have been made in the development of single-pass VDD pacing systems. These have been shown in long-term prospective studies to effectively preserve atrioventricular (AV)synchrony in patients with AV block and normal sinus node function. What remains problematic is the development of a single-pass pacing system capable of DDD pacing. Such a lead configuration would be useful in those patients with peripheral venous anomalies and in younger patients with congenital anomalies, which may require lead revisions in the future. In addition, with the increased use of resynchronization (biventricular pacing) therapy, the availability of a reliable single-pass lead will minimize operative time, enhance patient safety, and minimize the amount of hardware within the heart. The feasibility of DDD pacing via a Medtronic Capsure VDD-2 (Model #5038) pacing lead was evaluated. Twenty patients who presented with AV block and normal sinus node function were recruited for this study. Atrial pacing thresholds and sensitivities were assessed intraoperatively in the supine position with various respiratory maneuvers. Five patients who agreed to participate in long-term follow-up received a dual-chamber generator and were evaluated periodically over a 12-month period. Mean atrial sensitivity was 2.35 +/- 0.83 mV at the time of implantation. Effective atrial stimulation was possible in all patients at the time of implantation (mean stimulation threshold 3.08 +/- 1.04 V at 0.5 ms [bipolar], 3.34 +/- 0.95 V at 0.5 ms [unipolar]). Five of the 20 patients received a Kappa KDR701 generator, and atrial electrical properties were followed up over a 1-year period. There was no significant change in atrial pacing threshold or incidence of phrenic nerve stimulation over the 1-year follow-up. A standard single-pass VDD pacing lead system was capable of DDD pacing intraoperatively and during long-term follow-up. Despite higher than usual thresholds via the atrial dipole, pacemaker telemetry revealed < 10% use of atrial pacing dipole over a 12-month period, which would minimally deplete the pacemaker's battery. In addition, the telemetry confirmed appropriate sensing and pacing of the atrial dipole throughout the study period. At this time such systems can serve as back-up DDD pacing systems with further refinements required to optimize atrial thresholds in all patients.

Haloperidol Disrupts Opioid-Antinociceptive Tolerance and Physical Dependence

PubMed Central

Yang, Cheng; Chen, Yan; Tang, Lei

2011-01-01

Previous studies from our laboratory and others have implicated a critical role of Ca2+/calmodulin-dependent protein kinase II (CaMKII) in opioid tolerance and dependence. Translational research targeting the CaMKII pathway is challenging, if not impossible, because of a lack of selective inhibitors. We discovered in a preliminary study that haloperidol, a butyrophenone antipsychotic drug, inhibited CaMKII, which led us to hypothesize that haloperidol can attenuate opioid tolerance and dependence by inhibiting CaMKII. The hypothesis was tested in two rodent models of opioid tolerance and dependence. Pretreatment with haloperidol (0.2–1.0 mg/kg i.p.) prevented the development of morphine tolerance and dependence in a dose-dependent manner. Short-term treatment with haloperidol (0.06–0.60 mg/kg i.p.) dose-dependently reversed the established morphine-antinociceptive tolerance and physical dependence. Correlating with behavioral effects, pretreatment or short-term treatment with haloperidol dose-dependently inhibited morphine-induced up-regulation of supraspinal and spinal CaMKIIα activity. Moreover, haloperidol given orally was also effective in attenuating morphine-induced CaMKIIα activity, antinociceptive tolerance, and physical dependence. Taken together, these data suggest that haloperidol attenuates opioid tolerance and dependence by suppressing CaMKII activity. Because haloperidol is a clinically used drug that can be taken orally, we propose that the drug may be of use in attenuating opioid tolerance and dependence. PMID:21436292

Utilization of triptans in Sweden; analyses of over the counter and prescription sales.

PubMed

von Euler, Mia; Keshani, Sara; Baatz, Katarina; Wettermark, Bjorn

2014-12-01

To enable easier access to triptans, the drug of choice for moderate to severe migraine, some countries have made triptans available without prescription, that is, over the counter (OTC). Concern has been raised about this. The aim of this study was to describe the utilization pattern of triptans in Sweden before and after the OTC switch. Wholesaler and aggregated sales data from all Swedish pharmacies 1991 to 2011 and patient identity data on dispensed prescriptions 2007 and 2011 from the Swedish National Prescribed Drug Register were used to investigate volume and expenditure of triptans. The databases contain complete data for all drugs sold in Sweden or dispensed to all Swedish inhabitants (9.5 million in 2012). Volumes of triptans have increased to 7.0 million defined daily doses (DDD) on prescriptions and 0.7 million DDDs OTC in 2011. Prescriptions were dispensed to 10.0 and 10.1 per 1000 inhabitants in 2007 and 2011, respectively. Although half of those dispensed triptans in 2007 were not in 2011, the incidence remained stable at 2.8 patients per thousand person-years. In 2011, the 10% of the heaviest users accounted for 44% and 48% of dispensed triptans in women and men, respectively. Triptans OTC and the volumes dispensed on prescription have increased as has the DDD per patient purchasing triptans on prescription. However, the number of patient's dispensed triptans on prescription has remained stable. A concern is that almost half of prescribed triptans are purchased by 10% of the users. Copyright © 2014 John Wiley & Sons, Ltd.

Lifetime use of psychiatric medications and cognition at 43years of age in schizophrenia in the Northern Finland Birth Cohort 1966.

PubMed

Hulkko, A P; Murray, G K; Moilanen, J; Haapea, M; Rannikko, I; Jones, P B; Barnett, J H; Huhtaniska, S; Isohanni, M K; Koponen, H; Jääskeläinen, E; Miettunen, J

2017-09-01

Higher lifetime antipsychotic exposure has been associated with poorer cognition in schizophrenia. The cognitive effects of adjunctive psychiatric medications and lifetime trends of antipsychotic use remain largely unclear. We aimed to study how lifetime and current benzodiazepine and antidepressant medications, lifetime trends of antipsychotic use and antipsychotic polypharmacy are associated with cognitive performance in midlife schizophrenia. Sixty participants with DSM-IV schizophrenia from the Northern Finland Birth Cohort 1966 were examined at 43years of age with an extensive cognitive test battery. Cumulative lifetime and current use of psychiatric medications were collected from medical records and interviews. The associations between medication and principal component analysis-based cognitive composite score were analysed using linear regression. Lifetime cumulative DDD years of benzodiazepine and antidepressant medications were not significantly associated with global cognition. Being without antipsychotic medication (for minimum 11months) before the cognitive examination was associated with better cognitive performance (P=0.007) and higher lifetime cumulative DDD years of antipsychotics with poorer cognition (P=0.020), when adjusted for gender, onset age and lifetime hospital treatment days. Other lifetime trends of antipsychotic use, such as a long antipsychotic-free period earlier in the treatment history, and antipsychotic polypharmacy, were not significantly associated with cognition. Based on these naturalistic data, low exposure to adjunctive benzodiazepine and antidepressant medications does not seem to affect cognition nor explain the possible negative effects of high dose long-term antipsychotic medication on cognition in schizophrenia. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Epidemiology of psychotropic medication use: comparison of sales, prescriptions and survey data in Iceland.

PubMed

Tómasson, Kristinn; Tómasson, Helgi; Zoëga, Tómas; Sigfússon, Eggert; Helgason, Tómas

2007-01-01

Public health issues, medical and socio-demographics, related to use of psychotropic medications and to increasing sale of antidepressants and hypnotics need to be explored. The aim of this study was to investigate the use of antidepressants, tranquillizers and sedatives nationally and its connection with health and demographic factors, by comparing: 1) sales data and 2) prescription data for outpatients with 3) self-reported use of a random sample of the population aged 18-75 years. In 2001, the sales of psychopharmaca was 168.8 daily defined doses (DDD)/1000/day, thereof 46.6% were antidepressants mainly for outpatients; one-third of hypnotics and tranquillizers were used for inpatients; 134.2 DDD/1000/day were filled by outpatients. Almost 20% of the respondents in the survey had used one or more of these drugs for some time during the preceding 12 months. Treatment adherence for antidepressants was 56%, lower for women than men. The probability of psychotropic drug use for mental complaints is 52% when controlled for other covariates. Any observed gender difference in the community survey is related to differences in the covariates, e.g. women are more likely to seek a doctor than men. The age effect on self-reported use in the community survey is related to hypnotics. The use of psychotropic medicaments is primarily driven by mental health complaints, but not by gender or age, except the use of hypnotics, which increases with age. The difference between self-reported use and prescriptions filled may reflect compliance problems in psychiatric treatment.

Introducing an antibiotic stewardship program in a pediatric center in China.

PubMed

Zhang, Zhi-Gang; Chen, Fei; Chen, Jian-Zhong

2018-06-01

This study aimed to investigate the effect of antibiotic stewardship programs (ASP) on reducing antimicrobial resistance rate, antibiotics consumption and multi-drug resistance bacterial infections in the pediatric patients. This study was carried out in the Pediatric Center of a tertiary hospital of Shandong Province, China. The study duration was separated into two periods according to introduction of ASP (began from April 2011). Before intervention: from April 2009 to March 2011; after intervention: from April 2012 to March 2014. The consumption of antibiotics, defined daily dose (DDD), isolation of multidrug-resistant organisms (MDRO) and resistance rate of antibiotics were analyzed and compared between the two study periods. Total antibiotics consumption (DDDs) reduced from 56,725 in 2011 to 31,380 in 2014; antibiotic use density (AUD) reduced from 93.8 to 43.5; mean (± SD) antibiotic costs per patient (per quarter) decreased from 637 (± 29) RMB to 462 (± 49) RMB; and the mean total drug consumption (g)/DDD (DDDs) for inpatients decreased from 90.4 (± 3.3) to 56.4 (± 9.5). Multidrug-resistant microorganisms isolation reduced significantly from 463 (20.0) to 216 (6.9%). Resistance rate of general spectrum antibiotics reduced remarkably after intervention. The proportion of patients colonized or infected with Carbapenems-resistant Acinetobacter baumannii was correlated with DDDs of carbapenem. Implementation of ASP leads to reduced medical expense, decrease of improper and abuse of antibiotics, and reduced antibiotics resistance rate and MDRO isolation. Continuous efforts to improve antibiotic use are required.

[Surveillance of healthcare associated infections, bacterial resistance and antibiotic consumption in high-complexity hospitals in Colombia, 2011].

PubMed

Villalobos, Andrea Patricia; Barrero, Liliana Isabel; Rivera, Sandra Milena; Ovalle, María Victoria; Valera, Danik

2014-04-01

Preventing healthcare associated infections, especially for resistant microorganisms, is a priority. In Colombia, the surveillance of such events was started through a national pilot study. To describe the epidemiology of device-associated infections, bacterial resistance and antibiotic consumption patterns in institutions with intensive care units (ICU), 2011. Descriptive observational study in 10 health institutions from three Colombian provinces: Antioquia, Valle del Cauca, and Bogotá. Surveillance protocols were designed and implemented by trained health professionals in each hospital. A web tool was designed for data reporting and analysis. Infection rates, device-use percentages and antibiotics defined daily dose (DDD) were calculated. Bacterial resistance phenotypes and profiles were reported and analyzed using Whonet 5.6. The most common event was bloodstream infection (rate > 4.8/1000 catheter-days) followed by ventilator-associated pneumonia (VAP) and catheter-related urinary tract infection, showing a wide variability among institutions. A high consumption of meropenem in the ICU (DDD 22.5/100 beds-day) was observed, as well as a high carbapenem resistance (> 11.6%) and a high frequency of third generation cephalosporins resistance (> 25.6%) in Enterobacteriaceae in ICUs and hospitalization wards. The percentage of methicillin-resistant Staphylococcus aureus was higher in hospitalization wards (34.3%). This is the first experience in measuring these events in Colombia. It is necessary to implement a national surveillance system aimed at guiding governmental and institutional actions oriented to infection prevention and control, to resistance management and to the promotion of antibiotics rational use, along with a follow-up and monitoring process.

Overdosing of benzodiazepines/Z-drugs and falls in older adults: Costs for the health system.

PubMed

Díaz-Gutiérrez, María José; Cengotitabengoa, Mónica Martínez; Bermúdez-Ampudia, Cristina; García, Sainza; López, Purificación; Martínez-Cengotitabengoa, Mayte; González-Pinto, Ana

2018-05-08

Benzodiazepines and Z drugs (BZD/Z drugs) are commonly used for the treatment of insomnia and anxiety in older adults for long periods of time. Given the physiological and metabolic characteristics of this group of patients, they are more prone to the adverse effects of these drugs which include falls. The recommendations for use of BZD/Z drugs include the need to adjust the dose and select those with a short half-life, to avoid adverse events, which as well as potentially affecting patient outcome, increase healthcare costs. In this study, we have evaluated the hospital-related costs associated with falls in older adults who use BZD/Z drugs at doses higher than recommended for this age group. We conducted a cross-sectional observational study assessing the BZD/Z drug prescriptions of older adults attending the emergency department after a fall. Cost analysis was performed for cases in which the prescriptions exceeded the maximum recommended dose for this age group. A total of 40.6% of the prescriptions recorded were higher than the defined daily dose in older adults (DDD olderadults ). Of the 57 patients who used BZD/Z drugs at higher-than-recommended doses, 53 experienced trauma and 33 required hospitalisation. The costs associated with emergency department services, tests performed and hospitalisation amounted to €1850/patient. Appropriate dosage of BZD/Z drugs in older adults could reduce both patient suffering and costs for the health system. Copyright © 2017. Published by Elsevier Inc.

Intravenous Single-Dose Toxicity of Redaporfin-Based Photodynamic Therapy in Rodents

PubMed Central

Rocha, Luis B.; Schaberle, Fábio; Dąbrowski, Janusz M.; Simões, Sérgio; Arnaut, Luis G.

2015-01-01

We assessed the tolerability and safety in rodents of a single intravenous (i.v.) dose of redaporfin, a novel photosensitizer for Photodynamic Therapy (PDT) of cancer. Two approaches were used to evaluate acute toxicity: (i) a dose escalation study in BALB/c mice to evaluate the maximum tolerated dose of redaporfin; and (ii) a safety toxicology study in Wistar rats, of a single dose of redaporfin, with or without illumination, to evaluate possible signs of systemic toxicity. Redaporfin formulation was well tolerated by mice, with no signs of adverse reactions up to 75 mg/kg. In rats, there were no relevant changes, except for a significant, but transient, increase in the blood serum markers for hepatic function and muscle integrity, and also on neutrophil counts, observed after the application of light. The overall results showed that redaporfin-PDT is very well tolerated. No abnormalities were observed, including reactions at the injection site or skin phototoxicity, although the animals were maintained in normal indoor lighting. Redaporfin also showed a high efficacy in the treatment of male BALB/c mice with subcutaneously implanted colon (CT26) tumours. Vascular-PDT with 1.5 mg/kg redaporfin and a light dose of 74 J/cm2 led to the complete tumour regression in 83% of the mice. PMID:26670231

Phase I study on the pharmacokinetics and tolerance of ZT-1, a prodrug of huperzine A, for the treatment of Alzheimer's disease

PubMed Central

Jia, Jing-ying; Zhao, Qian-hua; Liu, Yun; Gui, Yu-zhou; Liu, Gang-yi; Zhu, Da-yuan; Yu, Chen; Hong, Zhen

2013-01-01

Aim: Huperzine A isolated from the Chinese herb Huperzia serrata (Thunb) Trev is a novel reversible and selective AChE inhibitor. The aim of this study was to evaluate the pharmacokinetics and tolerance of single and multiple doses of ZT-1, a novel analogue of huperzine A, in healthy Chinese subjects. Methods: This was a double-blinded, placebo-controlled, randomized, single- and multiple-dose study. For the single-dose study, 9 subjects were randomly divided into 3 groups receiving ZT-1 (0.5, 0.75 or 1 mg, po) according to a Three-way Latin Square Design. For the multiple-dose study, 9 subjects receiving ZT-1 (0.75 mg/d, po) for 8 consecutive days. In the tolerance study, 40 subjects were randomly divided into 5 groups receiving a single dose of ZT-1 (0.5, 0.75, 1, 1.25 or 1.5 mg, po). Plasma and urine concentrations of ZT-1 and Hup A were determined using LC-MS/MS. Pharmacokinetic parameters, including Cmax, AUC0–72 h and AUC0–∞ were calculated. Tolerance assessments were conducted throughout the study. Results: ZT-1 was rapidly absorbed and converted into huperzine A, thus the plasma and urine concentrations of ZT-1 were below the limit of quantification (<0.05 ng/mL). After single-dose administration of ZT-1, the mean tmax of huperzine A was 0.76–0.82 h; the AUC0–72 h and Cmax of huperzine A showed approximately dose-proportional increase over the dose range of 0.5–1 mg. After the multiple-dose administration of ZT-1, a steady-state level of huperzine A was achieved within 2 d. No serious adverse events were observed. Conclusion: ZT-1 is a pro-drug that is rapidly absorbed and converted into huperzine A, and ZT-1 is well tolerated in healthy Chinese volunteers. PMID:23624756

Tolerance to effects of high-dose oral δ9-tetrahydrocannabinol and plasma cannabinoid concentrations in male daily cannabis smokers.

PubMed

Gorelick, David A; Goodwin, Robert S; Schwilke, Eugene; Schwope, David M; Darwin, William D; Kelly, Deanna L; McMahon, Robert P; Liu, Fang; Ortemann-Renon, Catherine; Bonnet, Denis; Huestis, Marilyn A

2013-01-01

Oral cannabinoids are taken for medicinal or recreational purposes, yet little is known about tolerance to their effects after high-dose extended exposure. The development of tolerance to effects of around-the-clock oral synthetic Δ9-tetrahydrocannabinol (THC) (20 mg every 3.5-6 h) was evaluated in 13 healthy male daily cannabis smokers residing on a secure research unit: 40 mg on Day 1; 100 mg on Days 2-4; 120 mg on Days 5-6. Systolic and diastolic blood pressure (BP), heart rate, and symptoms of subjective intoxication (100 mm visual-analogue scales, VAS) were assessed the morning of Day 1 (before any oral THC), and on Days 2, 4 and 6, every 30 min for 3 h after the first morning THC dose. Morning subjective intoxication ratings increased from Days 1 to 2, and then declined on Days 4 and 6. The morning THC dose increased intoxication ratings on Day 2, but had less effect on Days 4 and 6, a pattern consistent with tolerance. THC lowered BP and increased heart rate over the six days. Plasma THC and 11-OH-THC concentrations increased significantly over the first five days of dosing. Six days of around-the-clock, oral THC produced tolerance to subjective intoxication, but not to cardiovascular effects.

[Usefulness of Bolus Administration Using the FLEX Mode(Bolus Infusion Mode)for Baclofen Tolerance].

PubMed

Tanaka, Kazunori

2017-02-01

Intrathecal baclofen(ITB)is used to treat intractable spasticity of various etiologies and can provide better control of spasticity through the adjustment of the dose administered through the pump. However, in patients who develop tolerance to baclofen with the standard simple continuous mode, a sharp increase in dose becomes necessary, and spasticity can become harder to control. We investigated whether switching from the simple continuous mode to the bolus infusion mode was effective in controlling spasticity in patients with baclofen tolerance. We reported four patients undergoing ITB therapy at our facility who were considered to have developed baclofen tolerance. We observed the number of bolus infusions and total dose suitable for maintaining spasticity control after switching from the simple continuous mode to the bolus infusion mode. After switching to the bolus infusion mode, the total dose could be reduced in the short term; however, in the long term, the frequency of bolus infusions had to be increased to maintain spasticity control. Two years after changing to bolus infusion six times a day, the total dose was higher than that in the simple continuous mode for two of the four patients, and was the same level in the other two patients. Our four cases suggest that bolus infusion is effective in patients with baclofen tolerance during ITB therapy. Therefore, the conditions of bolus infusion should be further investigated.

Oxycodone recycling: a novel hypothesis of opioid tolerance development in humans.

PubMed

Linares, Oscar A; Fudin, Jeffrey; Schiesser, William E; Linares, Annemarie Daly; Boston, Raymond C

2014-09-01

We hypothesize that oxycodone (OC) recycling promotes sustained synaptic OC content, which prolongs OC's exposure to local μ-opioid receptors (μORs). In that way, OC recycling gives rise to OC tolerance in humans. To pilot test our hypothesis, we developed a whole-body OC mass transport tolerance recovery model. The model derived quantifiable measure of tolerance is TΩ. TΩ estimates OC's tolerance recovery in days; It is defined as the rate of recovery of OC's pharmacologic response after OC is stopped. We studied a random sample of five opioid intolerant healthy male subjects with no history of opioid or illicit drug use, or comorbidities in silico. Subjects were age 24.5 ± 2.3 yr (all values mean ± SD), weight 93 ± 20 kg, and CYP2D6 EM phenotype. Each subject was studied under two experimental conditions: (1) administration of a single oral dose of OC 12 ± 7 mg; and, after complete washout of OC from the intravascular pool, (2) administration of repetitive oral OC doses every 4h for 5 half-lives (t1/2 = 4.5h)-after which time steady-state was assumed. Repetitive OC dose TΩ fell 61% compared to single OC dose TΩ (5.2 ± 1.1 vs. 3.5 ± 0.7 days, p = 0.001). The fall in TΩ was associated with a significant 3-fold increase in extravascular OC content, which was accompanied by 2-fold increase in OC spillover from the extravascular pool, into the intravascular pool. Thus, the model predicted that a single dose of orally administered OC could give rise to tolerance. This is consistent with the widely held view of acute opioid tolerance. In addition, the dynamic changes accompanying repetitive OC dosing suggested that local unbound OC gave rise to both higher extravascular OC content and increased OC spillover. This reflects that OC stimulated endocytosis of μORs was accompanied by a reduction in the availability OC responsive neuroeffector cell surface μOR binding sites. We conclude that our hypothesis extends current concepts of opioid tolerance development to include OC recycling. OC recycling is a novel hypothesis of OC tolerance development in humans. Copyright © 2014 Elsevier Ltd. All rights reserved.

Follicular Dowling Degos disease: a rare variant of an evolving dermatosis.

PubMed

Singh, Saurabh; Khandpur, Sujay; Verma, Parul; Singh, Manoj

2013-01-01

Dowling Degos disease is a rare, reticulate pigmentary disorder with variable phenotypic expression that manifests as hyperpigmented macules and reticulate pigmentary anomaly of the flexures. Many variants of this condition and its overlap with other reticulate pigmentary disorders have been reported in the literature. We present here two cases of DDD with follicular localization, both clinically and histologically. It was associated with ichthyosis vulgaris in one case. Follicular DDD is an uncommon variant of this evolving dermatosis. Our report supports the possible role for disordered follicular keratinisation in its pathogenesis.

Research progress of infrared detecting and display integrated device based on infrared-visible up-conversion technology

NASA Astrophysics Data System (ADS)

Xu, Junfeng; Li, Weile; He, Bo; Wang, Haowei; Song, Yong; Yang, Shengyi; Ni, Guoqiang

2018-01-01

Infrared detecting and display device (IR-DDD) is a newly developed optical up-conversion device that integrates the light-emitting diode (LED) onto the infrared (IR) photo-detector, in order to convert IR light into the carriers photo-generated in detection materials and inject them into LED to emit visible light. This IR-DDD can achieve the direct up-conversion from IR ray to visible light, showing the considerable potential in night-vision application. This paper attempts a review of its working principle and current research progresses.

Dissipative Particle Dynamics at Isoenergetic Conditions Using Shardlow-Like Splitting Algorithms

DTIC Science & Technology

2013-09-01

i.e., as cond i mech ii uuu ddd  . The dynamics of the system is then governed by the following equations- of-motion (EOMs):   q ij Rq ij Dq jiij...ij ij ijD ij i-j ij i W r t rr pp rr v r p dd ddd            , (8a) jimech i jimech j j i-ji-j i i-ji-j jimech i uu mm u jjii

Dislocation Dissociation Strongly Influences on Frank—Read Source Nucleation and Microplasticy of Materials with Low Stacking Fault Energy

NASA Astrophysics Data System (ADS)

Huang, Min-Sheng; Zhu, Ya-Xin; Li, Zhen-Huan

2014-04-01

The influence of dislocation dissociation on the evolution of Frank—Read (F-R) sources is studied using a three-dimensional discrete dislocation dynamics simulation (3D-DDD). The classical Orowan nucleation stress and recently proposed Benzerga nucleation time models for F-R sources are improved. This work shows that it is necessary to introduce the dislocation dissociation scheme into 3D-DDD simulation, especially for simulations on micro-plasticity of small sized materials with low stacking fault energy.

Immune tolerance improves the efficacy of enzyme replacement therapy in canine mucopolysaccharidosis I

PubMed Central

Dickson, Patricia; Peinovich, Maryn; McEntee, Michael; Lester, Thomas; Le, Steven; Krieger, Aimee; Manuel, Hayden; Jabagat, Catherine; Passage, Merry; Kakkis, Emil D.

2008-01-01

Mucopolysaccharidoses (MPSs) are lysosomal storage diseases caused by a deficit in the enzymes needed for glycosaminoglycan (GAG) degradation. Enzyme replacement therapy with recombinant human α-l-iduronidase successfully reduces lysosomal storage in canines and humans with iduronidase-deficient MPS I, but therapy usually also induces antibodies specific for the recombinant enzyme that could reduce its efficacy. To understand the potential impact of α-l-iduronidase–specific antibodies, we studied whether inducing antigen-specific immune tolerance to iduronidase could improve the effectiveness of recombinant iduronidase treatment in canines. A total of 24 canines with MPS I were either tolerized to iduronidase or left nontolerant. All canines received i.v. recombinant iduronidase at the FDA-approved human dose or a higher dose for 9–44 weeks. Nontolerized canines developed iduronidase-specific antibodies that proportionally reduced in vitro iduronidase uptake. Immune-tolerized canines achieved increased tissue enzyme levels at either dose in most nonreticular tissues and a greater reduction in tissue GAG levels, lysosomal pathology, and urinary GAG excretion. Tolerized MPS I dogs treated with the higher dose received some further benefit in the reduction of GAGs in tissues, urine, and the heart valve. Therefore, immune tolerance to iduronidase improved the efficacy of enzyme replacement therapy with recombinant iduronidase in canine MPS I and could potentially improve outcomes in patients with MPS I and other lysosomal storage diseases. PMID:18654665

Safety, tolerability, pharmacokinetics and pharmacodynamics of single doses of empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, in healthy Japanese subjects.

PubMed

Sarashina, Akiko; Koiwai, Kazuki; Seman, Leo J; Yamamura, Norio; Taniguchi, Atsushi; Negishi, Takahiro; Sesoko, Shogo; Woerle, Hans J; Dugi, Klaus A

2013-01-01

This randomized, placebo-controlled within dose groups, double-blind, single rising dose study investigated the safety, tolerability, pharmacokinetics and pharmacodynamics of 1 mg to 100 mg doses of empagliflozin in 48 healthy Japanese male subjects. Empagliflozin was rapidly absorbed, reaching peak levels in 1.25 to 2.50 h; thereafter, plasma concentrations declined in a biphasic fashion, with mean terminal elimination half-life ranging from 7.76 to 11.7 h. Increase in empagliflozin exposure was proportional to dose. Oral clearance was dose independent and ranged from 140 to 172 mL/min. In the 24 h following 100 mg empagliflozin administration, the mean (%CV) amount of glucose excreted in urine was 74.3 (17.1) g. The amount and the maximum rate of glucose excreted via urine increased with dose of empagliflozin. Nine adverse events, all of mild intensity, were reported by 8 subjects (7 with empagliflozin and 1 with the placebo). No hypoglycemia was reported. In conclusion, 1 mg to 100 mg doses of empagliflozin had a good safety and tolerability profile in healthy Japanese male subjects. Exposure to empagliflozin was dose proportional. The amount and rate of urinary glucose excretion were higher with empagliflozin than with the placebo, and increased with empagliflozin dose.

A phase I study with neratinib (HKI-272), an irreversible pan ErbB receptor tyrosine kinase inhibitor, in patients with solid tumors.

PubMed

Wong, Kwok-K; Fracasso, Paula M; Bukowski, Ronald M; Lynch, Thomas J; Munster, Pamela N; Shapiro, Geoffrey I; Jänne, Pasi A; Eder, Joseph P; Naughton, Michael J; Ellis, Matthew J; Jones, Suzanne F; Mekhail, Tarek; Zacharchuk, Charles; Vermette, Jennifer; Abbas, Richat; Quinn, Susan; Powell, Christine; Burris, Howard A

2009-04-01

The dose-limiting toxicities, maximum tolerated dose, pharmacokinetic profile, and preliminary antitumor activity of neratinib (HKI-272), an irreversible pan ErbB inhibitor, were determined in patients with advanced solid tumors. Neratinib was administered orally as a single dose, followed by a 1-week observation period, and then once daily continuously. Planned dose escalation was 40, 80, 120, 180, 240, 320, 400, and 500 mg. For pharmacokinetic analysis, timed blood samples were collected after administration of the single dose and after the first 14 days of continuous daily administration. Dose-limiting toxicity was grade 3 diarrhea, which occurred in one patient treated with 180 mg and in four patients treated with 400 mg neratinib; hence, the maximum tolerated dose was determined to be 320 mg. Other common neratinib-related toxicities included nausea, vomiting, fatigue, and anorexia. Exposure to neratinib was dose dependent, and the pharmacokinetic profile of neratinib supports a once-a-day dosing regimen. Partial response was observed for 8 (32%) of the 25 evaluable patients with breast cancer. Stable disease >or=24 weeks was observed in one evaluable breast cancer patient and 6 (43%) of the 14 evaluable non-small cell lung cancer patients. The maximum tolerated dose of once-daily oral neratinib is 320 mg. The most common neratinib-related toxicity was diarrhea. Antitumor activity was observed in patients with breast cancer who had previous treatment with trastuzumab, anthracyclines, and taxanes, and tumors with a baseline ErbB-2 immunohistochemical staining intensity of 2+ or 3+. The antitumor activity, tolerable toxicity profile, and pharmacokinetic properties of neratinib warrant its further evaluation.

NUDT15 and TPMT genetic polymorphisms are related to 6-mercaptopurine intolerance in children treated for acute lymphoblastic leukemia at the Children's Cancer Center of Lebanon.

PubMed

Zgheib, Nathalie K; Akika, Reem; Mahfouz, Rami; Aridi, Carol Al; Ghanem, Khaled M; Saab, Raya; Abboud, Miguel R; Tarek, Nidale; El Solh, Hassan; Muwakkit, Samar A

2017-01-01

Interindividual variability in thiopurine-related toxicity could not be completely explained by thiopurine S-methyltransferase (TPMT) polymorphisms, as a number of patients who are homozygous wild type or normal for TPMT still develop toxicity that necessitates 6-mercaptopurine (MP) dose reduction or protocol interruption. Recently, few studies reported on an inherited nucleoside diphosphate-linked moiety X motif 15 (NUDT15) c.415C>T low-function variant that is associated with decreased thiopurine metabolism and leukopenia in childhood acute lymphoblastic leukemia (ALL) and other diseases. The aim of this study is to measure the frequency of TPMT and NUDT15 polymorphisms and assess whether they are predictors of MP intolerance in children treated for ALL. One hundred thirty-seven patients with ALL of whom 121 were Lebanese were evaluated. MP dose intensity was calculated as the ratio of the tolerated MP dose to planned dose during continuation phase to maintain an absolute neutrophil count (ANC) dose above 300 per μl. One patient was NUDT15 heterozygous TC and tolerated only 33.33% of the planned MP dose, which was statistically significantly different from the median-tolerated MP dose intensity of the rest of the cohort (76.00%). Three patients had the TPMT*3A haplotype and tolerated 40.00-66.66% of the planned MP dose, which was also statistically significantly different from the rest of the cohort. This is the first report on the association of TPMT and NUDT15 polymorphisms with MP dose intolerance in Arab patients with ALL. Genotyping for additional polymorphisms may be warranted for potential gene/allele-dose effect. © 2016 Wiley Periodicals, Inc.

A Phase I study of bizelesin (NSC 615291) in patients with advanced solid tumors.

PubMed

Pitot, Henry C; Reid, Joel M; Sloan, Jeff A; Ames, Matthew M; Adjei, Alex A; Rubin, Joseph; Bagniewski, Pamela G; Atherton, Pamela; Rayson, Daniel; Goldberg, Richard M; Erlichman, Charles

2002-03-01

To evaluate the toxicities, characterize the pharmacokinetics, and determine the maximum-tolerated dose of bizelesin administered once every 4 weeks. Patients with advanced solid tumors received escalating doses of bizelesin as an i.v. push every 4 weeks. Pharmacokinetic studies were performed with the first treatment cycle. Nineteen eligible patients received a total of 54 courses of bizelesin at doses ranging from 0.1 to 1 microg/m(2). Dose-limiting toxicity of neutropenia was seen in 2 of 4 patients treated at the 1 microg/m(2) dose level. Nonhematological toxicity was generally mild with maximum toxicity being

Switching to aripiprazole in outpatients with schizophrenia experiencing insufficient efficacy and/or safety/tolerability issues with risperidone: a randomized, multicentre, open-label study.

PubMed

Ryckmans, V; Kahn, J P; Modell, S; Werner, C; McQuade, R D; Kerselaers, W; Lissens, J; Sanchez, R

2009-05-01

This study evaluated the safety/tolerability and effectiveness of aripiprazole titrated-dose versus fixed-dose switching strategies from risperidone in patients with schizophrenia experiencing insufficient efficacy and/or safety/tolerability issues. Patients were randomized to an aripiprazole titrated-dose (starting dose 5 mg/day) or fixed-dose (dose 15 mg/day) switching strategy with risperidone down-tapering. Primary endpoint was rate of discontinuation due to adverse events (AEs) during the 12-week study. Secondary endpoints included positive and negative syndrome scale (PANSS), clinical global impressions - improvement of illness scale (CGI-I), preference of medication (POM), subjective well-being under neuroleptics (SWN-K) and GEOPTE (Grupo Español para la Optimización del Tratamiento de la Esquizofrenia) scales. Rates of discontinuations due to AEs were similar between titrated-dose and fixed-dose strategies (3.5% vs. 5.0%; p=0.448). Improvements in mean PANSS total scores were similar between aripiprazole titrated-dose and fixed-dose strategies (-14.8 vs. -17.2; LOCF), as were mean CGI-I scores (2.9 vs. 2.8; p=0.425; LOCF) and SWN-K scores (+8.6 vs.+10.3; OC,+7.8 vs.+9.8; LOCF). Switching can be effectively and safely achieved through a titrated-dose or fixed-dose switching strategy for aripiprazole, with down-titration of risperidone.

Pharmacokinetics and Safety of MP-376 (Levofloxacin Inhalation Solution) in Cystic Fibrosis Subjects▿

PubMed Central

Geller, David E.; Flume, Patrick A.; Griffith, David C.; Morgan, Elizabeth; White, Dan; Loutit, Jeffery S.; Dudley, Michael N.

2011-01-01

The pharmacokinetics and tolerability of nebulized MP-376 (levofloxacin inhalation solution [Aeroquin]) were determined in cystic fibrosis (CF) subjects. Ten CF subjects received single 180-mg doses of two formulations of MP-376, followed by a multiple-dose phase of 240 mg once daily for 7 days. Serum and expectorated-sputum samples were assayed for levofloxacin content. Safety was evaluated following the single- and multiple-dose study phases. Nebulized MP-376 produced high concentrations of levofloxacin in sputum. The mean maximum plasma concentration (Cmax) ranged between 2,563 and 2,932 mg/liter for 180-mg doses of the 50- and 100-mg/ml formulations, respectively. After 7 days of dosing, the mean Cmax for the 240-mg dose was 4,691 mg/liter. The mean serum levofloxacin Cmax ranged between 0.95 and 1.28 for the 180-mg doses and was 1.71 for the 240-mg dose. MP-376 was well tolerated. Nebulized MP-376 produces high sputum and low serum levofloxacin concentrations. The pharmacokinetics, safety, and tolerability were similar for the two formulations. MP-376 240 mg (100 mg/ml) is being advanced into late-stage clinical development. PMID:21444699

Safety and tolerability of the first-in-class agent CPI-613 in combination with modified FOLFIRINOX in patients with metastatic pancreatic cancer: a single-centre, open-label, dose-escalation, phase 1 trial.

PubMed

Alistar, Angela; Morris, Bonny B; Desnoyer, Rodwige; Klepin, Heidi D; Hosseinzadeh, Keyanoosh; Clark, Clancy; Cameron, Amy; Leyendecker, John; D'Agostino, Ralph; Topaloglu, Umit; Boteju, Lakmal W; Boteju, Asela R; Shorr, Rob; Zachar, Zuzana; Bingham, Paul M; Ahmed, Tamjeed; Crane, Sandrine; Shah, Riddhishkumar; Migliano, John J; Pardee, Timothy S; Miller, Lance; Hawkins, Gregory; Jin, Guangxu; Zhang, Wei; Pasche, Boris

2017-06-01

Pancreatic cancer statistics are dismal, with a 5-year survival of less than 10%, and more than 50% of patients presenting with metastatic disease. Metabolic reprogramming is an emerging hallmark of pancreatic adenocarcinoma. CPI-613 is a novel anticancer agent that selectively targets the altered form of mitochondrial energy metabolism in tumour cells, causing changes in mitochondrial enzyme activities and redox status that lead to apoptosis, necrosis, and autophagy of tumour cells. We aimed to establish the maximum tolerated dose of CPI-613 when used in combination with modified FOLFIRINOX chemotherapy (comprising oxaliplatin, leucovorin, irinotecan, and fluorouracil) in patients with metastatic pancreatic cancer. In this single-centre, open-label, dose-escalation phase 1 trial, we recruited adult patients (aged ≥18 years) with newly diagnosed metastatic pancreatic adenocarcinoma from the Comprehensive Cancer Center of Wake Forest Baptist Medical Center (Winston-Salem, NC, USA). Patients had good bone marrow, liver and kidney function, and good performance status (Eastern Cooperative Oncology Group [ECOG] performance status 0-1). We studied CPI-613 in combination with modified FOLFIRINOX (oxaliplatin at 65 mg/m 2 , leucovorin at 400 mg/m 2 , irinotecan at 140 mg/m 2 , and fluorouracil 400 mg/m 2 bolus followed by 2400 mg/m 2 over 46 h). We applied a two-stage dose-escalation scheme (single patient and traditional 3+3 design). In the single-patient stage, one patient was accrued per dose level. The starting dose of CPI-613 was 500 mg/m 2 per day; the dose level was then escalated by doubling the previous dose if there were no adverse events worse than grade 2 within 4 weeks attributed as probably or definitely related to CPI-613. The traditional 3+3 dose-escalation stage was triggered if toxic effects attributed as probably or definitely related to CPI-613 were grade 2 or worse. The dose level for CPI-613 for the first cohort in the traditional dose-escalation stage was the same as that used in the last cohort of the single-patient dose-escalation stage. The primary objective was to establish the maximum tolerated dose of CPI-613 (as assessed by dose-limiting toxicities). This trial is registered with ClinicalTrials.gov, number NCT01835041, and is closed to recruitment. Between April 22, 2013, and Jan 8, 2016, we enrolled 20 patients. The maximum tolerated dose of CPI-613 was 500 mg/m 2 . The median number of treatment cycles given at the maximum tolerated dose was 11 (IQR 4-19). Median follow-up of the 18 patients treated at the maximum tolerated dose was 378 days (IQR 250-602). Two patients enrolled at a higher dose of 1000 mg/m 2 , and both had a dose-limiting toxicity. Two unexpected serious adverse events occurred, both for the first patient enrolled. Expected serious adverse events were: thrombocytopenia, anaemia, and lymphopenia (all for patient number 2; anaemia and lymphopenia were dose-limiting toxicities); hyperglycaemia (in patient number 7); hypokalaemia, hypoalbuminaemia, and sepsis (patient number 11); and neutropenia (patient number 20). No deaths due to adverse events were reported. For the 18 patients given the maximum tolerated dose, the most common grade 3-4 non-haematological adverse events were hyperglycaemia (ten [55%] patients), hypokalaemia (six [33%]), peripheral sensory neuropathy (five [28%]), diarrhoea (five [28%]), and abdominal pain (four [22%]). The most common grade 3-4 haematological adverse events were neutropenia (five [28%] of 18 patients), lymphopenia (five [28%]), anaemia (four [22%], and thrombocytopenia in three [17%]). Sensory neuropathy (all grade 1-3) was recorded in 17 (94%) of the 18 patients and was managed with dose de-escalation or discontinuation per standard of care. No patients died while on active treatment; 11 study participants died, with cause of death as terminal pancreatic cancer. Of the 18 patients given the maximum tolerated dose, 11 (61%) achieved an objective (complete or partial) response. A maximum tolerated dose of CPI-613 was established at 500 mg/m 2 when used in combination with modified FOLFIRINOX in patients with metastatic pancreatic cancer. The findings of clinical activity will require validation in a phase 2 trial. Comprehensive Cancer Center of Wake Forest Baptist Medical Center. Copyright © 2017 Elsevier Ltd. All rights reserved.

Effect of statin on hepatocellular carcinoma in patients with type 2 diabetes: A nationwide nested case-control study.

PubMed

Kim, Gyuri; Jang, Suk-Yong; Han, Eugene; Lee, Yong-Ho; Park, Se-Young; Nam, Chung Mo; Kang, Eun Seok

2017-02-15

Relationship on new statin use and the risk of hepatocellular carcinoma (HCC) in patients with incident type 2 diabetes mellitus (T2DM), who might be at the risk of developing HCC, is uncertained. A nationwide population-based nested case-control study was conducted within the National Health Insurance Service National Sample Cohort 2002-2013 in Korea. Newly prescribed statin after newly diagnosed T2DM was defined as statin use. Controls were matched to case patients on age, sex, follow-up time, and the date of diabetes diagnosis at a five-to-one ratio. Odds ratios (ORs) for associations of statin use with HCC were calculated using conditional logistic regression. After at least a 5-year HCC-free period, there were 229 incident HCC cases and 1,145 matched controls from 47,738 patients with incident diabetes. Of these 229 incident HCC cases, 27 (11.8%) were statin users, whereas 378 (33.0%) were statin users among 1,145 controls. Statin use was associated with a reduced risk of HCC development (adjusted OR [AOR]= 0.36, 95% confidence interval [CI] 0.22-0.60) after adjustment for chronic viral hepatitis, liver cirrhosis, alcoholic liver disease, previous cancer, aspirin use, insulin use, sulfonylurea use, metformin use, thiazolidinedione use, history of chronic obstructive pulmonary disease, Charlson comorbidity score, household income level, and residential area. Risk reduction was accentuated with an increase of cumulative defined daily doses (cDDD) compared with non-users (AORs 0.53, 0.36, 0.32, and 0.26 in ≤60, 60-180, 181-365, and >365cDDD, respectively; P for trend <0.0001). The risk reduction was apparent in the presence of liver disease (AOR = 0.27, 95% CI 0.14-0.50), including heterogeneous groups of clinical diagnosis of liver disease, but not significant in the absence of liver disease (AOR = 0.64, 95% CI 0.32-1.29). Among patients with new onset T2DM, statin use before HCC diagnosis may have a beneficial inhibitory effect on HCC development in a dose-dependent manner, especially in individuals with liver disease. © 2016 UICC.

Phase I Trial Using Patupilone (Epothilone B) and Concurrent Radiotherapy for Central Nervous System Malignancies

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fogh, Shannon; Machtay, Mitchell; Werner-Wasik, Maria

Purpose: Based on preclinical data indicating the radiosensitizing potential of epothilone B, the present study was designed to evaluate the toxicity and response rate of patupilone, an epothilone B, with concurrent radiotherapy (RT) for the treatment of central nervous system malignancies. Methods and Materials: The present Phase I study evaluated the toxicities associated with patupilone combined with RT to establish the maximal tolerated dose. Eligible patients had recurrent gliomas (n = 10) primary (n = 5) or metastatic (n = 17) brain tumors. Dose escalation occurred if no dose-limiting toxicities, defined as any Grade 4-5 toxicity or Grade 3 toxicitymore » requiring hospitalization, occurred during treatment. Results: Of 14 patients, 5 were treated with weekly patupilone at 1.5 mg/m{sup 2}, 4 at 2.0 mg/m{sup 2}, 4 at 2.5 mg/m{sup 2}, and 1 at 4 mg/m{sup 2}. Of 18 patients, 7 were treated in the 6-mg/m{sup 2} group, 6 in the 8-mg/m{sup 2} group, and 5 in the 10-mg/m{sup 2} group. Primary central nervous system malignancies received RT to a median dose of 60 Gy. Central nervous system metastases received whole brain RT to a median dose of 37.4 Gy, and patients with recurrent gliomas underwent stereotactic RT to a median dose of 37.5 Gy. One dose-limiting toxicity (pneumonia) was observed in group receiving 8-mg/m{sup 2} every 3 weeks. At the subsequent dose level (10 mg/m{sup 2}), two Grade 4 dose-limiting toxicities occurred (renal failure and pulmonary hemorrhage); thus, 8 mg/m{sup 2} every 3 weeks was the maximal tolerated dose and the recommended Phase II dose. Conclusion: Combined with a variety of radiation doses and fractionation schedules, concurrent patupilone was well tolerated and safe, with a maximal tolerated dose of 8 mg/m{sup 2} every 3 weeks.« less

Triaspartate: a model system for conformationally flexible DDD motifs in proteins.

PubMed

Duitch, Laura; Toal, Siobhan; Measey, Thomas J; Schweitzer-Stenner, Reinhard

2012-05-03

Understanding the interactions that govern turn formation in the unfolded state of proteins is necessary for a complete picture of the role that these turns play in both normal protein folding and functionally relevant yet disordered linear motifs. It is still unclear, however, whether short peptides can adopt stable turn structures in aqueous environments in the absence of any nonlocal interactions. To explore the effect that nearest-neighbor interactions and the local peptide environment have on the turn-forming capability of individual amino acid residues in short peptides, we combined vibrational (IR, Raman, and VCD), UV-CD, and (1)H NMR spectroscopies in order to probe the conformational ensemble of the central aspartic acid residue of the triaspartate peptide (DDD). The study was motivated by the recently discovered turn propensities of aspartic acid in GDG (Hagarman; et al. Chem.-Eur. J. 2011, 17, 6789). We investigated the DDD peptide under both acidic and neutral conditions in order to elucidate the effect that side-chain protonation has on the conformational propensity of the central aspartic acid residue. Amide I' profiles were analyzed in terms of two-dimensional Gaussian distributions representing conformational subdistributions in Ramachandran space. Interestingly, our results show that while the protonated form of the DDD peptide samples various turn-like conformations similar to GDG, deprotonation of the peptide eliminates this propensity for turns, causing the fully ionized peptide to exclusively sample pPII and β-strand-like structures. To further explore the factors stabilizing these more extended conformations in fully ionized DDD, we analyzed the temperature dependence of both the UV-CD spectrum and the (3)J(H(N),H(α)) coupling constants of the two amide protons (N- and C-terminal) in terms of a simple two-state (pPII-β) thermodynamic model. Thus, we were able to obtain the enthalpic and entropic differences between the pPII and β-strand conformations of the central and C-terminal residue. For the central residue, we obtained ΔH(3) = -12.0 kJ/mol and ΔS(3) = -73.8 J/mol·K, resulting in a much larger room-temperature Gibbs free energy of 10.0 kJ/mol, which effectively locks the C-terminal in a β-like conformation. A comparison of the temperature dependence of the chemical shifts reveals that there is indeed some type of protection of the amide protons from solvent in ionized DDD. This finding and several other lines of evidence suggest that both conformations of ionized DDD are stabilized by hydrogen bonding between the carboxylate groups of the central and C-terminal residue and the respective amide protons. These hydrogen bonds can be expected to be eliminated by side-chain protonation and substituted by hydrogen bonds between the N-terminal amide proton and the C-terminal carbonyl group as well as between the central aspartate side chain and the N-terminal amide proton. Hence, our results are indicative of a pH-induced switch in hydrogen-bonding patterns of aspartic acid motifs.

Impact of adolescent alcohol use across the lifespan: Long-lasting tolerance to high-dose alcohol coupled with potentiated spatial memory impairments to moderate-dose alcohol.

PubMed

Matthews, Douglas B; Novier, Adelle; Diaz-Granados, Jaime L; Van Skike, Candice E; Ornelas, Laura; Mittleman, G

2017-06-01

Understanding how alcohol exposure during adolescence affects aging is a critical but understudied area. In the present study, male rats were exposed to either alcohol or saline during adolescence, then tested every 4 months following either an ethanol or saline challenge; animals were tested until postnatal day (PD) 532. It was found that long-lasting tolerance to high-dose ethanol exists through the test period, as measured by loss of righting reflex, while tolerance to lower doses of ethanol is not found. In addition, alcohol exposure during adolescence facilitated spatial memory impairments to acute ethanol challenges later in life. The current work demonstrates that exposure to ethanol during adolescent development can produce long-lasting detrimental impairments. Copyright © 2017 Elsevier Inc. All rights reserved.

Bioavailability of a Sustained Release Formulation of Curcumin

PubMed Central

Madhavi, Doddabele; Kagan, Daniel

2014-01-01

Context Curcumin has a number of beneficial effects, such as functioning as a potent antioxidant,1 anti-inflammatory, 2 and anticancer agent. Because of its poor oral bioavailability, very high oral doses and repeated dosing have been used to obtain effective plasma levels, with mixed results. High doses of curcumin may cause gastric disturbance, often resulting in poor patient compliance. Objective The objective of this study was to compare the relative bioavailability of MicroActive Curcumin—an advanced, micronized formulation of curcumin that is 25% curcuminoids in a sustained release matrix—with that of an unformulated, 95% pure curcumin powder. Design A dissolution study compared the solubility of the formulated and the unformulated curcumin. The research team also performed a single-dose, 12-h, crossover uptake study with 10 participants and a high-dose tolerability and accumulation study with 3 participants, comparing the 2 forms of curcumin. Setting The study was done in MAZE Laboratories (Purchase, NY, USA). Participants Ten healthy male and female volunteers, aged 21–66 y, took part in the single-dose study. Three participants, 2 female and 1 male aged 40–55 y, took part in the tolerability and accumulation study. The participants were people from the community. Intervention For the dissolution study, the research team filled hard gelatin capsules with unformulated 95% curcumin powder and the MicroActive Curcumin powder to the equivalent of 25 mg curcuminoids. For the single-dose study, participants received 500 mg of curcumin in 2 forms. MicroActive Curcumin capsules were administered after breakfast, and blood samples were drawn at 1, 2, 4, 8, and 12 h postdose. After a 7-d washout period, the protocol was repeated for unformulated, 95% curcumin powder capsules. For the tolerability study, the unformulated, 95% curcumin powder was given at a dose that provided 2 g of curcumin for 7 d followed by 5 g of curcumin for an additional 7 d. After a washout period of 14 d, the protocol was repeated with MicroActive Curcumin. Participants then continued to take the MicroActive Curcumin for >3 mo. Outcome Measures For the dissolution study, the curcumin was quantified at room temperature using reverse-phase, high-performance liquid chromatography (HPLC) with a Phenomenex Luna column (150 × 4.6 mm, 5 μm) (Phenomenex Inc, Torrance, CA, USA). For the single-dose and the tolerability studies, hydrolysis of conjugates and extraction of curcuminoids from the plasma were performed. The curcuminoids were quantified using reverse-phase HPLC with an ultraviolet-visible detector as described above. Results The dissolution study indicated that the sustained-release curcumin had greater dissolution for 12 h at all points tested, compared with the unformulated curcumin. Very little of the unformulated curcumin powder had been released at the end of the 12 h. The results of the single-dose uptake study indicated that the sustained-release formula was 9.7 × more bioavailable than the unformulated powder (P < .001, paired t test). Additionally, all participants showed uptake from the sustained-release formulation. That formulation also resulted in significant increases in the plasma demethoxylated curcuminoids, but the research team did not observe the same increases for the unformulated curcumin powder. The sustained-release formulation was well tolerated, without adverse effects in the high-dose tolerability study. Conclusions Formulation of micronized curcumin in a combination of surfactants, oils, and polymers improves the absorption of curcumin. In addition, the unique plasma demethylated curcuminoid profile may enhance the therapeutic effects of MicroActive Curcumin not observed with unformulated curcumin at moderate and well-tolerated doses. MicroActive Curcumin was well tolerated, without any adverse effects in a high-dose tolerability study. These properties have the potential to make high-dose curcumin supplementation more accessible through simplified incorporation into food and beverage preparations. PMID:26770097

Ondansetron reduces naturalistic drinking in non-treatment seeking alcohol dependent individuals with the LL 5′-HTTLPR genotype: a laboratory study

PubMed Central

Kenna, George A.; Zywiak, William H.; Swift, Robert M.; McGeary, John E.; Clifford, James S.; Shoaff, Jessica R.; Vuittonet, Cynthia; Fricchione, Samuel; Brickley, Michael; Beaucage, Kayla; Haass-Koffler, Carolina L.; Leggio, Lorenzo

2014-01-01

Background One hypothesis suggests that the differential response to ondansetron and serotonin specific re-uptake inhibitors (SSRIs) may be due to a functional polymorphism of the 5′-HTTLPR promoter region in SLC6A4, the gene that codes for the serotonin transporter (5-HTT). The LL 5′-HTTLPR genotype is postulated to be specifically sensitive to the effects of ondansetron with SS/SL 5′-HTTLPR genotypes sensitive to SSRIs. This study tests this hypothesis by matching non-treatment seeking alcohol dependent (AD) individuals with LL genotype to ondansetron and SS/SL genotypes to the SSRI sertraline, and mis-matching them assessing naturalistic and bar-laboratory alcohol drinking. Methods Seventy-seven AD individuals were randomized to one of two counterbalanced arms to receive sertraline 200mg/day or ondansetron 0.5 mg/day for three weeks followed by an alcohol self-administration experiment (ASAE), then received placebo for three weeks followed by a second ASAE. Individuals then received the alternate drug for three weeks followed by a third ASAE. Drinks per drinking day (DDD with drinks in SDUs) for 7 days prior to each ASAE and milliliters consumed during each ASAE were the primary outcomes. Results Fifty-five participants completed the study. The genotype x order interaction was significant [F(1,47) = 8.42, p = .006] for DDD. Three ANCOVAs were conducted for DDD during the week before each ASAE. Ondansetron compared to sertraline resulted in a significant reduction in DDD during the week before the first [F(1,47) = 7.64, p = .008] but not the third ASAE. There was no difference in milliliters consumed during each ASAE. Conclusion This study modestly supports the hypothesis that ondansetron may reduce DDD in AD individuals with the LL genotype as measured naturalistically. By contrast there was no support that ondansetron reduces drinking during the ASAEs or that sertraline reduces alcohol use in individuals who have SS/SL genotypes. We provide limited support that ondansetron may reduce drinking in non-treatment seeking individuals with the LL genotype. PMID:24773166

Radiation response and electrical properties of polymer energy storage capacitors: PVF2, Polysulfone, and Mylar

NASA Technical Reports Server (NTRS)

Edwards, L. R.

1981-01-01

Efforts were made to develop a polymer film capacitor that is tolerant to radiation. The capacitors are to be utilized in a high voltage pulse discharge application. Radiation response data at high dose/dose rate levels are presented for polyvinylidene fluoride (PVF2), polysulfone, and Mylar. The results show that PVF2 is the most radiation tolerant while Mylar is the least tolerant. The data also show that the radiation response is quite dependent on operating electric stress.

Binocular disparity tuning and visual-vestibular congruency of multisensory neurons in macaque parietal cortex

PubMed Central

Yang, Yun; Liu, Sheng; Chowdhury, Syed A.; DeAngelis, Gregory C.; Angelaki, Dora E.

2012-01-01

Many neurons in the dorsal medial superior temporal (MSTd) and ventral intraparietal (VIP) areas of the macaque brain are multisensory, responding to both optic flow and vestibular cues to self-motion. The heading tuning of visual and vestibular responses can be either congruent or opposite, but only congruent cells have been implicated in cue integration for heading perception. Because of the geometric properties of motion parallax, however, both congruent and opposite cells could be involved in coding self-motion when observers fixate a world-fixed target during translation, if congruent cells prefer near disparities and opposite cells prefer far disparities. We characterized the binocular disparity selectivity and heading tuning of MSTd and VIP cells using random-dot stimuli. Most (70%) MSTd neurons were disparity-selective with monotonic tuning, and there was no consistent relationship between depth preference and congruency of visual and vestibular heading tuning. One-third of disparity-selective MSTd cells reversed their depth preference for opposite directions of motion (direction-dependent disparity tuning, DDD), but most of these cells were unisensory with no tuning for vestibular stimuli. Inconsistent with previous reports, the direction preferences of most DDD neurons do not reverse with disparity. By comparison to MSTd, VIP contains fewer disparity-selective neurons (41%) and very few DDD cells. On average, VIP neurons also preferred higher speeds and nearer disparities than MSTd cells. Our findings are inconsistent with the hypothesis that visual/vestibular congruency is linked to depth preference, and also suggest that DDD cells are not involved in multisensory integration for heading perception. PMID:22159105

High-dose octreotide acetate for management of gastroenteropancreatic neuroendocrine tumors.

PubMed

Chadha, Manpreet K; Lombardo, Jeffrey; Mashtare, Terry; Wilding, Gregory E; Litwin, Alan; Raczyk, Cheryl; Gibbs, John F; Kuvshinoff, Boris; Javle, Milind M; Iyer, Renuka V

2009-10-01

Long-acting sandostatin (S-LAR; octreotide acetate) is well tolerated and effective for symptom control and possibly disease control in gastroenteropancreatic neuroendocrine tumors (GEP-NETs). We undertook a retrospective analysis to study the efficacy and tolerability of higher doses (more than 20-30 mg/month) of S-LAR in GEP-NETs. With IRB approval, charts of all patients with GEP-NET who received S-LAR between June 2002 to September 2007 at Roswell Park Cancer Institute were reviewed and their data analyzed. Fifty-four patients with GEP-NET received S-LAR; thirty required dose escalation. Patients received a median of 5 doses of S-LAR at conventional dose followed by up-titration of the dose for symptom control (20) and radiological progression (17). Median high dose of S-LAR was 40 mg (range: 40-90 mg) with a median of 8.5 high doses received. No treatment related toxicities were seen. The estimated 1-year survival for patients on conventional dose alone was 0.77 (95% CI of 0.50 to 0.91) and those on high-dose was 0.88 (95% CI of 0.68 to 0.96) (p=0.4777) while median time to any other intervention was 2.9 months versus 17.7 months (p=0.12). Dose escalation of S-LAR is well tolerated and may provide longer disease control.

Pupillography as a sensitive, noninvasive biomarker in healthy volunteers: first-in-man study of BAY 63-9044, a new 5-HT1A-receptor agonist with dopamine agonistic properties.

PubMed

Wensing, Georg; Haase, Claus; Brendel, Erich; Böttcher, Michael Friedrich

2007-12-01

BAY 63-9044 is a new full 5-HT(1A)-agonist with functional dopamine agonist properties aimed for the treatment of Parkinson's disease. This first-in-man study investigated the pharmacodynamics, safety and tolerability as well as the pharmacokinetics of BAY 63-9044 in a randomized, single-blind, placebo-controlled group-comparison dose escalation study. 45 healthy men received BAY 63-9044 as an oral solution in single doses of 0.25 mg, 0.5 mg, 1.2 mg, 2.5 mg and 5.0 mg. Pupil reaction (baseline pupil diameter (DIAM), constriction amplitude (CA)), body temperature, electroencephalography (EEG) and prolactin, cortisol and adrenocorticotrophic hormone (ACTH) served as pharmacodynamic measures and were monitored up to 24 h after drug intake. Safety, tolerability and plasma samples for determination of BAY 63-9044 were followed up to 72 h. Up to a dose of 2.5 mg, BAY 63-9044 was safe and well tolerated. Dose-limiting adverse events (nausea, vomiting, and dizziness) occurred in 5 out of 6 volunteers at the 5 mg dose. Adverse events resolved spontaneously in all but one volunteers who was treated with an antihistaminergic for vomiting. Dose-dependent changes of DIAM and CA were observed at doses higher than 0.5 mg and 1.2 mg, respectively. Body temperature showed a trend for reduction starting at C(max) in the highest two doses only. No clear effect was found on prolactin, cortisol and ACTH levels. The pharmacokinetics of BAY 63-9044 showed a dose-dependent increase with maximum plasma concentrations reached within 1 h. Plasma concentrations declined in a bi-phased manner with an apparent terminal half-life of 5.2-8.1 h. Up to the maximum tolerated dose (MTD) of 2.5 mg BAY 63-9044 was safe and well tolerated and showed predictable linear pharmacokinetics. Pupil reaction may serve as a non-invasive biomarker for pharmacodynamic effects of 5-HT(1A)-compounds with DIAM being the most sensitive parameter.

A double-blind, placebo-controlled, ascending-dose, randomized study to evaluate the safety, tolerability and effects on cognition of AL-108 after 12 weeks of intranasal administration in subjects with mild cognitive impairment.

PubMed

Morimoto, Bruce H; Schmechel, Don; Hirman, Joe; Blackwell, Andrew; Keith, Julian; Gold, Michael

2013-01-01

AL-108-211 was a placebo-controlled, ascending-dose study that explored the safety, tolerability and efficacy of 12 weeks of treatment with AL-108 in subjects with amnestic mild cognitive impairment. A total of 144 subjects were randomized in a 2:1 drug:placebo ratio. Subjects were enrolled into the low-dose group or placebo and then to the high-dose group or placebo. Pooling of the placebo groups yielded 3 groups (approx. 48/group) whose baseline demographics and disease characteristics were well matched. AL-108 was generally safe and well tolerated. Analyses of efficacy data failed to detect a statistically significant difference between the treatment groups on the composite cognitive memory score. Analyses of the individual cognitive tasks identified signals of potential efficacy in 2 tests of memory and attention. These data suggest that AL-108 was generally safe, well tolerated and merits additional investigation as a treatment for Alzheimer's disease. Copyright © 2013 S. Karger AG, Basel.

DDTs-induced antioxidant responses in plants and their influence on phytoremediation process.

PubMed

Mitton, Francesca M; Gonzalez, Mariana; Monserrat, José M; Miglioranza, Karina S B

2018-01-01

Phytoremediation is a low cost technology based on the use of plants to remove a wide range of pollutants from the environment, including the insecticide DDT. However, some pollutants are known to enhance generation of reactive oxygen species (ROS), which can generate toxic effects on plants affecting the phytoremediation efficiency. This study aims to analyze the potential use of antioxidant responses as a measure of tolerance to select plants for phytoremediation purposes. Tomato and zucchini plants were grown for 15 days in soils contaminated with DDTs (DDT + DDE + DDD). Protein content, glutathione-S-transferase (GST), glutathione reductase (GR), glutathione peroxidase (GPx) and catalase (CAT) activities were measured in plant tissues. Exposure to DDTs did not affect protein content or CAT activity in any of the species. GST, GR and GPx activity showed different responses in exposed and control tomato plants. After DDTs exposure, tomato showed increased GR and GPX activity in stems and leaves, respectively, and a decrease in the GST activity in roots. As no effects were observed in zucchini, results suggest different susceptibility and/or defense mechanisms involved after pesticide exposure. Finally, both species differed also in terms of DDTs uptake and translocation. The knowledge about antioxidant responses induced by pesticides exposure could be helpful for planning phytoremediation strategies and for the selection of tolerant species according to particular scenarios. Copyright © 2017 Elsevier Inc. All rights reserved.

A phase I dose escalation study of TTI-237 in patients with advanced malignant solid tumors.

PubMed

Wang-Gillam, Andrea; Arnold, Susanne M; Bukowski, Ronald M; Rothenberg, Mace L; Cooper, Wendy; Wang, Kenneth K; Gauthier, Eric; Lockhart, A Craig

2012-02-01

This study was to determine the maximum tolerated dose, dose-limiting toxicities, and pharmacokinetic profile of TTI-237, a novel anti-tubulin drug, administered weekly in patients with refractory solid tumors. Using an accelerated dose escalation design, patients with refractory solid tumors were enrolled in this study and treated with TTI-237 intravenously on days 1, 8 and 15 of a 28-day cycle. The starting dose was 4.5 mg/m(2). Pharmacokinetic studies were performed in patients at all dose levels. Twenty-eight patients were enrolled and treated with TTI-237 at dose of 4.5, 9, 15, 22.5 and 31.5 mg/m(2). One dose-limiting toxicity neutropenia fever was observed at 31.5 mg/m(2), and all seven patients developed grade 3 or 4 neutropenia at that dose level. TTI-237 dosage was de-escalated to 22.5 and 18 mg/m(2). Six patients were treated at the 18 mg/m(2) dose level without dose-limiting toxicity prior to trial termination. The mean terminal-phase elimination half-life (t(1/2)) for TTI-237 was 25-29 h, and the mean area under the concentration time curve at 31.5 mg/m(2) was 2,768 ng•h/mL. A protocol defined maximum tolerated dose was not determined because of early termination of the TTI-237 trial by the sponsor. 18 mg/m(2) may be a tolerable dose of TTI-237.

Single- and multiple-dose pharmacokinetics and absolute bioavailability of tedizolid.

PubMed

Flanagan, Shawn; Fang, Edward; Muñoz, Kelly A; Minassian, Sonia L; Prokocimer, Philippe G

2014-09-01

Tedizolid phosphate is a novel antibacterial under investigation for the treatment of gram-positive infections. This study was conducted to assess the pharmacokinetics, safety, and tolerability of intravenous tedizolid phosphate as well as the oral bioavailability of tedizolid phosphate. Double-blind, single-ascending dose, multiple-dose pharmacokinetics study, as well as tolerability and open-label crossover studies. Single center in the United States (Covance Clinical Research Unit, Madison, WI) between September 2009 and January 2010. Ninety healthy volunteers. Single intravenous (IV) doses of tedizolid phosphate 50 mg (lead-in) and 100-400 mg. Single oral and IV dose of tedizolid phosphate 200 mg in crossover fashion. Multiple IV doses of tedizolid phosphate 200 and 300 mg for up to 7 days. A dose-dependent increase was observed in the maximum plasma concentration (1.2-5.1 μg/ml) and the area under the concentration-time curve (17.4-58.7 μg × hr/ml) of tedizolid (the microbiologically active moiety of tedizolid phosphate) after single IV doses of tedizolid phosphate 100-400 mg. Administration of IV tedizolid phosphate 200 mg once/day for 7 days resulted in minimal (28%) tedizolid accumulation. The absolute oral bioavailability of tedizolid after a single 200-mg dose of tedizolid phosphate was 91%; pharmacokinetic parameters of tedizolid were similar with oral and IV administration. Treatment-related adverse events occurred in 41% of subjects. Most adverse events were related to infusion site and became more frequent with multiple dosing. In an additional 3-day tolerability study, IV tedizolid phosphate 200 mg and placebo were similarly tolerated, based on visual infusion phlebitis scores. These results from a population of healthy volunteers support once/day dosing of tedizolid phosphate 200 mg with both the oral and IV formulations, without the need for dose adjustment when switching administration routes. © 2014 Cubist Pharmaceuticals. Pharmacotherapy published by Wiley Periodicals, Inc. on behalf of Pharmacotherapy Publications, Inc.

Preconceptional motivational interviewing interventions to reduce alcohol-exposed pregnancy risk.

PubMed

Ingersoll, Karen S; Ceperich, Sherry D; Hettema, Jennifer E; Farrell-Carnahan, Leah; Penberthy, J Kim

2013-04-01

Alcohol exposed pregnancy (AEP) is a leading cause of preventable birth defects. While randomized controlled trials (RCTs) have shown that multi-session motivational interviewing-based interventions reduce AEP risk, a one-session intervention could facilitate broader implementation. The purposes of this study were to: (1) test a one-session motivational AEP prevention intervention for community women and (2) compare outcomes to previous RCTs. Participants at risk for AEP (N=217) were randomized to motivational interviewing+assessment feedback (EARLY), informational video, or informational brochure conditions. Outcomes were drinks per drinking day (DDD), ineffective contraception rate, and AEP risk at 3 and 6 months. All interventions were associated with decreased DDD, ineffective contraception rate, and AEP risk. Participants who received EARLY had larger absolute risk reductions in ineffective contraception and AEP risk, but not DDD. Effect sizes were compared to previous RCTs. The one-session EARLY intervention had less powerful effects than multi-session AEP prevention interventions among community women, but may provide a new option in a continuum of preventive care. Copyright © 2013 Elsevier Inc. All rights reserved.

3D DDD modelling of dislocation-precipitate interaction in a nickel-based single crystal superalloy under cyclic deformation

NASA Astrophysics Data System (ADS)

Lin, Bing; Huang, Minsheng; Zhao, Liguo; Roy, Anish; Silberschmidt, Vadim; Barnard, Nick; Whittaker, Mark; McColvin, Gordon

2018-06-01

Strain-controlled cyclic deformation of a nickel-based single crystal superalloy has been modelled using three-dimensional (3D) discrete dislocation dynamics (DDD) for both [0 0 1] and [1 1 1] orientations. The work focused on the interaction between dislocations and precipitates during cyclic plastic deformation at elevated temperature, which has not been well studied yet. A representative volume element with cubic γ‧-precipitates was chosen to represent the material, with enforced periodical boundary conditions. In particular, cutting of superdislocations into precipitates was simulated by a back-force method. The global cyclic stress-strain responses were captured well by the DDD model when compared to experimental data, particularly the effects of crystallographic orientation. Dislocation evolution showed that considerably high density of dislocations was produced for [1 1 1] orientation when compared to [0 0 1] orientation. Cutting of dislocations into the precipitates had a significant effect on the plastic deformation, leading to material softening. Contour plots of in-plane shear strain proved the development of heterogeneous strain field, resulting in the formation of shear-band embryos.

Modulation of opioid analgesia by agmatine.

PubMed

Kolesnikov, Y; Jain, S; Pasternak, G W

1996-01-18

Administered alone, agmatine at doses of 0.1 or 10 mg/kg is without effect in the mouse tailflick assay. However, agmatine enhances morphine analgesia in a dose-dependent manner, shifting morphine's ED50 over 5-fold. A far greater effect is observed when morphine is given intrathecally (9-fold shift) than after intracerebroventricular administration (2-fold). In contrast to the potentiation of morphine analgesia, agmatine (10 mg/kg) has no effect on morphine's inhibition of gastrointestinal transit. delta-Opioid receptor-mediated analgesia also is potentiated by agmatine, but kappa1-receptor-mediated (U50,488H; trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl] benzeneacetemide) and kappa3-opioid receptor-mediated (naloxone benzoylhydrazone) analgesia is not significantly enhanced by any dose of agmatine tested in this acute model. In chronic studies, agmatine at a low dose (0.1 mg/kg) which does not affect morphine analgesia acutely prevents tolerance following chronic morphine dosing for 10 days. A higher agmatine dose (10 mg/kg) has a similar effect. Agmatine also blocks tolerance to the delta-opioid receptor ligand [D-Pen2,D-Pen5]enkephalin given intrathecally, but not to the kappa3-opioid receptor agonist naloxone benzoylhydrazone. Despite its inactivity on kappa1-opioid analgesia in the acute model, agmatine prevents kappa1-opioid receptor-mediated tolerance. These studies demonstrate the dramatic interactions between agmatine and opioid analgesia and tolerance.

Single dose pharmacokinetics, pharmacodynamics, tolerability and safety of BAY 60-5521, a potent inhibitor of cholesteryl ester transfer protein.

PubMed

Boettcher, Michael-Friedrich; Heinig, Roland; Schmeck, Carsten; Kohlsdorfer, Christian; Ludwig, Matthias; Schaefer, Anja; Gelfert-Peukert, Sabine; Wensing, Georg; Weber, Olaf

2012-02-01

To determine pharmacokinetics (PK), pharmacodynamics (PD), tolerability and safety of BAY 60-5521, a potent inhibitor of cholesteryl ester transfer protein (CETP). The first in man (FIM) study investigated the safety, tolerability, pharmacodynamics and pharmacokinetics in healthy male subjects following administration of single oral doses. The study was performed using a randomized, single-blind, placebo-controlled, single dose-escalation design. Thirty-eight young healthy male subjects (aged 20-45 years) received an oral dose of 5, 12.5, 25 or 50 mg BAY 60-5521 (n= 28) or were treated with a placebo (n= 10). In all four dose steps, only one adverse event (25 mg; mild skin rash) was considered drug related. Clinical laboratory parameters showed no clinically relevant changes. A clear dose-dependent CETP inhibition could be demonstrated starting at a dose of 5 mg. At a dose of 25 mg, a CETP inhibition >50% over 18 h was observed. After 50 mg, CETP inhibition >50% lasted more than 50 h. Twenty-four h after administration mean HDL-C-values showed a nearly dose-proportional increase. Following administration of 50 mg, a significant HDL-C increase of about 30% relative to baseline values was found. BAY 60-5521 was slowly absorbed reaching maximum concentrations in plasma after 4 to 6 h. The disposition in plasma was multi-exponential with an estimated mean terminal half-life of 76 to 144 h. BAY 60-5521 was clinically safe and well tolerated. No effects on heart rate, blood pressure and ECG recordings were observed during the study. A clear pharmacodynamic effect on CETP inhibition and HDL could be demonstrated. © 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.

A Phase I Trial of High-Dose Lenalidomide and Melphalan as Conditioning for Autologous Stem Cell Transplantation in Relapsed or Refractory Multiple Myeloma.

PubMed

Mark, Tomer M; Guarneri, Danielle; Forsberg, Peter; Rossi, Adriana; Pearse, Roger; Perry, Arthur; Pekle, Karen; Tegnestam, Linda; Greenberg, June; Shore, Tsiporah; Gergis, Usama; Mayer, Sebastian; Van Besien, Koen; Ely, Scott; Jayabalan, David; Sherbenou, Daniel; Coleman, Morton; Niesvizky, Ruben

2017-06-01

Autologous stem cell transplantation (ASCT) conditioned with high-dose chemotherapy has long been established as the standard of care for eligible patients with newly diagnosed multiple myeloma. Despite recent therapeutic advances, high-dose melphalan (HDM) remains the chemotherapy regimen of choice in this setting. Lenalidomide (LEN) in combination with low-dose dexamethasone is recognized as a standard of care for patients with relapsed or refractory multiple myeloma (RRMM), and there is growing support for the administration of LEN as maintenance therapy post-ASCT. In view of the above, the present phase I clinical trial was designed to evaluate the safety and tolerability of high-dose LEN (HDLEN) in patients with RRMM, and to determine the maximum tolerated dose of HDLEN when added to HDM before ASCT. Despite administering HDLEN at doses of up to 350 mg/day, the maximum tolerated dose could not be determined, owing to an insufficient number of dose-limiting toxicities in the 21 patients enrolled in the trial. Conditioning with HDLEN plus HDM was associated with a favorable tolerability profile. Adverse events following ASCT were as expected with HDM. Median progression-free and overall survival were 10 months and 22 months, respectively, in this population of heavily pretreated patients. Our findings suggest that HDLEN in combination with HDM may offer significant potential as a conditioning regimen before ASCT in patients with RRMM. These preliminary findings are now being evaluated further in an ongoing phase II clinical trial. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Phase I study of olaparib plus gemcitabine in patients with advanced solid tumours and comparison with gemcitabine alone in patients with locally advanced/metastatic pancreatic cancer.

PubMed

Bendell, J; O'Reilly, E M; Middleton, M R; Chau, I; Hochster, H; Fielding, A; Burke, W; Burris, H

2015-04-01

Olaparib (Lynparza) is an oral poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitor that induces synthetic lethality in cancers with homologous recombination defects. In this phase I, dose-escalation trial, patients with advanced solid tumours received olaparib (50-200 mg capsules b.i.d.) continuously or intermittently (days 1-14, per 28-day cycle) plus gemcitabine [i.v. 600-800 mg/m(2); days 1, 8, 15, and 22 (cycle 1), days 1, 8, and 15 (subsequent cycles)] to establish the maximum tolerated dose. A separate dose-escalation phase evaluated olaparib in tablet formulation (100 mg o.d./b.i.d.; days 1-14) plus gemcitabine (600 mg/m(2)). In an expansion phase, patients with genetically unselected locally advanced or metastatic pancreatic cancer were randomised 2 : 1 to the tolerated olaparib capsule combination dose or gemcitabine alone (1000 mg/m(2)). Sixty-six patients were treated [dose-escalation phase, n = 44 (tablet cohort, n = 12); dose-expansion phase, n = 22 (olaparib plus gemcitabine, n = 15; gemcitabine alone, n = 7)]. In the dose-escalation phase, four patients (6%) experienced dose-limiting toxicities (raised alanine aminotransferase, n = 2; neutropenia, n = 1; febrile neutropenia, n = 1). Grade ≥3 adverse events were reported in 38/47 patients (81%) treated with olaparib capsules plus gemcitabine; most common were haematological toxicities (55%). Tolerated combinations were olaparib 100 mg b.i.d. capsule (intermittently, days 1-14) plus gemcitabine 600 mg/m(2) and olaparib 100 mg o.d. tablet (intermittently, days 1-14) plus gemcitabine 600 mg/m(2). There were no differences in efficacy observed during the dose-expansion phase. Olaparib 100 mg b.i.d. (intermittent dosing; capsules) plus gemcitabine 600 mg/m(2) is tolerated in advanced solid tumour patients, with no unmanageable/unexpected toxicities. Continuous dosing of olaparib or combination with gemcitabine at doses >600 mg/m(2) was not considered to have an acceptable tolerability profile for further study. NCT00515866. © The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Opioid agonist efficacy predicts the magnitude of tolerance and the regulation of mu-opioid receptors and dynamin-2.

PubMed

Pawar, Mohit; Kumar, Priyank; Sunkaraneni, Soujanya; Sirohi, Sunil; Walker, Ellen A; Yoburn, Byron C

2007-06-01

It has been proposed that opioid agonist efficacy may play a role in tolerance and the regulation of opioid receptor density. To address this issue, the present studies estimated the in vivo efficacy of three opioid agonists and then examined changes in spinal mu-opioid receptor density following chronic treatment in the mouse. In addition, tolerance and regulation of the trafficking protein dynamin-2 were determined. To evaluate efficacy, the method of irreversible receptor alkylation was employed and the efficacy parameter tau estimated. Mice were injected with the irreversible mu-opioid receptor antagonist clocinnamox (0.32-25.6 mg/kg, i.p), and 24 h later, the analgesic potency of s.c. morphine, oxycodone and etorphine were determined. Clocinnamox dose-dependently antagonized the analgesic effects of morphine, etorphine and oxycodone. The shift to the right of the dose-response curves was greater for morphine and oxycodone compared to etorphine and the highest dose of clocinnamox reduced the maximal effect of morphine and oxycodone, but not etorphine. The order of efficacy calculated from these results was etorphine>morphine>oxycodone. Other mice were infused for 7 days with oxycodone (10-150 mg/kg/day, s.c.) or etorphine (50-250 microg/kg/day, s.c.) and the analgesic potency of s.c. morphine determined. The low efficacy agonist (oxycodone) produced more tolerance than the high efficacy agonist (etorphine) at equi-effective infusion doses. In saturation binding experiments, the low efficacy opioid agonists (morphine, oxycodone) did not regulate the density of spinal mu-opioid receptors, while etorphine produced approximately 40% reduction in mu-opioid receptor density. Furthermore, etorphine increased spinal dynamin-2 abundance, while oxycodone did not produce any significant change in dynamin-2 abundance. Overall, these data indicate that high efficacy agonists produce less tolerance at equi-effective doses. Furthermore, increased efficacy was associated with mu-opioid receptor downregulation and dynamin-2 upregulation. Conversely, lower efficacy agonists produced more tolerance at equi-effective doses, but did not regulate mu-opioid receptor density or dynamin-2 abundance. Taken together, these studies indicate that agonist efficacy plays an important role in tolerance and regulation of receptors and trafficking proteins.

The safety, tolerability, pharmacokinetics and cognitive effects of GSK239512, a selective histamine H₃ receptor antagonist in patients with mild to moderate Alzheimer's disease: a preliminary investigation.

PubMed

Nathan, Pradeep J; Boardley, Rebecca; Scott, Nicola; Berges, Alienor; Maruff, Paul; Sivananthan, Tharani; Upton, Neil; Lowy, Martin T; Nestor, Peter J; Lai, Robert

2013-03-01

The histamine H3 receptor plays a critical role in the negative neuromodulation of neurotransmitters involved in cognitive function. H3 receptor antagonists/inverse agonists have been shown to exert pro-cognitive effects in pre-clinical models. GSK239512 is a potent and selective H₃ receptor antagonist developed for the treatment of cognitive dysfunction in neurodegenerative disorders. In this study we examined the safety, tolerability, pharmacokinetics and pro-cognitive effects of GSK239512 (oral) in patients with mild to moderate Alzheimer's disease using ascending dose titration regimens. The study was conducted in two parts. Part A was a single-blind, placebo run-in, flexible dose titration over 9 days in two cohorts, each consisting of two patients. Part B was a double-blind, randomised, placebo controlled, parallel group, which investigated 3 flexible dose titration regimens over 4 weeks in 3 cohorts, each consisting of eight patients. Overall, the 5/10/20/40 μg and 10/20/40/80 μg regimens were well-tolerated. The regimen of 20/40/80/150 μg showed the poorest tolerability likely due to the higher starting dose. There were no clinically significant abnormalities in haematology, clinical chemistry, urinalysis parameters and cardiovascular parameters. GSK239512 had positive effects on tasks of attention and memory with effect sizes between 0.56 and 1.37. GSK239512 displayed asatisfactory level of tolerability in patients with Alzheimer's disease with evidence for positive effects on attention and memory. The findings suggest that a titration regimen with a starting dose of 5-10 μg and a maximum dose of 80 μg is likely to be a well-tolerated and potentially efficacious regimen for future clinical trials in patients with Alzheimer's disease. These findings await replication in a larger study.

Case Example of Dose Optimization Using Data From Bortezomib Dose-Finding Clinical Trials

PubMed Central

Backenroth, Daniel; Cheung, Ying Kuen Ken; Hershman, Dawn L.; Vulih, Diana; Anderson, Barry; Ivy, Percy; Minasian, Lori

2016-01-01

Purpose The current dose-finding methodology for estimating the maximum tolerated dose of investigational anticancer agents is based on the cytotoxic chemotherapy paradigm. Molecularly targeted agents (MTAs) have different toxicity profiles, which may lead to more long-lasting mild or moderate toxicities as well as to late-onset and cumulative toxicities. Several approved MTAs have been poorly tolerated during long-term administration, leading to postmarketing dose optimization studies to re-evaluate the optimal treatment dose. Using data from completed bortezomib dose-finding trials, we explore its toxicity profile, optimize its dose, and examine the appropriateness of current designs for identifying an optimal dose. Patients and Methods We classified the toxicities captured from 481 patients in 14 bortezomib dose-finding studies conducted through the National Cancer Institute Cancer Therapy Evaluation Program, computed the incidence of late-onset toxicities, and compared the incidence of dose-limiting toxicities (DLTs) among groups of patients receiving different doses of bortezomib. Results A total of 13,008 toxicities were captured: 46% of patients’ first DLTs and 88% of dose reductions or discontinuations of treatment because of toxicity were observed after the first cycle. Moreover, for the approved dose of 1.3 mg/m2, the estimated cumulative incidence of DLT was > 50%, and the estimated cumulative incidence of dose reduction or treatment discontinuation because of toxicity was nearly 40%. Conclusions When considering the entire course of treatment, the approved bortezomib dose exceeds the conventional ceiling DLT rate of 20% to 33%. Retrospective analysis of trial data provides an opportunity for dose optimization of MTAs. Future dose-finding studies of MTAs should take into account late-onset toxicities to ensure that a tolerable dose is identified for future efficacy and comparative trials. PMID:26926682

Case Example of Dose Optimization Using Data From Bortezomib Dose-Finding Clinical Trials.

PubMed

Lee, Shing M; Backenroth, Daniel; Cheung, Ying Kuen Ken; Hershman, Dawn L; Vulih, Diana; Anderson, Barry; Ivy, Percy; Minasian, Lori

2016-04-20

The current dose-finding methodology for estimating the maximum tolerated dose of investigational anticancer agents is based on the cytotoxic chemotherapy paradigm. Molecularly targeted agents (MTAs) have different toxicity profiles, which may lead to more long-lasting mild or moderate toxicities as well as to late-onset and cumulative toxicities. Several approved MTAs have been poorly tolerated during long-term administration, leading to postmarketing dose optimization studies to re-evaluate the optimal treatment dose. Using data from completed bortezomib dose-finding trials, we explore its toxicity profile, optimize its dose, and examine the appropriateness of current designs for identifying an optimal dose. We classified the toxicities captured from 481 patients in 14 bortezomib dose-finding studies conducted through the National Cancer Institute Cancer Therapy Evaluation Program, computed the incidence of late-onset toxicities, and compared the incidence of dose-limiting toxicities (DLTs) among groups of patients receiving different doses of bortezomib. A total of 13,008 toxicities were captured: 46% of patients' first DLTs and 88% of dose reductions or discontinuations of treatment because of toxicity were observed after the first cycle. Moreover, for the approved dose of 1.3 mg/m(2), the estimated cumulative incidence of DLT was > 50%, and the estimated cumulative incidence of dose reduction or treatment discontinuation because of toxicity was nearly 40%. When considering the entire course of treatment, the approved bortezomib dose exceeds the conventional ceiling DLT rate of 20% to 33%. Retrospective analysis of trial data provides an opportunity for dose optimization of MTAs. Future dose-finding studies of MTAs should take into account late-onset toxicities to ensure that a tolerable dose is identified for future efficacy and comparative trials. © 2016 by American Society of Clinical Oncology.

Preclinical safety profile of trastuzumab emtansine (T-DM1): Mechanism of action of its cytotoxic component retained with improved tolerability

DOE Office of Scientific and Technical Information (OSTI.GOV)

Poon, Kirsten Achilles, E-mail: achilles.kirsten@gene.com; Flagella, Kelly; Beyer, Joseph

2013-12-01

Trastuzumab emtansine (T-DM1) is the first antibody-drug conjugate (ADC) approved for patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. The therapeutic premise of ADCs is based on the hypothesis that targeted delivery of potent cytotoxic drugs to tumors will provide better tolerability and efficacy compared with non-targeted delivery, where poor tolerability can limit efficacious doses. Here, we present results from preclinical studies characterizing the toxicity profile of T-DM1, including limited assessment of unconjugated DM1. T-DM1 binds primate ErbB2 and human HER2 but not the rodent homolog c-neu. Therefore, antigen-dependent and non-antigen-dependent toxicity was evaluated in monkeysmore » and rats, respectively, in both single- and repeat-dose studies; toxicity of DM1 was assessed in rats only. T-DM1 was well tolerated at doses up to 40 mg/kg (∼ 4400 μg DM1/m{sup 2}) and 30 mg/kg (∼ 6000 μg DM1/m{sup 2}) in rats and monkeys, respectively. In contrast, DM1 was only tolerated up to 0.2 mg/kg (1600 μg DM1/m{sup 2}). This suggests that at least two-fold higher doses of the cytotoxic agent are tolerated in T-DM1, supporting the premise of ADCs to improve the therapeutic index. In addition, T-DM1 and DM1 safety profiles were similar and consistent with the mechanism of action of DM1 (i.e., microtubule disruption). Findings included hepatic, bone marrow/hematologic (primarily platelet), lymphoid organ, and neuronal toxicities, and increased numbers of cells of epithelial and phagocytic origin in metaphase arrest. These adverse effects did not worsen with chronic dosing in monkeys and are consistent with those reported in T-DM1-treated patients to date. - Highlights: • T-DM1 was well tolerated in preclinical studies in rats and cynomolgus monkeys. • T-DM1 is associated with bone marrow/hematologic, hepatic, and neuronal toxicities. • T-DM1 toxicities are related to DM1 mechanisms of action and pharmacologic activity. • When conjugated in T-DM1, higher doses of DM1 can be tolerated. • Antibody-drug conjugates may improve the therapeutic window for cytotoxic agents.« less

Is oral immunotherapy the cure for food allergies?

PubMed

Nowak-Wegrzyn, Anna; Fiocchi, Alessandro

2010-06-01

To review current evidence on food oral immunotherapy (OIT). Desensitized state, defined as the ingestion of a substantial amount of food in the home diet that protects from severe reactions to accidental exposures, can be achieved by approximately 50-75% of the children treated with OIT. The rate of permanent tolerance is unknown; the longer duration of OIT may result in permanent tolerance. Side effects are common both during the initial dose escalation and during home dosing. Most reactions are mild (oral pruritus, abdominal discomfort, and rashes) and decrease in frequency with the longer duration of OIT. Severe reactions treated with epinephrine have been reported during home dosing. Factors associated with increased risk of reactions to previously tolerated doses during home dosing include exercise, viral infection, dosing on empty stomach, menses, and asthma exacerbation. These preliminary data on OIT are encouraging. Additional studies must answer multiple questions including optimal dose, ideal duration of oral/sublingual immunotherapy, degree of protection, efficacy for different ages, severity and type of food allergy responsive to treatment and need for patient protection during home administration. Until these questions are answered in rigorous multicenter randomized and placebo-controlled trials, OIT remains an experimental approach with not sufficiently well established risk-to-benefit ratio.

Sodium phenylbutyrate in Huntington's disease: a dose-finding study.

PubMed

Hogarth, Penelope; Lovrecic, Luca; Krainc, Dimitri

2007-10-15

Transcriptional dysregulation in Huntington's disease (HD) is mediated in part by aberrant patterns of histone acetylation. We performed a dose-finding study in human HD of sodium phenylbutyrate (SPB), a histone deacetylase inhibitor that ameliorates the HD phenotype in animal models. We used a dose-escalation/de-escalation design, using prespecified toxicity criteria and standard clinical and laboratory safety measures. The maximum tolerated dose was 15 g/day. At higher doses, toxicity included vomiting, lightheadedness, confusion, and gait instability. We saw no significant laboratory or electrocardiographic abnormalities. Gene expression changes in blood suggested an inverse dose-response. In conclusion, SPB at 12 to 15 g/day appears to be safe and well-tolerated in human HD. 2007 Movement Disorder Society

New approach for food allergy management using low-dose oral food challenges and low-dose oral immunotherapies.

PubMed

Yanagida, Noriyuki; Okada, Yu; Sato, Sakura; Ebisawa, Motohiro

2016-04-01

A number of studies have suggested that a large subset of children (approximately 70%) who react to unheated milk or egg can tolerate extensively heated forms of these foods. A diet that includes baked milk or egg is well tolerated and appears to accelerate the development of regular milk or egg tolerance when compared with strict avoidance. However, the indications for an oral food challenge (OFC) using baked products are limited for patients with high specific IgE values or large skin prick test diameters. Oral immunotherapies (OITs) are becoming increasingly popular for the management of food allergies. However, the reported efficacy of OIT is not satisfactory, given the high frequency of symptoms and requirement for long-term therapy. With food allergies, removing the need to eliminate a food that could be consumed in low doses could significantly improve quality of life. This review discusses the importance of an OFC and OIT that use low doses of causative foods as the target volumes. Utilizing an OFC or OIT with a low dose as the target volume could be a novel approach for accelerating the tolerance to causative foods. Copyright © 2015 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.

Safety and tolerability of the Easy Vax™ clinical epidermal electroporation system in healthy adults.

PubMed

El-Kamary, Samer S; Billington, Melissa; Deitz, Stephen; Colby, Elaina; Rhinehart, Howard; Wu, Yukun; Blackwelder, William; Edelman, Robert; Lee, Albert; King, Alan

2012-01-01

DNA vaccines are cost-effective and versatile, though intracellular delivery has been challenging in humans. Alternative delivery modalities such as electroporation have demonstrated improved immune responses, but are painful. In this single-center, double-blind, medical device trial, we evaluated the safety and tolerability of Easy Vax™ dermal electroporation system, alone (without DNA) in healthy adults. Three randomized protocol doses were administered to 10 subjects (80% white, 60% female, mean age: 32.1 years) in each of two areas (total of six doses). Two subjects complained of shooting pain, burning and/or tingling when doses were administered to the forearm region, but not the lateral deltoid regions. Subsequent doses for the remaining eight subjects were restricted to the deltoid regions only. Tolerability pain scores never exceeded 3 of 10 in the 11-Point Pain Rating scale, and 12 of 100 in the Visual Analog Scale (VAS), and lower in follow-up evaluations (P < 0.0001), with no significant difference between the three dosing protocols. Electrical properties of the skin, measured automatically by the device, showed no correlation between pain intensity and skin conductance. In conclusion, the Easy Vax™ electroporation device is safe and well tolerated when administered over the lateral deltoid skin regions in healthy volunteers.

Dose-dependent response of Trichoderma harzianum in improving drought tolerance in rice genotypes.

PubMed

Pandey, Veena; Ansari, Mohammad W; Tula, Suresh; Yadav, Sandep; Sahoo, Ranjan K; Shukla, Nandini; Bains, Gurdeep; Badal, Shail; Chandra, Subhash; Gaur, A K; Kumar, Atul; Shukla, Alok; Kumar, J; Tuteja, Narendra

2016-05-01

This study demonstrates a dose-dependent response of Trichoderma harzianum Th-56 in improving drought tolerance in rice by modulating proline, SOD, lipid peroxidation product and DHN / AQU transcript level, and the growth attributes. In the present study, the effect of colonization of different doses of T. harzianum Th-56 strain in rice genotypes were evaluated under drought stress. The rice genotypes treated with increasing dose of T. harzianum strain Th-56 showed better drought tolerance as compared with untreated control plant. There was significant change in malondialdehyde, proline, higher superoxide dismutase level, plant height, total dry matter, relative chlorophyll content, leaf rolling, leaf tip burn, and the number of scorched/senesced leaves in T. harzianum Th-56 treated rice genotypes under drought stress. This was corroborated with altered expression of aquaporin and dehydrin genes in T. harzianum Th-56 treated rice genotypes. The present findings suggest that a dose of 30 g/L was the most effective in improving drought tolerance in rice, and its potential exploitation will contribute to the advancement of rice genotypes to sustain crop productivity under drought stress. Interaction studies of T. harzianum with three aromatic rice genotypes suggested that PSD-17 was highly benefitted from T. harzianum colonization under drought stress.

Safety, tolerability, and cerebrospinal fluid penetration of ursodeoxycholic Acid in patients with amyotrophic lateral sclerosis.

PubMed

Parry, Gareth J; Rodrigues, Cecilia M P; Aranha, Marcia M; Hilbert, Sarah J; Davey, Cynthia; Kelkar, Praful; Low, Walter C; Steer, Clifford J

2010-01-01

Amyotrophic lateral sclerosis is a progressive degenerative disease, which typically leads to death in 3 to 5 years. Neuronal cell death offers a potential target for therapeutic intervention. Ursodeoxycholic acid is a cytoprotective, endogenous bile acid that has been shown to be neuroprotective in experimental Huntington and Alzheimer diseases, retinal degeneration, and ischemic and hemorrhagic stroke. The objective of this research was to study the safety and the tolerability of ursodeoxycholic acid in amyotrophic lateral sclerosis and document effective and dose-dependent cerebrospinal fluid penetration. Eighteen patients were randomly assigned to receive ursodeoxycholic acid at doses of 15, 30, and 50 mg/kg of body weight per day. Serum and cerebrospinal fluid were obtained for analysis after 4 weeks of treatment. Treatment-emergent clinical and laboratory events were monitored weekly. Our data indicated that ursodeoxycholic acid is well tolerated by all subjects at all doses. We also showed that ursodeoxycholic acid is well absorbed after oral administration and crosses the blood-brain barrier in a dose-dependent manner. These results show excellent safety and tolerability of ursodeoxycholic acid. The drug penetrates the cerebrospinal fluid in a dose-dependent manner. A large, placebo-controlled clinical trial is needed to assess the efficacy of ursodeoxycholic acid in treating amyotrophic lateral sclerosis.

DDD pacemaker for severe heart failure-alternate to CRT.

PubMed

Krishnamani, N C

Patients with severe systolic Heart Failure continue to have poor quality of life and increased mortality in spite of optimal medical management. Cardiac Resynchronization Therapy [CRT] is promising modality in patients with systolic heart failure and electrocardiographic [ECG] evidence of left bundle branch block [LBBB]. Cost issues continue to elude many deserving cases of this therapy in our society. Relatively cost effective Dual chamber pacing [DDD] with right atrial and isolated left ventricular pacing [RA-LV] can be a good alternative. Copyright © 2016 Cardiological Society of India. Published by Elsevier B.V. All rights reserved.

Microstructural comparison of the kinematics of discrete and continuum dislocations models

NASA Astrophysics Data System (ADS)

Sandfeld, Stefan; Po, Giacomo

2015-12-01

The Continuum Dislocation Dynamics (CDD) theory and the Discrete Dislocation Dynamics (DDD) method are compared based on concise mathematical formulations of the coarse graining of discrete data. A numerical tool for converting from a discrete to a continuum representation of a given dislocation configuration is developed, which allows to directly compare both simulation approaches based on continuum quantities (e.g. scalar density, geometrically necessary densities, mean curvature). Investigating the evolution of selected dislocation configurations within analytically given velocity fields for both DDD and CDD reveals that CDD contains a surprising number of important microstructural details.

High ventricular lead impedance of a DDD pacemaker after cranial magnetic resonance imaging.

PubMed

Baser, Kazim; Guray, Umit; Durukan, Mine; Demirkan, Burcu

2012-09-01

Management of electromagnetic interference in the form of magnetic resonance imaging (MRI) in patients with pacemakers (PMs) may be challenging. Serious consequences, especially in PM-dependent patients, may be encountered. Changes in device programming, asynchronous pacing, heating of the lead tip(s), and increased thresholds or even device dislocation may be experienced. We report of a patient with a DDD PM who underwent an emergent MRI, after which there was an increase in ventricular impedance as well as increased cardiac biomarkers. ©2011, The Authors. Journal compilation ©2012 Wiley Periodicals, Inc.

DDTs in mothers' milk, placenta and hair, and health risk assessment for infants at two coastal and inland cities in China.

PubMed

Man, Yu Bon; Chan, Janet Kit Yan; Wang, Hong Sheng; Wu, Sheng Chun; Wong, Ming Hung

2014-04-01

This study is a one of the very few investigating the dichloro-diphenyl-trichloroethanes (DDTs) (summation of o,p'-DDE, p,p'-DDE, o,p'-DDD, p,p'-DDD, o,p'-DDT, and p,p'-DDT) in multiple human matrices in mothers' milk, placenta and hair collected from residents from two coastal cities: Guiyu (GY) and Taizhou (TZ) and one inland city: Lin'an (LA). TZ (milk: 360±319ng/g lipid wt.) showed significantly higher concentrations of DDTs than those from LA (milk: 190±131ng/g lipid wt.), whereas, concentrations of DDTs in GY (milk: 305±109ng/g lipid wt.) were in between TZ and LA. In addition, levels of DDTs in the human tissues from TZ (placenta: 122±109ng/g lipid wt.; hair: 79.9±215ng/g dry wt.) were significantly higher than those from Lin'an (placenta: 49.2±30.2ng/g lipid wt.; hair: 10.8±7.09ng/g dry wt.). The above concentrations of DDTs in milk exceeded the Codex Maximum Residue Limits/Extraneous Maximum Residue Limits for milk (20ng/g lipid wt. whole milk), indicating that the human milk samples were grossly polluted. The present study revealed that human specimens collected from the coastal city (TZ) were more contaminated with inland one (LA), based on the levels of DDTs contained in samples which may be due to the higher dietary exposure to DDTs via consumption of contaminated seafood. The estimated daily intakes of DDTs by GY, TZ and LA infants were 1.69±1.86, 1.48±0.79, and 0.95±0.73μg/kg body wt./day, respectively which did not exceed 10μg/kg body wt./day, the provisional tolerable daily intake proposed by the Food and Agriculture Organization/World Health Organization. Copyright © 2014 Elsevier Ltd. All rights reserved.

SU-E-T-586: Optimal Determination of Tolerance Level for Radiation Dose Delivery Verification in An in Vivo Dosimetry System

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chen, Y; Souri, S; Gill, G

Purpose: To statistically determine the optimal tolerance level in the verification of delivery dose compared to the planned dose in an in vivo dosimetry system in radiotherapy. Methods: The LANDAUER MicroSTARii dosimetry system with screened nanoDots (optically stimulated luminescence dosimeters) was used for in vivo dose measurements. Ideally, the measured dose should match with the planned dose and falls within a normal distribution. Any deviation from the normal distribution may be redeemed as a mismatch, therefore a potential sign of the dose misadministration. Randomly mis-positioned nanoDots can yield a continuum background distribution. A percentage difference of the measured dose tomore » its corresponding planned dose (ΔD) can be used to analyze combined data sets for different patients. A model of a Gaussian plus a flat function was used to fit the ΔD distribution. Results: Total 434 nanoDot measurements for breast cancer patients were collected across a period of three months. The fit yields a Gaussian mean of 2.9% and a standard deviation (SD) of 5.3%. The observed shift of the mean from zero is attributed to the machine output bias and calibration of the dosimetry system. A pass interval of −2SD to +2SD was applied and a mismatch background was estimated to be 4.8%. With such a tolerance level, one can expect that 99.99% of patients should pass the verification and at most 0.011% might have a potential dose misadministration that may not be detected after 3 times of repeated measurements. After implementation, a number of new start breast cancer patients were monitored and the measured pass rate is consistent with the model prediction. Conclusion: It is feasible to implement an optimal tolerance level in order to maintain a low limit of potential dose misadministration while still to keep a relatively high pass rate in radiotherapy delivery verification.« less

Pharmacokinetics, Pharmacodynamics, and Tolerability of Single and Multiple Doses of Trandolapril, an Effective Angiotensin-Converting Enzyme Inhibitor, in Healthy Chinese Subjects.

PubMed

Li, Xiaojiao; Liu, Chang; Wu, Min; Zhang, Hong; Sun, Yanfu; Cheng, Longmei; Chen, Hong; Liu, Chengjiao; Yang, Lizhi; Zhang, Qi; Cao, Yuchen; Gu, Jingkai; Ding, Yanhua

2016-08-01

Trandolapril is the pro-drug of trandolaprilat, a non-sulfhydryl angiotensin-converting enzyme inhibitor. This study was designed to assess the pharmacokinetics (PK), pharmacodynamics (PD), and tolerability of single and multiple doses of trandolapril in healthy Chinese subjects. Healthy subjects (six men and six women) were randomized into a single-dose, 3 × 3 crossover study (1-2-4 mg, 2-4-1 mg, and 4-1-2 mg), and a multiple-dose study (2 mg/day, 6 days). Serial blood and urine samples were collected after drug administration and analyzed using a validated LC-MS/MS method, and the trandolapril and trandolaprilat PK parameters were obtained. PD was evaluated by the changes in blood pressure and heart rates after dosing. Tolerability was assessed by monitoring adverse events, vital signs, ECGs, and changes in laboratory tests. In the single-dose study, trandolapril was absorbed rapidly, and peak plasma levels (C max, 1.57, 3.77, and 7.99 ng/mL) and AUCs (1.89, 3.46, and 6.47 ng/mL) were dose-dependent. The AUC0-∞ of trandolaprilat was dose-dependent, but in a non-linear fashion. The cumulative urine excretion of trandolapril and trandolaprilat was 5.51, 6.20, and 7.41 % for three doses, respectively. In the multiple-dose study, steady-state pharmacokinetics was observed; there was no trandolapril accumulation, but there was mild trandolaprilat accumulation (R = 1.67). Trandolapril was well tolerated. The most pronounced reductions in blood pressure were observed at 8 h after administration, which was later than T max. No orthostatic hypotension occurred. The pharmacokinetics and pharmacodynamics following single and multiple oral doses trandolapril in healthy Chinese subjects are similar to those observed in non-Chinese healthy subjects.

A rule-based, dose-finding design for use in stroke rehabilitation research: methodological development.

PubMed

Colucci, E; Clark, A; Lang, C E; Pomeroy, V M

2017-12-01

Dose-optimisation studies as precursors to clinical trials are rare in stroke rehabilitation. To develop a rule-based, dose-finding design for stroke rehabilitation research. 3+3 rule-based, dose-finding study. Dose escalation/de-escalation was undertaken according to preset rules and a mathematical sequence (modified Fibonacci sequence). The target starting daily dose was 50 repetitions for the first cohort. Adherence was recorded by an electronic counter. At the end of the 2-week training period, the adherence record indicated dose tolerability (adherence to target dose) and the outcome measure indicated dose benefit (10% increase in motor function). The preset increment/decrease and checking rules were then applied to set the dose for the subsequent cohort. The process was repeated until preset stopping rules were met. Participants had a mean age of 68 (range 48 to 81) years, and were a mean of 70 (range 9 to 289) months post stroke with moderate upper limb paresis. A custom-built model of exercise-based training to enhance ability to open the paretic hand. Repetitions per minute of extension/flexion of paretic digits against resistance. Usability of the preset rules and whether the maximally tolerated dose was identifiable. Five cohorts of three participants were involved. Discernibly different doses were set for each subsequent cohort (i.e. 50, 100, 167, 251 and 209 repetitions/day). The maximally tolerated dose for the model training task was 209 repetitions/day. This dose-finding design is a feasible method for use in stroke rehabilitation research. Copyright © 2017 Chartered Society of Physiotherapy. All rights reserved.

Temporal Lobe Reactions After Carbon Ion Radiation Therapy: Comparison of Relative Biological Effectiveness–Weighted Tolerance Doses Predicted by Local Effect Models I and IV

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gillmann, Clarissa, E-mail: clarissa.gillmann@med.uni-heidelberg.de; Jäkel, Oliver; Heidelberg Ion Beam Therapy Center

2014-04-01

Purpose: To compare the relative biological effectiveness (RBE)–weighted tolerance doses for temporal lobe reactions after carbon ion radiation therapy using 2 different versions of the local effect model (LEM I vs LEM IV) for the same patient collective under identical conditions. Methods and Materials: In a previous study, 59 patients were investigated, of whom 10 experienced temporal lobe reactions (TLR) after carbon ion radiation therapy for low-grade skull-base chordoma and chondrosarcoma at Helmholtzzentrum für Schwerionenforschung (GSI) in Darmstadt, Germany in 2002 and 2003. TLR were detected as visible contrast enhancements on T1-weighted MRI images within a median follow-up time ofmore » 2.5 years. Although the derived RBE-weighted temporal lobe doses were based on the clinically applied LEM I, we have now recalculated the RBE-weighted dose distributions using LEM IV and derived dose-response curves with Dmax,V-1 cm³ (the RBE-weighted maximum dose in the remaining temporal lobe volume, excluding the volume of 1 cm³ with the highest dose) as an independent dosimetric variable. The resulting RBE-weighted tolerance doses were compared with those of the previous study to assess the clinical impact of LEM IV relative to LEM I. Results: The dose-response curve of LEM IV is shifted toward higher values compared to that of LEM I. The RBE-weighted tolerance dose for a 5% complication probability (TD{sub 5}) increases from 68.8 ± 3.3 to 78.3 ± 4.3 Gy (RBE) for LEM IV as compared to LEM I. Conclusions: LEM IV predicts a clinically significant increase of the RBE-weighted tolerance doses for the temporal lobe as compared to the currently applied LEM I. The limited available photon data do not allow a final conclusion as to whether RBE predictions of LEM I or LEM IV better fit better clinical experience in photon therapy. The decision about a future clinical application of LEM IV therefore requires additional analysis of temporal lobe reactions in a comparable photon-treated collective using the same dosimetric variable as in the present study.« less

Dual specific oral tolerance induction using interferon gamma for IgE-mediated anaphylactic food allergy and the dissociation of local skin allergy and systemic oral allergy: tolerance or desensitization?

PubMed

Noh, G; Jang, E H

2014-01-01

Specific oral tolerance induction (SOTI) for IgE-mediated food allergy (IFA) can be successfully achieved using interfero gamma (classic SOTI). In this study, a tolerable dose was introduced during tolerance induction with interferon gamma (dual SOTI), and its effectiveness was evaluated. The study population comprised 25 IFA patients. Blood samples were taken for analysis, including complete blood count with differential counts of eosinophils, serum total IgE levels, and specific IgE for allergenic foods. Skin prick tests were conducted with the allergens. Oral food challenges were performed to diagnose IFA. Ten patients received dual SOTI, 5 received classic SOTI, 5 received SOTI without interferon gamma (original SOTI), and 5 were not treated (controls). Patients treated with dual SOTI and classic SOTI using interferon gamma became tolerant to the allergenic food. The tolerable dose was introduced successfully in dual SOTI. It was difficult to proceed with the same dosing protocol used for classic SOTI in cases treated with original SOTI. Following dual SOTI, the systemic reaction to oral intake subsided, but the local skin reaction to contact with the allergenic food persisted. Dual SOTI is an improved protocol for SOTI using interferon gamma for IFA.The local skin reaction and systemic reaction to oral intake were dissociated following dual SOTI. In cases of food allergy, tolerance appears to result from desensitization to allergens.

LJM716 in Japanese patients with head and neck squamous cell carcinoma or HER2-overexpressing breast or gastric cancer.

PubMed

Takahashi, Shunji; Kobayashi, Takayuki; Tomomatsu, Junichi; Ito, Yoshinori; Oda, Hisanobu; Kajitani, Tatsuhiro; Kakizume, Tomoyuki; Tajima, Takeshi; Takeuchi, Hiromi; Maacke, Heiko; Esaki, Taito

2017-01-01

Human epidermal growth factor receptor 3 (HER3) has been identified as an important component of many receptor tyrosine kinase-driven cancers. LJM716 is a human IgG monoclonal antibody that binds HER3, trapping it in an inactive conformation. In this study, a phase I dose escalation was performed with a primary objective to establish the maximum tolerated dose and/or the recommended dose of LJM716 in Japanese patients with selected advanced solid tumors. Secondary objectives included the evaluation of the safety and tolerability, preliminary antitumor activity, and pharmacokinetics of LJM716 in Japanese patients. LJM716 was administered intravenously at doses of 10, 20, or 40 mg/kg once weekly, in 28-day cycles, to 12 patients with HER2-amplified breast cancer or gastric cancer, or with esophageal squamous cell carcinoma or squamous cell carcinoma of the head and neck, regardless of HER2 status. The maximum tolerated dose was not reached, and the recommended dose was established at 40 mg/kg. No dose-limiting toxicities were observed in the first cycle. The most frequently reported adverse events were diarrhea, fatigue, stomatitis, pyrexia, and paronychia. One unconfirmed partial response was observed in a patient with breast cancer, and 50% of the patients achieved stable disease as the best overall response. Exposure increased with ascending dose, and half-life was estimated to be 11-14 days. No anti-LJM716 antibodies were detected. LJM716 was well tolerated in Japanese patients, and a degree of tumor shrinkage was observed. ClinicalTrials.gov NCT01911936.

Half doses of PEG-ES and senna vs. high-dose senna for bowel cleansing before colonoscopy: a randomized, investigator-blinded trial.

PubMed

Amato, Arnaldo; Radaelli, Franco; Paggi, Silvia; Terruzzi, Vittorio

2010-03-01

Patients' compliance with and tolerance of large-volume polyethylene glycol electrolyte solution (PEG-ES) have prompted continuous investigation with alternative forms of cleansing. High-dose senna is superior to PEG-ES for the quality of bowel cleansing, patient compliance, and tolerance, but its acceptance may be influenced by the incidence of abdominal pain. We hypothesized that a combination of half doses of PEG-ES and senna could minimize the incidence of abdominal pain without affecting the quality of bowel preparation. This randomized, investigator-blinded trial has been conducted on consecutive outpatients scheduled for elective colonoscopy at a single community-based hospital. Patients were randomly assigned to receive either 12 tablets of 12 mg senna and 2 l of PEG-ES (half-dose group, HDG) or 24 tablets of senna divided in two doses (senna group, SG) the day before colonoscopy. The main outcome measures were the quality of colon cleansing (Aronchick scoring scale) and the incidence of preparation-related abdominal pain. Secondary outcome measures were patients' compliance with the cleansing regimen, overall tolerability, prevalence of predefined side effects, and quality of right colon cleansing. A total of 296 patients were enrolled (HDG=151 and SG=145). Overall cleansing was excellent to good in 90.1 and 88.3% patients in HDG and SG, respectively (P=0.62). Preparation-related moderate-to-severe abdominal pain was reported by 6% patients in HDG and 15.2% in SG (P=0.009). No significant differences were observed for secondary outcomes. The regimen combining half doses of PEG-ES and senna provides high-quality bowel preparation and acceptable patient tolerance, with less abdominal pain compared with high-dose senna.

Biomarker-guided clinical development of the first-in-class anti-inflammatory FPR2/ALX agonist ACT-389949.

PubMed

Stalder, Anna K; Lott, Dominik; Strasser, Daniel S; Cruz, Hans G; Krause, Andreas; Groenen, Peter M A; Dingemanse, Jasper

2017-03-01

The main objectives of these two phase I studies were to investigate safety and tolerability as well as the pharmacokinetic/pharmacodynamic profile of the novel potent and selective formyl peptide receptor type 2 (FPR2)/Lipoxin A 4 receptor (ALX) agonist ACT-389949. A challenge model was used to assess the drug's anti-inflammatory potential, with the aim of selecting a dosing regimen for future patient studies. Two double-blind, randomized phase I studies investigated the safety, tolerability, pharmacokinetics and pharmacodynamics of ACT-389949 at different doses and dosing regimens. Drug exposure was correlated with target engagement markers such as receptor internalization and cytokine measurements. The effect of FPR2/ALX agonism on neutrophil migration was studied in a lipopolysaccharide (LPS) inhalation model. ACT-389949 was well tolerated. Maximum concentrations were reached around 2 h after dosing, with a mean terminal half-life of 29.3 h [95% confidence interval (CI) 25.5, 33.7]. After multiple-dose administration, exposure increased by 111% (95% CI 89, 136), indicating drug accumulation. Administration of ACT-389949 resulted in a dose-dependent, long-lasting internalization of FPR2/ALX into leukocytes. Pro- and anti-inflammatory cytokines were dose-dependently but transiently upregulated only after the first dose. No pharmacological effect on neutrophil count was observed in the LPS challenge test performed at steady state. FPR2/ALX agonism with ACT-389949 was shown to be safe and well tolerated in healthy subjects. Receptor internalization and downstream mediators pointed towards a desensitization of the system, which may explain the lack of effect on neutrophil recruitment in the LPS challenge model. © 2016 The British Pharmacological Society.

Evaluation of Emergency Department Management of Opioid-Tolerant Cancer Patients With Acute Pain.

PubMed

Patel, Pina M; Goodman, Lauren F; Knepel, Sheri A; Miller, Charles C; Azimi, Asma; Phillips, Gary; Gustin, Jillian L; Hartman, Amber

2017-10-01

There are no previously published studies examining opioid doses administered to opioid-tolerant cancer patients during emergency department (ED) encounters. To determine if opioid-tolerant cancer patients presenting with acute pain exacerbations receive adequate initial doses of as needed (PRN) opioids during ED encounters based on home oral morphine equivalent (OME) use. We performed a retrospective cohort study of opioid-tolerant cancer patients who received opioids in our ED over a two-year period. The percentage of patients who received an adequate initial dose of PRN opioid (defined as ≥10% of total 24-hour ambulatory OME) was evaluated. Logistic regression was used to establish the relationship between 24-hour ambulatory OME and initial ED OME to assess whether higher home usage was associated with higher likelihood of being undertreated. Out of 216 patients, 61.1% of patients received an adequate initial PRN dose of opioids in the ED. Of patients taking <200 OMEs per day at home, 77.4% received an adequate initial dose; however, only 3.2% of patients taking >400 OMEs per day at home received an adequate dose. Patients with ambulatory 24-hour OME greater than 400 had 99% lower odds of receiving an adequate initial dose of PRN opioid in the ED compared to patients with ambulatory 24-hour OME less than 100 (OR <0.01, CI 0.00-0.02, P < 0.001). Patients with daily home use less than 200 OMEs generally received adequate initial PRN opioid doses during their ED visit. However, patients with higher home opioid usage were at increased likelihood of being undertreated. Copyright © 2017 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.

Biosimilar granulocyte colony-stimulating factor uptakes in the EU-5 markets: a descriptive analysis.

PubMed

Bocquet, François; Paubel, Pascal; Fusier, Isabelle; Cordonnier, Anne-Laure; Le Pen, Claude; Sinègre, Martine

2014-06-01

Biosimilars are copies of biological reference medicines. Unlike generics (copies of chemical molecules), biologics are complex, expensive and complicated to produce. The knowledge of the factors affecting the competition following patent expiry for biologics remains limited. The aims of this study were to analyse the EU-5 Granulocyte-Colony Stimulating Factor (G-CSF) markets and to determine the factors affecting the G-CSF biosimilar uptakes, particularly that of biosimilar prices relative to originators. Data on medicine volumes, values, and ex-manufacturer prices for all G-CSF categories were provided by IMS Health. Volumes were calculated in defined daily doses (DDD) and prices in Euros per DDD. In the EU-5 countries, there is 5 years of experience with biosimilar G-CSFs (2007-2011). Two G-CSF market profiles exist: (1) countries with a high retail market distribution, which are the largest G-CSF markets with low global G-CSF biosimilar uptakes (5.4% in France and 8.5% in Germany in 2011); and (2) countries with a dominant hospital channel, which are the smallest markets with higher G-CSF biosimilar uptakes (12.4% in Spain and 20.4% in the UK). The more the decisions are decentralized, the more their uptakes are high. The price difference between G-CSF biosimilars and their reference plays a marginal role at a global level (price differences of +13.3% in the UK and -20.4% in France). The competition with G-CSF biosimilars varies significantly between EU-5 countries, probably because of G-CSF distribution channel differences. Currently, this competition is not mainly based on prices, but on local political options to stimulate tendering between them and recently branded second- or third-generation products.

European Surveillance of Antimicrobial Consumption (ESAC): outpatient parenteral antibiotic treatment in Europe.

PubMed

Coenen, Samuel; Muller, Arno; Adriaenssens, Niels; Vankerckhoven, Vanessa; Hendrickx, Erik; Goossens, Herman

2009-07-01

To assess the proportion of parenteral treatment of the total outpatient antibiotic use in Europe, and to identify the antibiotic groups and individual antibiotics most commonly administered in this way. Within the European Surveillance of Antimicrobial Consumption (ESAC; www.esac.ua.ac.be), using the anatomic therapeutic chemical (ATC) and defined daily dose (DDD) classification, data on outpatient use of antibacterials for systemic use (ATC J01), aggregated at the level of the active substance and expressed in DDD per 1000 inhabitants per day (DID; WHO version 2007), were extracted for 2006 by route of administration and by country. Parenteral use was expressed as a percentage of the total outpatient use in DID. In 20 European countries, the total outpatient antibiotic use ranged from 27.91 DID in France to 9.58 DID in Russia. The proportion of outpatient parenteral antibiotic treatment ranged from 6.75% in Russia to 0.001% in Iceland. The three most commonly used antibiotic groups for parenteral treatment in Europe were the cephalosporins (J01D; 44.58%), the aminoglycosides (J01G; 25.27%) and the penicillins (J01C; 17.78%). Four antibiotics [gentamicin (J01GB03) 18.53%; ceftriaxone (J01DD04) 17.85%; cefazolin (J01DB04) 13.16%; and lincomycin (J01FF02) 5.47%] represented more than half of the use. In all 20 European countries studied together, 2.04% of outpatient antibiotics were used for parenteral treatment. However, as for the total outpatient antibiotic use and the use of different antibiotic groups and antibiotics, there is a striking variation in the proportions of parenteral antibiotic use in Europe. More in-depth data on outpatient antibiotic use are needed to explain this variation.

Impact of the implementation of a Sepsis Code hospital protocol in antibiotic prescription and clinical outcomes in an intensive care unit.

PubMed

García-López, L; Grau-Cerrato, S; de Frutos-Soto, A; Bobillo-De Lamo, F; Cítores-Gónzalez, R; Diez-Gutierrez, F; Muñoz-Moreno, M F; Sánchez-Sánchez, T; Gandía-Martínez, F; Andaluz-Ojeda, D

A study was performed to analyze the impact of an in-hospital Sepsis Code (SC) program on use of antibiotic and clinical outcomes. Quasi-experimental observational retrospective study. Polyvalent 11 beds ICU belonging to a tertiary Universitary hospital. Patients admitted consecutively to the ICU with diagnosis of severe sepsis or septic shock. A post intervention group (POST-SC) (September 2012-August 2013) was compared with a historical group (PRE-SC) used as control (January-December 2010). Antibiotic treatment, therapeutic antibiotic strategy, mortality and length of stay. Antibiotic consumption was expressed as defined daily doses (DDD)/ 100 stays. 42 patients with SS/SS in POST-SC group and 50 patients in PRE-SC group were consecutively recluted and further analyzed. Total antibiotic consumption (DDD) was similar in both groups. Rate of de-escalation therapy was significantly higher in POST-SC group (75% vs 30,8%, p<0,005) while prescription of restricted antibiotics was significantly lower (74% vs 52%, p=0,031). Finally POST-SC patients showed a significantly decrease in hospital and 28 days mortality rates [23% vs 44%, (p=0,035) and 31% vs 56% (p=0,014) respectively] as well as a reduction in ICU length of stay compared to PRE-SC cohort (5 days vs 10,5 days, p=0,05). The implementation of a Sepsis Code-hospital protocol is associated to an improvement in the management of antibiotic therapy with a significant increase in de-escalation therapy and lesser utilization of restricted use antibiotics, as well as a significant reduction in mortality, and a tendency towards shorter ICU length stay. Copyright © 2016 Elsevier España, S.L.U. y SEMICYUC. All rights reserved.

Antiretroviral drug expenditure, pricing and judicial demand: an analysis of federal procurement data in Brazil from 2004–2011

PubMed Central

2014-01-01

Background Previous studies have described expenditures for antiretroviral (ARV) medicines in Brazil through 2005. While prior studies examined overall expenditures, they have not have analyzed drug procurement data in order to describe the role of court litigation on access and pricing. Methods ARV drug procurement from private sector sources for the years 2004–2011 was obtained through the general procurement database of the Brazilian Federal Government (SIASG). Procurement was measured in Defined Daily Doses (DDD) per 1000 persons-under-treatment per day. Expenditures and price per DDD were calculated and expressed in U.S. Dollars. Justifications for ARV purchases were examined in order to determine the relationship between health litigation and incorporation into Brazil’s national treatment guidelines. Results Drug procurement of ARVs from private sources underwent marked expansion in 2005, peaked in 2009, and stabilized to 2008 levels by 2011. Expenditures followed procurement curves. Medications which were procured for the first time after 2007 cost more than medicines which were introduced before 2007. Judicial actions initially resulted in purchases of newer medications for a select number of patients in Brazil but ultimately expanded availability to a larger population through incorporation into the national treatment guidelines. Conclusions Drug procurement and expenditures for ARVs in Brazil varied between 2004–2011. The procurement of some drugs from the private sector ceased after public manufacturers started producing them locally. Judicial demand has resulted in the incorporation of newer drugs into the national treatment guidelines. In order for the AIDS treatment program to remain sustainable, efforts should be pursued to reduce prices through generic drugs, price negotiation and other public health flexibilities such as compulsory licensing. PMID:24735589

[Antimicrobial consumption reported through standardized reports on infection control activities, relationship with the ICATB public reporting indicator].

PubMed

Henard, S; Rahib, D; Léon, L; Amadéo, B; Dumartin, C; Cavalié, P; Coignard, B

2011-04-01

The study's objective was to describe the evolution of antibiotic consumption between 2006 and 2008 in French health care facilities (HCF) its relations with the national policy of good antibiotics use using the ICATB score. Data from standardized reports on infection control activities collected from 2006 to 2008 by the Ministry of Health (antibiotic consumptions and elements of antibiotic stewardship of every HCF) were analyzed with linear regression models to multilevel random intercept adjusted on HCF characteristics (public or private) and activity. The analysis was performed on 4062 (48,2%) observations after exclusion of HCF not concerned by the ICATB public reporting indicator (7.2% of observations), invalid or missing data (21,2% of observations) and irrelevant values (23.4%). The global antibiotic consumption was 343 defined daily doses (DDD) per 1000 patient-days (PD) and varied little between 2006 and 2008. However, the linear regression model showed an increase of 5.7 DDD per 1000 PDs per year (P<0.001). There was a positive association between antibiotic consumption and ICATB score, mainly concerning sub-scores ICATB-action and ICATB-organization. The recent lack of decrease in antibiotic consumption in French HCF between 2006 and 2008 is coherent with other available national data, but exclusion of more than 50% of observations limits the impact of this analysis. The relationship between policy of good use and consumption of antibiotics remain difficult to specify, because of the short (three years) study length and because of the nature of ICATB, a composite indicator assessing only partly antibiotic policies. Copyright © 2010 Elsevier Masson SAS. All rights reserved.

Twenty‐five years of prescription opioid use in Australia: a whole‐of‐population analysis using pharmaceutical claims

PubMed Central

Karanges, Emily A.; Blanch, Bianca; Buckley, Nicholas A.

2016-01-01

Aim The aim of this paper is to investigate 25‐year trends in community use of prescribed opioid analgesics in Australia, and to map these trends against major changes to opioid registration and subsidy. Methods We obtained dispensing data from 1990 to 2014 from two sources: dispensing claims processed under Australia's national drug subsidy programme, the Pharmaceutical Benefits Scheme, including under co‐payment records from 2012; and estimates of non‐subsidized medicine use from a survey of Australian pharmacies (until 2011). Utilization was expressed in defined daily doses (DDD)/1000 population/day. Results Opioid dispensing increased almost four‐fold between 1990 and 2014, from 4.6 to 17.4 DDD/1000 pop/day. In 1990, weak, short‐acting or orally administered opioids accounted for over 90% of utilization. Use of long‐acting opioids increased over 17‐fold between 1990 and 2000, due primarily to the subsidy of long‐acting morphine and increased use of methadone for pain management. Between 2000 and 2011, oxycodone, fentanyl, buprenorphine, tramadol and hydromorphone use increased markedly. Use of strong opioids, long‐acting and transdermal preparations also increased, largely following the subsidy of various opioids for noncancer pain. In 2011, the most dispensed opioids were codeine (41.1% of total opioid use), oxycodone (19.7%) and tramadol (16.1%); long‐acting formulations comprised approximately half, and strong opioids 40%, of opioid dispensing. Conclusions Opioid utilization in Australia is increasing, although these figures remain below levels reported in the US and Canada. The increased use of opioids was largely driven by the subsidy of long‐acting formulations and opioids for the treatment of noncancer pain. PMID:26991673

Antiretroviral drug expenditure, pricing and judicial demand: an analysis of federal procurement data in Brazil from 2004-2011.

PubMed

Luo, Jing; Oliveira, Maria A; Ramos, Mariana B C; Maia, Aurélio; Osorio-de-Castro, Claudia G S

2014-04-16

Previous studies have described expenditures for antiretroviral (ARV) medicines in Brazil through 2005. While prior studies examined overall expenditures, they have not have analyzed drug procurement data in order to describe the role of court litigation on access and pricing. ARV drug procurement from private sector sources for the years 2004-2011 was obtained through the general procurement database of the Brazilian Federal Government (SIASG). Procurement was measured in Defined Daily Doses (DDD) per 1000 persons-under-treatment per day. Expenditures and price per DDD were calculated and expressed in U.S. Dollars. Justifications for ARV purchases were examined in order to determine the relationship between health litigation and incorporation into Brazil's national treatment guidelines. Drug procurement of ARVs from private sources underwent marked expansion in 2005, peaked in 2009, and stabilized to 2008 levels by 2011. Expenditures followed procurement curves. Medications which were procured for the first time after 2007 cost more than medicines which were introduced before 2007. Judicial actions initially resulted in purchases of newer medications for a select number of patients in Brazil but ultimately expanded availability to a larger population through incorporation into the national treatment guidelines. Drug procurement and expenditures for ARVs in Brazil varied between 2004-2011. The procurement of some drugs from the private sector ceased after public manufacturers started producing them locally. Judicial demand has resulted in the incorporation of newer drugs into the national treatment guidelines. In order for the AIDS treatment program to remain sustainable, efforts should be pursued to reduce prices through generic drugs, price negotiation and other public health flexibilities such as compulsory licensing.

[Good morning, Mr. Representative. Anything new to tell us about? Analysis of the pharmacological products introduced by the drugs industry into a health district].

PubMed

Baena Díez, J M; López Mompó, C; López Gosp, D; Martínez Martínez, J L; Ellacuría Torres, A; Fuentes Rodríguez, S

2003-12-01

To study whether the visits of technical health representatives (ITS) mean that new drugs are introduced. Design. Prospective, descriptive study. Urban health centre. The products presented by 137 ITS from 83 drug laboratories in weekly sessions for a year were studied. The products presented, the year they were first marketed, intrinsic value (IV), newness and use potential, cost per package and defined daily dose and material handed over were studied. 472 drug products were introduced. The most common ones belonged to the cardiovascular group (27.3%), digestion and metabolism (14.8%) and anti-infection drugs (13.3%). 65.5% had been on the market for <5 years. 84.3% had a high IV. Only 31 products (6.6%) were new (95% CI, 4.5-9.2). 71% of these supposed no or very slight therapeutic improvement, 25.8% a modest improvement and 3.2% a major improvement. Mean cost was 19.3 euros per package and 2 euros per DDD, with significant differences found (P<.006) on stratifying by date of marketing (more recently marketed products cost more). 61% of the products were presented with additional material (leaflets, monographs, journals), 21.6% with gifts of symbolic value, and 19.9% with samples of the product. There were significant differences (P<.03) between the new drugs and the normal prescriptions issued at the centre. In the new drugs, there were fewer products with high IV and cost per package and per DDD was higher. The products introduced by the reps do not include any important new drugs. They are presented with abundant back-up and are more expensive than those normally prescribed.

European Surveillance of Antimicrobial Consumption (ESAC): outpatient penicillin use in Europe (1997-2009).

PubMed

Versporten, Ann; Coenen, Samuel; Adriaenssens, Niels; Muller, Arno; Minalu, Girma; Faes, Christel; Vankerckhoven, Vanessa; Aerts, Marc; Hens, Niel; Molenberghs, Geert; Goossens, Herman

2011-12-01

Data on 13 years (1997-2009) of outpatient penicillin use were collected from 33 European countries within the European Surveillance of Antimicrobial Consumption (ESAC) project and analysed in detail. For the period 1997-2009, data on outpatient use of systemic penicillins aggregated at the level of the active substance were collected using the Anatomical Therapeutic Chemical (ATC)/defined daily dose (DDD) method (WHO, version 2011) and expressed in DDD per 1000 inhabitants per day (DID). For detailed analysis of trends over time, seasonal variation and composition of outpatient penicillin use in 33 European countries, we distinguished between narrow-spectrum penicillins (NSP), broad-spectrum penicillins (BSP), penicillinase-resistant penicillins (PRP) and combinations with β-lactamase inhibitors (COP). Total outpatient penicillin (ATC group J01C) use in 2009 varied by a factor of 3.8 between the countries with the highest (16.08 DID in France) and lowest (4.23 DID in the Russian Federation) use. COP represented 45.8%, BSP 40.7%, NSP 10.8% and PRP 2.6% of total European outpatient penicillin use. Total outpatient penicillin use significantly increased over time by 1.53 (SD 0.71) DID between 1997 and 2009. COP (mainly co-amoxiclav) increased by 2.17 (SD 0.40) DID, which was the result of its absolute increase as well as the observed shift from NSP and BSP towards COP. This increase exceeded 10% in 20 countries, where it coincided with a similar decrease in either BSP (15 countries) or NSP (5 countries). Penicillins represented the most widely used antibiotic subgroup in all 33 participating countries, albeit with considerable variation in their use patterns. For Europe, a continuous increase in overall penicillin use and of COP use was observed during the period 1997-2009.

Variation of antibiotic consumption and its correlated factors in Turkey.

PubMed

Sahin, Ayfer; Akici, Ahmet; Aydin, Volkan; Melik, Bahar; Aksoy, Mesil; Alkan, Ali

2017-07-01

Presentation of antibiotic utilization data by reliable and comparable analyses constitutes an important way of ensuring rational use of antibiotics. This study aimed to evaluate antibiotic consumption (AC) of Turkey by each city/region and to investigate any association of such consumption with socio-economic factors. For 81 provinces and 12 regions in Turkey, AC data from IMS (Intercontinental Medical Statistics) in 2011 was analyzed in accordance with "ATC/DDD, DID" (Anatomical Therapeutic Chemical/Defined Daily Doses, DID = DDD/1000 inhabitants/day) methodology supported by World Health Organization. Association between provincial AC rates and socio-economic development index (SEDI)-2011 and between regional AC rates and some health indicators were analyzed. While provincial AC data of Turkey was detected to vary between 17.2 and 55.2 DID (Hakkari and Usak, respectively), regional AC ranged from 28.4 to 48.9 DID (Middle Eastern Anatolia and Western Anatolia, respectively). Mostly consumed antibiotic group among all regions were beta-lactamase inhibitor/penicillin combinations (range: 9.9-17.6 DID). SEDI and AC of each city showed positive correlation (rho = 0.683, p < 0.001). While regional AC was positively associated with percentage of 14-year-old population (p = 0.002) and pharmacist density (p < 0.001), it was negatively associated with physician density (p = 0.038). It is remarkable that Turkey, at both provincial and regional levels, exhibits important variations in AC, which is proportional to socio-economic status. Besides, the consumption is found to be closely associated with recognized critical factors of access to healthcare. These findings are expected to provide important insights to the activities promoting rational use of antibiotics.

Tolerance limits and methodologies for IMRT measurement-based verification QA: Recommendations of AAPM Task Group No. 218.

PubMed

Miften, Moyed; Olch, Arthur; Mihailidis, Dimitris; Moran, Jean; Pawlicki, Todd; Molineu, Andrea; Li, Harold; Wijesooriya, Krishni; Shi, Jie; Xia, Ping; Papanikolaou, Nikos; Low, Daniel A

2018-04-01

Patient-specific IMRT QA measurements are important components of processes designed to identify discrepancies between calculated and delivered radiation doses. Discrepancy tolerance limits are neither well defined nor consistently applied across centers. The AAPM TG-218 report provides a comprehensive review aimed at improving the understanding and consistency of these processes as well as recommendations for methodologies and tolerance limits in patient-specific IMRT QA. The performance of the dose difference/distance-to-agreement (DTA) and γ dose distribution comparison metrics are investigated. Measurement methods are reviewed and followed by a discussion of the pros and cons of each. Methodologies for absolute dose verification are discussed and new IMRT QA verification tools are presented. Literature on the expected or achievable agreement between measurements and calculations for different types of planning and delivery systems are reviewed and analyzed. Tests of vendor implementations of the γ verification algorithm employing benchmark cases are presented. Operational shortcomings that can reduce the γ tool accuracy and subsequent effectiveness for IMRT QA are described. Practical considerations including spatial resolution, normalization, dose threshold, and data interpretation are discussed. Published data on IMRT QA and the clinical experience of the group members are used to develop guidelines and recommendations on tolerance and action limits for IMRT QA. Steps to check failed IMRT QA plans are outlined. Recommendations on delivery methods, data interpretation, dose normalization, the use of γ analysis routines and choice of tolerance limits for IMRT QA are made with focus on detecting differences between calculated and measured doses via the use of robust analysis methods and an in-depth understanding of IMRT verification metrics. The recommendations are intended to improve the IMRT QA process and establish consistent, and comparable IMRT QA criteria among institutions. © 2018 American Association of Physicists in Medicine.

Tolerance to the Diuretic Effects of Cannabinoids and Cross-Tolerance to a κ-Opioid Agonist in THC-Treated Mice.

PubMed

Chopda, Girish R; Parge, Viraj; Thakur, Ganesh A; Gatley, S John; Makriyannis, Alexandros; Paronis, Carol A

2016-08-01

Daily treatment with cannabinoids results in tolerance to many, but not all, of their behavioral and physiologic effects. The present studies investigated the effects of 7-day exposure to 10 mg/kg daily of Δ(9)-tetrahydrocannabinol (THC) on the diuretic and antinociceptive effects of THC and the synthetic cannabinoid AM4054. Comparison studies determined diuretic responses to the κ-opioid agonist U50,488 and furosemide. After determination of control dose-response functions, mice received 10 mg/kg daily of THC for 7 days, and dose-response functions were re-determined 24 hours, 7 days, or 14 days later. THC and AM4054 had biphasic diuretic effects under control conditions with maximum effects of 30 and 35 ml/kg of urine, respectively. In contrast, antinociceptive effects of both drugs increased monotonically with dose to >90% of maximal possible effect. Treatment with THC produced 9- and 7-fold rightward shifts of the diuresis and antinociception dose-response curves for THC and, respectively, 7- and 3-fold rightward shifts in the AM4054 dose-response functions. U50,488 and furosemide increased urine output to >35 ml/kg under control conditions. The effects of U50,488 were attenuated after 7-day treatment with THC, whereas the effects of furosemide were unaltered. Diuretic effects of THC and AM4054 recovered to near-baseline levels within 14 days after stopping daily THC injections, whereas tolerance to the antinociceptive effects persisted longer than 14 days. The tolerance induced by 7-day treatment with THC was accompanied by a 55% decrease in the Bmax value for cannabinoid receptors (CB1). These data indicate that repeated exposure to THC produces similar rightward shifts in the ascending and descending limbs of cannabinoid diuresis dose-effect curves and to antinociceptive effects while resulting in a flattening of the U50,488 diuresis dose-effect function. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

Pharmacokinetics and safety of single doses of drisapersen in non-ambulant subjects with Duchenne muscular dystrophy: Results of a double-blind randomized clinical trial

PubMed Central

Flanigan, Kevin M.; Voit, Thomas; Rosales, Xiomara Q.; Servais, Laurent; Kraus, John E.; Wardell, Claire; Morgan, Allison; Dorricott, Susie; Nakielny, Joanna; Quarcoo, Naashika; Liefaard, Lia; Drury, Tom; Campion, Giles; Wright, Padraig

2014-01-01

Duchenne muscular dystrophy (DMD) is a progressive, lethal neuromuscular disorder caused by the absence of dystrophin protein due to mutations of the dystrophin gene. Drisapersen is a 2′-O-methyl-phosphorothioate oligonucleotide designed to skip exon 51 in dystrophin pre-mRNA to restore the reading frame of the mRNA. This study assessed safety, tolerability, and pharmacokinetics of drisapersen after a single subcutaneous administration in non-ambulatory subjects. Eligible subjects were non-ambulant boys aged ≥9 years, in wheelchairs for ≥1 to ≤4 years, with a diagnosis of DMD resulting from a mutation correctable by drisapersen treatment. Four dose cohorts were planned (3, 6, 9 and 12 mg/kg), but study objectives were met with the 9 mg/kg dose. Less than proportional increase in exposure was demonstrated over the 3–9 mg/kg dose range, though post hoc analysis showed dose proportionality was more feasible over the 3–6 mg/kg range. Single doses of drisapersen at 3 and 6 mg/kg did not result in significant safety or tolerability concerns; however, at the 9 mg/kg dose, pyrexia and transient elevations in inflammatory parameters were seen. The maximum tolerated dose of 6 mg/kg drisapersen was identified for further characterization in multiple dose studies in the non-ambulant DMD population. PMID:24321374

Safety and tolerability of adjunctive lacosamide intravenous loading dose in lacosamide-naive patients with partial-onset seizures.

PubMed

Fountain, Nathan B; Krauss, Gregory; Isojarvi, Jouko; Dilley, Deanne; Doty, Pamela; Rudd, G David

2013-01-01

To examine the safety and tolerability of rapidly initiating adjunctive lacosamide via a single intravenous loading dose followed by twice-daily oral lacosamide in lacosamide-naive adults with partial-onset seizures. This open-label, multicenter trial, enrolled patients with epilepsy who were taking 1-2 antiepileptic drugs (AEDs) in one of four sequential cohorts containing 25 subjects each. An intravenous lacosamide loading dose (200, 300, or 400 mg) was administered over 15 min followed 12 h later by initiation of oral dosing consisting of one-half of the loading dose administered twice daily for 6.5 days. The first cohort was administered lacosamide 200 mg/day, followed by a cohort at 300 mg/day, and then a cohort at 400 mg/day. The results from each cohort were evaluated before enrolling the next highest dose level. The fourth cohort enrolled patients at the highest dose with clinically acceptable safety and tolerability results. Safety evaluations included treatment-emergent adverse events (TEAEs), patient withdrawals due to TEAEs, and changes in vital signs, 12-lead electrocardiography (ECG) studies, laboratory parameters, and clinical examinations. Postinfusion lacosamide plasma concentrations were also evaluated. A total of 100 patients were enrolled, 25 in each cohort. The loading dose for the repeat cohort was 300 mg; therefore, 25 patients were enrolled at 200 mg/day, 50 at 300 mg/day, and 25 at 400 mg/day. Most TEAEs occurred within the first 4 h following infusion; dose-related TEAEs (incidence ≥10%) during this timeframe included dizziness, somnolence, and nausea. Seven patients withdrew, all due to TEAEs: three (6%) from the combined 300 mg group and four (16%) from the 400 mg group; four of these patients discontinued within 4 h following infusion. The most common TEAEs leading to discontinuation (overall incidence >1%) were dizziness (6%), nausea (5%), and vomiting (3%). No clinically relevant pattern of changes from baseline ECG, clinical laboratory parameters, or vital signs were observed. Trough plasma concentrations suggested that near steady-state lacosamide concentrations were achieved with a single intravenous loading dose. Intravenous loading doses of 200 and 300 mg lacosamide administered over 15 min followed by oral lacosamide were well tolerated in lacosamide-naive patients. The 400-mg loading dose was less well tolerated due to a higher frequency of dose-related TEAEs. These results support the feasibility of rapid initiation of adjunctive lacosamide treatment. Wiley Periodicals, Inc. © 2012 International League Against Epilepsy.

Hybrid Corpectomy and Disc Arthroplasty for Cervical Spondylotic Myelopathy Caused by Ossification of Posterior Longitudinal Ligament and Disc Herniation.

PubMed

Chang, Huang-Chou; Tu, Tsung-Hsi; Chang, Hsuan-Kan; Wu, Jau-Ching; Fay, Li-Yu; Chang, Peng-Yuan; Wu, Ching-Lan; Huang, Wen-Cheng; Cheng, Henrich

2016-11-01

The combination of anterior cervical discectomy and fusion (ACDF) and anterior cervical corpectomy and fusion (ACCF) has been demonstrated to be effective for multilevel cervical spondylotic myelopathy (CSM); however, the combination of ACCF and cervical disc arthroplasty (CDA) for 3-level CSM has never been addressed. Consecutive patients (>18 years of age) with CSM caused by segmental ossification of posterior longitudinal ligament (OPLL) and degenerative disc disease (DDD) were reviewed. Inclusion criteria were patients who underwent hybrid ACCF and CDA surgery for symptomatic 3-level CSM with OPLL and DDD. Medical and radiologic records were reviewed retrospectively. A total of 15 patients were analyzed with a mean follow-up of 18.1 ± 7.42 months. Every patient had hybrid surgery composed of 1-level ACCF (for segmental-type OPLL causing spinal stenosis) and 1-level CDA at the adjacent level (for DDD causing stenosis). All clinical outcomes, including visual analogue scale of neck and arm pain, Neck Disability Index, Japanese Orthopedic Association scores, and Nurick scores of myelopathy, demonstrated significant improvement at 12 months after surgery. All patients (100%) achieved arthrodesis for the ACCF (instrumented) and preserved mobility for CDA (preoperation 6.2 ± 3.81° vs. postoperation 7.0 ± 4.18°; P = 0.579). For patients with multilevel CSM caused by segmental OPLL and DDD, the hybrid surgery of ACCF and CDA demonstrated satisfactory clinical and radiologic outcomes. Moreover, although located next to each other, the instrumented ACCF construct and CDA still achieved solid arthrodesis and preserved mobility, respectively. Therefore, hybrid surgery may be a reasonable option for the management of CSM with OPLL. Copyright © 2016 Elsevier Inc. All rights reserved.

QTL mapping of genes controlling plasma insulin and leptin concentrations: metabolic effect of obesity QTLs identified in an F2 intercross between C57BL/6J and DDD.Cg-A(y) inbred mice.

PubMed

Suto, Jun-ichi

2013-07-31

DDD.Cg-A(y) female mice developed massive obesity as compared with B6.Cg-A(y) female mice. We previously identified quantitative trait loci (QTLs) for obesity on chromosomes 1, 6, 9 and 17 in F2 female mice, including F2A(y) (F2 mice with the A(y) allele) and F2 non- A(y) mice (F2 mice without the A(y) allele), produced by crossing C57BL/6J and DDD.Cg-A(y) strains. We here addressed the question whether the obesity QTLs share genetic bases with putative QTLs for plasma glucose, insulin and leptin concentrations. We performed QTL analyses for the first principal component (PC1) extracted from these metabolic measurements to identify the genes that contributed to the comprehensive evaluation of metabolic traits. By single QTL scans, we identified two significant QTLs for insulin concentration on chromosomes 6 and 12, three for leptin concentration on chromosomes 1, 6 and 17, and five for PC1 on chromosomes 1, 6, 12 (two loci) and 17. Although insulin and leptin concentrations and PC1 were not normally distributed in combined F2 mice, results of single QTL scans by parametric and non-parametric methods were very similar. Therefore, QTL scan by the parametric method was performed with the agouti locus genotype as a covariate. A significant QTL × covariate interaction was found for PC1 on chromosome 9. All obesity QTLs had significant metabolic effects. Thus, obesity- and diabetes-related traits in DDD.Cg-A(y) mice were largely controlled by QTLs on chromosomes 1, 6, 9, 12 and 17.

Determination of chlorinated insecticides in bottom sediment using an electron-capture gas chromatography screening method, Austin, Texas, 1991 and 1992

USGS Publications Warehouse

Brock, Robert D.; Murtagh, Lucinda K.

1994-01-01

Twenty-two bottom-sediment samples were collected from Town Lake in Austin, Texas, in 1991 and 1992 and analyzed for chlorinated insecticides by a reconnaissance-quality, electron-capture gas chromatography screening method developed by the U.S. Geological Survey (USGS). Four different chlorinated insecticides (aldrin, chlordane, dieldrin, and p,p'-DDT) and two degradation products of p,p'-DDT (p,p'-DDD and p,p'-DDE) were detected in these samples. The most significant insecticides detected were chlordane, which was detected in 20 of the 22 samples at concentrations that ranged from 26 to 140 micrograms per kilogram, and p,p'-DDT, which was detected in all 22 samples at concen- trations that ranged from 5 to 40 micrograms per kilogram. Degradation products of p,p'-DDT were detected in all 22 samples. Concentrations of p,p'-DDD ranged from not detected to 117 micrograms per kilogram and for p,p'-DDE from 9 to 97 micrograms per kilogram. Of the 22 samples collected, 15 also were analyzed by the standard USGS laboratory analytical method for chlorinated insecticides to determine the comparability of the two methods. Correlation coefficients were calculated for chlordane (0.8662), p,p'-DDT (0.6393), p,p'-DDD (0.9401), p,p'-DDE (0.8595), and dieldrin (0.3819). A paired sign test at the 95 percent confidence level showed no significant difference between the screening method and laboratory analytical method for all detected insecticides except aldrin. P-values were calculated from the data for chlordane (l.0000), p,p'-DDT (0.1796), p,p'-DDD (l,0000), p,p'-DDE (0.1796), and dieldrin (0.2891).

Residual levels and identify possible sources of organochlorine pesticides in Korea atmosphere

NASA Astrophysics Data System (ADS)

Park, Jin Soo; Shin, Sun Kyoung; Kim, Woo Il; Kim, Byung Hoon

2011-12-01

The nationwide monitoring program was established in 2008 to monitor of persistent organic pollutants (POPs) in Korea. Under this program, it was observed air concentrations of organochlorine pesticides (OCPs) at 37 sites from January to October of 2008, to determine the residue levels and identify possible sources in Korea atmosphere. Samples of OCPs including HCB, aldrin, dieldrin, endrin, p, p'-DDT, o, p'-DDT, p, p'-DDE, o, p'-DDE, p, p'-DDD, o, p'-DDD, trans-chlordane, cis-chlordane, trans-nonachlor, cis-nonachlor, oxychlordane, heptachlor, heptachlor epoxide were collected with high volume air sampler and analyzed by HRGC/HRMS. The concentrations were in the range of 41.2-344.3 pg m -3 for HCB, ND-47.55 pg m -3 for DDTs (sum of p, p'-DDT, o, p'-DDT, p, p'-DDE, o, p'-DDE, p, p'-DDD, o, p'-DDD), ND-38.97 pg m -3 for chlordanes (sum of trans-chlordane, cis-chlordane, trans-nonachlor, cis-nonachlor, oxychlordane), ND-9.19 pg m -3 for heptachlors (sum of heptachlor and heptachlor epoxide) and ND-4.32 pg m -3 for dieldrin. The predominant compound in air was HCB. However, HCB itself has not ever been registered and used as a pesticide in Korea. The elevated concentration of HCB in Korea might be contributed to geographical location and long range transport. For DDTs, it was found that no more fresh input occurred recently and technical type DDTs was prevailing in Korea. Higher concentration of chlordane was observed in winter, which was contributed to the fresh input technical chlordane and long range transport. Relatively lower levels of heptachlor and dieldrin despite much more consumption than other pesticides were resulted from shorter half-lives in environment.

Abundance and Distribution of Dimethylsulfoniopropionate Degradation Genes and the Corresponding Bacterial Community Structure at Dimethyl Sulfide Hot Spots in the Tropical and Subtropical Pacific Ocean

PubMed Central

Suzuki, Shotaro; Omori, Yuko; Wong, Shu-Kuan; Ijichi, Minoru; Kaneko, Ryo; Kameyama, Sohiko; Tanimoto, Hiroshi; Hamasaki, Koji

2015-01-01

Dimethylsulfoniopropionate (DMSP) is mainly produced by marine phytoplankton but is released into the microbial food web and degraded by marine bacteria to dimethyl sulfide (DMS) and other products. To reveal the abundance and distribution of bacterial DMSP degradation genes and the corresponding bacterial communities in relation to DMS and DMSP concentrations in seawater, we collected surface seawater samples from DMS hot spot sites during a cruise across the Pacific Ocean. We analyzed the genes encoding DMSP lyase (dddP) and DMSP demethylase (dmdA), which are responsible for the transformation of DMSP to DMS and DMSP assimilation, respectively. The averaged abundance (±standard deviation) of these DMSP degradation genes relative to that of the 16S rRNA genes was 33% ± 12%. The abundances of these genes showed large spatial variations. dddP genes showed more variation in abundances than dmdA genes. Multidimensional analysis based on the abundances of DMSP degradation genes and environmental factors revealed that the distribution pattern of these genes was influenced by chlorophyll a concentrations and temperatures. dddP genes, dmdA subclade C/2 genes, and dmdA subclade D genes exhibited significant correlations with the marine Roseobacter clade, SAR11 subgroup Ib, and SAR11 subgroup Ia, respectively. SAR11 subgroups Ia and Ib, which possessed dmdA genes, were suggested to be the main potential DMSP consumers. The Roseobacter clade members possessing dddP genes in oligotrophic subtropical regions were possible DMS producers. These results suggest that DMSP degradation genes are abundant and widely distributed in the surface seawater and that the marine bacteria possessing these genes influence the degradation of DMSP and regulate the emissions of DMS in subtropical gyres of the Pacific Ocean. PMID:25862229

Effect of bromocriptine on acute ethanol tolerance in UChB rats.

PubMed

Tampier, L; Prado, C; Quintanilla, M E; Mardones, J

1999-07-01

It has been suggested that a higher capacity to develop acute tolerance during a single dose of ethanol may promote higher ethanol consumption in alcohol-preferring rodents. Several studies have shown that the dopaminergic system may be involved in voluntary ethanol consumption. In the present paper we studied the effect of bromocriptine, a dopaminergic agonist drug, that is known to reduce voluntary consumption of ethanol, on acute tolerance in high (UChB) ethanol consumer rats. Acute tolerance was evaluated in bromocriptine and saline-treated rats by motor impairment induced by a subnarcotic dose of ethanol of 2.3 g/kg IP using a modified tilting plane test. Results showed a highly significant positive correlation between acute tolerance and the voluntary ethanol consumption by the rat. Bromocriptine treatment decreased ethanol consumption and also decreased acute tolerance development. This adds further support to the postulate that the acquisition of acute tolerance to ethanol may promote increased alcohol consumption. Moreover, these results also suggest that dopaminergic receptors involved in ethanol voluntary consumption may also be in acute tolerance development.

Attenuated microglial activation mediates tolerance to the neurotoxic effects of methamphetamine.

PubMed

Thomas, David M; Kuhn, Donald M

2005-02-01

Methamphetamine causes persistent damage to dopamine nerve endings of the striatum. Repeated, intermittent treatment of mice with low doses of methamphetamine leads to the development of tolerance to its neurotoxic effects. The mechanisms underlying tolerance are not understood but clearly involve more than alterations in drug bioavailability or reductions in the hyperthermia caused by methamphetamine. Microglia have been implicated recently as mediators of methamphetamine-induced neurotoxicity. The purpose of the present studies was to determine if a tolerance regimen of methamphetamine would attenuate the microglial response to a neurotoxic challenge. Mice treated with a low-dose methamphetamine tolerance regimen showed minor reductions in striatal dopamine content and low levels of microglial activation. When the tolerance regimen preceded a neurotoxic challenge of methamphetamine, the depletion of dopamine normally seen was significantly attenuated. The microglial activation that occurs after a toxic methamphetamine challenge was blunted likewise. Despite the induction of tolerance against drug-induced toxicity and microglial activation, a neurotoxic challenge with methamphetamine still caused hyperthermia. These results suggest that tolerance to methamphetamine neurotoxicity is associated with attenuated microglial activation and they further dissociate its neurotoxicity from drug-induced hyperthermia.

Better management of wheat allergy using a very low-dose food challenge: A retrospective study.

PubMed

Okada, Yu; Yanagida, Noriyuki; Sato, Sakura; Ebisawa, Motohiro

2016-01-01

Low-dose reactive wheat-allergic children are at a high risk of a positive oral food challenge (OFC). The present study aimed to evaluate whether the results of a very low-dose (VL) OFC would contribute to better wheat allergy management in this population. We retrospectively reviewed wheat-allergic subjects who underwent a VL OFC with 2 g of udon noodles (equivalent to 53 mg of wheat protein) and had a previous allergic reaction to <15 g of udon noodles (equivalent to 400 mg of wheat protein) within 2 years before the OFC. Subjects who passed the OFC were defined as VL tolerant; those who failed were considered VL reactive. In VL tolerant subjects, the dose was increased to 15 g of udon noodles either during an OFC in our hospital or gradually at home. Of the 57 included subjects (median age, 2.9 years; range, 1.0-11.8 years), 32 (56%) were VL tolerant and 25 (44%) were VL reactive. Most reactions during the OFC could be treated with an antihistamine and/or a nebulized β2 agonist. VL tolerant subjects consumed 2 g of udon noodles or a seasoning containing wheat. Within a year after the OFC, 18 VL tolerant subjects (56%), but no VL reactive subjects, were able to consume 15 g of udon noodles (p < 0.001). A VL OFC can shift the management of some low-dose reactive wheat-allergic children from complete avoidance to partial wheat intake. Copyright © 2015 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

Studies on cadmium-induced inhibition of hepatic microsomal drug biotransformation in the rat.

PubMed Central

Schnell, R C; Means, J R; Roberts, S A; Pence, D H

1979-01-01

Cadmium is a potent inhibitor of hepatic microsomal drug biotransformation in the rat. Male rats receiving a single intraperitoneal dose of cadmium exhibit significant decreases in hepatic microsomal metabolism of a variety of substrates. The threshold cadmium dose is 0.84 mg Cd/kg, and the effect lasts at least 28 days. Mechanistically, the inhibitory effect results from decreased cytochrome P-450 content since cadmium does not alter NADPH cytochrome c reductase activity. This effect is also observed following acute oral administration of cadmium in doses greater than 80 mg Cd/kg but is not observed following chronic administration of the metal via drinking water in concentrations of 5-200 ppm for periods ranging from 2 to 50 weeks. A tolerance to the inhibitory cadmium effect is observed if male rats are pretreated with subthreshold doses of the metal prior to the challenge cadmium dose. The degree of tolerance can be overcome by increasing the challenge dose of cadmium. Characterization of the tolerance phenomenon in terms of onset, duration, and intensity reveals a good correlation with the kinetics of metallothionein production, suggesting that the underlying basis for the tolerance phenomenon is likely the induction of metallothionein. A sex-related difference in the inhibitory effect of cadmium was observed. Cadmium did not inhibit the metabolism of hexobarbital or ethylmorphine in female rats but did inhibit that of aniline or zoxazolamine. Cadmium did not lower cytochrome P-450 content in female rats. PMID:488042

A 4-week study assessing the pharmacokinetics, pharmacodynamics, safety, and tolerability of the glucagon receptor antagonist PF-06291874 administered as monotherapy in subjects with type 2 diabetes mellitus.

PubMed

Bergman, Arthur; Tan, Beesan; Somayaji, Veena R; Calle, Roberto A; Kazierad, David J

2017-04-01

The glucagon receptor antagonist PF-06291874 has demonstrated robust glucose reductions in subjects with type 2 diabetes mellitus (T2DM) on background metformin. This study assessed the pharmacokinetics, pharmacodynamics, safety, and tolerability of PF-06291874 administered as monotherapy in subjects with T2DM. After a ≥4-week antidiabetic therapy washout period, 172 subjects were randomized to placebo or PF-06291874 15, 35, 75, or 150mg once daily for 28days. Mean daily glucose (MDG), fasting plasma glucose (FPG), and predefined safety endpoints were assessed at baseline and day 28. Dose-dependent reductions (placebo-adjusted) from baseline in MDG ranged from 40.3 to 68.8mg/dL and in FPG from 27.1 to 57.2mg/dL after 28days of dosing with PF-06291874. There were no significant changes in low-density lipoprotein cholesterol at doses ≤75mg relative to placebo. Small, dose-dependent increases in alanine aminotransferase and aspartate aminotransferase were observed; however, the incidence of these values >3×upper limit of normal was similar across doses. PF-06291874 exposures were consistent with previous studies and PF-06291874 was well tolerated, with minimal incidence of hypoglycemia. PF-06291874 as monotherapy was well tolerated and produced robust reductions in plasma glucose following 4weeks of dosing in subjects with T2DM. Copyright © 2017 Elsevier B.V. All rights reserved.

Effects of Age, Sex, and Race on the Safety and Pharmacokinetics of Single and Multiple Doses of Azilsartan Medoxomil in Healthy Subjects.

PubMed

Harrell, Robert E; Karim, Aziz; Zhang, Wencan; Dudkowski, Caroline

2016-05-01

Azilsartan medoxomil (AZL-M) is an angiotensin II receptor blocker approved to treat hypertension. After oral dosing, AZL-M is quickly hydrolyzed to azilsartan (AZL). The aims of this study were to assess the effects of age, sex, and race on the pharmacokinetics of AZL-M in healthy subjects, as well as safety and tolerability. Sixty-one healthy adults were enrolled in this phase I, single-blind, randomized placebo-controlled study (placebo control was for assessment of safety/tolerability only). Subjects were stratified by age (18-45 vs. 65-85 years), sex, and race (black vs. white) and given oral AZL-M 60 mg (3 × 20 mg capsules) or placebo as a single dose (Day 1) and consecutive daily doses (Days 4-8) (6:2 ratio for AZL-M:placebo per group). Pharmacokinetics were evaluated (AZL-M patients only) on Days 1-3 and 8-9 and safety/tolerability was monitored. Age, sex, and race had no clinically meaningful effect on AZL exposures after single or multiple dosing. Pharmacokinetic parameters remained similar between Days 1 and 8 for each age, sex, and race subgroup. The frequency of adverse events was similar for AZL-M (32%) and placebo (29%). No discontinuations or serious adverse events occurred. Based on these pharmacokinetic and safety/tolerability findings, no AZL-M dose adjustments are required based on age, sex, or race (black/white).

Phase I Trial of Bortezomib and Concurrent External Beam Radiation in Patients With Advanced Solid Malignancies

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pugh, Thomas J.; Chen Changhu; Rabinovitch, Rachel

Purpose: To determine the maximal tolerated dose of bortezomib with concurrent external beam radiation therapy in patients with incurable solid malignant tumors requiring palliative therapy. Methods and Materials: An open label, dose escalation, phase I clinical trial evaluated the safety of three dose levels of bortezomib administered intravenously (1.0 mg/m{sup 2}, 1.3 mg/m{sup 2}, and 1.6 mg/m{sup 2}/ dose) once weekly with concurrent radiation in patients with histologically confirmed solid tumors and a radiographically appreciable lesion suitable for palliative radiation therapy. All patients received 40 Gy in 16 fractions to the target lesion. Dose-limiting toxicity was the primary endpoint, definedmore » as any grade 4 hematologic toxicity, any grade {>=}3 nonhematologic toxicity, or any toxicity requiring treatment to be delayed for {>=}2 weeks. Results: A total of 12 patients were enrolled. Primary sites included prostate (3 patients), head and neck (3 patients), uterus (1 patient), abdomen (1 patient), breast (1 patient), kidney (1 patient), lung (1 patient), and colon (1 patient). The maximum tolerated dose was not realized with a maximum dose of 1.6 mg/m{sup 2}. One case of dose-limiting toxicity was appreciated (grade 3 urosepsis) and felt to be unrelated to bortezomib. The most common grade 3 toxicity was lymphopenia (10 patients). Common grade 1 to 2 events included nausea (7 patients), infection without neutropenia (6 patients), diarrhea (5 patients), and fatigue (5 patients). Conclusions: The combination of palliative external beam radiation with concurrent weekly bortezomib therapy at a dose of 1.6 mg/m{sup 2} is well tolerated in patients with metastatic solid tumors. The maximum tolerated dose of once weekly bortezomib delivered concurrently with radiation therapy is greater than 1.6 mg/m{sup 2}.« less

Total and free cortisol levels during 1 μg, 25 μg, and 250 μg cosyntropin stimulation tests compared to insulin tolerance test: results of a randomized, prospective, pilot study.

PubMed

Peechakara, Seenia; Bena, James; Clarke, Nigel J; McPhaul, Michael J; Reitz, Richard E; Weil, Robert J; Recinos, Pablo; Kennedy, Laurence; Hamrahian, Amir H

2017-09-01

The appropriate cosyntropin dose during cosyntropin stimulation tests remains uncertain. We conducted a prospective, randomized pilot study to compare 1 μg IV low dose cosyntropin test, 25 μg IM medium dose cosyntropin test, and 250 μg IM standard dose cosyntropin test to evaluate secondary adrenal insufficiency. Insulin tolerance test was used as the gold standard. The study included patients with hypothalamic/pituitary disease (n  = 10) with at least one pituitary axis deficiency other than ACTH deficiency and controls (n  = 12). All tests were done in random order. Sensitivity and specificity were calculated for total cortisol and serum free cortisol cut-off levels during cosyntropin stimulation tests. The median (range) age and F/M sex ratios for patients and controls were 54 years (23-62), 2/8, and 33 years (21-51), 6/6, respectively. The best total cortisol cut-off during low dose cosyntropin test, medium dose cosyntropin test, 30 min and 60 min standard dose cosyntropin test were 14.6 μg/dL (100% sensitivity & specificity), 18.7 μg/dL (100% sensitivity, 88% specificity), 16.1 (100% sensitivity & specificity), and 19.5 μg/dL (100% sensitivity & specificity), respectively. There was no difference in the ROC curve for cortisol values between the cosyntropin stimulation tests (p  > 0.41). Using a cortisol cut-off of 18 μg/dL during cosyntropin stimulation tests, only cortisol level at 30 min during standard dose cosyntropin test provided discrimination similar to insulin tolerance test. The best peak free cortisol cut-off levels were 1 μg/dL for insulin tolerance test, 0.9 μg/dL for low dose cosyntropin test, 0.9 μg/dL for medium dose cosyntropin test, and 0.9 μg/dL and 1.3 μg/dL for 30 min and 60 min standard dose cosyntropin test, respectively. All cosyntropin stimulation tests had excellent correlations with insulin tolerance test, when appropriate cut-offs were used. This pilot study does not suggest an advantage in using 25 μg cosyntropin dose during the cosyntropin stimulation test. A serum free cortisol cut-off of 0.9 μg/dL may be used as pass criterion during low dose cosyntropin test, standard dose cosyntropin test cosyntropin test, and 30 min standard dose cosyntropin test.

Melatonin for Sleep in Children with Autism: A Controlled Trial Examining Dose, Tolerability, and Outcomes

PubMed Central

Malow, Beth A.; Adkins, Karen W.; McGrew, Susan G.; Wang, Lily; Goldman, Suzanne E.; Fawkes, Diane; Burnette, Courtney

2011-01-01

Supplemental melatonin has shown promise in treating sleep onset insomnia in children with autism spectrum disorders (ASD). Twenty-four children, free of psychotropic medications, completed an open-label dose-escalation study to assess dose-response, tolerability, safety, feasibility of collecting actigraphy data, and ability of outcome measures to detect change during a 14-week intervention. Supplemental melatonin improved sleep latency, as measured by actigraphy, in most children at 1 or 3 mg dosages. It was effective in week 1 of treatment, maintained effects over several months, was well tolerated and safe, and showed improvement in sleep, behavior, and parenting stress. Our findings contribute to the growing literature on supplemental melatonin for insomnia in ASD and inform planning for a large randomized trial in this population. PMID:22160300

Melatonin for sleep in children with autism: a controlled trial examining dose, tolerability, and outcomes.

PubMed

Malow, Beth; Adkins, Karen W; McGrew, Susan G; Wang, Lily; Goldman, Suzanne E; Fawkes, Diane; Burnette, Courtney

2012-08-01

Supplemental melatonin has shown promise in treating sleep onset insomnia in children with autism spectrum disorders (ASD). Twenty-four children, free of psychotropic medications, completed an open-label dose-escalation study to assess dose-response, tolerability, safety, feasibility of collecting actigraphy data, and ability of outcome measures to detect change during a 14-week intervention. Supplemental melatonin improved sleep latency, as measured by actigraphy, in most children at 1 or 3 mg dosages. It was effective in week 1 of treatment, maintained effects over several months, was well tolerated and safe, and showed improvement in sleep, behavior, and parenting stress. Our findings contribute to the growing literature on supplemental melatonin for insomnia in ASD and inform planning for a large randomized trial in this population.

Hemopoietic Response to Low Dose-Rates of Ionizing Radiation Shows Stem Cell Tolerance and Adaptation

PubMed Central

Fliedner, Theodor M.; Graessle, Dieter H.; Meineke, Viktor; Feinendegen, Ludwig E.

2012-01-01

Chronic exposure of mammals to low dose-rates of ionizing radiation affects proliferating cell systems as a function of both dose-rate and the total dose accumulated. The lower the dose-rate the higher needs to be the total dose for a deterministic effect, i.e., tissue reaction to appear. Stem cells provide for proliferating, maturing and functional cells. Stem cells usually are particularly radiosensitive and damage to them may propagate to cause failure of functional cells. The paper revisits 1) medical histories with emphasis on the hemopoietic system of the victims of ten accidental chronic radiation exposures, 2) published hematological findings of long-term chronically gamma-irradiated rodents, and 3) such findings in dogs chronically exposed in large life-span studies. The data are consistent with the hypothesis that hemopoietic stem and early progenitor cells have the capacity to tolerate and adapt to being repetitively hit by energy deposition events. The data are compatible with the “injured stem cell hypothesis”, stating that radiation–injured stem cells, depending on dose-rate, may continue to deliver clones of functional cells that maintain homeostasis of hemopoiesis throughout life. Further studies perhaps on separated hemopoietic stem cells may unravel the molecular-biology mechanisms causing radiation tolerance and adaptation. PMID:23304110

Phase I Study of Preoperative Chemoradiation With S-1 and Oxaliplatin in Patients With Locally Advanced Resectable Rectal Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hong, Yong Sang; Lee, Jae-Lyun; Park, Jin Hong

Purpose: To perform a Phase I study of preoperative chemoradiation (CRT) with S-1, a novel oral fluoropyrimidine, plus oxaliplatin in patients with locally advanced rectal cancer, to determine the maximum tolerated dose and the recommended dose. Methods and Materials: Radiotherapy was delivered to a total of 45 Gy in 25 fractions and followed by a coned-down boost of 5.4 Gy in 3 fractions. Concurrent chemotherapy consisted of a fixed dose of oxaliplatin (50 mg/m{sup 2}/week) on Days 1, 8, 22, and 29 and escalated doses of S-1 on Days 1-14 and 22-35. The initial dose of S-1 was 50 mg/m{supmore » 2}/day, gradually increasing to 60, 70, and 80 mg/m{sup 2}/day. Surgery was performed within 6 {+-} 2 weeks. Results: Twelve patients were enrolled and tolerated up to Dose Level 4 (3 patients at each dose level) without dose-limiting toxicity. An additional 3 patients were enrolled at Dose Level 4, with 1 experiencing a dose-limiting toxicity of Grade 3 diarrhea. Although maximum tolerated dose was not attained, Dose Level 4 (S-1 80 mg/m{sup 2}/day) was chosen as the recommended dose for further Phase II studies. No Grade 4 toxicity was observed, and Grade 3 toxicities of leukopenia and diarrhea occurred in the same patient (1 of 15, 6.7%). Pathologic complete responses were observed in 2 of 15 patients (13.3%). Conclusions: The recommended dose of S-1 was determined to be 80 mg/m{sup 2}/day when combined with oxaliplatin in preoperative CRT, and a Phase II trial is now ongoing.« less

A phase 2 study of the safety, tolerability, and pharmacodynamics of FBS0701, a novel oral iron chelator, in transfusional iron overload.

PubMed

Neufeld, Ellis J; Galanello, Renzo; Viprakasit, Vip; Aydinok, Yesim; Piga, Antonio; Harmatz, Paul; Forni, Gian Luca; Shah, Farrukh T; Grace, Rachael F; Porter, John B; Wood, John C; Peppe, Jennifer; Jones, Amber; Rienhoff, Hugh Young

2012-04-05

This was a 24-week, multicenter phase-2 study designed to assess safety, tolerability, and pharmacodynamics of FBS0701, a novel oral chelator, in adults with transfusional iron overload. Fifty-one patients, stratified by transfusional iron intake, were randomized to FBS0701 at either 14.5 or 29 mg/kg/d (16 and 32 mg/kg/d salt form). FBS0701 was generally well tolerated at both doses. Forty-nine patients (96%) completed the study. There were no drug-related serious adverse events. No adverse events (AEs) showed dose-dependency in frequency or severity. Treatment-related nausea, vomiting, abdominal pain, and diarrhea were each noted in < 5% of patients. Mean serum creatinine did not change significantly from Baseline or between dose groups. Transaminases wer increased in 8 (16%), three of whom acquired HCV on-study from a single blood bank while five had an abnormal baseline ALT. The 24 week mean change in liver iron concentration (ΔLIC) at 14.5 mg/kg/d was +3.1 mg/g (dw); 29% achieved a decrease in LIC. Mean ΔLIC at 29 mg/kg/d was -0.3 mg/g (dw); 44% achieved a decrease in LIC (P < .03 for ΔLIC between doses). The safety and tolerability profile at therapeutic doses compare favorably to other oral chelators.

Phase I Trial and Pharmacokinetic Study of Lexatumumab in Pediatric Patients With Solid Tumors

PubMed Central

Merchant, Melinda S.; Geller, James I.; Baird, Kristin; Chou, Alexander J.; Galli, Susana; Charles, Ava; Amaoko, Martha; Rhee, Eunice H.; Price, Anita; Wexler, Leonard H.; Meyers, Paul A.; Widemann, Brigitte C.; Tsokos, Maria; Mackall, Crystal L.

2012-01-01

Purpose Lexatumumab is an agonistic, fully human monoclonal antibody against tumor necrosis factor–related apoptosis-inducing ligand receptor 2 with preclinical evidence of activity in pediatric solid tumors. Patients and Methods This phase I dose-escalation study examined the safety, tolerability, pharmacokinetics, and immunogenicity of lexatumumab at doses up to, but not exceeding, the adult maximum-tolerated dose (3, 5, 8, and 10 mg/kg), administered once every 2 weeks to patients age ≤ 21 years with recurrent or progressive solid tumors. Results Twenty-four patients received a total of 56 cycles of lexatumumab over all four planned dose levels. One patient had grade 2 pericarditis consistent with radiation recall, and one patient developed grade 3 pneumonia with hypoxia during the second cycle. Five patients experienced stable disease for three to 24 cycles. No patients experienced complete or partial response, but several showed evidence of antitumor activity, including one patient with recurrent progressive osteosarcoma who experienced resolution of clinical symptoms and positron emission tomography activity, ongoing more than 1 year off therapy. One patient with hepatoblastoma showed a dramatic biomarker response. Conclusion Pediatric patients tolerate 10 mg/kg of lexatumumab administered once every 14 days, the maximum-tolerated dose identified in adults. The drug seems to mediate some clinical activity in pediatric solid tumors and may work with radiation to enhance antitumor effects. PMID:23071222

Safety and tolerability of guadecitabine (SGI-110) in patients with myelodysplastic syndrome and acute myeloid leukaemia: a multicentre, randomised, dose-escalation phase 1 study.

PubMed

Issa, Jean-Pierre J; Roboz, Gail; Rizzieri, David; Jabbour, Elias; Stock, Wendy; O'Connell, Casey; Yee, Karen; Tibes, Raoul; Griffiths, Elizabeth A; Walsh, Katherine; Daver, Naval; Chung, Woonbok; Naim, Sue; Taverna, Pietro; Oganesian, Aram; Hao, Yong; Lowder, James N; Azab, Mohammad; Kantarjian, Hagop

2015-09-01

Hypomethylating agents are used to treat cancers driven by aberrant DNA methylation, but their short half-life might limit their activity, particularly in patients with less proliferative diseases. Guadecitabine (SGI-110) is a novel hypomethylating dinucleotide of decitabine and deoxyguanosine resistant to degradation by cytidine deaminase. We aimed to assess the safety and clinical activity of subcutaneously given guadecitabine in patients with acute myeloid leukaemia or myelodysplastic syndrome. In this multicentre, open-label, phase 1 study, patients from nine North American medical centres with myelodysplastic syndrome or acute myeloid leukaemia that was refractory to or had relapsed after standard treatment were randomly assigned (1:1) to receive subcutaneous guadecitabine, either once-daily for 5 consecutive days (daily × 5), or once-weekly for 3 weeks, in a 28-day treatment cycle. Patients were stratified by disease. A 3 + 3 dose-escalation design was used in which we treated patients with guadecitabine doses of 3-125 mg/m(2) in separate dose-escalation cohorts. A twice-weekly treatment schedule was added to the study after a protocol amendment. The primary objective was to assess safety and tolerability of guadecitabine, determine the maximum tolerated and biologically effective dose, and identify the recommended phase 2 dose of guadecitabine. Safety analyses included all patients who received at least one dose of guadecitabine. Pharmacokinetic and pharmacodynamic analyses to determine the biologically effective dose included all patients for whom samples were available. This study is registered with ClinicalTrials.gov, number NCT01261312. Between Jan 4, 2011, and April 11, 2014, we enrolled and treated 93 patients: 35 patients with acute myeloid leukaemia and nine patients with myelodysplastic syndrome in the daily × 5 dose-escalation cohorts, 28 patients with acute myeloid leukaemia and six patients with myelodysplastic syndrome in the once-weekly dose-escalation cohorts, and 11 patients with acute myeloid leukaemia and four patients with myelodysplastic syndrome in the twice-weekly dose-escalation cohorts. The most common grade 3 or higher adverse events were febrile neutropenia (38 [41%] of 93 patients), pneumonia (27 [29%] of 93 patients), thrombocytopenia (23 [25%] of 93 patients), anaemia (23 [25%] of 93 patients), and sepsis (16 [17%] of 93 patients). The most common serious adverse events were febrile neutropenia (29 [31%] of 93 patients), pneumonia (26 [28%] of 93 patients), and sepsis (16 [17%] of 93 patients). Six of the 74 patients with acute myeloid leukaemia and six of the 19 patients with myelodysplastic syndrome had a clinical response to treatment. Two dose-limiting toxicities were noted in patients with myelodysplastic syndrome at 125 mg/m(2) daily × 5, thus the maximum tolerated dose in patients with myelodysplastic syndrome was 90 mg/m(2) daily × 5. The maximum tolerated dose was not reached in patients with acute myeloid leukaemia. Potent dose-related DNA demethylation occurred on the daily × 5 regimen, reaching a plateau at 60 mg/m(2) (designated as the biologically effective dose). Guadecitabine given subcutaneously at 60 mg/m(2) daily × 5 is well tolerated and is clinically and biologically active in patients with myelodysplastic syndrome and acute myeloid leukaemia. Guadecitabine 60 mg/m(2) daily × 5 is the recommended phase 2 dose, and these findings warrant further phase 2 studies. Astex Pharmaceuticals, Stand Up To Cancer. Copyright © 2015 Elsevier Ltd. All rights reserved.

Recent Progress in Discrete Dislocation Dynamics and Its Applications to Micro Plasticity

NASA Astrophysics Data System (ADS)

Po, Giacomo; Mohamed, Mamdouh S.; Crosby, Tamer; Erel, Can; El-Azab, Anter; Ghoniem, Nasr

2014-10-01

We present a self-contained review of the discrete dislocation dynamics (DDD) method for the numerical investigation of plasticity in crystals, focusing on recent development and implementation progress. The review covers the theoretical foundations of DDD within the framework of incompatible elasticity, its numerical implementation via the nodal method, the extension of the method to finite domains and several implementation details. Applications of the method to current topics in micro-plasticity are presented, including the size effects in nano-indentation, the evolution of the dislocation microstructure in persistent slip bands, and the phenomenon of dislocation avalanches in micro-pillar compression.

Modelling Coastal Cliff Recession Based on the GIM-DDD Method

NASA Astrophysics Data System (ADS)

Gong, Bin; Wang, Shanyong; Sloan, Scott William; Sheng, Daichao; Tang, Chun'an

2018-04-01

The unpredictable and instantaneous collapse behaviour of coastal rocky cliffs may cause damage that extends significantly beyond the area of failure. Gravitational movements that occur during coastal cliff recession involve two major stages: the small deformation stage and the large displacement stage. In this paper, a method of simulating the entire progressive failure process of coastal rocky cliffs is developed based on the gravity increase method (GIM), the rock failure process analysis method and the discontinuous deformation analysis method, and it is referred to as the GIM-DDD method. The small deformation stage, which includes crack initiation, propagation and coalescence processes, and the large displacement stage, which includes block translation and rotation processes during the rocky cliff collapse, are modelled using the GIM-DDD method. In addition, acoustic emissions, stress field variations, crack propagation and failure mode characteristics are further analysed to provide insights that can be used to predict, prevent and minimize potential economic losses and casualties. The calculation and analytical results are consistent with previous studies, which indicate that the developed method provides an effective and reliable approach for performing rocky cliff stability evaluations and coastal cliff recession analyses and has considerable potential for improving the safety and protection of seaside cliff areas.

What can nanosafety learn from drug development? The feasibility of "safety by design".

PubMed

Hjorth, Rune; van Hove, Lilian; Wickson, Fern

2017-04-01

"Safety by design" (SbD) is an intuitively appealing concept that is on the rise within nanotoxicology and nanosafety research, as well as within nanotechnology research policy. It leans on principles established within drug discovery and development (DDD) and seeks to address safety early, as well as throughout product development. However, it remains unclear what the concept of SbD exactly entails for engineered nanomaterials (ENMs) or how it is envisioned to be implemented. Here, we review the concept as it is emerging in European research and compare its resemblance with the safety testing and assessment practices in DDD. From this comparison, it is clear that "safety" is not obtained through DDD, and that SbD should be considered a starting point rather than an end, meaning that products will still need to progress through thorough safety evaluations and regulation. We conclude that although risk reduction is clearly desirable, the way SbD is currently communicated tends to treat safety as an inherent material property and that this is fundamentally problematic as it represents a recasting and reduction of societal issues into technical problems. SbD therefore faces a multitude of challenges, from practical implementation to unrealistic stakeholder expectations.

Groundwater modelling in conceptual hydrological models - introducing space

NASA Astrophysics Data System (ADS)

Boje, Søren; Skaugen, Thomas; Møen, Knut; Myrabø, Steinar

2017-04-01

The tiny Sæternbekken Minifelt (Muren) catchment (7500 m2) in Bærumsmarka, Norway, was during the 1990s, densely instrumented with more than a 100 observation points for measuring groundwater levels. The aim was to investigate the link between shallow groundwater dynamics and runoff. The DDD (Distance Distribution Dynamics) model is a newly developed rainfall-runoff model used operationally by the Norwegian Flood-Forecasting service at NVE. The model estimates the capacity of the subsurface reservoir at different levels of saturation and predicts overland flow. The subsurface in the DDD model has a 2-D representation that calculates the saturated and unsaturated soil moisture along a hillslope representing the entire catchment in question. The groundwater observations from more than two decades ago are used to verify assumptions of the subsurface reservoir in the DDD model and to validate its spatial representation of the subsurface reservoir. The Muren catchment will, during 2017, be re-instrumented in order to continue the work to bridge the gap between conceptual hydrological models, with typically single value or 0-dimension representation of the subsurface, and models with more realistic 2- or 3-dimension representation of the subsurface.

Water-quality assessment of part of the Upper Mississippi River Basin, Minnesota and Wisconsin: Organochlorine compounds in streambed sediments and fish tissues, 1995-97

USGS Publications Warehouse

McNellis, R.P.; Fallon, J.D.; Lee, K.E.

2001-01-01

Streambed sediments and fish tissues were collected in part of the Upper Mississippi River Basin to assess the presence and distribution of organochlorine compounds (OCs) including PCBs. A total of 13 OCs were detected among 14 of 27 streambed sediment sampling locations. In fish tissues analyzed, 9 OCs were detected among 17 of 24 sites sampled. Eight OCs were detected in both fish and streambed sediment samples, they were: cis-chlordane, o,p'-DDD; p,p'-DDD; p,p'-DDE; p,p'-DDT; hexachlorobenzene; transnonachlor; and PCBs. The most frequently detected OCs were: p,p'-DDE; and p,p'-DDD in streambed sediment and p,p'-DDE and PCBs in fish tissues. No OCs were detected in streambed sediment at agricultural sites; however, the agricultural sites had 17 detections of OCs in fish tissue. Urban streams had concentrations of total DDT and metabolites in streambed sediment that exceed guidelines for classification of sites with high probabilities of adverse effects to aquatic organisms. Total DDT was the only OC within an urban land use that exceeded guidelines for piscivorous wildlife.

Organochlorines and mercury in osprey eggs from the eastern United States

USGS Publications Warehouse

Audet, D.J.; Scott, D.S.; Wiemeyer, Stanley N.

1992-01-01

Organochlorine and mercury concentrations were determined in Osprey eggs collected from Maryland, Virginia, and Massachusetts during 1986-87. DDE concentrations were significantly different among locations. Median DDE concentrations did not decline significantly in eggs from Glenn L. Martin National Wildlife Refuge, Maryland, between 1973 and 1986. The median DDE residue for eggs from Martin Refuge in 1986 surpassed the value associated with 10% eggshell thinning, but was below the value associated with production of 1.0 young per active nest, a level assumed to represent a stable population. DDD, DDT, dieldrin, PCB, and mercury residues in all eggs appeared insignificant with regard to potential effects on shell thickness or reproduction. DDE and PCB residues were lower in eggs collected in 1986-87 than in those collected in the 1970s for each area. DDD, DDT, and dieldrin were not detected in Martin Refuge eggs in 1986, representing a significant reduction since 1973. DDD, DDT, and dieldrin levels in Massachusetts and Virginia eggs in 1986-87 were similar to those in eggs from the 1970s for each state. Mercury residues in eggs from Martin Refuge may be increasing and although not significant in this study, may warrant future monitoring.

Gray bats and pollution in Missouri and northern Alabama

USGS Publications Warehouse

Clark, D.R.; Bunck, C.M.; Cromartie, E.; LaVal, R.K.; Tuttle, M.D.

1981-01-01

Gray bats died with lethal brain concentrations of dieldrin and rising levels of heptachlor epoxide in 1976, 1977, and 1978 at Bat Caves No. 2-3, Franklin County, Missouri. The colony disappeared in 1979. Dieldrin was banned in 1974 and 1981 was the last year for heptachlor use in Missouri. The State is recommendiing three organophosphates (chlorpyrifos or Dursban, dyfonate or Fonophos, and ethoprop or Mocap) as substitutes for heptachlor. All three compounds have excellent records in the environment. Analyses of insects collected where bats of this colony fed showed beetles, particularly rove beetles (Staphylinidae), to be the most heavily contaminated part of the bat's diet. Lactation concentrated these residues so that levels in milk were approximately 30 times those in the insect diet. Gray bats found dead in caves in northern Alabama showed DDD (a DDT derivative) contamination. Bats from the colony at Cave Springs Cave on the Wheeler National Wildlife Refuge contained up to 29 ppm DDD in their brains, but this is probably less than one-half the lethal level. Bats from other colonies contained less. The DDD contamination enters the Terinessee River just above the Wheeler Refuge and is seen in gray bat colonies as far as 60 miles downriver.

Quantitative trait locus mapping of genes associated with vacuolation in the adrenal X-zone of the DDD/Sgn inbred mouse

PubMed Central

2012-01-01

Background Adrenal gland of mice contains a transient zone between the adrenal cortex and the adrenal medulla: the X-zone. There are clear strain differences in terms of X-zone morphology. Nulliparous females of the inbred mouse DDD strain develop adrenal X-zones containing exclusively vacuolated cells, whereas females of the inbred mouse B6 strain develop X-zones containing only non-vacuolated cells. The X-zone vacuolation is a physiologic process associated with the X-zone degeneration and is tightly regulated by genetic factors. Identification of the genetic factors controlling such strain differences should help analyze the X-zone function. In this study, a quantitative trait locus (QTL) analysis for the extent of X-zone vacuolation was performed for two types of F2 female mice: F2Ay mice (F2 mice with the Ay allele) and F2 non-Ay mice (F2 mice without the Ay allele). These were produced by crossing B6 females and DDD.Cg-Ay males. DDD.Cg-Ay is a congenic mouse strain for the Ay allele at the agouti locus and is used for this study because a close association between the X-zone morphology and the agouti locus genotype has been suggested. The Ay allele is dominant and homozygous lethal; therefore, living Ay mice are invariably heterozygotes. Results Single QTL scans identified significant QTLs on chromosomes 1, 2, 6, and X for F2 non-Ay mice, and on chromosomes 2, 6, and 12 for F2Ay mice. The QTL on chromosome 2 was considered to be because of the agouti locus, which has been suggested to be associated with X-zone vacuolation. A significant QTL that interacted with the agouti locus was identified on chromosome 8. Conclusions The extent of X-zone vacuolation in DDD females was controlled by multiple genes with complex interactions. The murine X-zone is considered analogous structure to the human fetal zone. Therefore, the results of this study will aid in understanding function of not only of the X-zone but also of the human fetal zone. Identifying the genes responsible for the QTLs will be essential for understanding the molecular basis of X-zone function, which is currently unclear. PMID:23131041

Quantitative trait locus mapping of genes associated with vacuolation in the adrenal X-zone of the DDD/Sgn inbred mouse.

PubMed

Suto, Jun-Ichi

2012-11-06

Adrenal gland of mice contains a transient zone between the adrenal cortex and the adrenal medulla: the X-zone. There are clear strain differences in terms of X-zone morphology. Nulliparous females of the inbred mouse DDD strain develop adrenal X-zones containing exclusively vacuolated cells, whereas females of the inbred mouse B6 strain develop X-zones containing only non-vacuolated cells. The X-zone vacuolation is a physiologic process associated with the X-zone degeneration and is tightly regulated by genetic factors. Identification of the genetic factors controlling such strain differences should help analyze the X-zone function. In this study, a quantitative trait locus (QTL) analysis for the extent of X-zone vacuolation was performed for two types of F2 female mice: F2Ay mice (F2 mice with the Ay allele) and F2 non-Ay mice (F2 mice without the Ay allele). These were produced by crossing B6 females and DDD.Cg-Ay males. DDD.Cg-Ay is a congenic mouse strain for the Ay allele at the agouti locus and is used for this study because a close association between the X-zone morphology and the agouti locus genotype has been suggested. The Ay allele is dominant and homozygous lethal; therefore, living Ay mice are invariably heterozygotes. Single QTL scans identified significant QTLs on chromosomes 1, 2, 6, and X for F2 non-Ay mice, and on chromosomes 2, 6, and 12 for F2Ay mice. The QTL on chromosome 2 was considered to be because of the agouti locus, which has been suggested to be associated with X-zone vacuolation. A significant QTL that interacted with the agouti locus was identified on chromosome 8. The extent of X-zone vacuolation in DDD females was controlled by multiple genes with complex interactions. The murine X-zone is considered analogous structure to the human fetal zone. Therefore, the results of this study will aid in understanding function of not only of the X-zone but also of the human fetal zone. Identifying the genes responsible for the QTLs will be essential for understanding the molecular basis of X-zone function, which is currently unclear.

Comparison of two melphalan protocols and evaluation of outcome and prognostic factors in multiple myeloma in dogs

PubMed Central

Fernández, Ricardo

2018-01-01

Background Multiple myeloma (MM) in dogs typically is treated with melphalan. A daily melphalan dosing schedule reportedly is well tolerated and associated with favorable outcome. Although anecdotally a pulse dose regimen has resulted in successful responses, little long‐term outcome and safety data is available regarding this dosing regimen for dogs with MM. Hypothesis/objectives (1) To compare outcome and adverse event profiles between pulse dose and daily dose melphalan schedules and (2) to report prognostic factors in dogs with MM treated with melphalan. We hypothesized that both protocols would have similar outcomes and tolerability. Animals Thirty‐eight client‐owned dogs diagnosed with MM receiving pulse dose (n = 17) or daily dose (n = 21) melphalan. Methods Retrospective cohort study assessing outcome and adverse events in dogs receiving either protocol. Risk factors were evaluated for their prognostic relevance. Results Both regimens were well tolerated and similarly effective, with an overall median survival time of 930 days. Renal disease and neutrophil‐to‐lymphocyte ratio (NLR) were negative prognostic factors, whereas hypercalcemia and osteolytic lesions were not prognostic factors in this study population. Conclusions and Clinical Importance Positive results support the use of either dosing regimen for the treatment of dogs with MM, and renal disease and NLR were negative prognostic factors. Prospective, controlled, and randomized studies are warranted to confirm these findings. PMID:29566439

DOE Office of Scientific and Technical Information (OSTI.GOV)

Medin, Paul M., E-mail: Paul.medin@utsouthwestern.ed; Boike, Thomas P.

Clinical implementation of spinal radiosurgery has increased rapidly in recent years, but little is known regarding human spinal cord tolerance to single-fraction irradiation. In contrast, preclinical studies in single-fraction spinal cord tolerance have been ongoing since the 1970s. The influences of field length, dose rate, inhomogeneous dose distributions, and reirradiation have all been investigated. This review summarizes literature regarding single-fraction spinal cord tolerance in preclinical models with an emphasis on practical clinical significance. The outcomes of studies that incorporate uniform irradiation are surprisingly consistent among multiple small- and large-animal models. Extensive investigation of inhomogeneous dose distributions in the rat hasmore » demonstrated a significant dose-volume effect while preliminary results from one pig study are contradictory. Preclinical spinal cord dose-volume studies indicate that dose distribution is more critical than the volume irradiated suggesting that neither dose-volume histogram analysis nor absolute volume constraints are effective in predicting complications. Reirradiation data are sparse, but results from guinea pig, rat, and pig studies are consistent with the hypothesis that the spinal cord possesses a large capacity for repair. The mechanisms behind the phenomena observed in spinal cord studies are not readily explained and the ability of dose response models to predict outcomes is variable underscoring the need for further investigation. Animal studies provide insight into the phenomena and mechanisms of radiosensitivity but the true significance of animal studies can only be discovered through clinical trials.« less

Safety and tolerability of ibrutinib monotherapy in Japanese patients with relapsed/refractory B cell malignancies.

PubMed

Tobinai, Kensei; Ogura, Michinori; Ishizawa, Kenichi; Suzuki, Tatsuya; Munakata, Wataru; Uchida, Toshiki; Aoki, Tomohiro; Morishita, Takanobu; Ushijima, Yoko; Takahara, Satoko

2016-01-01

In this phase I dose-escalation study we evaluated the safety, tolerability, pharmacokinetics, and antitumor activity of ibrutinib, an oral covalent inhibitor of Bruton's tyrosine kinase (BTK, in Japanese patients with relapsed/refractory B cell malignancies (RRBCM). Fifteen patients aged 42-78 years were enrolled to one of three cohorts. Cohort 1 (n = 3) consisted of two phases, a single-dose (140 and 280 mg) phase and a multiple-dose (420 mg) phase of ibrutinib; cohort 2 (n = 6) included multiple doses of ibrutinib 560 mg; and cohort 3 (n = 6) included only patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) dosed at ibrutinib 420 mg. One patient (CLL/SLL cohort) experienced grade 3 pneumonia and sepsis, which were considered dose-limiting toxicities. No deaths were reported. The most common (≥ 20% patients) adverse events were neutropenia, anemia, nasopharyngitis, increased bilirubin, and rash. Dose-dependent increase in maximum plasma concentration and area under the concentration from 0 to the last quantifiable time was observed, while time to reach maximum plasma concentration and elimination half-life was similar between doses. The overall response rate was 73.3% (11/15) for all cohorts combined. Overall, ibrutinib (420 and 560 mg) was tolerable with acceptable safety profiles and effective for Japanese patients with RRBCM including CLL/SLL. NCT01704963.

Pregabalin role in inhibition of morphine analgesic tolerance and physical dependency in rats.

PubMed

Hasanein, Parisa; Shakeri, Saeed

2014-11-05

Pregabalin is recently proposed as analgesic or adjuvant in pain management. While previous preclinical investigations have evaluated pregabalin-opioid interactions, the effect of pregabalin on opioid tolerance and dependency has not yet been studied. Here we evaluated the effects of different doses of pregabalin (50, 100 and 200mg/kg, s.c.) on morphine-induced tolerance and dependency in rats. Adult male Wistar rats were rendered tolerant to analgesic effect of morphine by injection of morphine (10mg/kg, s.c.) twice daily for 7 days. To develop morphine dependence, rats were given escalating doses of morphine. To determine the effect of pregabalin on the development of morphine tolerance and dependence, different doses of pregabalin were administrated before morphine. The tail-flick and naloxone precipitation withdrawal tests were used to evaluate the degree of tolerance and dependence, respectively. Chronic morphine-injected rats showed significant decrements in the percentage maximum possible effect (%MPE) of morphine on the days 5 and 7 (32.5%±3.5, 21.5%±4, respectively) compared to the first day (100%) which showed morphine tolerance. Pregabalin 200mg/kg completely prevented the development of morphine tolerance. In addition, concomitant treatment of morphine with pregabalin attenuated almost all of the naloxone-induced withdrawal signs which include weight loss, jumping, penis licking, teeth chattering, wet dog shakes, rearing, standing, sniffing, face grooming and paw tremor. These data show that pregabaline has a potential anti-tolerant/anti-dependence property against chronic usage of morphine. Therefore, pregabalin appears to be a promising candidate for the treatment of opioid addiction after confirming by future clinical studies. Copyright © 2014 Elsevier B.V. All rights reserved.

Curcumin Attenuates Opioid Tolerance and Dependence by Inhibiting Ca2+/Calmodulin-Dependent Protein Kinase II α Activity

PubMed Central

Hu, Xiaoyu; Huang, Fang; Szymusiak, Magdalena

2015-01-01

Chronic use of opioid analgesics has been hindered by the development of opioid addiction and tolerance. We have reported that curcumin, a natural flavonoid from the rhizome of Curcuma longa, attenuated opioid tolerance, although the underlying mechanism remains unclear. In this study, we tested the hypothesis that curcumin may inhibit Ca2+/calmodulin-dependent protein kinase II α (CaMKIIα), a protein kinase that has been previously proposed to be critical for opioid tolerance and dependence. In this study, we used state-of-the-art polymeric formulation technology to produce poly(lactic-co-glycolic acid) (PLGA)-curcumin nanoparticles (nanocurcumin) to overcome the drug’s poor solubility and bioavailability, which has made it extremely difficult for studying in vivo pharmacological actions of curcumin. We found that PLGA-curcumin nanoparticles reduced the dose requirement by 11- to 33-fold. Pretreatment with PLGA-curcumin (by mouth) prevented the development of opioid tolerance and dependence in a dose-dependent manner, with ED50 values of 3.9 and 3.2 mg/kg, respectively. PLGA-curcumin dose-dependently attenuated already-established opioid tolerance (ED50 = 12.6 mg/kg p.o.) and dependence (ED50 = 3.1 mg/kg p.o.). Curcumin or PLGA-curcumin did not produce antinociception by itself or affect morphine (1–10 mg/kg) antinociception. Moreover, we found that the behavioral effects of curcumin on opioid tolerance and dependence correlated with its inhibition of morphine-induced CaMKIIα activation in the brain. These results suggest that curcumin may attenuate opioid tolerance and dependence by suppressing CaMKIIα activity. PMID:25515789

Pre- and postnatal toxicity induced in guinea pigs by N-nitrosomethylurea.

PubMed

Hasumi, K; Wilber, J H; Berkowitz, J; Wilber, R G; Epstein, S S

1975-10-01

Oral administration of N-nitrosomethylurea at maximally tolerated doses to guinea pigs on alternate days from days 34-58 of pregnancy induced prenatal toxicity, as evidenced by a high frequency of stillbirths and intrauterine growth retardation, and postnatal toxicity, as evidenced by stunting and progressive mortality. Similar administration of N-nitrosomethylurethane at maximally tolerated doses did not induce such toxic effects.

Regulatory Forum Opinion Piece*: Retrospective Evaluation of Doses in the 26-week Tg.rasH2 Mice Carcinogenicity Studies: Recommendation to Eliminate High Doses at Maximum Tolerated Dose in Future Studies. A Response to the Counterpoints.

PubMed

Paranjpe, Madhav G; Denton, Melissa D; Vidmar, Tom J; Elbekai, Reem H

2016-01-01

We recently conducted a retrospective analysis of data collected from 29 Tg.rasH2 carcinogenicity studies conducted at our facility to determine how successful was the strategy of choosing the high dose of the 26-week studies based on an estimated maximum tolerated dose (MTD). As a result of our publication, 2 counterviews were expressed. Both counterviews illustrate very valid points in their interpretation of our data. In this article, we would like to highlight clarifications based on several points and issues they have raised in their papers, namely, the dose-level selection, determining if MTD was exceeded in 26-week studies, and a discussion on the number of dose groups to be used in the studies. © The Author(s) 2015.

Phase I dose-escalation study to examine the safety and tolerability of LY2603618, a checkpoint 1 kinase inhibitor, administered 1 day after pemetrexed 500 mg/m2 every 21 days in patients with cancer

PubMed Central

Iyengar, Tara; Ramanathan, Ramesh K.; Lewandowski, Karen; Anthony, Stephen P.; Donehower, Ross C.; Westin, Eric; Hurt, Karla; Hynes, Scott M.; McKane, Scott

2013-01-01

Summary Purpose This phase I study aims at assessing the safety and tolerability of LY2603618, a selective inhibitor of Checkpoint Kinase 1, in combination with pemetrexed and determining the maximum tolerable dose and the pharmacokinetic parameters. Experimental design This was an open-label, multicenter, dose-escalation study in patients with advanced solid tumors. Increasing doses of LY2603618 (40–195 mg/m2) were combined with 500 mg/m2 of pemetrexed. LY2603618 was administered on Days 1 and 9 and pemetrexed on Day 8 in a 28-day cycle. For all subsequent 21-day cycles, pemetrexed was administered on Day 1 and LY2603618 on Day 2. Anti-tumor activity was evaluated as per Response Evaluation Criteria in Solid Tumors 1.0. Results A total of 31 patients were enrolled into six cohorts (three at 40 mg/m2 over 4.5-hour infusion, 1-hour infusion in subsequent cohorts: three each at 40 mg/m2, 70 mg/m2, and 195 mg/m2; 13 at 105 mg/m2; six at 150 mg/m2). Four patients experienced a dose-limiting toxicity: diarrhea (105 mg/m2); reversible infusion-related reaction (150 mg/m2); thrombocytopenia (195 mg/m2); and fatigue (195 mg/m2). The maximum tolerated dose was defined as 150 mg/m2. The pharmacokinetic data demonstrated that the exposure of LY2603618 increased in a dose-dependent manner, displayed a suitable half-life for maintaining required human exposures while minimizing the intra- and inter-cycle accumulation, and was unaffected by the pemetrexed administration. The pharmacokinetic-defined biologically efficacious dose was achieved at doses ≥105 mg/m2. Conclusion LY2603618 administered approximately 24 h after pemetrexed showed acceptable safety and pharmacokinetic profiles. PMID:22492020

Phase I dose-escalation study to examine the safety and tolerability of LY2603618, a checkpoint 1 kinase inhibitor, administered 1 day after pemetrexed 500 mg/m(2) every 21 days in patients with cancer.

PubMed

Weiss, Glen J; Donehower, Ross C; Iyengar, Tara; Ramanathan, Ramesh K; Lewandowski, Karen; Westin, Eric; Hurt, Karla; Hynes, Scott M; Anthony, Stephen P; McKane, Scott

2013-02-01

This phase I study aims at assessing the safety and tolerability of LY2603618, a selective inhibitor of Checkpoint Kinase 1, in combination with pemetrexed and determining the maximum tolerable dose and the pharmacokinetic parameters. This was an open-label, multicenter, dose-escalation study in patients with advanced solid tumors. Increasing doses of LY2603618 (40-195 mg/m(2)) were combined with 500 mg/m(2) of pemetrexed. LY2603618 was administered on Days 1 and 9 and pemetrexed on Day 8 in a 28-day cycle. For all subsequent 21-day cycles, pemetrexed was administered on Day 1 and LY2603618 on Day 2. Antitumor activity was evaluated as per Response Evaluation Criteria in Solid Tumors 1.0. A total of 31 patients were enrolled into six cohorts (three at 40 mg/m(2) over 4.5-hour infusion, 1-hour infusion in subsequent cohorts: three each at 40 mg/m(2), 70 mg/m(2), and 195 mg/m(2); 13 at 105 mg/m(2); six at 150 mg/m(2)). Four patients experienced a dose-limiting toxicity: diarrhea (105 mg/m(2)); reversible infusion-related reaction (150 mg/m(2)); thrombocytopenia (195 mg/m(2)); and fatigue (195 mg/m(2)). The maximum tolerated dose was defined as 150 mg/m(2). The pharmacokinetic data demonstrated that the exposure of LY2603618 increased in a dose-dependent manner, displayed a suitable half-life for maintaining required human exposures while minimizing the intra- and inter-cycle accumulation, and was unaffected by the pemetrexed administration. The pharmacokinetic-defined biologically efficacious dose was achieved at doses ≥105 mg/m(2). LY2603618 administered approximately 24 h after pemetrexed showed acceptable safety and pharmacokinetic profiles.

SU-F-T-313: Clinical Results of a New Customer Acceptance Test for Elekta VMAT

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rusk, B; Fontenot, J

Purpose: To report the results of a customer acceptance test (CAT) for VMAT treatments for two matched Elekta linear accelerators. Methods: The CAT tests were performed on two clinically matched Elekta linear accelerators equipped with a 160-leaf MLC. Functional tests included performance checks of the control system during dynamic movements of the diaphragms, MLC, and gantry. Dosimetric tests included MLC picket fence tests at static and variable dose rates and a diaphragm alignment test, all performed using the on-board EPID. Additionally, beam symmetry during arc delivery was measured at the four cardinal angles for high and low dose rate modesmore » using a 2D detector array. Results of the dosimetric tests were analyzed using the VMAT CAT analysis tool. Results: Linear accelerator 1 (LN1) met all stated CAT tolerances. Linear accelerator 2 (LN2) passed the geometric, beam symmetry, and MLC position error tests but failed the relative dose average test for the diaphragm abutment and all three picket fence fields. Though peak doses in the abutment regions were consistent, the average dose was below the stated tolerance corresponding to a leaf junction that was too narrow. Despite this, no significant differences in patient specific VMAT quality assurance measured were observed between the accelerators and both passed monthly MLC quality assurance performed with the Hancock test. Conclusion: Results from the CAT showed LN2 with relative dose averages in the abutment regions of the diaphragm and MLC tests outside the tolerances resulting from differences in leaf gap distances. Tolerances of the dose average tests from the CAT may be small enough to detect MLC errors which do not significantly affect patient QA or the routine MLC tests.« less

Space Radiation Environment Prediction for VLSI microelectronics devices onboard a LEO Satellite using OMERE-Trad Software

NASA Astrophysics Data System (ADS)

Sajid, Muhammad

This tutorial/survey paper presents the assessment/determination of level of hazard/threat to emerging microelectronics devices in Low Earth Orbit (LEO) space radiation environment with perigee at 300 Km, apogee at 600Km altitude having different orbital inclinations to predict the reliability of onboard Bulk Built-In Current Sensor (BBICS) fabricated in 350nm technology node at OptMA Lab. UFMG Brazil. In this context, the various parameters for space radiation environment have been analyzed to characterize the ionizing radiation environment effects on proposed BBICS. The Space radiation environment has been modeled in the form of particles trapped in Van-Allen radiation belts(RBs), Energetic Solar Particles Events (ESPE) and Galactic Cosmic Rays (GCR) where as its potential effects on Device- Under-Test (DUT) has been predicted in terms of Total Ionizing Dose (TID), Single-Event Effects (SEE) and Displacement Damage Dose (DDD). Finally, the required mitigation techniques including necessary shielding requirements to avoid undesirable effects of radiation environment at device level has been estimated /determined with assumed standard thickness of Aluminum shielding. In order to evaluate space radiation environment and analyze energetic particles effects on BBICS, OMERE toolkit developed by TRAD was utilized.

Clinical relevance of cannabis tolerance and dependence.

PubMed

Jones, R T; Benowitz, N L; Herning, R I

1981-01-01

Psychoactive drugs are often widely used before tolerance and dependence is fully appreciated. Tolerance to cannabis-induced cardiovascular and autonomic changes, decreased intraocular pressure, sleep and sleep EEG, mood and behavioral changes is acquired and, to a great degree, lost rapidly with optimal conditions. Mechanisms appear more functional than metabolic. Acquisition rate depends on dose and dose schedule. Dependence, manifested by withdrawal symptoms after as little as 7 days of THC administration, is characterized by irritability, restlessness, insomnia, anorexia, nausea, sweating, salivation, increased body temperature, altered sleep and waking EEG, tremor, and weight loss. Mild and transient in the 120 subjects studied, the syndrome was similar to sedative drug withdrawal. Tolerance to drug side effects can be useful. Tolerance to therapeutic effects or target symptoms poses problems. Clinical significance of dependence is difficult to assess since drug-seeking behavior has many determinants. Cannabis-induced super sensitivity should be considered wherever chronic drug administration is anticipated in conditions like epilepsy, glaucoma or chronic pain. Cannabis pharmacology suggests ways of minimizing tolerance and dependence problems.

T cell priming versus T cell tolerance induced by synthetic peptides

PubMed Central

1995-01-01

It is well known that synthetic peptides are able to both induce and tolerize T cells. We have examined the parameters leading either to priming or tolerance of CD8+ cytotoxic T lymphocytes (CTL) in vivo with a major histocompatibility complex class I (H-2 Db) binding peptide derived from the glycoprotein (GP aa33-41) of lymphocytic choriomeningitis virus (LCMV). By varying dose, route, and frequency of LCMV GP peptide application, we found that a single local subcutaneous injection of 50-500 micrograms peptide emulsified in incomplete Freund's adjuvant protected mice against LCMV infection, whereas repetitive and systemic intraperitoneal application of the same dose caused tolerance of LCMV-specific CTL. The peptide-induced tolerance was transient in euthymic mice but permanent in thymectomized mice. These findings are relevant for a selective use of peptides as a therapeutic approach: peptide-induced priming of T cells for vaccination and peptide-mediated T cell tolerance for intervention in immunopathologies and autoimmune diseases. PMID:7540654

Pharmacology of ayahuasca administered in two repeated doses.

PubMed

Dos Santos, Rafael G; Grasa, Eva; Valle, Marta; Ballester, Maria Rosa; Bouso, José Carlos; Nomdedéu, Josep F; Homs, Rosa; Barbanoj, Manel J; Riba, Jordi

2012-02-01

Ayahuasca is an Amazonian tea containing the natural psychedelic 5-HT(2A/2C/1A) agonist N,N-dimethyltryptamine (DMT). It is used in ceremonial contexts for its visionary properties. The human pharmacology of ayahuasca has been well characterized following its administration in single doses. To evaluate the human pharmacology of ayahuasca in repeated doses and assess the potential occurrence of acute tolerance or sensitization. In a double-blind, crossover, placebo-controlled clinical trial, nine experienced psychedelic drug users received PO the two following treatment combinations at least 1 week apart: (a) a lactose placebo and then, 4 h later, an ayahuasca dose; and (b) two ayahuasca doses 4 h apart. All ayahuasca doses were freeze-dried Amazonian-sourced tea encapsulated to a standardized 0.75 mg DMT/kg bodyweight. Subjective, neurophysiological, cardiovascular, autonomic, neuroendocrine, and cell immunity measures were obtained before and at regular time intervals until 12 h after first dose administration. DMT plasma concentrations, scores in subjective and neurophysiological variables, and serum prolactin and cortisol were significantly higher after two consecutive doses. When effects were standardized by plasma DMT concentrations, no differences were observed for subjective, neurophysiological, autonomic, or immunological effects. However, we observed a trend to reduced systolic blood pressure and heart rate, and a significant decrease for growth hormone (GH) after the second ayahuasca dose. Whereas there was no clear-cut tolerance or sensitization in the psychological sphere or most physiological variables, a trend to lower cardiovascular activation was observed, together with significant tolerance to GH secretion.

Better management of cow's milk allergy using a very low dose food challenge test: a retrospective study.

PubMed

Okada, Yu; Yanagida, Noriyuki; Sato, Sakura; Ebisawa, Motohiro

2015-07-01

Low dose reactive cow's milk (CM) allergic children are at high risk of persistent CM allergy and a positive oral food challenge (OFC). The present study aimed to evaluate if the results of a very low dose (VL) OFC with these children contributes to better management of CM allergy. We retrospectively reviewed subjects with CM allergy who underwent a VL OFC with 3 mL heated CM and had a previous allergic reaction to <25 mL heated CM in the 2 years before the OFC. Subjects who passed the OFC were defined as VL tolerant, and subjects who failed were defined as VL reactive. VL tolerant subjects increased the dose to 25 mL heated CM either during an OFC in our hospital or gradually at home. Of the 83 subjects (median age, 4.3 years; range, 1.0-12.9 years) who were included, 41 (49.4%) were VL tolerant, and 42 (51.6%) were VL reactive. Thirty-nine VL reactive subjects had skin and/or respiratory symptoms during the OFC. Most reactions could be treated with an antihistamine and/or a nebulized β2 agonist. The VL tolerant subjects consumed 3 mL heated CM or 10 g butter. Within the year following the OFC, 18 VL tolerant subjects (45.0%), but none of the VL reactive subjects, were able to consume 25 mL heated CM (p < 0.001). A VL OFC allows the management of some low dose reactive CM allergic children to change from complete avoidance to partial intake of CM. Copyright © 2015 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.

Improving spot-scanning proton therapy patient specific quality assurance with HPlusQA, a second-check dose calculation engine.

PubMed

Mackin, Dennis; Li, Yupeng; Taylor, Michael B; Kerr, Matthew; Holmes, Charles; Sahoo, Narayan; Poenisch, Falk; Li, Heng; Lii, Jim; Amos, Richard; Wu, Richard; Suzuki, Kazumichi; Gillin, Michael T; Zhu, X Ronald; Zhang, Xiaodong

2013-12-01

The purpose of this study was to validate the use of HPlusQA, spot-scanning proton therapy (SSPT) dose calculation software developed at The University of Texas MD Anderson Cancer Center, as second-check dose calculation software for patient-specific quality assurance (PSQA). The authors also showed how HPlusQA can be used within the current PSQA framework. The authors compared the dose calculations of HPlusQA and the Eclipse treatment planning system with 106 planar dose measurements made as part of PSQA. To determine the relative performance and the degree of correlation between HPlusQA and Eclipse, the authors compared calculated with measured point doses. Then, to determine how well HPlusQA can predict when the comparisons between Eclipse calculations and the measured dose will exceed tolerance levels, the authors compared gamma index scores for HPlusQA versus Eclipse with those of measured doses versus Eclipse. The authors introduce the αβγ transformation as a way to more easily compare gamma scores. The authors compared measured and calculated dose planes using the relative depth, z∕R × 100%, where z is the depth of the measurement and R is the proton beam range. For relative depths than less than 80%, both Eclipse and HPlusQA calculations were within 2 cGy of dose measurements on average. When the relative depth was greater than 80%, the agreement between the calculations and measurements fell to 4 cGy. For relative depths less than 10%, the Eclipse and HPlusQA dose discrepancies showed a negative correlation, -0.21. Otherwise, the correlation between the dose discrepancies was positive and as large as 0.6. For the dose planes in this study, HPlusQA correctly predicted when Eclipse had and had not calculated the dose to within tolerance 92% and 79% of the time, respectively. In 4 of 106 cases, HPlusQA failed to predict when the comparison between measurement and Eclipse's calculation had exceeded the tolerance levels of 3% for dose and 3 mm for distance-to-agreement. The authors found HPlusQA to be reasonably effective (79% ± 10%) in determining when the comparison between measured dose planes and the dose planes calculated by the Eclipse treatment planning system had exceeded the acceptable tolerance levels. When used as described in this study, HPlusQA can reduce the need for patient specific quality assurance measurements by 64%. The authors believe that the use of HPlusQA as a dose calculation second check can increase the efficiency and effectiveness of the QA process.

Tolerance to X-rays and Heavy Ions (Fe, He) in the Tardigrade Richtersius coronifer and the Bdelloid Rotifer Mniobia russeola.

PubMed

Jönsson, K Ingemar; Wojcik, Andrzej

2017-02-01

The aim of this study was to analyze tolerance to heavy ions in desiccated animals of the eutardigrade Richtersius coronifer and the bdelloid rotifer Mniobia russeola within the STARLIFE project. Both species were exposed to iron (Fe) and helium (He) ions at the Heavy Ion Medical Accelerator in Chiba (HIMAC) in Chiba, Japan, and to X-rays at the German Aerospace Center (DLR) in Cologne, Germany. Results show no effect of Fe and He on viability up to 7 days post-rehydration in both R. coronifer and M. russeola, while X-rays tended to reduce viability in R. coronifer at the highest doses. Mean egg production rate tended to decline with higher doses in R. coronifer for all radiation types, but the pattern was not statistically confirmed. In M. russeola, there was no such tendency for a dose response in egg production rate. These results confirm the previously reported high tolerance to high linear energy transfer (LET) radiation in tardigrades and show for the first time that bdelloid rotifers are also very tolerant to high-LET radiation. These animal phyla represent the most desiccation- and radiation-tolerant animals on Earth and provide excellent eukaryotic models for astrobiological research. Key Words: Tardigrada-Rotifera-Radiation tolerance-Heavy ions-X-rays. Astrobiology 17, 163-167.

Pharmacokinetic Profile and Tolerability of Liposomal Bupivacaine Following a Repeated Dose via Local Subcutaneous Infiltration in Healthy Volunteers.

PubMed

Rice, David; Heil, Justin W; Biernat, Lukasz

2017-03-01

Liposomal bupivacaine is indicated for administration into the surgical site to produce post-surgical analgesia. The objectives of this study were to characterize the pharmacokinetic and safety profiles of liposomal bupivacaine following a repeated dose in healthy volunteers. Healthy adults were assigned to receive liposomal bupivacaine via subcutaneous infiltration in a single 266 mg dose (cohort 1) or in two 266 mg doses, with the second dose given immediately, 24, 48, or 72 h after the first dose (cohorts 2-5). Pharmacokinetic parameters were estimated from blood samples collected up to day 14. Subjects were monitored for adverse events and assessed for neurologic function, cardiac function, and infiltration area abnormalities. Twelve subjects were assigned to each cohort. The mean ± standard deviation maximum observed plasma concentration (C max ) of bupivacaine after a single dose was 129 ± 47 ng/mL. The mean C max after the second dose was higher, but always less than double the C max for cohort 1. The highest individual C max (589 ng/mL) was observed in a subject who received the second dose 24 h after the first dose (cohort 4), but was well below the reported thresholds for neurotoxicity and cardiac toxicity (2000 and 4000 ng/mL, respectively). A single and repeated dose were well-tolerated, and there were no clinically meaningful findings regarding neurologic examinations and electrocardiography. The mean C max following a repeated dose of liposomal bupivacaine remained well below accepted values for central nervous system and cardiac toxicity. Liposomal bupivacaine was well-tolerated and revealed no clinically important safety signals. CLINICALTRIALS. NCT02210247.

Modeling adverse event counts in phase I clinical trials of a cytotoxic agent.

PubMed

Muenz, Daniel G; Braun, Thomas M; Taylor, Jeremy Mg

2018-05-01

Background/Aims The goal of phase I clinical trials for cytotoxic agents is to find the maximum dose with an acceptable risk of severe toxicity. The most common designs for these dose-finding trials use a binary outcome indicating whether a patient had a dose-limiting toxicity. However, a patient may experience multiple toxicities, with each toxicity assigned an ordinal severity score. The binary response is then obtained by dichotomizing a patient's richer set of data. We contribute to the growing literature on new models to exploit this richer toxicity data, with the goal of improving the efficiency in estimating the maximum tolerated dose. Methods We develop three new, related models that make use of the total number of dose-limiting and low-level toxicities a patient experiences. We use these models to estimate the probability of having at least one dose-limiting toxicity as a function of dose. In a simulation study, we evaluate how often our models select the true maximum tolerated dose, and we compare our models with the continual reassessment method, which uses binary data. Results Across a variety of simulation settings, we find that our models compare well against the continual reassessment method in terms of selecting the true optimal dose. In particular, one of our models which uses dose-limiting and low-level toxicity counts beats or ties the other models, including the continual reassessment method, in all scenarios except the one in which the true optimal dose is the highest dose available. We also find that our models, when not selecting the true optimal dose, tend to err by picking lower, safer doses, while the continual reassessment method errs more toward toxic doses. Conclusion Using dose-limiting and low-level toxicity counts, which are easily obtained from data already routinely collected, is a promising way to improve the efficiency in finding the true maximum tolerated dose in phase I trials.

A Phase I study of intermittently dosed vorinostat in combination with bortezomib in patients with advanced solid tumors.

PubMed

Deming, Dustin A; Ninan, Jacob; Bailey, Howard H; Kolesar, Jill M; Eickhoff, Jens; Reid, Joel M; Ames, Matthew M; McGovern, Renee M; Alberti, Dona; Marnocha, Rebecca; Espinoza-Delgado, Igor; Wright, John; Wilding, George; Schelman, William R

2014-04-01

Accumulating evidence shows evidence of efficacy with the combination of vorinostat and bortezomib in solid tumors. We previously examined a once-daily continuous dosing schedule of vorinostat in combination with bortezomib which was well tolerated in cycles 1 and 2; however, there was concern regarding the tolerability through multiple cycles. This study was conducted to evaluate an intermittent dosing schedule of vorinostat with bortezomib. Vorinostat was initially administered orally twice daily on days 1-14 with bortezomib IV on days 1, 4, 8, and 11 of a 21 day cycle. Two DLTs (elevated ALT and fatigue) were observed at dose level 1, thus the protocol was amended to administer vorinostat intermittently twice daily on days 1-4 and 8-11. 29 patients were enrolled; 13 men and 16 women. Common cancer types included sarcoma, pancreatic, colorectal, GIST, and breast. The most common Grade 3-4 toxicities at any dose level included thrombocytopenia, fatigue, increased ALT, elevated INR, and diarrhea. DLTs in the intermittent dosing scheduled included thrombocytopenia and fatigue. The Cmax and AUC for the intermittent dosing regimen were similar to those observed in the daily dosing. In this heavily pretreated population, stable disease was observed in patients with sarcoma, colorectal adenocarcinoma and GIST. The MTD was established at vorinostat 300 mg BID on days 1-4 and 8-11 and bortezomib 1.3 mg/m(2) IV on days 1, 4, 8, and 11 of a 21 day cycle. Tolerability was not improved with the intermittent dosing schedule of vorinostat when compared to continuous dosing.

Safety, pharmacokinetics, and pharmacodynamics of BMS-986142, a novel reversible BTK inhibitor, in healthy participants.

PubMed

Lee, Sun Ku; Xing, Jun; Catlett, Ian M; Adamczyk, Robert; Griffies, Amber; Liu, Ang; Murthy, Bindu; Nowak, Miroslawa

2017-06-01

BMS-986142 is an oral, small-molecule reversible inhibitor of Bruton's tyrosine kinase. The main objectives of our phase I studies were to characterize the safety and tolerability, pharmacokinetics, and pharmacodynamics of BMS-986142 in healthy participants, and to investigate the potential for the effect of BMS-986142 on the PK of methotrexate (MTX) in combination. In a combined single ascending dose and multiple ascending dose study, the safety, pharmacokinetics, and pharmacodynamics of BMS-986142 were assessed in healthy non-Japanese participants following administration of a single dose (5-900 mg) or multiple doses (25-350 mg, once daily for 14 days). In a drug-drug interaction study, the effect of BMS-986142 (350 mg, once daily for 5 days) on the single-dose pharmacokinetics of MTX (7.5 mg) was assessed in healthy participants. BMS-986142 was generally well tolerated, alone and in combination with MTX. BMS-986142 was rapidly absorbed with peak concentrations occurring within 2 h, and was eliminated with a mean half-life ranging from 7 to 11 h. Exposure of BMS-986142 appeared dose proportional within the dose ranges tested. A dose- and concentration-dependent inhibition of CD69 expression was observed following administration of BMS-986142. BMS-986142 did not affect the pharmacokinetics of MTX. BMS-986142 was well tolerated at the doses tested, had pharmacokinetic and pharmacodynamic profiles which support once-daily dosing, and can be coadministered with MTX without the pharmacokinetic interaction of BMS-986142 on MTX.

Prenatal and postnatal toxicity induced in guinea-pigs by nitrosomethylurea.

PubMed

Epstein, S S; Hasumi, K; Iobal, Z M

1976-01-01

Oral administration of NMU at maximally tolerated doses of guinea-pigs from day 34 to 58 of pregnancy induced embryotoxic effects, as evidenced by a high incidence of stillbirths and reduction in birth weight, and postnatal toxic effects, as evidenced by stunting, progressive mortality and extensive fatty degeneration of the liver in F1 progeny. Similar administration of NMUT at maximally tolerated doses did not induce such toxic effects.

Caffeine tolerance: behavioral, electrophysiological and neurochemical evidence

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chou, D.T.; Khan, S.; Forde, J.

The development of tolerance to the stimulatory action of caffeine upon mesencephalic reticular neurons and upon spontaneous locomotor activity was evaluated in rats after two weeks of chronic exposure to low doses of caffeine (5-10 mg/kg/day via their drinking water). These doses are achievable through dietary intake of caffeine-containing beverages in man. Concomitant measurement of (/sup 3/H)-CHA binding in the mesencephalic reticular formation was also carried out in order to explore the neurochemical basis of the development of tolerance. Caffeine, 2.5 mg/kg i.v., markedly increased the firing rate of reticular neurons in caffeine naive rats but failed to modify themore » neuronal activity in a group exposed chronically to low doses of caffeine. In addition, in spontaneous locomotor activity studies, the data show a distinct shift to the right of the caffeine dose-response curve in caffeine pretreated rats. These results clearly indicate that tolerance develops to the stimulatory action of caffeine upon the reticular formation at the single neuronal activity level as well as upon spontaneous locomotor activity. Furthermore, in chronically caffeine exposed rats, an increase in the number of binding sites for (/sup 3/H)-CHA was observed in reticular formation membranes without any change in receptor affinity. 28 references, 4 figures.« less

Changes in the retreatment radiation tolerance of the spinal cord with time after the initial treatment.

PubMed

Woolley, Thomas E; Belmonte-Beitia, Juan; Calvo, Gabriel F; Hopewell, John W; Gaffney, Eamonn A; Jones, Bleddyn

2018-06-01

To estimate, from experimental data, the retreatment radiation 'tolerances' of the spinal cord at different times after initial treatment. A model was developed to show the relationship between the biological effective doses (BEDs) for two separate courses of treatment with the BED of each course being expressed as a percentage of the designated 'retreatment tolerance' BED value, denoted [Formula: see text] and [Formula: see text]. The primate data of Ang et al. ( 2001 ) were used to determine the fitted parameters. However, based on rodent data, recovery was assumed to commence 70 days after the first course was complete, and with a non-linear relationship to the magnitude of the initial BED (BED init ). The model, taking into account the above processes, provides estimates of the retreatment tolerance dose after different times. Extrapolations from the experimental data can provide conservative estimates for the clinic, with a lower acceptable myelopathy incidence. Care must be taken to convert the predicted [Formula: see text] value into a formal BED value and then a practical dose fractionation schedule. Used with caution, the proposed model allows estimations of retreatment doses with elapsed times ranging from 70 days up to three years after the initial course of treatment.

Pharmacokinetic study of single- and multiple-dosing with metolazone tablets in healthy Chinese population.

PubMed

Li, Xueqing; Wang, Rutao; Liu, Yang; Liu, Yun; Zheng, Heng; Feng, Yabo; Zhao, Na; Geng, Hongbin; Zhang, Wanzhi; Wen, Aidong

2017-11-16

Metolazone is a diuretic, saluretic and antihypertensive chemical compound from the quinazoline category that possesses medicinal features similar to those of other thiazide diuretic drugs. However, the pharmacokinetics of metolazone in the Chinese population has rarely been studied. This study aimed to examine the pharmacokinetic characteristics, safety characteristic, and tolerability of metolazone in healthy Chinese subjects after single and multiple doses taken orally as well as the effects that food and gender have on oral metolazone pharmacokinetic parameters. An open-label, randomized, and single- and multiple-dosing investigation was performed in healthy Chinese subjects. The investigation included 3 study groups: the 0.5 mg, 1 mg and 2 mg dose groups were the single-dose study groups in the first stage. Eligible volunteers were randomly and orally administered a single 0.5 mg, 1 mg, or 2 mg metolazone tablet. The 0.5 mg dose group was also part of the multiple-dose study group, and the 1 mg dose group was the food-effect study group in the second stage. Human plasma samples were gathered pre-dosing and up to 48 h after dosing. The human plasma sample concentration of metolazone was quantified using a validated liquid chromatography tandem mass spectrometry method. Pharmacokinetic data were calculated by a noncompartmental analysis method using WinNonlin version 6.4. Tolerability was evaluated based on adverse events, medical examination, 12-lead ECG, and other clinical laboratory exams. Thirty eligible subjects (15 men and 15 women) were registered in our investigation and completed all of the study stages. The AUC and C max showed dose proportionality after a single dose based on the linear-regression analysis. A comparison of the pharmacokinetic data revealed that the differences between the male and female groups were not statistically significant. The t max of metolazone was increased by approximately 100% in the fed condition. Metolazone was well tolerated at the tested dose, and no adverse effects were observed. Single dosing with 0.5 mg, 1 mg, or 2 mg metolazone yielded linear plasma pharmacokinetic properties in healthy Chinese subjects. Multiple oral doses of metolazone did not display significantly different distributions or elimination characteristics from those observed for a single dose. Gender factors did not appear to influence the pharmacokinetic parameter variation of metolazone. The t max of metolazone increased in the fed condition. Metolazone was well tolerated at the tested dose in this study. This investigation is retrospectively registered at chictr.org.cn (ChiCTR-IIR-17012929, October 09 2017).

Tolerance to Gamma Radiation in the Tardigrade Hypsibius dujardini from Embryo to Adult Correlate Inversely with Cellular Proliferation.

PubMed

Beltrán-Pardo, Eliana; Jönsson, K Ingemar; Harms-Ringdahl, Mats; Haghdoost, Siamak; Wojcik, Andrzej

2015-01-01

Tardigrades are highly tolerant to desiccation and ionizing radiation but the mechanisms of this tolerance are not well understood. In this paper, we report studies on dose responses of adults and eggs of the tardigrade Hypsibius dujardini exposed to gamma radiation. In adults the LD50/48h for survival was estimated at ~ 4200 Gy, and doses higher than 100 Gy reduced both fertility and hatchability of laid eggs drastically. We also evaluated the effect of radiation (doses 50 Gy, 200 Gy, 500 Gy) on eggs in the early and late embryonic stage of development, and observed a reduced hatchability in the early stage, while no effect was found in the late stage of development. Survival of juveniles from irradiated eggs was highly affected by a 500 Gy dose, both in the early and the late stage. Juveniles hatched from eggs irradiated at 50 Gy and 200 Gy developed into adults and produced offspring, but their fertility was reduced compared to the controls. Finally we measured the effect of low temperature during irradiation at 4000 Gy and 4500 Gy on survival in adult tardigrades, and observed a slight delay in the expressed mortality when tardigrades were irradiated on ice. Since H. dujardini is a freshwater tardigrade with lower tolerance to desiccation compared to limno-terrestrial tardigrades, the high radiation tolerance in adults, similar to limno-terrestrial tardigrades, is unexpected and seems to challenge the idea that desiccation and radiation tolerance rely on the same molecular mechanisms. We suggest that the higher radiation tolerance in adults and late stage embryos of H. dujardini (and in other studied tardigrades) compared to early stage embryos may partly be due to limited mitotic activity, since tardigrades have a low degree of somatic cell division (eutely), and dividing cells are known to be more sensitive to radiation.

Tolerance to Gamma Radiation in the Tardigrade Hypsibius dujardini from Embryo to Adult Correlate Inversely with Cellular Proliferation

PubMed Central

Beltrán-Pardo, Eliana; Jönsson, K. Ingemar; Harms-Ringdahl, Mats; Haghdoost, Siamak; Wojcik, Andrzej

2015-01-01

Tardigrades are highly tolerant to desiccation and ionizing radiation but the mechanisms of this tolerance are not well understood. In this paper, we report studies on dose responses of adults and eggs of the tardigrade Hypsibius dujardini exposed to gamma radiation. In adults the LD50/48h for survival was estimated at ~ 4200 Gy, and doses higher than 100 Gy reduced both fertility and hatchability of laid eggs drastically. We also evaluated the effect of radiation (doses 50 Gy, 200 Gy, 500 Gy) on eggs in the early and late embryonic stage of development, and observed a reduced hatchability in the early stage, while no effect was found in the late stage of development. Survival of juveniles from irradiated eggs was highly affected by a 500 Gy dose, both in the early and the late stage. Juveniles hatched from eggs irradiated at 50 Gy and 200 Gy developed into adults and produced offspring, but their fertility was reduced compared to the controls. Finally we measured the effect of low temperature during irradiation at 4000 Gy and 4500 Gy on survival in adult tardigrades, and observed a slight delay in the expressed mortality when tardigrades were irradiated on ice. Since H. dujardini is a freshwater tardigrade with lower tolerance to desiccation compared to limno-terrestrial tardigrades, the high radiation tolerance in adults, similar to limno-terrestrial tardigrades, is unexpected and seems to challenge the idea that desiccation and radiation tolerance rely on the same molecular mechanisms. We suggest that the higher radiation tolerance in adults and late stage embryos of H. dujardini (and in other studied tardigrades) compared to early stage embryos may partly be due to limited mitotic activity, since tardigrades have a low degree of somatic cell division (eutely), and dividing cells are known to be more sensitive to radiation. PMID:26208275

The Effect of Ezetimibe/Statin Combination and High-Dose Statin Therapy on Thyroid Autoimmunity in Women with Hashimoto's Thyroiditis and Cardiovascular Disease: A Pilot Study.

PubMed

Krysiak, R; Szkróbka, W; Okopień, B

2016-10-01

Background: Intensive statin therapy was found to reduce thyroid autoimmunity in women with Hashimoto's thyroiditis. No similar data are available for other hypolipidemic agents. Methods: The participants of the study were 16 women with Hashimoto's thyroiditis and coronary artery disease. On the basis of statin tolerance, they were divided into 2 groups. 8 patients who did not tolerate high-dose statin therapy were treated with a statin, the dose of which was reduced by half, together with ezetimibe. The remaining 8 patients tolerating the treatment continued high-dose statin therapy. Plasma lipids, serum levels of thyrotropin, free thyroxine and free triiodothyronine, as well as titers of thyroid peroxidase and thyroglobulin antibodies were measured at the beginning of the study and 6 months later. Results: Replacing high-dose statin therapy with ezetimibe/statin combination therapy increased serum titers of thyroid peroxidase as well as led to an insignificant increase in serum titers of thyroglobulin antibodies. At the end of the study, thyroid peroxidase and thyroglobulin antibody titers were higher in patients receiving the combination therapy than in those treated only with high-dose statin. Conclusions: Our study shows that high-dose statin therapy produces a stronger effect on thyroid autoimmunity than ezetimibe/statin combination therapy. © Georg Thieme Verlag KG Stuttgart · New York.

Dose-Response Effects of Long-Acting Liquid Methylphenidate in Children with Attention Deficit/Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD): A Pilot Study.

PubMed

Kim, Soo-Jeong; Shonka, Sophia; French, William P; Strickland, Jennifer; Miller, Lindsey; Stein, Mark A

2017-08-01

Attention deficit/hyperactivity disorder (ADHD) symptoms are common in youth with autism spectrum disorders (ASD) and are frequently treated with stimulant medications. Twenty-seven children were randomized to different dose titration schedules, and ADHD symptoms, tolerability, and aberrant behaviors were assessed weekly during a 6-week trial with long-acting liquid methylphenidate (MPH). MPH at low to moderate doses was effective in reducing ADHD symptoms and was well tolerated in young children with ASD and ADHD. Future studies are needed to assess generalization and maintenance of efficacy.

A phase 2 study of the safety, tolerability, and pharmacodynamics of FBS0701, a novel oral iron chelator, in transfusional iron overload

PubMed Central

Neufeld, Ellis J.; Galanello, Renzo; Viprakasit, Vip; Aydinok, Yesim; Piga, Antonio; Harmatz, Paul; Forni, Gian Luca; Shah, Farrukh T.; Grace, Rachael F.; Porter, John B.; Wood, John C.; Peppe, Jennifer; Jones, Amber

2012-01-01

This was a 24-week, multicenter phase- 2 study designed to assess safety, tolerability, and pharmacodynamics of FBS0701, a novel oral chelator, in adults with transfusional iron overload. Fifty-one patients, stratified by transfusional iron intake, were randomized to FBS0701 at either 14.5 or 29 mg/kg/d (16 and 32 mg/kg/d salt form). FBS0701 was generally well tolerated at both doses. Forty-nine patients (96%) completed the study. There were no drug-related serious adverse events. No adverse events (AEs) showed dose-dependency in frequency or severity. Treatment-related nausea, vomiting, abdominal pain, and diarrhea were each noted in < 5% of patients. Mean serum creatinine did not change significantly from Baseline or between dose groups. Transaminases wer increased in 8 (16%), three of whom acquired HCV on-study from a single blood bank while five had an abnormal baseline ALT. The 24 week mean change in liver iron concentration (ΔLIC) at 14.5 mg/kg/d was +3.1 mg/g (dw); 29% achieved a decrease in LIC. Mean ΔLIC at 29 mg/kg/d was −0.3 mg/g (dw); 44% achieved a decrease in LIC (P < .03 for ΔLIC between doses). The safety and tolerability profile at therapeutic doses compare favorably to other oral chelators. This trial was registered at www.clinicaltrials.gov as NCT01186419. PMID:22251482

Pharmacokinetics, pharmacodynamics, tolerability, and safety of exenatide in Japanese patients with type 2 diabetes mellitus.

PubMed

Kothare, Prajakti A; Linnebjerg, Helle; Isaka, Yoshitaka; Uenaka, Kazunori; Yamamura, Ayuko; Yeo, Kwee Poo; de la Peña, Amparo; Teng, Choo Hua; Mace, Kenneth; Fineman, Mark; Shigeta, Hirofumi; Sakata, Yukikuni; Irie, Shin

2008-12-01

In this single-blind, parallel, placebo-controlled study, the pharmacokinetics, pharmacodynamics, tolerability, and safety of subcutaneous exenatide were evaluated in 40 Japanese patients with type 2 diabetes. Patients were allocated to 4 groups and randomized to receive exenatide (n = 8/group) or placebo (n = 2/group), with all receiving placebo on day 1. On day 2, patients received single-dose exenatide (2.5 microg [group A] or 5 microg [groups B, C, and D]) or placebo and then bid on days 3 to 5. On days 6 to 10, groups A and B continued on 2.5 and 5 microg bid; groups C and D received 10 and 15 microg bid, respectively. The last dose was given on the morning of day 10. All adverse events were mild or moderate in severity. Exenatide was generally well tolerated up to 10 microg. Exenatide was well absorbed with a median t(max) of 1.5 hours and mean t((1/2)) of 1.6 hours; exposure increased with dose. Up to 10 microg, exenatide reduced postprandial glucose concentrations in a dose-dependent fashion compared with placebo; decreases were similar for 10 and 15 microg. An E(max) model demonstrated that doses higher than 2.5 microg were necessary for adequate glycemic response. Based on tolerability and pharmacokinetic/pharmacodynamic relationships, 5 and 10 microg exenatide may be considered for further clinical development in Japanese patients with type 2 diabetes.

[Study of Flexible Doses of Paliperidone ER in Pacients with Schizophrenia who Have Undergone Inefficient Treatment with other Antipsychotics].

PubMed

Córdoba, Rodrigo; Cano, Juan Fernando; Arango-Dávila, César Augusto; Miranda, Carlos; Holguín, Jorge; Fernández, Darío; Márquez, Miguel; Lupo, Christian; Gargoloff, Pedro; Petracca, Gustavo; Lucchetti, César

2012-06-01

Extended-release (ER) paliperidone is an innovative atypical antipsychotic that allows minimal peak-to-through fluctuations with once-daily dosing. To evaluate effectiveness, safety and tolerability of flexible, once-daily doses of paliperidone ER (3-12 mg/day) in patients with schizophrenia from Argentina and Colombia who had previously failed treatment with other antipsychotic agents. The authors conducted a 6-month, open-label, prospective and multicentric study. Effectiveness was assessed with Positive and Negative Syndrome Scale (PANSS) and Personal and Social Performance scale (PSP). Other measures of effectiveness, safety and tolerability, were also conducted. Paliperidone ER 3-12 mg/day improved Positive and Negative Syndrome Scale (PANSS) total scores (primary endpoint) from baseline to study end (p < 0,001). In the PANSS total score, the mean change from baseline (83, 9 units) to end point (53,7 units) was significant (p < 0,001). Flexible doses of paliperidone ER demonstrated a ≥20% reduction in the PANSS total score (p<0.001) in almost two-thirds of patients. PSP mean change from baseline (52 units) to end point (85 units) was significant (p < 0,001). Secondary effectiveness assessments, as well as safety and tolerability measures, demonstrated favourable results throughout the study. Flexible doses of paliperidone ER over 6 months were effective, safe and well tolerated in patients with schizophrenia from Argentina and Colombia. Copyright © 2012 Asociación Colombiana de Psiquiatría. Publicado por Elsevier España. All rights reserved.

Late effects of radiation on the lumbar spinal cord of guinea pigs: Re-treatment tolerance

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mason, K.A.; Withers, H.R.; Chiang, Chi-Shiun

Using a guinea pig model of lumbar myelopathy, various factors affecting the tolerance of spinal cord to irradiation were assessed: (a) extent of initial injury; (b) time interval between priming and test doses; and (c) animal age at the time of initial radiation treatment. A 3 cm section of lumbar spinal cord of guinea pigs was irradiated with fractionated doses of 4.5 Gy gamma rays given as 9 fractions per week. Guinea pigs were primed with 9 x 4.5 Gy in 7 days which is 60% of the ED[sub 50] for a continuous course of treatment. After 28 or 40more » weeks, animal were retreated with 6-14 fractions of 4.5 Gy. Animals were observed for 2 years following the priming dose and both the incidence and latency of myelopathy recorded. Young adult guinea pigs (8 wk old) showed both a decreased radiation tolerance and latency compared to old individuals (40 wk old). At 28 or 40 wk after 9 x 4.5 Gy, only about 8% of the initial injury was remembered in young adult guinea pigs. The amount of residual injury was dependent on the initial damage as a proportion of the tolerance dose. The spinal cord shows a greater capacity for long-term recovery than generally appreciated and re-treatment doses clinically prescribed may be lower than necessary. 8 refs., 3 figs., 2 tabs.« less

The Use of Glyburide Compared With Other Sulfonylureas and the Risk of Cancer in Patients With Type 2 Diabetes.

PubMed

Tuccori, Marco; Wu, Jennifer W; Yin, Hui; Majdan, Agnieszka; Azoulay, Laurent

2015-11-01

To determine whether the use of glyburide is associated with an increased risk of cancer compared with the use of other second-generation sulfonylureas among patients with type 2 diabetes. The U.K. Clinical Practice Research Datalink was used to conduct a cohort study among 52,600 patients newly prescribed glyburide or other second-generation sulfonylureas between 1 January 1988 and 31 July 2013. A time-dependent Cox proportional hazards model was used to estimate adjusted hazard ratios (HRs) and 95% CIs of any cancer associated with the use of glyburide compared with the use of second-generation sulfonylureas. Secondary analyses were conducted to determine whether the association varied with cumulative duration of use and cumulative dose (expressed as defined daily dose [DDD]). During 280,288 person-years of follow-up, 4,105 patients were given a new diagnosis of cancer (incidence rate 14.6 per 1,000 person-years). Overall, when compared with the use of other second-generation sulfonylureas, the use of glyburide was associated with a nonsignificant increased risk of any cancer (HR 1.09 [95% CI 0.98-1.22]). In secondary analyses, duration- and dose-response relationships were observed, with longer cumulative durations and cumulative doses associated with an increased risk of any cancer (>36 months: HR 1.21 [95% CI: 1.03-1.42]; >1,096 DDDs: HR 1.27 [95% CI 1.06-1.51]). In this population-based cohort study, longer cumulative durations and higher cumulative doses of glyburide were associated with an increased risk of cancer. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

Phase I Study of Oxaliplatin in Combination With Capecitabine and Radiotherapy as Postoperative Treatment for Stage II and III Rectal Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jin Jing; Li Yexiong; Wang Jinwan

Purpose: A Phase I study was conducted to determine the maximal tolerated dose and the dose-limiting toxicity (DLT) of oxaliplatin (OXA) combined with capecitabine and radiotherapy as adjuvant treatment in patients with operable rectal cancer. Patients and Methods: A total of 21 patients with Stage II or III rectal adenocarcinoma after curative surgery were treated with radiotherapy to a total dose of 50 Gy in 5 weeks. OXA was administered at a dosage of 40 (n = 6), 50 (n = 3),60 (n = 3), 70 (n = 3), or 80 mg/m{sup 2} (n = 6) once a week formore » 2 weeks (first cycle) followed by a second cycle after a 7-day break. Capecitabine at a fixed dose of 1,300 mg/m{sup 2}/d was administered orally at the same schedule as for OXA. DLT was defined as Grade 3 or 4 hematologic and nonhematologic toxicity. Results: Grade 1-3 leukopenia, diarrhea, and nausea/vomiting were the most common toxic side effects, and most were Grade 1-2. A DLT was first observed in 1 of 3 patients at 40 mg/m{sup 2} (Grade 3 diarrhea) but was not observed in the next 3 patients at the same level or in patients who received a dose level of 50-70 mg/m{sup 2}. At 80 mg/m{sup 2}, DLT occurred in 3 of 6 patients (1 Grade 4 leukopenia and 2 Grade 3 diarrhea). Conclusions: OXA combined with a fixed dose of capecitabine at 625 mg/m{sup 2} twice daily by mouth plus radiotherapy in the adjuvant setting was tolerable and clinically feasible. The maximal tolerated dose of OXA in this setting was 80 mg/m{sup 2}, comparable to the maximal tolerated dose of OXA in the neoadjuvant setting.« less

Phase I Pharmacokinetic and Pharmacodynamic Study of the Oral, Small-Molecule Mitogen-Activated Protein Kinase Kinase 1/2 Inhibitor AZD6244 (ARRY-142886) in Patients With Advanced Cancers

PubMed Central

Adjei, Alex A.; Cohen, Roger B.; Franklin, Wilbur; Morris, Clive; Wilson, David; Molina, Julian R.; Hanson, Lorelei J.; Gore, Lia; Chow, Laura; Leong, Stephen; Maloney, Lara; Gordon, Gilad; Simmons, Heidi; Marlow, Allison; Litwiler, Kevin; Brown, Suzy; Poch, Gregory; Kane, Katie; Haney, Jerry; Eckhardt, S. Gail

2009-01-01

Purpose To assess the tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of the mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor AZD6244 (ARRY-142886) in patients with advanced cancer. Patients and Methods In part A, patients received escalating doses to determine the maximum-tolerated dose (MTD). In both parts, blood samples were collected to assess PK and PD parameters. In part B, patients were stratified by cancer type (melanoma v other) and randomly assigned to receive the MTD or 50% MTD. Biopsies were collected to determine inhibition of ERK phosphorylation, Ki-67 expression, and BRAF, KRAS, and NRAS mutations. Results Fifty-seven patients were enrolled. MTD in part A was 200 mg bid, but this dose was discontinued in part B because of toxicity. The 50% MTD (100 mg bid) was well tolerated. Rash was the most frequent and dose-limiting toxicity. Most other adverse events were grade 1 or 2. The PKs were less than dose proportional, with a median half-life of approximately 8 hours and inhibition of ERK phosphorylation in peripheral-blood mononuclear cells at all dose levels. Paired tumor biopsies demonstrated reduced ERK phosphorylation (geometric mean, 79%). Five of 20 patients demonstrated ≥ 50% inhibition of Ki-67 expression, and RAF or RAS mutations were detected in 10 of 26 assessable tumor samples. Nine patients had stable disease (SD) for ≥ 5 months, including two patients with SD for 19 (thyroid cancer) and 22 (uveal melanoma plus renal cancer) 28-day cycles. Conclusion AZD6244 was well tolerated with target inhibition demonstrated at the recommended phase II dose. PK analyses supported twice-daily dosing. Prolonged SD was seen in a variety of advanced cancers. Phase II studies are ongoing. PMID:18390968

A Randomized Dose-Ranging Study of Neuropeptide Y in Patients with Posttraumatic Stress Disorder.

PubMed

Sayed, Sehrish; Van Dam, Nicholas T; Horn, Sarah R; Kautz, Marin M; Parides, Michael; Costi, Sara; Collins, Katherine A; Iacoviello, Brian; Iosifescu, Dan V; Mathé, Aleksander A; Southwick, Steven M; Feder, Adriana; Charney, Dennis S; Murrough, James W

2018-01-01

Anxiety and trauma-related disorders are among the most prevalent and disabling medical conditions in the United States, and posttraumatic stress disorder in particular exacts a tremendous public health toll. We examined the tolerability and anxiolytic efficacy of neuropeptide Y administered via an intranasal route in patients with posttraumatic stress disorder. Twenty-six individuals were randomized in a cross-over, single ascending dose study into 1 of 5 cohorts: 1.4 mg (n=3), 2.8 mg (n=6), 4.6 mg (n=5), 6.8 mg (n=6), and 9.6 mg (n=6). Each individual was dosed with neuropeptide Y or placebo on separate treatment days 1 week apart in random order under double-blind conditions. Assessments were conducted at baseline and following a trauma script symptom provocation procedure subsequent to dosing. Occurrence of adverse events represented the primary tolerability outcome. The difference between treatment conditions on anxiety as measured by the Beck Anxiety Inventory and the State-Trait Anxiety Inventory immediately following the trauma script represented efficacy outcomes. Twenty-four individuals completed both treatment days. Neuropeptide Y was well tolerated up to and including the highest dose. There was a significant interaction between treatment and dose; higher doses of neuropeptide Y were associated with a greater treatment effect, favoring neuropeptide Y over placebo on Beck Anxiety Inventory score (F1,20=4.95, P=.038). There was no significant interaction for State-Trait Anxiety Inventory score. Our study suggests that a single dose of neuropeptide Y is well tolerated up to 9.6 mg and may be associated with anxiolytic effects. Future studies exploring the safety and efficacy of neuropeptide Y in stress-related disorders are warranted. The reported study is registered at: http://clinicaltrials.gov (ID: NCT01533519). © The Author(s) 2017. Published by Oxford University Press on behalf of CINP.

A phase I study of amrubicin and fixed dose of irinotecan (CPT-11) in relapsed small cell lung cancer: Japan multinational trial organization LC0303.

PubMed

Kawahara, Masaaki; Kubo, Akihito; Komuta, Kiyoshi; Fujita, Yuka; Sasaki, Yoshiaki; Fukushima, Masanori; Daimon, Takashi; Furuse, Kiyoyuki; Mishima, Michiaki; Mio, Tadashi

2012-12-01

To determine the maximum tolerated dose of amrubicin (AMR) with a fixed dose of irinotecan (CPT-11). Patients having pathologically proven small cell lung cancer (SCLC) relapsed after one or two chemotherapies, and Eastern Cooperative Oncology Group performance status of 0 to 2 were eligible for the study. CPT-11 was delivered as 50 mg/m2 on days 1 and 8, every 21 days. AMR was delivered on day 1. Doses of AMR were level 1: 80 mg/m2, level 2: 90 mg/m2, and level 3: 100 mg/m2. Dose elevation was determined using the modified continuous reassessment method. Tolerability was assessed after the first cycle. Another two cycles were conducted when disease progression or unacceptable toxicities were not observed. Eighteen patients (mean age: 66.3 years) were enrolled. A total of 40 courses were conducted. Grade 3/4 toxicities of the first cycle were leukocytopenia: 11 (61%, grade 3/4: 8/3); neutropenia: 15 (83%, grade 3/4: 6/9); and thrombocytopenia: three (17%, grade 3/4: 2/1). Other grade 3 toxicities observed were febrile neutropenia, one; infection, three; diarrhea, one; and dyspnea, one. Dose-limiting toxicity was observed in two of six patients at level 2 (neutropenia and febrile neutropenia) and in one of six at level 3 (thrombocytopenia and infection). The maximum tolerated dose was level 3, and so, the recommended dose for phase II trials was judged to be 90 mg/m2. Objective response was obtained in four of eight patients who were able to evaluate responses. Median survival time was 13 months, with 68% at 1-year survival rate. This combination was well tolerated and showed encouraging activities in SCLC. Randomized phase II trials are being planned in chemonaive SCLC.

A FFT-based formulation for discrete dislocation dynamics in heterogeneous media

NASA Astrophysics Data System (ADS)

Bertin, N.; Capolungo, L.

2018-02-01

In this paper, an extension of the DDD-FFT approach presented in [1] is developed for heterogeneous elasticity. For such a purpose, an iterative spectral formulation in which convolutions are calculated in the Fourier space is developed to solve for the mechanical state associated with the discrete eigenstrain-based microstructural representation. With this, the heterogeneous DDD-FFT approach is capable of treating anisotropic and heterogeneous elasticity in a computationally efficient manner. In addition, a GPU implementation is presented to allow for further acceleration. As a first example, the approach is used to investigate the interaction between dislocations and second-phase particles, thereby demonstrating its ability to inherently incorporate image forces arising from elastic inhomogeneities.

Phase I trial and pharmacokinetic study of raltitrexed in children with recurrent or refractory leukemia: a pediatric oncology group study.

PubMed

Horton, Terzah M; Blaney, Susan M; Langevin, Anne-Marie; Kuhn, John; Kamen, Barton; Berg, Stacey L; Bernstein, Mark; Weitman, Steven

2005-03-01

To evaluate the toxicity, antileukemic activity, and pharmacology of raltitrexed administered weekly for 3 weeks to patients with refractory or recurrent leukemia. Raltitrexed was administered as a 15-minute infusion for 3 consecutive weeks every 5 weeks, at doses ranging from 1.3 to 2.8 mg/m(2). The first course was used to determine the dose-limiting toxicities and maximum tolerated dose. Correlative studies included an assessment of raltitrexed pharmacokinetics and measurement of plasma 2'-deoxyuridine concentrations, a surrogate measure of thymidylate synthase inhibition. Twenty-one children (18 evaluable) with refractory leukemia received 25 courses of raltitrexed. The dose-limiting toxicity was reversible elevation in liver transaminases at the 2.8-mg/m(2) dose level and the maximum tolerated dose was 2.1 mg/m(2) per dose. Pharmacokinetics were best characterized by a two-compartment model with a clearance of 139 mL/min/m(2) (8.3 L/h/m(2)), a 2.4-L volume of distribution, an initial half-life (t(1/2alpha)) of 6 minutes, and a terminal half-life (t(1/2beta)) of 45 minutes. There were three objective responses. Raltitrexed was well tolerated when administered as a single agent to children with recurrent or refractory leukemia. We observed preliminary evidence of antileukemia activity using this weekly dosing schedule and these observations support further evaluation of raltitrexed in this population.

Safety, efficacy and pharmacokinetics of neratinib (HKI-272) in Japanese patients with advanced solid tumors: a Phase 1 dose-escalation study.

PubMed

Ito, Yoshinori; Suenaga, Mitsukuni; Hatake, Kiyohiko; Takahashi, Shunji; Yokoyama, Masahiro; Onozawa, Yusuke; Yamazaki, Kentaro; Hironaka, Shuichi; Hashigami, Kiyoshi; Hasegawa, Hirotaka; Takenaka, Nobuko; Boku, Narikazu

2012-04-01

Neratinib (HKI-272), a potent, irreversible, small-molecule, orally administered, pan-ErbB inhibitor that blocks signal transduction via inhibition of three epidermal growth factor receptors [ErbB1, ErbB2 (Her2) and ErbB4], is being developed for the treatment of solid tumors, including breast cancer. This Phase 1 dose-escalation study assessed the safety, tolerability, maximum-tolerated dose, antitumor activity and pharmacokinetics of neratinib in Japanese patients with advanced solid tumors. Patients received neratinib 80, 160, 240 or 320 mg orally; each patient enrolled in only one dose cohort. Patients received a single dose in week 1, followed by daily continuous doses. Blood samples collected were on days 1 and 21 for pharmacokinetic analyses. Twenty-one patients were enrolled (3 breast cancer; 17 colorectal cancer; 1 gastric cancer). Neratinib-related adverse events (all grades) included diarrhea (20 patients), fatigue (14 patients), nausea and abdominal pain (9 patients each) and anorexia (8 patients). Grade ≥3 neratinib-related adverse events in two or more patients were diarrhea and anorexia (two patients each). Dose-limiting toxicities were diarrhea and anorexia (two patients, 320 mg dose). The maximum-tolerated dose and recommended dose was neratinib 240 mg once daily. Of 21 evaluable patients, 2 with breast cancer had partial response, 3 had stable disease ≥24 weeks, 7 had stable disease ≥16 weeks and 9 had progressive disease. Pharmacokinetic analyses indicated that neratinib exposures increased with dose. The safety, efficacy and pharmacokinetic profiles of neratinib are consistent with those reported for non-Japanese patients and warrant further investigation of neratinib in Japanese patients with solid tumors.

Dose-Finding and Pharmacokinetic Study to Optimize the Dosing of Irinotecan According to the UGT1A1 Genotype of Patients With Cancer

PubMed Central

Innocenti, Federico; Schilsky, Richard L.; Ramírez, Jacqueline; Janisch, Linda; Undevia, Samir; House, Larry K.; Das, Soma; Wu, Kehua; Turcich, Michelle; Marsh, Robert; Karrison, Theodore; Maitland, Michael L.; Salgia, Ravi; Ratain, Mark J.

2014-01-01

Purpose The risk of severe neutropenia from treatment with irinotecan is related in part to UGT1A1*28, a variant that reduces the elimination of SN-38, the active metabolite of irinotecan. We aimed to identify the maximum-tolerated dose (MTD) and dose-limiting toxicity (DLT) of irinotecan in patients with advanced solid tumors stratified by the *1/*1, *1/*28, and *28/*28 genotypes. Patients and Methods Sixty-eight patients received an intravenous flat dose of irinotecan every 3 weeks. Forty-six percent of the patients had the *1/*1 genotype, 41% had the *1/*28 genotype, and 13% had the *28/*28 genotype. The starting dose of irinotecan was 700 mg in patients with the *1/*1 and *1/*28 genotypes and 500 mg in patients with the *28/*28 genotype. Pharmacokinetic evaluation was performed at cycle 1. Results In patients with the *1/*1 genotype, the MTD was 850 mg (four DLTs per 16 patients), and 1,000 mg was not tolerated (two DLTs per six patients). In patients with the *1/*28 genotype, the MTD was 700 mg (five DLTs per 22 patients), and 850 mg was not tolerated (four DLTs per six patients). In patients with the *28/*28 genotype, the MTD was 400 mg (one DLT per six patients), and 500 mg was not tolerated (three DLTs per three patients). The DLTs were mainly myelosuppression and diarrhea. Irinotecan clearance followed linear kinetics. At the MTD for each genotype, dosing by genotype resulted in similar SN-38 areas under the curve (AUCs; r2 = 0.0003; P = .97), but the irinotecan AUC was correlated with the actual dose (r2 = 0.39; P < .001). Four of 48 patients with disease known to be responsive to irinotecan achieved partial response. Conclusion The UGT1A1*28 genotype can be used to individualize dosing of irinotecan. Additional studies should evaluate the effect of genotype-guided dosing on efficacy in patients receiving irinotecan. PMID:24958824

A comprehensive analysis of the IMRT dose delivery process using statistical process control (SPC)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gerard, Karine; Grandhaye, Jean-Pierre; Marchesi, Vincent

The aim of this study is to introduce tools to improve the security of each IMRT patient treatment by determining action levels for the dose delivery process. To achieve this, the patient-specific quality control results performed with an ionization chamber--and which characterize the dose delivery process--have been retrospectively analyzed using a method borrowed from industry: Statistical process control (SPC). The latter consisted in fulfilling four principal well-structured steps. The authors first quantified the short term variability of ionization chamber measurements regarding the clinical tolerances used in the cancer center ({+-}4% of deviation between the calculated and measured doses) by calculatingmore » a control process capability (C{sub pc}) index. The C{sub pc} index was found superior to 4, which implies that the observed variability of the dose delivery process is not biased by the short term variability of the measurement. Then, the authors demonstrated using a normality test that the quality control results could be approximated by a normal distribution with two parameters (mean and standard deviation). Finally, the authors used two complementary tools--control charts and performance indices--to thoroughly analyze the IMRT dose delivery process. Control charts aim at monitoring the process over time using statistical control limits to distinguish random (natural) variations from significant changes in the process, whereas performance indices aim at quantifying the ability of the process to produce data that are within the clinical tolerances, at a precise moment. The authors retrospectively showed that the analysis of three selected control charts (individual value, moving-range, and EWMA control charts) allowed efficient drift detection of the dose delivery process for prostate and head-and-neck treatments before the quality controls were outside the clinical tolerances. Therefore, when analyzed in real time, during quality controls, they should improve the security of treatments. They also showed that the dose delivery processes in the cancer center were in control for prostate and head-and-neck treatments. In parallel, long term process performance indices (P{sub p}, P{sub pk}, and P{sub pm}) have been analyzed. Their analysis helped defining which actions should be undertaken in order to improve the performance of the process. The prostate dose delivery process has been shown statistically capable (0.08% of the results is expected to be outside the clinical tolerances) contrary to the head-and-neck dose delivery process (5.76% of the results are expected to be outside the clinical tolerances).« less

A comprehensive analysis of the IMRT dose delivery process using statistical process control (SPC).

PubMed

Gérard, Karine; Grandhaye, Jean-Pierre; Marchesi, Vincent; Kafrouni, Hanna; Husson, François; Aletti, Pierre

2009-04-01

The aim of this study is to introduce tools to improve the security of each IMRT patient treatment by determining action levels for the dose delivery process. To achieve this, the patient-specific quality control results performed with an ionization chamber--and which characterize the dose delivery process--have been retrospectively analyzed using a method borrowed from industry: Statistical process control (SPC). The latter consisted in fulfilling four principal well-structured steps. The authors first quantified the short-term variability of ionization chamber measurements regarding the clinical tolerances used in the cancer center (+/- 4% of deviation between the calculated and measured doses) by calculating a control process capability (C(pc)) index. The C(pc) index was found superior to 4, which implies that the observed variability of the dose delivery process is not biased by the short-term variability of the measurement. Then, the authors demonstrated using a normality test that the quality control results could be approximated by a normal distribution with two parameters (mean and standard deviation). Finally, the authors used two complementary tools--control charts and performance indices--to thoroughly analyze the IMRT dose delivery process. Control charts aim at monitoring the process over time using statistical control limits to distinguish random (natural) variations from significant changes in the process, whereas performance indices aim at quantifying the ability of the process to produce data that are within the clinical tolerances, at a precise moment. The authors retrospectively showed that the analysis of three selected control charts (individual value, moving-range, and EWMA control charts) allowed efficient drift detection of the dose delivery process for prostate and head-and-neck treatments before the quality controls were outside the clinical tolerances. Therefore, when analyzed in real time, during quality controls, they should improve the security of treatments. They also showed that the dose delivery processes in the cancer center were in control for prostate and head-and-neck treatments. In parallel, long-term process performance indices (P(p), P(pk), and P(pm)) have been analyzed. Their analysis helped defining which actions should be undertaken in order to improve the performance of the process. The prostate dose delivery process has been shown statistically capable (0.08% of the results is expected to be outside the clinical tolerances) contrary to the head-and-neck dose delivery process (5.76% of the results are expected to be outside the clinical tolerances).

Single and Multiple Ascending-dose Studies of Oral Delafloxacin: Effects of Food, Sex, and Age.

PubMed

Hoover, Randall; Hunt, Thomas; Benedict, Michael; Paulson, Susan K; Lawrence, Laura; Cammarata, Sue; Sun, Eugene

2016-01-01

The objective of this report is describe the results of 2 studies that examined the pharmacokinetic parameters, safety profile, and tolerability of single and multiple ascending doses of oral delafloxacin and the effects of food, sex, and age on oral delafloxacin pharmacokinetic parameters, safety profile, and tolerability. The first study contained 3 parts and used unformulated delafloxacin in a capsule. Part 1 was a randomized, double-blind, placebo-controlled, single (50, 100, 200, 400, 800, 1200, and 1600 mg) ascending-dose study of oral delafloxacin in healthy men. Part 2 was a single-dose crossover study in which 20 men received 250 mg delafloxacin with or without food. Part 2 also included a parallel group, double-blind, placebo-controlled study in 16 women and 16 elderly men and women who were randomized (3:1) to receive 250 mg delafloxacin or placebo. Part 3 was a randomized, double-blind, placebo-controlled, multiple (100, 200, 400, 800, 1200 mg once daily for 5 days) ascending-dose study of oral delafloxacin in healthy men. The second study was a single-dose, randomized, 3-period crossover study in which participants received 900 mg delafloxacin (2 × 450-mg tablets) under fasted conditions, with a high-fat meal, or fasted with a high-fat meal 2 hours after dosing. Serial blood samples were collected, and plasma pharmacokinetic parameters of delafloxacin were determined. Delafloxacin Cmax and AUC0-∞ increased with increasing oral dose over the dose range of 50 to 1600 mg. The increases in delafloxacin AUC0-∞ were dose proportional at doses of ≥200 mg. Steady state was reached by day 3 of dosing with minimal accumulation of delafloxacin. The Cmax of delafloxacin was decreased slightly in the presence of food. No sex difference in delafloxacin pharmacokinetic parameters was observed. In the elderly men and women, mean delafloxacin Cmax and AUC0-∞ were 35% higher than observed for young adults, which could be partially explained by a decrease in the creatinine clearance in the elderly men and women. Delafloxacin was well tolerated at the tested doses, with gastrointestinal adverse effects observed more commonly at doses ≥1200 mg. Delafloxacin exhibits linear pharmacokinetic parameters that reached steady state after 3 days of daily oral dosing with minimal accumulation. Delafloxacin was well tolerated throughout both studies, with gastrointestinal effects observed at the higher doses (≥1200 mg). Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Positron Emission Tomography-Guided, Focal-Dose Escalation Using Intensity-Modulated Radiotherapy for Head and Neck Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Madani, Indira; Duthoy, Wim; Derie, Cristina R.N.

2007-05-01

Purpose: To assess the feasibility of intensity-modulated radiotherapy (IMRT) using positron emission tomography (PET)-guided dose escalation, and to determine the maximum tolerated dose in head and neck cancer. Methods and Materials: A Phase I clinical trial was designed to escalate the dose limited to the [{sup 18}-F]fluoro-2-deoxy-D-glucose positron emission tomography ({sup 18}F-FDG-PET)-delineated subvolume within the gross tumor volume. Positron emission tomography scanning was performed in the treatment position. Intensity-modulated radiotherapy with an upfront simultaneously integrated boost was employed. Two dose levels were planned: 25 Gy (level I) and 30 Gy (level II), delivered in 10 fractions. Standard IMRT was appliedmore » for the remaining 22 fractions of 2.16 Gy. Results: Between 2003 and 2005, 41 patients were enrolled, with 23 at dose level I, and 18 at dose level II; 39 patients completed the planned therapy. The median follow-up for surviving patients was 14 months. Two cases of dose-limiting toxicity occurred at dose level I (Grade 4 dermitis and Grade 4 dysphagia). One treatment-related death at dose level II halted the study. Complete response was observed in 18 of 21 (86%) and 13 of 16 (81%) evaluated patients at dose levels I and II (p < 0.7), respectively, with actuarial 1-year local control at 85% and 87% (p n.s.), and 1-year overall survival at 82% and 54% (p = 0.06), at dose levels I and II, respectively. In 4 of 9 patients, the site of relapse was in the boosted {sup 18}F-FDG-PET-delineated region. Conclusions: For head and neck cancer, PET-guided dose escalation appears to be well-tolerated. The maximum tolerated dose was not reached at the investigated dose levels.« less

Tolerance to X-rays and Heavy Ions (Fe, He) in the Tardigrade Richtersius coronifer and the Bdelloid Rotifer Mniobia russeola

NASA Astrophysics Data System (ADS)

Jønsson, K. Ingemar; Wojcik, Andrzej

2017-02-01

The aim of this study was to analyze tolerance to heavy ions in desiccated animals of the eutardigrade Richtersius coronifer and the bdelloid rotifer Mniobia russeola within the STARLIFE project. Both species were exposed to iron (Fe) and helium (He) ions at the Heavy Ion Medical Accelerator in Chiba (HIMAC) in Chiba, Japan, and to X-rays at the German Aerospace Center (DLR) in Cologne, Germany. Results show no effect of Fe and He on viability up to 7 days post-rehydration in both R. coronifer and M. russeola, while X-rays tended to reduce viability in R. coronifer at the highest doses. Mean egg production rate tended to decline with higher doses in R. coronifer for all radiation types, but the pattern was not statistically confirmed. In M. russeola, there was no such tendency for a dose response in egg production rate. These results confirm the previously reported high tolerance to high linear energy transfer (LET) radiation in tardigrades and show for the first time that bdelloid rotifers are also very tolerant to high-LET radiation. These animal phyla represent the most desiccation- and radiation-tolerant animals on Earth and provide excellent eukaryotic models for astrobiological research.

Clinical impact of dosimetric changes for volumetric modulated arc therapy in log file-based patient dose calculations.

PubMed

Katsuta, Yoshiyuki; Kadoya, Noriyuki; Fujita, Yukio; Shimizu, Eiji; Matsunaga, Kenichi; Matsushita, Haruo; Majima, Kazuhiro; Jingu, Keiichi

2017-10-01

A log file-based method cannot detect dosimetric changes due to linac component miscalibration because log files are insensitive to miscalibration. Herein, clinical impacts of dosimetric changes on a log file-based method were determined. Five head-and-neck and five prostate plans were applied. Miscalibration-simulated log files were generated by inducing a linac component miscalibration into the log file. Miscalibration magnitudes for leaf, gantry, and collimator at the general tolerance level were ±0.5mm, ±1°, and ±1°, respectively, and at a tighter tolerance level achievable on current linac were ±0.3mm, ±0.5°, and ±0.5°, respectively. Re-calculations were performed on patient anatomy using log file data. Changes in tumor control probability/normal tissue complication probability from treatment planning system dose to re-calculated dose at the general tolerance level was 1.8% on planning target volume (PTV) and 2.4% on organs at risk (OARs) in both plans. These changes at the tighter tolerance level were improved to 1.0% on PTV and to 1.5% on OARs, with a statistically significant difference. We determined the clinical impacts of dosimetric changes on a log file-based method using a general tolerance level and a tighter tolerance level for linac miscalibration and found that a tighter tolerance level significantly improved the accuracy of the log file-based method. Copyright © 2017 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.

78 FR 60715 - Sedaxane; Pesticide Tolerances

Federal Register 2010, 2011, 2012, 2013, 2014

2013-10-02

... 28-day dermal study did not show systemic toxicity at the limit dose of 1,000 milligrams/kilogram/day... Enforcement Methodology Adequate enforcement methodology is available to enforce the tolerance expression. A...

Overcoming the Practical Barriers to Spinal Cord Cell Transplantation for ALS

DTIC Science & Technology

2012-10-01

ABSTRACT: This grant will provide critical data on tolerance and toxicity of cell dosing and numbers of permissible spinal cord injections. Rigorous...Surgical Technique) will provide critical data on tolerance and toxicity of cell dosing and numbers of permissible spinal cord injections. Aim 2 (Graft...connected to a rigid needle of the same gauge as the floating cannula one – Figure 7) using the maximum volume/number of injections could result in

Oxytrex: an oxycodone and ultra-low-dose naltrexone formulation.

PubMed

Webster, Lynn R

2007-08-01

Oxytrex (Pain Therapeutics, Inc.) is an oral opioid that combines a therapeutic amount of oxycodone with an ultra-low dose of the antagonist naltrexone. Animal data indicate that this combination minimizes the development of physical dependence and analgesic tolerance while prolonging analgesia. Oxytrex is in late-stage clinical development by Pain Therapeutics for the treatment of moderate-to-severe chronic pain. To evaluate the safety and efficacy of the oxycodone/naltrexone combination, three clinical studies have been conducted, one in healthy volunteers and the other two in patients with chronic pain. The putative mechanism of ultra-low-dose naltrexone is to prevent an alteration in G-protein coupling by opioid receptors that is associated with opioid tolerance and dependence. Opioid agonists are initially inhibitory but become excitatory through constant opioid receptor activity. The agonist/antagonist combination of Oxytrex may reduce the conversion from an inhibitory to an excitatory receptor, thereby decreasing the development of tolerance and physical dependence.

Fault Tolerant Characteristics of Artificial Neural Network Electronic Hardware

NASA Technical Reports Server (NTRS)

Zee, Frank

1995-01-01

The fault tolerant characteristics of analog-VLSI artificial neural network (with 32 neurons and 532 synapses) chips are studied by exposing them to high energy electrons, high energy protons, and gamma ionizing radiations under biased and unbiased conditions. The biased chips became nonfunctional after receiving a cumulative dose of less than 20 krads, while the unbiased chips only started to show degradation with a cumulative dose of over 100 krads. As the total radiation dose increased, all the components demonstrated graceful degradation. The analog sigmoidal function of the neuron became steeper (increase in gain), current leakage from the synapses progressively shifted the sigmoidal curve, and the digital memory of the synapses and the memory addressing circuits began to gradually fail. From these radiation experiments, we can learn how to modify certain designs of the neural network electronic hardware without using radiation-hardening techniques to increase its reliability and fault tolerance.

Sequence-Selective Formation of Synthetic H-Bonded Duplexes

PubMed Central

2017-01-01

Oligomers equipped with a sequence of phenol and pyridine N-oxide groups form duplexes via H-bonding interactions between these recognition units. Reductive amination chemistry was used to synthesize all possible 3-mer sequences: AAA, AAD, ADA, DAA, ADD, DAD, DDA, and DDD. Pairwise interactions between the oligomers were investigated using NMR titration and dilution experiments in toluene. The measured association constants vary by 3 orders of magnitude (102 to 105 M–1). Antiparallel sequence-complementary oligomers generally form more stable complexes than mismatched duplexes. Mismatched duplexes that have an excess of H-bond donors are stabilized by the interaction of two phenol donors with one pyridine N-oxide acceptor. Oligomers that have a H-bond donor and acceptor on the ends of the chain can fold to form intramolecular H-bonds in the free state. The 1,3-folding equilibrium competes with duplex formation and lowers the stability of duplexes involving these sequences. As a result, some of the mismatch duplexes are more stable than some of the sequence-complementary duplexes. However, the most stable mismatch duplexes contain DDD and compete with the most stable sequence-complementary duplex, AAA·DDD, so in mixtures that contain all eight sequences, sequence-complementary duplexes dominate. Even higher fidelity sequence selectivity can be achieved if alternating donor–acceptor sequences are avoided. PMID:28857551