Model-based adaptive phase I trial design of post-transplant decitabine maintenance in myelodysplastic syndrome.

PubMed

Han, Seunghoon; Kim, Yoo-Jin; Lee, Jongtae; Jeon, Sangil; Hong, Taegon; Park, Gab-Jin; Yoon, Jae-Ho; Yahng, Seung-Ah; Shin, Seung-Hwan; Lee, Sung-Eun; Eom, Ki-Seong; Kim, Hee-Je; Min, Chang-Ki; Lee, Seok; Yim, Dong-Seok

2015-10-23

This report focuses on the adaptive phase I trial design aimed to find the clinically applicable dose for decitabine maintenance treatment after allogeneic hematopoietic stem cell transplantation in patients with higher-risk myelodysplastic syndrome and secondary acute myeloid leukemia. The first cohort (three patients) was given the same initial daily dose of decitabine (5 mg/m(2)/day, five consecutive days with 4-week intervals). In all cohorts, the doses for Cycles 2 to 4 were individualized using pharmacokinetic-pharmacodynamic modeling and simulations. The goal of dose individualization was to determine the maximum dose for each patient at which the occurrence of grade 4 (CTC-AE) toxicities for both platelet and neutrophil counts could be avoided. The initial doses for the following cohorts were also estimated with the data from the previous cohorts in the same manner. In all but one patient (14 out of 15), neutrophil count was the dose-limiting factor throughout the cycles. In cycles where doses were individualized, the median neutrophil nadir observed was 1100/mm(3) (grade 2) and grade 4 toxicity occurred in 5.1 % of all cycles (while it occurred in 36.8 % where doses were not individualized). The initial doses estimated for cohorts 2 to 5 were 4, 5, 5.5, and 5 mg/m(2)/day, respectively. The median maintenance dose was 7 mg/m(2)/day. We determined the acceptable starting dose and individualized the maintenance dose for each patient, while minimizing the toxicity using the adaptive approach. Currently, 5 mg/m(2)/day is considered to be the most appropriate starting dose for the regimen studied. Clinicaltrials.gov NCT01277484.

The effect of budesonide/formoterol maintenance and reliever therapy on the risk of severe asthma exacerbations following episodes of high reliever use: an exploratory analysis of two randomised, controlled studies with comparisons to standard therapy

PubMed Central

2012-01-01

Background Divergent strategies have emerged for the management of severe asthma. One strategy utilises high and fixed doses of maintenance treatment, usually inhaled corticosteroid/long-acting β2-agonist (ICS/LABA), supplemented by a short-acting β2-agonist (SABA) as needed. Alternatively, budesonide/formoterol is used as both maintenance and reliever therapy. The latter is superior to fixed-dose treatment in reducing severe exacerbations while achieving similar or better asthma control in other regards. Exacerbations may be reduced by the use of budesonide/formoterol as reliever medication during periods of unstable asthma. We examined the risk of a severe exacerbation in the period after a single day with high reliever use. Methods Episodes of high reliever use were quantified and exacerbations occurring post-index day with these episodes were examined post hoc in two double-blind studies comparing the efficacy and safety of budesonide/formoterol maintenance and reliever therapy (Symbicort SMART™, Turbuhaler®) 160/4.5 μg twice daily plus as needed with similar or higher maintenance doses of ICS/LABA plus SABA or formoterol. Results Budesonide/formoterol maintenance and reliever therapy significantly reduced the risk of episodes of high reliever use (>6 inhalations/day) vs. all alternative ICS/LABA regimens. With conventional fixed-dose treatment the need for exacerbation treatment within 21 days ranged from 6.0–10.1% of days post-index for all regimens compared with 2.5–3.4% of days with budesonide/formoterol maintenance and reliever therapy. Conclusions Budesonide/formoterol maintenance and reliever therapy reduces the incidence of high reliever episodes and the exacerbation burden immediately following these episodes vs. alternative ICS/LABA plus SABA regimens at up to double the maintenance dose of ICS. Trial registration These studies do not have registration numbers as they were conducted before clinical trial registration was required PMID:22816878

Personalized tacrolimus doses determined by CYP3A5 genotype for induction and maintenance phases of kidney transplantation.

PubMed

Vannaprasaht, Suda; Reungjui, Sirirat; Supanya, Darika; Sirivongs, Dhavee; Pongskul, Cholatip; Avihingsanon, Yingyos; Tassaneeyakul, Wichittra

2013-11-01

Cytochrome P450 (CYP) 3A4 and 3A5 are major isoforms involved in the metabolism of tacrolimus, with the CYP3A5 gene being more polymorphic. It is hypothesized that individual variation in the metabolism of tacrolimus drug may result from genetic polymorphism of CYP3A5. It has been reported that the clearance of tacrolimus in patients with the CYP3A5*1 allele was ~2.5-fold greater than that in those with the CYP3A5*3/*3 genotype. Recent data have also shown that polymorphism in exon 26 (C3435T) of the multidrug resistance gene (MDR1) was correlated with the expression level and function of P-glycoprotein in the lower duodenum, making the relationship between polymorphism of MDR1 and the effective dose of tacrolimus a source of controversy. This study investigated the influence of genetic polymorphisms of CYP3A5 and MDR1 on the dose requirements for the induction and maintenance phases of tacrolimus therapy in kidney transplant recipients. Sixty-eight kidney transplant recipients were enrolled, and their clinical and laboratory data were retrospectively reviewed after 6 months of tacrolimus administration. Genotypes of CYP3A5*1 and CYP3A5*3 and exon 26 of MDR1 (C3435T) were determined by the single-nucleotide polymorphism genotyping method. The frequencies of CYP3A5*3/*3, CYP3A5*1/*3, and CYP3A5*1/*1 were 44.1%, 35.3%, and 20.6%, respectively. The mean dose of tacrolimus required for the induction phase was significantly greater in the CYP3A5*1/*1 group (0.142 [0.050] mg/kg/d) than that required in the CYP3A5*1/*3 group (0.097 [0.040] mg/kg/d; P = 0.072) and in the CYP3A5*3/*3 group (0.077 [0.020] mg/kg/d; P = 0.005). The maintenance dose of tacrolimus required in the CYP3A5*1/*1 group (0.12 [0.03] mg/kg/d) was 1.3-fold higher than that in the CYP3A5*1/*3 group (0.09 [0.03] mg/kg/d; P = 0.018) and 2.4-fold higher than in the CYP3A5*3/*3 group (0.05 [0.02] mg/kg/d; P < 0.0001). No statistically significant relationship was observed between the doses of tacrolimus required for the induction and maintenance phases and MDR1 polymorphism. Determination of the CYP3A5 genotype would be helpful in the design of adequate immunosuppressive treatment and in lowering toxicity by predicting the doses of tacrolimus required for the induction and maintenance phases in individual kidney transplant recipients. © 2013 Elsevier HS Journals, Inc. All rights reserved.

Effect of caffeine on superior mesenteric artery blood flow velocities in preterm neonates.

PubMed

Abdel Wahed, Mohamed A; Issa, Hanan M; Khafagy, Soha M; Abdel Raouf, Shaimaa M

2017-09-22

To investigate the effect of caffeine infusion on superior mesenteric artery (SMA) blood flow velocities (BFV) in preterm infants. Prospective observational study on 38 preterm neonates 28-33 +6 weeks gestation, who developed apnea on their first day of life, and caffeine citrate infusion was initiated at a loading dose of 20 mg/kg, followed by a maintenance dose of 5-10 mg/kg/day. Duplex ultrasound measurements of SMA BFV were recorded: peak systolic velocity (PSV), end diastolic velocity (EDV) and resistive index (RI), at 15 min before, 1-, 2- and 6-h after caffeine loading dose, and 2 h after two maintenance doses. There was a significant reduction in PSV 1-h (p = .008), a significant decrease in EDV 1- and 2-h (p = .000 and p = .005, respectively) and a significant increase in RI 1- and 2-h (p = .003 and p = .005, respectively) following caffeine loading dose, as compared to values before caffeine infusion. No significant effect of caffeine maintenance doses on SMA BFV was observed (p > .05). Blood flow in SMA is significantly reduced after caffeine citrate infusion at a loading dose of 20 mg/kg. This effect continues for at least 2 h. Meanwhile, SMA BFV seems not affected by maintenance doses.

Rationale and design of the German-Speaking Myeloma Multicenter Group (GMMG) trial ReLApsE: a randomized, open, multicenter phase III trial of lenalidomide/dexamethasone versus lenalidomide/dexamethasone plus subsequent autologous stem cell transplantation and lenalidomide maintenance in patients with relapsed multiple myeloma.

PubMed

Baertsch, Marc-Andrea; Schlenzka, Jana; Mai, Elias K; Merz, Maximilian; Hillengaß, Jens; Raab, Marc S; Hose, Dirk; Wuchter, Patrick; Ho, Anthony D; Jauch, Anna; Hielscher, Thomas; Kunz, Christina; Luntz, Steffen; Klein, Stefan; Schmidt-Wolf, Ingo G H; Goerner, Martin; Schmidt-Hieber, Martin; Reimer, Peter; Graeven, Ullrich; Fenk, Roland; Salwender, Hans; Scheid, Christof; Nogai, Axel; Haenel, Mathias; Lindemann, Hans W; Martin, Hans; Noppeney, Richard; Weisel, Katja; Goldschmidt, Hartmut

2016-04-25

Despite novel therapeutic agents, most multiple myeloma (MM) patients eventually relapse. Two large phase III trials have shown significantly improved response rates (RR) of lenalidomide/dexamethasone compared with placebo/dexamethasone in relapsed MM (RMM) patients. These results have led to the approval of lenalidomide for RMM patients and lenalidomide/dexamethasone has since become a widely accepted second-line treatment. Furthermore, in RMM patients consolidation with high-dose chemotherapy plus autologous stem cell transplantation has been shown to significantly increase progression free survival (PFS) as compared to cyclophosphamide in a phase III trial. The randomized prospective ReLApsE trial is designed to evaluate PFS after lenalidomide/dexamethasone induction, high-dose chemotherapy consolidation plus autologous stem cell transplantation and lenalidomide maintenance compared with the well-established lenalidomide/dexamethasone regimen in RMM patients. ReLApsE is a randomized, open, multicenter phase III trial in a planned study population of 282 RMM patients. All patients receive three lenalidomide/dexamethasone cycles and--in absence of available stem cells from earlier harvesting--undergo peripheral blood stem cell mobilization and harvesting. Subsequently, patients in arm A continue on consecutive lenalidomide/dexamethasone cycles, patients in arm B undergo high dose chemotherapy plus autologous stem cell transplantation followed by lenalidomide maintenance until discontinuation criteria are met. Therapeutic response is evaluated after the 3(rd) (arm A + B) and the 5(th) lenalidomide/dexamethasone cycle (arm A) or 2 months after autologous stem cell transplantation (arm B) and every 3 months thereafter (arm A + B). After finishing the study treatment, patients are followed up for survival and subsequent myeloma therapies. The expected trial duration is 6.25 years from first patient in to last patient out. The primary endpoint is PFS, secondary endpoints include overall survival (OS), RR, time to best response and the influence of early versus late salvage high dose chemotherapy plus autologous stem cell transplantation on OS. This phase III trial is designed to evaluate whether high dose chemotherapy plus autologous stem cell transplantation and lenalidomide maintenance after lenalidomide/dexamethasone induction improves PFS compared with the well-established continued lenalidomide/dexamethasone regimen in RMM patients. ISRCTN16345835 (date of registration 2010-08-24).

198 AAAAI Survey on Immunotherapy Practice Patterns Concerning Dosing, Dose-Adjustment after Missed Doses and Duration of Immunotherapy

PubMed Central

Linnemann, Désirée Larenas; Gupta, Payel; Mithani, Sima; Ponda, Punita

2012-01-01

Background Several practical issues dealing with the exact application of allergen immunotherapy (AIT) among European and US allergists are not well known. Guidelines on AIT give recommendations and suggestions for only some of them. We present this unique survey with worldwide response. Methods The AAAAI immunotherapy committee conducted a web-based practice patterns survey (program: Survey Monkey) among all members in&outside US on dosing, dose-adjustment after missed doses and duration of AIT. Results 1201 Returned questionnaires (almost 25% response rate). 21% were non-US-Canada members. Maintenance doses in USCan are (mean/median): Dermatophagoides farinae (Df) combined with Dermatophagoides pteronyssinus (Dpt): 2155/1000AU; Df solo 2484/1000AU. Dpt when combined with Df 1937/1000AU; Dpt solo: 2183/1000AU.Cat 3224/2000BAU. Grass 11,410/4000BAU. 57-65% of the dosing falls within the recommended Practice Parameters recommended ranges. Non-USCan allergists expressed maintenance doses in many different units making analysis impossible. Dose-adjustment after missed doses is based on ‘time elapsed since the last applied dose’ by 77% of USCan and 58% of non-USCan allergists and on ‘time since missed scheduled dose’ by the rest. Doses are adjusted when a patient comes in more than 14 d/5 wk after the last administration at build-up/maintenance by both USCan and non-USCan colleagues. The mostly followed dose-adjustment schedules after 1, 2, 3 missed doses are: Build-up: repeat last dose, reduce by one dose, reduce by 2 doses; maintenance: reduce by one dose, reduce by 2 doses, reduce by 3 doses. 26% uses a different approach reducing doses by a certain percentage or volume. AIT is restarted after a gap in build-up of >30 days and of >12 weeks during maintenance in both groups (median). Outside USCan AIT is prescribed for 3 years (Median). However, 75% of USCan allergists prescribes AIT for 5 years. Main reasons why to continue AIT beyond 5 years: ‘symptoms came back after stopping’ or “patient afraid to relapse.” Conclusions These results show regional differences on some points (especially AIT duration) and they suggest in which direction to plan further research in 2 areas to establish universal dose-adjustment plans for missed applications and define the usefulness (or lack of) of long-term AIT. Moreover, there is still room for improvement in the way AIT is dosed.

Predicting Maintenance Doses of Vancomycin for Hospitalized Patients Undergoing Hemodialysis.

PubMed

El Nekidy, Wasim S; El-Masri, Maher M; Umstead, Greg S; Dehoorne-Smith, Michelle

2016-01-01

Methicillin-resistant Staphylococcus aureus is a leading cause of death in patients undergoing hemodialysis. However, controversy exists about the optimal dose of vancomycin that will yield the recommended pre-hemodialysis serum concentration of 15-20 mg/L. To develop a data-driven model to optimize the accuracy of maintenance dosing of vancomycin for patients undergoing hemodialysis. A prospective observational cohort study was performed with 164 observations obtained from a convenience sample of 63 patients undergoing hemodialysis. All vancomycin doses were given on the floor after completion of a hemodialysis session. Multivariate linear generalized estimating equation analysis was used to examine independent predictors of pre-hemodialysis serum vancomycin concentration. Pre-hemodialysis serum vancomycin concentration was independently associated with maintenance dose ( B = 0.658, p < 0.001), baseline pre-hemodialysis serum concentration of the drug ( B = 0.492, p < 0.001), and interdialytic interval ( B = -2.133, p < 0.001). According to the best of 4 models that were developed, the maintenance dose of vancomycin required to achieve a pre-hemodialysis serum concentration of 15-20 mg/L, if the baseline serum concentration of the drug was also 15-20 mg/L, was 5.9 mg/kg with interdialytic interval of 48 h and 7.1 mg/kg with interdialytic interval of 72 h. However, if the baseline pre-hemodialysis serum concentration was 10-14.99 mg/L, the required dose increased to 9.2 mg/kg with an interdialytic interval of 48 h and 10.0 mg/kg with an interdialytic interval of 72 h. The maintenance dose of vancomycin varied according to baseline pre-hemodialysis serum concentration of the drug and interdialytic interval. The current practice of targeting a pre-hemodialysis concentration of 15-20 mg/L may be difficult to achieve for the majority of patients undergoing hemodialysis.

Dose-related difference in progression rates of cytomegalovirus retinopathy during foscarnet maintenance therapy. AIDS Clinical Trials Group Protocol 915 Team.

PubMed

Holland, G N; Levinson, R D; Jacobson, M A

1995-05-01

A previous dose-ranging study of foscarnet maintenance therapy for cytomegalovirus retinopathy showed a positive relationship between dose and survival but could not confirm a relationship between dose and time to first progression. This retrospective analysis of data from that study was undertaken to determine whether there was a relationship between dose and progression rates, which reflects the amount of retina destroyed when progression occurs. Patients were randomly given one of two foscarnet maintenance therapy doses (90 mg/kg of body weight/day [FOS-90 group] or 120 mg/kg of body weight/day [FOS-120 group] after induction therapy. Using baseline and follow-up photographs and pre-established definitions and methodology in a masked analysis, posterior progression rates and foveal proximity rates for individual lesions, selected by prospectively defined criteria, were calculated in each patient. Rates were compared between groups. The following median rates were greater for the FOS-90 group (N = 8) than for the FOS-120 group (N = 10): greatest maximum rate at which lesions enlarged in a posterior direction (43.5 vs 12.5 microns/day; P = .002); posterior progression rate for lesions closest to the fovea (42.8 vs 5.5 microns/day; P = .010); and maximum foveal proximity rate for either eye (32.3 vs 3.4 microns/day; P = .031). Patients receiving higher doses of foscarnet have slower rates of progression and therefore less retinal tissue damage during maintenance therapy. A foscarnet maintenance therapy dose of 120 mg/kg of body weight/day instead of 90 mg/kg of body weight/day may help to preserve vision in patients with cytomegalovirus retinopathy.

Correlation between Colon Transit Time Test Value and Initial Maintenance Dose of Laxative in Children with Chronic Functional Constipation.

PubMed

Kim, Mock Ryeon; Park, Hye Won; Son, Jae Sung; Lee, Ran; Bae, Sun Hwan

2016-09-01

To evaluate the correlation between colon transit time (CTT) test value and initial maintenance dose of polyethylene glycol (PEG) 4000 or lactulose. Of 415 children with chronic functional constipation, 190 were enrolled based on exclusion criteria using the CTT test, defecation diary, and clinical chart. The CTT test was performed with prior disimpaction. The laxative dose for maintenance was determined on the basis of the defecation diary and clinical chart. The Shapiro-Wilk test and Pearson's and Spearman's correlations were used for statistical analysis. The overall group median value and interquartile range of the CTT test was 43.8 (31.8) hours. The average PEG 4000 dose for maintenance in the overall group was 0.68±0.18 g/kg/d; according to age, the dose was 0.73±0.16 g/kg/d (<8 years), 0.53±0.12 g/kg/d (8 to <12 years), and 0.36±0.05 g/kg/d (12 to 15 years). The dose of lactulose was 1.99±0.43 mL/kg/d (<8 years) or 1.26±0.25 mL/kg/d (8 to <12 years). There was no significant correlation between CTT test value and initial dose of laxative, irrespective of the subgroup (encopresis, abnormal CTT test subtype) for either laxative. Even in the largest group (overall, n=109, younger than 8 years and on PEG 4000), the correlation was weak (Pearson's correlation coefficient [R]=0.268, p =0.005). Within the abnormal transit group, subgroup (n=73, younger than 8 years and on PEG 4000) correlation was weak (R=0.267, p =0.022). CTT test value cannot predict the initial maintenance dose of PEG 4000 or lactulose with linear correlation.

Cytochrome P450 2C9 gene polymorphism and warfarin maintenance dosage in pediatric patients: A systematic review and meta-analysis.

PubMed

Zhang, Jinhua; Tian, Lihong; Huang, Jinlong; Huang, Sihan; Chai, Tingting; Shen, Jianzhen

2017-02-01

To assess the effect of Cytochrome P450 2C9 (CYP2C9) gene polymorphism on pediatric warfarin maintenance dosage requirement. A previously developed search strategy was conducted in PubMed, EMBASE, and the Cochrane Library. Eligible studies published prior to January 27, 2016, were identified and compared against strict inclusion/exclusion criteria. Required data were extracted, and researchers were consulted for additional data if needed. Review Manager version 5.2.3 software was used to analyze the relationship between CYP2C9 polymorphisms and warfarin maintenance doses in pediatric patients. Eight articles with a combined total of 507 pediatric patients were included in the meta-analysis. Maintenance warfarin doses in patients with CYP2C9 *1/*2 genotype, CYP2C9 *1/*3 genotype, and CYP2C9 variant carriers which contain at least one variant allele (*2 or *3) were from 15% to 41% lower than doses in patients with the wild-type allele (CYP2C9 *1/*1): All differences were significant with P-values <.05. The Fontan procedure as a medical indication for anticoagulation was also associated with a lower warfarin maintenance dose; however, target INR range was not. We found that CYP2C9 gene polymorphism (referring to the presence of *1/*2, *1/*3, and variant genotypes in the population in addition to the wild type) was significantly associated with decreased warfarin maintenance dose requirements. Additionally, a specific indication for warfarin, the Fontan procedure, was associated with a lower daily warfarin dose. However, the results of our study require confirmation from more research with larger numbers of pediatric patients. © 2016 John Wiley & Sons Ltd.

Influence of whole-body irradiation on calcium and phosphate homeostasis in the rat

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

Pento, J.T.; Kenny, A.D.

1975-09-01

Previous irradiation studies have revealed marked alterations in calcium metabolism. Moreover, the maintenance of calcium homeostasis with parathyroid hormone or calcium salts has been reported to reduce radiation lethality. Therefore, the present study was designed to evaluate the influence of irradiation on calcium homeostasis in the rat. Nine hundred rad of whole-body irradiation produced a significant depression of both plasma calcium and phosphate at 4 days postirradiation. This effect of irradiation was observed to be dose-dependent over a range of 600 to 1200 rad, and possibly related to irradiation-induced anorexia. The physiological significance of these observations is discussed. (auth)

The effect of high-dose dronabinol (oral THC) maintenance on cannabis self-administration.

PubMed

Schlienz, Nicolas J; Lee, Dustin C; Stitzer, Maxine L; Vandrey, Ryan

2018-06-01

There is a clear need for advancing the treatment of cannabis use disorders. Prior research has demonstrated that dronabinol (oral THC) can dose-dependently suppress cannabis withdrawal and reduce the acute effects of smoked cannabis. The present study was conducted to evaluate whether high-dose dronabinol could reduce cannabis self-administration among daily users. Non-treatment seeking daily cannabis users (N = 13) completed a residential within-subjects crossover study and were administered placebo, low-dose dronabinol (120 mg/day; 40 mg tid), or high-dose dronabinol (180-240 mg/day; 60-80 mg tid) for 12 consecutive days (order counterbalanced). During each 12-day dronabinol maintenance phase, participants were allowed to self-administer smoked cannabis containing <1% THC (placebo) or 5.7% THC (active) under forced-choice (drug vs. money) or progressive ratio conditions. Participants self-administered significantly more active cannabis compared with placebo in all conditions. When active cannabis was available, self-administration was significantly reduced during periods of dronabinol maintenance compared with placebo maintenance. There was no difference in self-administration between the low- and high-dose dronabinol conditions. Chronic dronabinol dosing can reduce cannabis self-administration in daily cannabis users and suppress withdrawal symptoms. Cannabinoid agonist medications should continue to be explored for therapeutic utility in the treatment of cannabis use disorders. Copyright © 2018 Elsevier B.V. All rights reserved.

Clinical and genetic factors associated with warfarin maintenance dose in northern Chinese patients with mechanical heart valve replacement

PubMed Central

Liu, Rui; Cao, Jian; Zhang, Qian; Shi, Xin-Miao; Pan, Xiao-Dong; Dong, Ran

2017-01-01

Abstract The effects of genetic variants on warfarin dosing vary among different ethnic groups, especially in the Chinese population. The objective of this study was to recruit patients through a rigorous experimental design and to perform a comprehensive screen to identify gene polymorphisms that may influence warfarin dosing in northern Han Chinese patients with mechanical heart valve replacement. Consenting patients (n = 183) with a stable warfarin dose were included in this study. Ninety-six single nucleotide polymorphisms (SNPs) in 30 genes involved in warfarin pharmacological pathways were genotyped using the Illumina SNP GoldenGate Assay, and their associations with warfarin dosing were assessed using univariate regression analysis with post hoc comparison using least significant difference analysis. Multiple linear regression was performed by incorporating patients’ clinical and genetic data to create a new algorithm for warfarin dosing. From the 96 SNPs analyzed, VKORC1 rs9923231, CYP1A2 rs2069514, CYP3A4 rs28371759, and APOE rs7412 were associated with higher average warfarin maintenance doses, whereas CYP2C9 rs1057910, EPHX1 rs2260863, and CYP4F2 rs2189784 were associated with lower warfarin doses (P < 0.05). Multiple linear regression analysis could estimate 44.4% of warfarin dose variability consisting of, in decreasing order, VKORC1 rs9923231 (14.2%), CYP2C9∗3 (9.6%), body surface area (6.7%), CYP1A2 rs2069514 (3.7%), age (2.7%), CYP3A4 rs28371759 (2.5%), CYP4F2 rs2108622 (1.9%), APOE rs7412 (1.7%), and VKORC1 rs2884737 (1.4%). In the dosing algorithm we developed, we confirmed the strongest effects of VKORC1, CYP2C9 on warfarin dosing. In the limited sample set, we also found that novel genetic predictors (CYP1A2, CYP3A4, APOE, EPHX1, CYP4F2, and VKORC1 rs2884737) may be associated with warfarin dosing. Further validation is needed to assess our results in larger independent northern Chinese samples. PMID:28079798

Therapeutic drug monitoring of eculizumab: Rationale for an individualized dosing schedule.

PubMed

Gatault, Philippe; Brachet, Guillaume; Ternant, David; Degenne, Danielle; Récipon, Guillaume; Barbet, Christelle; Gyan, Emmanuel; Gouilleux-Gruart, Valérie; Bordes, Cécile; Farrell, Alexandra; Halimi, Jean Michel; Watier, Hervé

2015-01-01

The annual cost of eculizumab maintenance therapy in paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic-uremic syndrome (aHUS) exceeds $300,000 per patient. A better understanding of eculizumab pharmacokinetics and subsequent individual dose adjustment could reduce this cost. We measured the trough eculizumab concentration in 9 patients with maintenance therapy (aHUS, n = 7; PNH, n = 2) and determined: 1) the intra- and inter-individual variability; 2) the influence of weight on eculizumab pharmacokinetics; and 3) the rate of elimination of eculizumab following discontinuation. A one-compartment model was developed to describe the pharmacokinetics of eculizumab and predicted complement activity by body weight. Trough eculizumab concentrations were >50 µg/mL in 9/9, >100 µg/mL in 8/9, and >300 µg/mL in 5/9 of patients. Intra-individual variability was low but eculizumab concentrations, closely correlated with patient weight (R(2) = 0.66, p = 0.034), varied broadly (55 ± 12 to 733 ± 164 µg/mL). Pharmacokinetic modeling showed that the elimination half-life varied greatly, with an increase from 7.8 d in a patient weighing 100 kg to 19.5 d in a 40 kg patient. We predicted that infusions of 1200 mg could be spaced every 4 or 6 weeks in patients weighing <90 and <70 kg, respectively. In this pilot study, the current recommended use of a fixed eculizumab dose for maintenance therapy is associated with excessively high trough concentrations in many patients. Further prospective larger studies are now required to support an individualized schedule adjusted for patient weight and based on the observed trough serum eculizumab concentration.

Therapeutic drug monitoring of eculizumab: Rationale for an individualized dosing schedule

PubMed Central

Gatault, Philippe; Brachet, Guillaume; Ternant, David; Degenne, Danielle; Récipon, Guillaume; Barbet, Christelle; Gyan, Emmanuel; Gouilleux-Gruart, Valérie; Bordes, Cécile; Farrell, Alexandra; Halimi, Jean Michel; Watier, Hervé

2015-01-01

The annual cost of eculizumab maintenance therapy in paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic–uremic syndrome (aHUS) exceeds $300,000 per patient. A better understanding of eculizumab pharmacokinetics and subsequent individual dose adjustment could reduce this cost. We measured the trough eculizumab concentration in 9 patients with maintenance therapy (aHUS, n = 7; PNH, n = 2) and determined: 1) the intra- and inter-individual variability; 2) the influence of weight on eculizumab pharmacokinetics; and 3) the rate of elimination of eculizumab following discontinuation. A one-compartment model was developed to describe the pharmacokinetics of eculizumab and predicted complement activity by body weight. Trough eculizumab concentrations were >50 µg/mL in 9/9, >100 µg/mL in 8/9, and >300 µg/mL in 5/9 of patients. Intra-individual variability was low but eculizumab concentrations, closely correlated with patient weight (R2 = 0.66, p = 0.034), varied broadly (55 ± 12 to 733 ± 164 µg/mL). Pharmacokinetic modeling showed that the elimination half-life varied greatly, with an increase from 7.8 d in a patient weighing 100 kg to 19.5 d in a 40 kg patient. We predicted that infusions of 1200 mg could be spaced every 4 or 6 weeks in patients weighing <90 and <70 kg, respectively. In this pilot study, the current recommended use of a fixed eculizumab dose for maintenance therapy is associated with excessively high trough concentrations in many patients. Further prospective larger studies are now required to support an individualized schedule adjusted for patient weight and based on the observed trough serum eculizumab concentration. PMID:26337866

Maintenance treatment of duodenal ulceration: ranitidine 300 mg at night is better than 150 mg in cigarette smokers.

PubMed Central

Lee, F I; Hardman, M; Jaderberg, M E

1991-01-01

Two hundred patients received either ranitidine 150 mg or 300 mg at night for 18 months to prevent duodenal ulcer relapse. Recurrence rates were lower in patients receiving the higher dose of ranitidine (3.1% v 9.7%, p = 0.78; 6.5% v 16.7%, p = 0.037; and 8.9% v 17.0%, p = 0.121 at six, 12, and 18 months respectively). In patients receiving ranitidine 150 mg, recurrences were significantly more common in smokers than non-smokers after 12 and 18 months, while in patients receiving ranitidine 300 mg recurrence rates were similar in smokers and non-smokers. Ranitidine 300 mg at night abolishes the adverse effect of smoking observed during maintenance treatment with ranitidine 150 mg at night and may therefore be an appropriate maintenance dose for smokers who relapse during standard dose maintenance treatment. PMID:1864532

Correlation between Colon Transit Time Test Value and Initial Maintenance Dose of Laxative in Children with Chronic Functional Constipation

PubMed Central

Kim, Mock Ryeon; Park, Hye Won; Son, Jae Sung; Lee, Ran

2016-01-01

Purpose To evaluate the correlation between colon transit time (CTT) test value and initial maintenance dose of polyethylene glycol (PEG) 4000 or lactulose. Methods Of 415 children with chronic functional constipation, 190 were enrolled based on exclusion criteria using the CTT test, defecation diary, and clinical chart. The CTT test was performed with prior disimpaction. The laxative dose for maintenance was determined on the basis of the defecation diary and clinical chart. The Shapiro-Wilk test and Pearson's and Spearman's correlations were used for statistical analysis. Results The overall group median value and interquartile range of the CTT test was 43.8 (31.8) hours. The average PEG 4000 dose for maintenance in the overall group was 0.68±0.18 g/kg/d; according to age, the dose was 0.73±0.16 g/kg/d (<8 years), 0.53±0.12 g/kg/d (8 to <12 years), and 0.36±0.05 g/kg/d (12 to 15 years). The dose of lactulose was 1.99±0.43 mL/kg/d (<8 years) or 1.26±0.25 mL/kg/d (8 to <12 years). There was no significant correlation between CTT test value and initial dose of laxative, irrespective of the subgroup (encopresis, abnormal CTT test subtype) for either laxative. Even in the largest group (overall, n=109, younger than 8 years and on PEG 4000), the correlation was weak (Pearson's correlation coefficient [R]=0.268, p=0.005). Within the abnormal transit group, subgroup (n=73, younger than 8 years and on PEG 4000) correlation was weak (R=0.267, p=0.022). Conclusion CTT test value cannot predict the initial maintenance dose of PEG 4000 or lactulose with linear correlation. PMID:27738600

The antiplatelet effect of higher loading and maintenance dose regimens of clopidogrel: the PRINC (Plavix Response in Coronary Intervention) trial.

PubMed

Gladding, Patrick; Webster, Mark; Zeng, Irene; Farrell, Helen; Stewart, Jim; Ruygrok, Peter; Ormiston, John; El-Jack, Seif; Armstrong, Guy; Kay, Patrick; Scott, Douglas; Gunes, Arzu; Dahl, Marja-Liisa

2008-12-01

This study evaluated the antiplatelet effect of a higher loading and maintenance dose regimen of clopidogrel and a possible drug interaction with verapamil. Clopidogrel loading doses above 600 mg have not resulted in more rapid or complete platelet inhibition. Higher maintenance dosages may be more effective than 75 mg/day. A double-blind, randomized, placebo-controlled trial was undertaken in 60 patients undergoing percutaneous coronary intervention. All patients received clopidogrel 600 mg at the start of the procedure. Using a 2 x 2 design, patients were allocated to clopidogrel 600 mg given 2 h later or matching placebo, and to verapamil 5 mg intra-arterial or placebo. Platelet function was measured using the VerifyNow P2Y12 analyzer (Accumetrics Ltd., San Diego, California) at 2, 4, and 7 h. Patients were further randomized to receive a clopidogrel 75 or 150 mg once daily, with platelet function assessed after 1 week. Two hours after the second dose of clopidogrel or placebo, platelet inhibition was 42 +/- 27% with clopidogrel, compared with 24 +/- 22% with placebo (p = 0.0006). By 5 h after the second dose, platelet inhibition was 49 +/- 30% with clopidogrel, compared with 29 +/- 22% with placebo (p = 0.01). No drug interaction was seen with verapamil. A clopidogrel maintenance dosage of 150 mg daily for 1 week resulted in greater platelet inhibition than 75 mg daily (50 +/- 28% vs. 29 +/- 19%, p = 0.01). In an unselected population undergoing percutaneous coronary intervention a clopidogrel 1,200-mg loading dose, given as two 600-mg doses 2 h apart, results in more rapid and complete platelet inhibition than a single 600-mg dose. A maintenance dosage of 150 mg daily produces greater platelet inhibition than 75 mg daily. (The PRINC trial; ACTRN12606000129583).

A simple 3-day "rush" venom immunotherapy protocol: documentation of safety.

PubMed

Kalogeromitros, D; Makris, M; Koti, I; Chliva, C; Mellios, A; Avgerinou, G; Theoharides, T C

2010-01-01

Venom immunotherapy (VIT) is the only effective treatment for hymenoptera hypersensitivity, but conventional protocols require a few weeks. We present the safety of a 3-day "rush" protocol that requires only 7 injections and 255 mgr cumulative dose before the 100 microg maintenance dose. Forty-nine patients (33 males, 16 females) of mean age 43.57+/-12.9 yrs received "rush" VIT. Only 7 injections were required until the maintenance dose of 100 mgr was reached on Day 5. On Day 1, four injections were administered with initial dose of 5 mgr and total dose of 75 microg. On Day 3 a cumulative dose of 180 mgr was administered in three injections (40 mgr, 60 mgr and 80 mgr). A dose of 100 mgr was administered on Day 5. Twenty-nine individuals were treated with Honey-Bee venom; 18 with Common wasp; 5 with Paper Wasp; while 13 patients received Mixed Vespid preparation. Inclusion criteria were documented IgE-mediated allergy with intradermal sensitivity to < or =0.1 mgr/ml venom concentration and concomitant detection of specific venom IgE > or =0.35 kU/l. All patients reached the maintenance dose. Forty-nine patients received 65 immunotherapy courses, resulting in 1520 injections. Thirty-three systemic reactions: 7 during building phase (1.5%); and 26 in the maintenance dose (2.4%) were observed in 9 patients. The percentage of reactions/total injection number was 2.2%; all reactions were mild-to-moderate. Fourteen patients reported documented field stings at least two months after VIT onset with only one reported mild systemic reaction. We propose a simple "rush" VIT protocol in an outpatient setting as an easy-to-perform alternative option for VIT induction phase. Copyright 2009 SEICAP. Published by Elsevier Espana. All rights reserved.

Low-dose fotemustine as second-line chemotherapy for recurrent glioblastoma multiforme.

PubMed

De Felice, Francesca; Bulzonetti, Nadia; Musio, Daniela; D'Elia, Alessandro; Salvati, Maurizio; Tombolini, Vincenzo

2013-09-01

To test if fotemustine administrated at low doses during the maintenance phase of gioblastoma therapy could improve the toxicity profile, without reducing progression-free survival at six months (PFS-6). Patients enrolled were affected by recurrent glioblastoma multiforme, proven by magnetic resonance imaging (MRI), at least six months after radiochemotherapy completion. Fotemustine was administered at an induction dose of 100 mg/m(2) followed by a maintenance dose of 75 mg/m(2). All 15 patients completed the induction phase. Eight patients began maintenance-phase therapy and received a median of three cycles (range=2-6). Grade 3 or more haematological toxicity was not documented. The PFS-6 was 5/15 and the median overall survival was 7.5 months. Haematological toxicity compares favourably with trials using the conventional scheme: no grade 3-4 adverse effects were recorded. This low-dose approach could be considered a compromise treatment whilst waiting for definitive standardization of second-line therapy, in order to reduce severe hematological toxicity.

Rituximab maintenance for relapsed refractory thrombotic thrombocytopenic purpura.

PubMed

Bhagirath, Vinai C; Kelton, John G; Moore, Jane; Arnold, Donald M

2012-12-01

Rituximab, an anti-CD20 chimeric monoclonal antibody, has been used successfully to treat patients with relapsed or refractory thrombotic thrombocytopenic purpura (TTP); however, the optimal dose and frequency and the role of rituximab maintenance remain uncertain. We describe a 45-year-old woman with chronic relapsing immune thrombocytopenia who responded to rituximab retreatment administered in four doses over the course of 12 months. Previously, she had received four doses of rituximab and sustained a remission for 19 months. During her latest TTP relapse, multiple treatments were administered including rituximab retreatment. After the first dose (375 mg/m2), she developed serum sickness requiring further doses to be deferred. Three subsequent doses were administered at 4-month intervals over the course of 12 months. ADAMTS13 activity was measured by von Willebrand factor (VWF) digestion. ADAMTS13 inhibition was measured by a modification of the VWF digestion assay and anti-ADAMTS13 antibodies were measured by enzyme-linked immunoassay (enzyme-linked immunosorbent assay, American Diagnostica). Clinical and laboratory remission were achieved after one dose of rituximab, with normalization of ADAMTS13 activity and disappearance of ADAMTS13 inhibitor. Three subsequent doses of rituximab were given without incident and the patient remained in remission after 3.5 years of follow-up (2.5 years since her last dose of rituximab). Maintenance dosing of rituximab should be considered in some patients with relapsing TTP. © 2012 American Association of Blood Banks.

Can oral 5-aminosalicylic acid be administered once daily in the treatment of mild-to-moderate ulcerative colitis? A meta-analysis of randomized-controlled trials.

PubMed

Zhu, Ying; Tang, Ren-Kuan; Zhao, Peng; Zhu, Shi-sheng; Li, Yong-guo; Li, Jian-bo

2012-05-01

Several trials have demonstrated that oral delayed-release mesalamine might be administered once daily. We aimed to conduct a meta-analysis to investigate this. A comprehensive and multiple-source literature search was carried out. Only randomized-controlled trials (RCTs) were investigated by comparing a once daily-dosing regime with a divided (twice or thrice daily)-dosing regime of oral delayed-release mesalamine formulations for induction or maintenance of remission in patients with mild-to-moderate ulcerative colitis. The quality of RCTs was assessed using the Jadad scores. Meta-analysis of pooled odds ratios was carried out using Review Manager 5.1. Nine RCTs were finally included. With regard to meta-analyses for induction trials, there were no significant differences for all comparisons between the once daily and the divided groups, including maintenance of just clinical remission (P=0.52) and just endoscopic remission (P=0.23), maintenance of combined clinical and endoscopic remission (P=0.78), and the overall incidence of adverse events (P=0.61). With regard to meta-analyses for maintenance trials, there were also no significant differences for all comparisons between once daily and divided groups, including maintenance of just clinical remission (P=0.73) and just endoscopic remission (P=0.43), maintenance of combined clinical and endoscopic remission (P=0.43), the overall incidence of adverse events (P=0.12) as well as compliance with the prescribed medication (P=0.34). The present work showed that oral delayed-release mesalazine administered as a single or a divided dose demonstrated a good safety profile, which was well tolerated and effective as either maintenance or induction treatment. High clinical and/or endoscopic remission rates can be achieved with once-daily dosing.

[Personalized drug therapy-directed clinical pharmacology research based on genetic polymorphisms and pharmacokinetics analysis].

PubMed

Hayashi, Hideki

2013-01-01

In this decade, the field of pharmacogenomics (PGx), which is related to pharmacokinetics (PK) or pharmacodynamics (PD), has attracted much attention because it may provide a possible explanation for individual differences in the clinical efficacy of drugs. For the development of personalized drug therapy, it is important to accumulate evidence from PK/PD/PGx analysis in clinical trials. Warfarin (WF) is one of the most widely prescribed anticoagulants for the prevention and treatment of venous and arterial thromboembolism. However, large interindividual and interethnic differences have been observed in the WF dose required to elicit the anticoagulant effect. We investigated the factors influencing the WF maintenance dose in Japanese patients. Our study confirmed a large interindividual variability in the WF maintenance dose that was due to a VKORC1 1639 G>A polymorphism and differences in body weight, age, and serum albumin. In addition, we found that the CYP4F2 genotype affects the plasma concentration of menaquinone-4, and that this finding was correlated with the WF sensitivity index in Japanese pediatric patients. Methotrexate (MTX) is an antifolate that is widely used to treat rheumatoid arthritis (RA) and cancer. The response to low-dose MTX demonstrated wide interpatient variability; however, the contributing factors remain unclear. We found that the frequency of the RFC1 80A allele was higher in RA patients treated with MTX alone compared with patients who received biological disease-modifying antirheumatic drugs (bDMARDs). This finding may support the combined use of bDMARDs and MTX. Further large-scale prospective clinical trials are required to confirm these findings.

Rocuronium duration of action under sevoflurane, desflurane or propofol anaesthesia.

PubMed

Maidatsi, P G; Zaralidou, A Th; Gorgias, N K; Amaniti, E N; Karakoulas, K A; Giala, M M

2004-10-01

We conducted a prospective randomized study to evaluate whether the duration of action of a single bolus dose of rocuronium is influenced by maintenance of anaesthesia with sevoflurane, desflurane or propofol infusion. Fifty-seven ASA I-II patients undergoing elective abdominal surgery were enrolled in this study. Anaesthesia was induced with thiopental 3-5 mg kg(-1) or propofol 2.5 mg kg(-1) and fentanyl 5 microg kg(-1) and tracheal intubation was facilitated with rocuronium 0.9 mg kg(-1). Thereafter patients were randomly allocated to three different groups to receive sevoflurane, desflurane or propofol for maintenance of anaesthesia. Recovery of neuromuscular function was monitored by single twitch stimulation of the ulnar nerve and by recording the adductor pollicis response using accelerometry. Intergroup recovery times to 5% of control value of single twitch were analysed using analysis of variance with Bonferroni correction. The mean (95% confidence interval) recovery time to 5% of control value of single twitch during desflurane anaesthesia was 90.18 (86.11-94.25) min. Significantly shorter recovery times were observed during sevoflurane or propofol anaesthesia, 58.86 (54.73-62.99) min and 51.11 (45.47-56.74) min, respectively (P < 0.001). There were also significant differences in the recovery time between groups receiving desflurane vs. sevoflurane (P < 0.001) and desflurane vs. propofol (P < 0.001). Desflurane anaesthesia significantly prolongs the duration of action of rocuronium at 0.9 mg kg(-1) single bolus dose, compared to sevoflurane or propofol anaesthesia maintenance regimens.

Evaluation of dose reduction versus standard dosing for maintenance of remission in patients with spondyloarthritis and clinical remission with anti-TNF (REDES-TNF): study protocol for a randomized controlled trial.

PubMed

Pontes, Caridad; Gratacós, Jordi; Torres, Ferran; Avendaño, Cristina; Sanz, Jesús; Vallano, Antoni; Juanola, Xavier; de Miguel, Eugenio; Sanmartí, Raimon; Calvo, Gonzalo

2015-08-20

Dose reduction schedules of tumor necrosis factor antagonists (anti-TNF) as maintenance therapy in patients with spondyloarthritis are used empirically in clinical practice, despite the lack of clinical trials providing evidence for this practice. To address this issue the Spanish Society of Rheumatology (SER) and Spanish Society of Clinical Pharmacology (SEFC) designed a 3-year multicenter, randomized, open-label, controlled clinical trial (2 years for inclusion and 1 year of follow-up). The study is expected to include 190 patients with axial spondyloarthritis on stable maintenance treatment (≥4 months) with any anti-TNF agent at doses recommended in the summary of product characteristics. Patients will be randomized to either a dose reduction arm or maintenance of the dosing regimen as per the official labelling recommendations. Randomization will be stratified according to the anti-TNF agent received before study inclusion. Patient follow-up, visit schedule, and examinations will be maintained as per normal clinical practice recommendations according to SER guidelines. The study aims to test the hypothesis of noninferiority of the dose reduction strategy compared with standard treatment. The first patients were recruited in July 2012, and study completion is scheduled for the end of April 2015. The REDES-TNF study is a pragmatic clinical trial that aims to provide evidence to support a medical decision now made empirically. The study results may help inform clinical decisions relevant to both patients and healthcare decision makers. EudraCT 2011-005871-18 (21 December 2011).

A randomized trial using motivational interviewing for maintenance of blood pressure improvements in a community-engaged lifestyle intervention: HUB city steps

PubMed Central

Landry, Alicia; Madson, Michael; Thomson, Jessica; Zoellner, Jamie; Connell, Carol; Yadrick, Kathleen

2015-01-01

Little is known about the effective dose of motivational interviewing for maintaining intervention-induced health outcome improvements. The purpose of this study was to compare effects of two doses of motivational interviewing for maintaining blood pressure improvements in a community-engaged lifestyle intervention conducted with African-Americans. Participants were tracked through a 12-month maintenance phase following a 6-month intervention targeting physical activity and diet. For the maintenance phase, participants were randomized to receive a low (4) or high (10) dose of motivational interviewing delivered via telephone by trained research staff. Generalized linear models were used to test for group differences in blood pressure. Blood pressure significantly increased during the maintenance phase. No differences were apparent between randomized groups. Results suggest that 10 or fewer motivational interviewing calls over a 12-month period may be insufficient to maintain post-intervention improvements in blood pressure. Further research is needed to determine optimal strategies for maintaining changes. PMID:26590242

Pitfalls associated with the therapeutic reference pricing practice of asthma medication

PubMed Central

2012-01-01

Background Therapeutic reference pricing (TRP) based on the WHO daily defined dose (DDD) is a method frequently employed for the cost-containment of pharmaceuticals. Our objective was to compare average drug use in the real world with DDD and to evaluate whether TRP based on DDD could result in cost savings on maintenance medication and the total direct health expenditures for asthma patients treated with Symbicort Turbuhaler (SYT) and Seretide Diskus (SED) in Hungary. Methods Real-world data were derived from the Hungarian National Health Insurance Fund database. Average doses and costs were compared between the high-dose and medium-dose SYT and SED groups. Multiple linear regressions were employed to adjust the data for differences in the gender and age distribution of patients. Results 27,779 patients with asthma were included in the analysis. Average drug use was lower than DDD in all groups, 1.38-1.95 inhalations in both SED groups, 1.28-1.97 and 1.74-2.49 inhalations in the medium and high-dose SYT groups, respectively. Although the cost of SED based on the DDD would be much lower than the cost of SYT in the medium-dose groups, no difference was found in the actual cost of the maintenance therapy. No significant differences were found between the groups in terms of total medical costs. Conclusions Cost-containment initiatives by payers may influence clinical decisions. TRP for inhalation asthma drugs raises special concern, because of differences in the therapeutic profile of pharmaceuticals and the lack of proven financial benefits after exclusion of the effect of generic price erosion. Our findings indicate that the presented TRP approach of asthma medications based on the daily therapeutic costs according to the WHO DDD does not result in reduced public healthcare spending in Hungary. Further analysis is required to show whether TRP generates additional expenditures by inducing switching costs and reducing patient compliance. Potential confounding factors may limit the generalisability of our conclusions. PMID:22818402

Myelotoxicity after high-dose methotrexate in childhood acute leukemia is influenced by 6-mercaptopurine dosing but not by intermediate thiopurine methyltransferase activity

PubMed Central

Levinsen, Mette; Rosthøj, Susanne; Nygaard, Ulrikka; Heldrup, Jesper; Harila-Saari, Arja; Jonsson, Olafur G.; Bechensteen, Anne Grete; Abrahamsson, Jonas; Lausen, Birgitte; Frandsen, Thomas L.; Weinshilboum, Richard M.; Schmiegelow, Kjeld

2015-01-01

Purpose Through enhancement of 6-mercaptopurine (6MP) bioavailability and inhibition of purine de novo synthesis high-dose methotrexate (HD-MTX) may increase incorporation into DNA of 6-thioguanine nucleotides (6TGN), the cytotoxic metabolites of 6MP. Patients with intermediate activity of thiopurine methyltransferase (TPMTIA) have higher cytosol 6-thioguanine nucleotide levels. We investigated toxicity following HD-MTX during MTX/6MP maintenance therapy in relation to 6MP and TPMT. Methods Using linear mixed models, we explored myelo- and hepatotoxicity in relation to 6MP dosage and TPMT phenotype following 1,749 HD-MTX courses to 411 children with acute lymphoblastic leukemia on maintenance therapy. Results The degree of myelosuppression following HD-MTX was similar for patients with TPMTIA and patients with high TPMT activity (TPMTHA), when HD-MTX started with same blood counts and 6MP doses. However, since TPMTIA had lower blood counts at initiation of HD-MTX compared to TPMTHA patients (median WBC 2.8 vs. 3.3 ×109/L, P=0.01; median ANC 1.4 vs. 1.7 ×109/L, P=0.02), TPMTIA continued to have lower WBC and ANC levels compared to TPMTHA during all 28 days after HD-MTX (relative difference: 9% (95% CI: 2-17%), P=0.02 and 21% (95% CI: 6-39%), P=0.005). Still, the fractional decrease in WBC and ANC levels after HD-MTX did not differ between TPMTIA and TPMTHA patients (P=0.47 and P=0.38). The degree of leukopenia, neutropenia, thrombocytopenia and rise in aminotransferases were all significantly related to 6MP dose (P<0.001 for all analyses). Conclusion For both TPMTIA and TPMTHA patients dose of 6MP prior to HD-MTX should be guided by pre-HD-MTX blood counts, but not by TPMT activity. PMID:25347948

Myelotoxicity after high-dose methotrexate in childhood acute leukemia is influenced by 6-mercaptopurine dosing but not by intermediate thiopurine methyltransferase activity.

PubMed

Levinsen, Mette; Rosthøj, Susanne; Nygaard, Ulrikka; Heldrup, Jesper; Harila-Saari, Arja; Jonsson, Olafur G; Bechensteen, Anne Grete; Abrahamsson, Jonas; Lausen, Birgitte; Frandsen, Thomas L; Weinshilboum, Richard M; Schmiegelow, Kjeld

2015-01-01

Through enhancement of 6-mercaptopurine (6MP) bioavailability and inhibition of purine de novo synthesis, high-dose methotrexate (HD-MTX) may increase incorporation into DNA of 6-thioguanine nucleotides, the cytotoxic metabolites of 6MP. Patients with intermediate activity of thiopurine methyltransferase (TPMT(IA)) have higher cytosol 6-thioguanine nucleotide levels. We investigated toxicity following HD-MTX during MTX/6MP maintenance therapy in relation to 6MP and TPMT. Using linear mixed models, we explored myelo- and hepatotoxicity in relation to 6MP dosage and TPMT phenotype following 1,749 HD-MTX courses to 411 children with acute lymphoblastic leukemia on maintenance therapy. The degree of myelosuppression following HD-MTX was similar for patients with TPMT(IA) and patients with high TPMT activity (TPMT(HA)), when HD-MTX started with same blood counts and 6MP doses. However, since TPMT(IA) had lower blood counts at initiation of HD-MTX compared with TPMT(HA) patients (median WBC 2.8 vs. 3.3 × 10⁹/L, P = 0.01; median ANC 1.4 vs. 1.7 × 10⁹/L, P = 0.02), TPMT(IA) continued to have lower WBC and ANC levels compared with TPMT(HA) during all 28 days after HD-MTX [relative difference 9 % (95 % CI 2-17), P = 0.02 and 21 % (95 % CI 6-39), P = 0.005]. Still, the fractional decrease in WBC and ANC levels after HD-MTX did not differ between TPMT(IA) and TPMT(HA) patients (P = 0.47; P = 0.38). The degree of leukopenia, neutropenia, thrombocytopenia and rise in aminotransferases were all significantly related to 6MP dose (P < 0.001 for all analyses). For both TPMT(IA) and TPMT(HA) patients, dose of 6MP prior to HD-MTX should be guided by pre-HD-MTX blood counts, but not by TPMT activity.

Pitfalls associated with the therapeutic reference pricing practice of asthma medication.

PubMed

Kalo, Zoltan; Abonyi-Toth, Zsolt; Bartfai, Zoltan; Voko, Zoltan

2012-07-20

Therapeutic reference pricing (TRP) based on the WHO daily defined dose (DDD) is a method frequently employed for the cost-containment of pharmaceuticals. Our objective was to compare average drug use in the real world with DDD and to evaluate whether TRP based on DDD could result in cost savings on maintenance medication and the total direct health expenditures for asthma patients treated with Symbicort Turbuhaler (SYT) and Seretide Diskus (SED) in Hungary. Real-world data were derived from the Hungarian National Health Insurance Fund database. Average doses and costs were compared between the high-dose and medium-dose SYT and SED groups. Multiple linear regressions were employed to adjust the data for differences in the gender and age distribution of patients. 27,779 patients with asthma were included in the analysis. Average drug use was lower than DDD in all groups, 1.38-1.95 inhalations in both SED groups, 1.28-1.97 and 1.74-2.49 inhalations in the medium and high-dose SYT groups, respectively. Although the cost of SED based on the DDD would be much lower than the cost of SYT in the medium-dose groups, no difference was found in the actual cost of the maintenance therapy. No significant differences were found between the groups in terms of total medical costs. Cost-containment initiatives by payers may influence clinical decisions. TRP for inhalation asthma drugs raises special concern, because of differences in the therapeutic profile of pharmaceuticals and the lack of proven financial benefits after exclusion of the effect of generic price erosion. Our findings indicate that the presented TRP approach of asthma medications based on the daily therapeutic costs according to the WHO DDD does not result in reduced public healthcare spending in Hungary. Further analysis is required to show whether TRP generates additional expenditures by inducing switching costs and reducing patient compliance. Potential confounding factors may limit the generalisability of our conclusions.

Accuracy of manual entry of drug administration data into an anesthesia information management system.

PubMed

Avidan, Alexander; Dotan, Koren; Weissman, Charles; Cohen, Matan J; Levin, Phillip D

2014-11-01

Data on drug administration are entered manually into anesthesia information management systems (AIMS). This study examined whether these data are accurate regarding drug name, dose administered, and time of administration, and whether the stage of anesthesia influences data accuracy. Real-time observational data on drug administration during elective operations were compared with computerized information on drug administration entered by anesthesiologists. A trained observer (K.D.) performed the observations. Data were collected during 57 operations which included 596 separate occasions of drug administration by 22 anesthesiologists. No AIMS records were found for 90 (15.1%) occasions of drug administration (omissions), while there were 11 (1.8%) AIMS records where drug administration was not observed. The AIMS and observer data matched for drug name on 495 of 596 (83.1%) occasions, for dose on 439 of 495 (92.5%) occasions, and for time on 476 of 495 (96.2%) occasions. Amongst the 90 omitted records, 34 (37.8%) were for vasoactive drugs with 24 (27.7%) for small doses of hypnotics. Omissions occurred mostly during maintenance: 50 of 153 (24.6%), followed by induction: 30 of 325 (9.2%) and emergence: 10 of 57 (17.5%) (P < 0.001). Time and dose inaccuracies occurred mainly during induction, followed by maintenance and emergence; time inaccuracies were 7/325 (8.3%), 10/203 (4.9%), and 0/57 (0%), respectively (P = 0.07), and dose inaccuracies were 15/325 (4.6%), 3/203 (1.5%), and 1/57 (1.7%), respectively (P = 0.11). The range of accuracy varies when anesthesiologists manually enter drug administration data into an AIMS. Charting omissions represent the largest cause of inaccuracy, principally by omissions of records for vasopressors and small doses of hypnotic drugs. Manually entered drug administration data are not without errors. Accuracy of entering drug administration data remains the responsibility of the anesthesiologist.

Effective chemotherapy of heterogeneous and drug-resistant early colon cancers by intermittent dose schedules: a computer simulation study.

PubMed

Axelrod, David E; Vedula, Sudeepti; Obaniyi, James

2017-05-01

The effectiveness of cancer chemotherapy is limited by intra-tumor heterogeneity, the emergence of spontaneous and induced drug-resistant mutant subclones, and the maximum dose to which normal tissues can be exposed without adverse side effects. The goal of this project was to determine if intermittent schedules of the maximum dose that allows colon crypt maintenance could overcome these limitations, specifically by eliminating mixtures of drug-resistant mutants from heterogeneous early colon adenomas while maintaining colon crypt function. A computer model of cell dynamics in human colon crypts was calibrated with measurements of human biopsy specimens. The model allowed simulation of continuous and intermittent dose schedules of a cytotoxic chemotherapeutic drug, as well as the drug's effect on the elimination of mutant cells and the maintenance of crypt function. Colon crypts can tolerate a tenfold greater intermittent dose than constant dose. This allows elimination of a mixture of relatively drug-sensitive and drug-resistant mutant subclones from heterogeneous colon crypts. Mutants can be eliminated whether they arise spontaneously or are induced by the cytotoxic drug. An intermittent dose, at the maximum that allows colon crypt maintenance, can be effective in eliminating a heterogeneous mixture of mutant subclones before they fill the crypt and form an adenoma.

Warfarin Dosing Algorithms Underpredict Dose Requirements in Patients Requiring ≥7 mg Daily: A Systematic Review and Meta-analysis.

PubMed

Saffian, S M; Duffull, S B; Wright, Dfb

2017-08-01

There is preliminary evidence to suggest that some published warfarin dosing algorithms produce biased maintenance dose predictions in patients who require higher than average doses. We conducted a meta-analysis of warfarin dosing algorithms to determine if there exists a systematic under- or overprediction of dose requirements for patients requiring ≥7 mg/day across published algorithms. Medline and Embase databases were searched up to September 2015. We quantified the proportion of over- and underpredicted doses in patients whose observed maintenance dose was ≥7 mg/day. The meta-analysis included 47 evaluations of 22 different warfarin dosing algorithms from 16 studies. The meta-analysis included data from 1,492 patients who required warfarin doses of ≥7 mg/day. All 22 algorithms were found to underpredict warfarin dosing requirements in patients who required ≥7 mg/day by an average of 2.3 mg/day with a pooled estimate of underpredicted doses of 92.3% (95% confidence interval 90.3-94.1, I 2 = 24%). © 2017 American Society for Clinical Pharmacology and Therapeutics.

21 CFR 522.2005 - Propofol.

Code of Federal Regulations, 2011 CFR

2011-04-01

...—(i) As a single injection to provide general anesthesia for short procedures; for induction and maintenance of general anesthesia using incremental doses to effect; for induction of general anesthesia where maintenance is provided by inhalant anesthetics. (ii) For the induction and maintenance of anesthesia and for...

21 CFR 522.2005 - Propofol.

Code of Federal Regulations, 2014 CFR

2014-04-01

...—(i) As a single injection to provide general anesthesia for short procedures; for induction and maintenance of general anesthesia using incremental doses to effect; for induction of general anesthesia where maintenance is provided by inhalant anesthetics. (ii) For the induction and maintenance of anesthesia and for...

Overcoming severe adverse reactions to venom immunotherapy using anti-IgE antibodies in combination with a high maintenance dose.

PubMed

Stretz, E; Oppel, E M; Räwer, H-C; Chatelain, R; Mastnik, S; Przybilla, B; Ruëff, F

2017-12-01

An omalizumab treatment and a high maintenance venom dose may both help to prevent recurrent systemic allergic reactions (SAR) to venom immunotherapy (VIT). The effectiveness of this combination therapy, however, is unclear. We wanted to explore the possibility whether a temporary treatment with the anti-IgE antibody omalizumab combined with a VIT using an elevated maintenance dose of >100 μg venom may establish a permanent tolerance of maintenance VIT. For this retrospective case series, we scoured our institutional data base for patients who had had an insect venom allergy, and in whom it had not been possible to continue VIT because of repeated unstoppable SAR during maintenance VIT. Patients were divided into those who had received the combination therapy (omalizumab group) and those who had not received omalizumab because its costs could not be covered (controls). Guided by the total IgE level and by body weight, omalizumab had been given subcutaneously 5, 3 and 1 weeks before VIT had been restarted. Three to 6 months after an elevated maintenance dose (200-300 μg venom) had been reached, omalizumab had been stopped. Between 2006 and 2011, 15 patients had qualified for an off-label use of omalizumab: 10 patients had received the combination therapy, and 5 patients had remained without such a therapy. The combination therapy leads to a durable tolerance of VIT in all patients even after omalizumab had been discontinued (median of follow-up time 5.8 years, IQR 2.7-8.6 years). Sting challenge tests were tolerated by all of the re-stung omalizumab patients (n = 8). In all controls, VIT had to be stopped permanently due to repeated SARs (P < .001 vs omalizumab group). Combining a temporary omalizumab therapy with an elevated maintenance dose seems a promising approach to achieve a tolerance of treatment in patients with a recurrent SAR to VIT. © 2017 John Wiley & Sons Ltd.

SCN1A, ABCC2 and UGT2B7 gene polymorphisms in association with individualized oxcarbazepine therapy.

PubMed

Ma, Chun-Lai; Wu, Xun-Yi; Jiao, Zheng; Hong, Zhen; Wu, Zhi-Yuan; Zhong, Ming-Kang

2015-01-01

Associations between the effects of SCN1A, SCN2A, ABCC2 and UGT2B7 genetic polymorphisms and oxcarbazepine (OXC) maintenance doses in Han Chinese epileptic patients were investigated. Genetic polymorphisms were detected in 184 epileptic patients receiving OXC monotherapy by high-resolution melting curve and TaqMan method. Carriers of the SCN1A IVS5-91G>A, UGT2B7 c.802T>C and ABCC2 c.1249G>A variant alleles required significantly higher OXC maintenance doses than noncarriers (p < 0.05). Corresponding relative ln (concentration-dose ratios) values for SCN1A IVS5-91 variants differed by the genotypic order GG > GA > AA. SCN1A, UGT2B7 and ABCC2 genetic polymorphisms are associated with OXC maintenance doses and may be useful for the personalization of OXC therapy in epileptic patients. Further studies are needed. Original submitted 6 June 2014; Revision submitted 5 September 2014.

Maintenance dosing for sublingual immunotherapy by prominent European allergen manufacturers expressed in bioequivalent allergy units.

PubMed

Larenas-Linnemann, Désirée; Esch, Robert; Plunkett, Greg; Brown, Shannon; Maddox, Daniel; Barnes, Charles; Constable, Derek

2011-11-01

Sublingual immunotherapy (SLIT) has become established in Europe, and its efficacy is being evaluated in the United States. The doses used for SLIT in Europe today are difficult to evaluate, because each manufacturer expresses the potency of its extracts differently. To compare in vitro European SLIT maintenance solutions against US licensed standardized allergenic extract concentrates and to determine the monthly SLIT doses delivered expressed in bioequivalent allergy units ([B]AU). We studied Dermatophagoides pteronyssinus, timothy grass pollen, cat (hair) and short ragweed pollen allergen extracts. The SLIT maintenance solutions of 4 leading European manufacturers and standardized concentrate extracts of 3 US manufacturers were analyzed with the following assays: protein content, relative potency (immunoglobulin E [IgE]-binding enzyme-linked immunosorbent assay [ELISA] inhibition) and major allergen content. The relative monthly allergen dose in (B)AU was calculated for each recommended SLIT schedule. Relative potency was approximately 10 times higher for US concentrate standardized extracts-which are meant to be diluted-than for European SLIT maintenance solutions of D pteronyssinus and timothy grass pollen. For cat (hair) and short ragweed pollen, the difference was less. Measurements of relative potency and major allergen content correlated well. In our assays, European mite extracts contain a very low quantity of Der p 2 compared with US mites. Recommended SLIT doses in Europe vary widely among the manufacturers, but are consistently lower (Eur1) or higher (Eur4) over all four allergens tested. SLIT efficacy probably depends on additional factors apart from the exact dose. SLIT dose finding studies should be done for each product. Copyright © 2011 American College of Allergy. Published by Elsevier Inc. All rights reserved.

[Clinical applications of dosing algorithm in the predication of warfarin maintenance dose].

PubMed

Huang, Sheng-wen; Xiang, Dao-kang; An, Bang-quan; Li, Gui-fang; Huang, Ling; Wu, Hai-li

2011-12-27

To evaluate the feasibility of clinical application for genetic based dosing algorithm in the predication of warfarin maintenance dose in Chinese population. The clinical data were collected and blood samples harvested from a total of 126 patients undergoing heart valve replacement. The genotypes of VKORC1 and CYP2C9 were determined by melting curve analysis after PCR. They were divided randomly into the study and control groups. In the study group, the first three doses of warfarin were prescribed according to the predicted warfarin maintenance dose while warfarin was initiated at 2.5 mg/d in the control group. The warfarin doses were adjusted according to the measured international normalized ratio (INR) values. And all subjects were followed for 50 days after an initiation of warfarin therapy. At the end of a 50-day follow-up period, the proportions of the patients on a stable dose were 82.4% (42/51) and 62.5% (30/48) for the study and control groups respectively. The mean durations of reaching a stable dose of warfarin were (27.5 ± 1.8) and (34.7 ± 1.8) days and the median durations were (24.0 ± 1.7) and (33.0 ± 4.5) days in the study and control groups respectively. Significant differences existed in the durations of reaching a stable dose between the two groups (P = 0.012). Compared with the control group, the hazard ratio (HR) for the duration of reaching a stable dose was 1.786 in the study group (95%CI 1.088 - 2.875, P = 0.026). The predicted dosing algorithm incorporating genetic and non-genetic factors may shorten the duration of achieving efficiently a stable dose of warfarin. And the present study validates the feasibility of its clinical application.

An Economic Analysis of Bromocriptine Versus Trans-Sphenoidal Surgery for the Treatment of Prolactinoma.

PubMed

Duan, Lian; Yan, Hua; Huang, Minqiang; Zhang, Yuhui; Gu, Feng

2017-06-01

Prolactinomas account for ∼40% of all pituitary adenomas and are important causes of infertility and gonadal dysfunction. In general, most prolactinomas are treated medically with dopaminergic agonists, while surgery is reserved for patients intolerant or nonresponsive to these medications. The aim of this study was to carry out a comparative analysis of the cost-effectiveness of medical therapy with bromocriptine and surgical therapy with trans-sphenoidal surgery. A Markov model was developed based on retrospective data from 126 patients with prolactinoma treated in our hospital between October 2008 and May 2009, and from data published previously. For patients with microadenoma, the cost of medical treatment was estimated to be ¥20,555, while the cost of surgery was calculated to be ¥22,527. For patients with macroadenoma, the cost of therapy with bromocriptine was ¥31,461 in males and ¥27,178 in females, while the cost of surgery was ¥42,357 in males and ¥44,094 in females. Sensitivity analyses (carried our using variations in patient age, bromocriptine therapeutic dose, bromocriptine maintenance dose, and the success rate of bromocriptine withdrawal) indicated that our model showed good stability, although our results were most heavily influenced by variations in the bromocriptine maintenance dose. It is concluded that, from an economic viewpoint, medical therapy with bromocriptine should be the first-line treatment option for patients with prolactinoma, irrespective of whether this is a microadenoma or macroadenoma.

Use of thalidomide for severe recurrent aphthous stomatitis: a multicenter cohort analysis.

PubMed

Hello, Muriel; Barbarot, Sébastien; Bastuji-Garin, Sylvie; Revuz, Jean; Chosidow, Olivier

2010-05-01

Severe recurrent aphthous stomatitis (SRAS) is a rare, disabling disorder of unknown etiology. Thalidomide is an effective second-line therapy for SRAS, but is suppressive rather than curative, and adverse events limit its use. Few reports describe the efficacy, tolerance, and safety of thalidomide, and how it is actually used as long-term (maintenance) therapy for SRAS. Therefore, we conducted this study to describe thalidomide use in the real-life management of a cohort of patients with SRAS. This multicenter retrospective cohort study covered a period of 5 years and 5 months (January 2003-May 2008). Patients who had started thalidomide monotherapy for SRAS during the 2003-2006 period were eligible. Data were collected from patients' medical charts and supplemented by patients' responses during a targeted telephone interview. Ninety-two patients followed at 14 centers were included: 76 had oral or bipolar aphthosis, and 16 had Behçet disease. Thalidomide was rapidly effective: 85% (78/92) entered complete remission (CR) within a median of 14 days. Response time was independent of the initial thalidomide dose (r = 0.04). Thalidomide was continued for > or =3 months (maintenance therapy) by 77/92 (84%) of the patients on 1 of 2 maintenance regimens: continuous therapy with regular intake (60/77) or intermittent therapy in response to attacks (17/77). Although intermittent therapy was less restrictive than continuous therapy, medical supervision under the former was less rigorous. The median maintenance dose was 100 mg/week, and did not reflect the initial dose (r = 0.18). The intermittent-treatment group's median dose was significantly lower and its median duration of thalidomide intake significantly longer than for patients on continuous therapy (19 vs. 150 mg/wk; p < 0.0001, and 32 vs. 19 mo; p = 0.002, respectively). Adverse events were reported by 84% (77/92) of patients. They were mostly mild (78% of patients), but sometimes severe (21%). Nevertheless, after 40 months of follow-up, 60% of patients were still receiving continuous or intermittent maintenance therapy with favorable efficacy/tolerance ratios. Despite its retrospective nature, this detailed study provides novel information on the different ways thalidomide is used as SRAS maintenance therapy in a large and unselected cohort of patients. Low-dose maintenance regimens appear to be widely used, effective, and relatively well tolerated. These observations suggest the value of undertaking a randomized trial to assess various maintenance regimens.

Comparison of Antivenom Dosing Strategies for Rattlesnake Envenomation.

PubMed

Spyres, Meghan B; Skolnik, Aaron B; Moore, Elizabeth C; Gerkin, Richard D; Padilla-Jones, Angela; Ruha, Anne-Michelle

2018-06-01

This study compares maintenance with clinical- and laboratory-triggered (as-needed [PRN]) antivenom dosing strategies with regard to patient-centered outcomes after rattlesnake envenomation. This is a retrospective cohort study of adult rattlesnake envenomations treated at a regional toxicology center. Data on demographics, envenomation details, antivenom administration, length of stay, and laboratory and clinical outcomes were compared between the PRN and maintenance groups. Primary outcomes were hospital length of stay and total antivenom used, with a hypothesis of no difference between the two dosing strategies. A single regional toxicology center PATIENTS:: Three-hundred ten adult patients envenomated by rattlesnakes between 2007 and 2014 were included. Patients were excluded if no antivenom was administered or for receiving an antivenom other than Crofab (BTG International, West Conshohocken, PA). This is a retrospective study of rattlesnake envenomations treated with and without maintenance antivenom dosing. One-hundred forty-eight in the maintenance group and 162 in the PRN group were included. There was no difference in demographics or baseline envenomation severity or hemotoxicity (32.7% vs 40.5%; respectively; p = 0.158) between the two groups. Comparing the PRN with the maintenance group, less antivenom was used (8 [interquartile range, 6-12] vs 16 [interquartile range, 12-18] vials, respectively; p < 0.001), and hospital length of stay was shorter (27 hr [interquartile range, 20-44 hr] vs 34 hr [interquartile range, 24-43 hr], respectively; p = 0.014). There were no differences in follow-up outcomes of readmission, retreatment, or bleeding and surgical complications. Hospital length of stay was shorter, and less antivenom was used in patients receiving a PRN antivenom dosing strategy after rattlesnake envenomation.

Continuous Low-Dose Oral Cyclophosphamide and Methotrexate as Maintenance Therapy in Patients With Advanced Ovarian Carcinoma After Complete Clinical Response to Platinum and Paclitaxel Chemotherapy.

PubMed

El-Husseiny, Khalid; Motawei, Helmy; Ali, Mohamad Sayed

2016-03-01

The aim of this study was to evaluate efficacy and safety of continuous, low dose of oral, metronomic chemotherapy as maintenance therapy in patients with advanced ovarian carcinoma after complete clinical response to platinum and paclitaxel chemotherapy. In this nonrandomized study, patients older than 18 years, with Eastern Cooperative Oncology Group performance status less than 2, with advanced ovarian carcinoma after complete clinical response to platinum and paclitaxel chemotherapy were enrolled in 2 arms--arm A (maintenance arm), treated with continuous low-dose oral cyclophosphamide 50 mg and methotrexate 2.5 mg, and arm B (observation arm). Both arms were followed up for progression-free survival and toxicity. Thirty patients were accrued in each arm from January 2009 to December 2010 in Ain Shams University Hospitals, where they received the treatment and followed up for disease progression and toxicity. Patients had a median age of 53 years in maintenance arm and 52.5 years in the observational arm, respectively. Over 80% had papillary serous adenocarcinoma, and over 40% of them had a stage IV disease in both arms. After median follow-up of 27 months, patients achieved median progression-free survival of 18 months in maintenance arm (A) and 15.5 months in observational arm (B), respectively. Toxicity profile was excellent with no grade 3 or 4 toxicity reported. Current study may provide an evidence of efficacy and tolerability of continuous low-dose oral cyclophosphamide and methotrexate as a maintenance therapy in patients with advanced ovarian carcinoma after complete clinical response to platinum and paclitaxel chemotherapy.

Mercaptopurine/Methotrexate Maintenance Therapy of Childhood Acute Lymphoblastic Leukemia: Clinical Facts and Fiction

PubMed Central

Nielsen, Stine N.; Frandsen, Thomas L.; Nersting, Jacob

2014-01-01

The antileukemic mechanisms of 6-mercaptopurine (6MP) and methotrexate (MTX) maintenance therapy are poorly understood, but the benefits of several years of myelosuppressive maintenance therapy for acute lymphoblastic leukemia are well proven. Currently, there is no international consensus on drug dosing. Because of significant interindividual and intraindividual variations in drug disposition and pharmacodynamics, vigorous dose adjustments are needed to obtain a target degree of myelosuppression. As the normal white blood cell counts vary by patients’ ages and ethnicity, and also within age groups, identical white blood cell levels for 2 patients may not reflect the same treatment intensity. Measurements of intracellular levels of cytotoxic metabolites of 6MP and MTX can identify nonadherent patients, but therapeutic target levels remains to be established. A rise in serum aminotransferase levels during maintenance therapy is common and often related to high levels of methylated 6MP metabolites. However, except for episodes of hypoglycemia, serious liver dysfunction is rare, the risk of permanent liver damage is low, and aminotransferase levels usually normalize within a few weeks after discontinuation of therapy. 6MP and MTX dose increments should lead to either leukopenia or a rise in aminotransferases, and if neither is experienced, poor treatment adherence should be considered. The many genetic polymorphisms that determine 6MP and MTX disposition, efficacy, and toxicity have precluded implementation of pharmacogenomics into treatment, the sole exception being dramatic 6MP dose reductions in patients who are homozygous deficient for thiopurine methyltransferase, the enzyme that methylates 6MP and several of its metabolites. In conclusion, maintenance therapy is as important as the more intensive and toxic earlier treatment phases, and often more challenging. Ongoing research address the applicability of drug metabolite measurements for dose adjustments, extensive host genome profiling to understand diversity in treatment efficacy and toxicity, and alternative thiopurine dosing regimens to improve therapy for the individual patient. PMID:24936744

Comparison of F(ab')2 versus Fab antivenom for pit viper envenomation: A prospective, blinded, multicenter, randomized clinical trial

PubMed Central

Ruha, Anne-Michelle; Seifert, Steven A.; Morgan, David L.; Lewis, Brandon J.; Arnold, Thomas C.; Clark, Richard F.; Meggs, William J.; Toschlog, Eric A.; Borron, Stephen W.; Figge, Gary R.; Sollee, Dawn R.; Shirazi, Farshad M.; Wolk, Robert; de Chazal, Ives; Quan, Dan; García-Ubbelohde, Walter; Alagón, Alejandro; Gerkin, Richard D.; Boyer, Leslie V.

2015-01-01

Background. Crotalidae Polyvalent Immune Fab (Ovine) has been the only antivenom commercially available in the US since 2007 for treatment of Crotalinae envenomation. Late coagulopathy can occur or recur after clearance of Fab antivenom, often after hospital discharge, lasting in some cases more than 2 weeks. There have been serious, even fatal, bleeding complications associated with recurrence phenomena. Frequent follow-up is required, and additional intervention or hospitalization is often necessary. F(ab')2 immunoglobulin derivatives have longer plasma half life than do Fab. We hypothesized that F(ab')2 antivenom would be superior to Fab in the prevention of late coagulopathy following treatment of patients with Crotalinae envenomation. Methods. We conducted a prospective, double-blind, randomized clinical trial, comparing late coagulopathy in snakebitten patients treated with F(ab')2 with maintenance doses [F(ab')2/F(ab')2], or F(ab')2 with placebo maintenance doses [F(ab')2/placebo], versus Fab with maintenance doses [Fab/Fab]. The primary efficacy endpoint was coagulopathy (platelet count < 150 K/mm3, fibrinogen level < 150 mg/dL) between end of maintenance dosing and day 8. Results. 121 patients were randomized at 18 clinical sites and received at least one dose of study drug. 114 completed the study. Of these, 11/37 (29.7%) in the Fab/Fab cohort experienced late coagulopathy versus 4/39 (10.3%, p < 0.05) in the F(ab')2/F(ab')2 cohort and 2/38 (5.3%, p < 0.05) in the F(ab')2/placebo cohort. The lowest heterologous protein exposure was with F(ab')2/placebo. No serious adverse events were related to study drug. In each study arm, one patient experienced an acute serum reaction and one experienced serum sickness. Conclusions. In this study, management of coagulopathic Crotalinae envenomation with longer-half-life F(ab')2 antivenom, with or without maintenance dosing, reduced the risk of subacute coagulopathy and bleeding following treatment of envenomation. PMID:25361165

Comparison of F(ab')2 versus Fab antivenom for pit viper envenomation: a prospective, blinded, multicenter, randomized clinical trial.

PubMed

Bush, Sean P; Ruha, Anne-Michelle; Seifert, Steven A; Morgan, David L; Lewis, Brandon J; Arnold, Thomas C; Clark, Richard F; Meggs, William J; Toschlog, Eric A; Borron, Stephen W; Figge, Gary R; Sollee, Dawn R; Shirazi, Farshad M; Wolk, Robert; de Chazal, Ives; Quan, Dan; García-Ubbelohde, Walter; Alagón, Alejandro; Gerkin, Richard D; Boyer, Leslie V

2015-01-01

Crotalidae Polyvalent Immune Fab (Ovine) has been the only antivenom commercially available in the US since 2007 for treatment of Crotalinae envenomation. Late coagulopathy can occur or recur after clearance of Fab antivenom, often after hospital discharge, lasting in some cases more than 2 weeks. There have been serious, even fatal, bleeding complications associated with recurrence phenomena. Frequent follow-up is required, and additional intervention or hospitalization is often necessary. F(ab')2 immunoglobulin derivatives have longer plasma half life than do Fab. We hypothesized that F(ab')2 antivenom would be superior to Fab in the prevention of late coagulopathy following treatment of patients with Crotalinae envenomation. We conducted a prospective, double-blind, randomized clinical trial, comparing late coagulopathy in snakebitten patients treated with F(ab')2 with maintenance doses [F(ab')2/F(ab')2], or F(ab')2 with placebo maintenance doses [F(ab')2/placebo], versus Fab with maintenance doses [Fab/Fab]. The primary efficacy endpoint was coagulopathy (platelet count < 150 K/mm(3), fibrinogen level < 150 mg/dL) between end of maintenance dosing and day 8. 121 patients were randomized at 18 clinical sites and received at least one dose of study drug. 114 completed the study. Of these, 11/37 (29.7%) in the Fab/Fab cohort experienced late coagulopathy versus 4/39 (10.3%, p < 0.05) in the F(ab')2/F(ab')2 cohort and 2/38 (5.3%, p < 0.05) in the F(ab')2/placebo cohort. The lowest heterologous protein exposure was with F(ab')2/placebo. No serious adverse events were related to study drug. In each study arm, one patient experienced an acute serum reaction and one experienced serum sickness. In this study, management of coagulopathic Crotalinae envenomation with longer-half-life F(ab')2 antivenom, with or without maintenance dosing, reduced the risk of subacute coagulopathy and bleeding following treatment of envenomation.

The Relationship of Genetics, Nursing Practice, and Informatics Tools in 6-Mercaptopurine Dosing in Pediatric Oncology [Formula: see text].

PubMed

Haylett, Wendy J

An antileukemic agent prescribed for pediatric oncology patients during the maintenance phase of therapy for acute lymphoblastic leukemia, 6-mercaptopurine (6-MP), is highly influenced by genetic variations in the thiopurine S-methyltransferase enzyme. As such, 6-MP must be dosed so that patients with 1 or 2 inactive thiopurine S-methyltransferase alleles will not incur an increased risk for myelosuppression or other toxicities. Informatics tools such as clinical decision support systems are useful for the application of this and similar pharmacogenetics information to the realm of nursing and clinical practice for safe and effective patient care. This article will discuss pharmacogenetics and the associated use of 6-MP; present implications for nursing practice; identify informatics tools such as clinical decision support systems, which can greatly enhance the care of patients whose treatment is based on critical genetic information; and examine the relationship of genetics, nursing practice, and informatics for 6-MP dosing in pediatric oncology.

The US Food and Drug Administration's perspective on the new antidepressant vortioxetine.

PubMed

Zhang, Jing; Mathis, Mitchell V; Sellers, Jenn W; Kordzakhia, George; Jackson, Andre J; Dow, Antonia; Yang, Peiling; Fossom, Linda; Zhu, Hao; Patel, Hiren; Unger, Ellis F; Temple, Robert J

2015-01-01

This article summarizes the US Food and Drug Administration's (FDA's) review of the New Drug Application for vortioxetine, especially the clinical efficacy and safety data. It emphasizes the issues that were important to the FDA's approval decision, particularly the difference in the effective dose in domestic and foreign studies, and notes several new labeling features, specifically, description of time course of treatment response and detailed sexual dysfunction evaluation. The data sources were the original raw data sets for all clinical trials included in the development program for vortioxetine, as well as the sponsor's original analyses of these data. Data were available from 51 human trials involving vortioxetine, and included a total of 7,666 healthy volunteers and patients with a diagnosis of major depressive disorder (MDD) or generalized anxiety disorder who were exposed to at least 1 dose of vortioxetine for a total of 2,743 patient-years. Vortioxetine was effective in treating MDD in the United States at a dose of 20 mg/d. The recommended starting dose is 10 mg once daily without regard to food, with increase to 20 mg/d if the 10 mg/d dose is tolerated. For patients who do not tolerate 20 mg/d, 10 mg/d can be used and 5-mg/d dose can be considered. Vortioxetine can be discontinued abruptly, but it is recommended that doses of 15 mg/d or 20 mg/d be reduced to 10 mg/d for 1 week prior to full discontinuation to avoid potential withdrawal symptoms. Although the non-US maintenance study showed that maintenance doses of 5 to 10 mg/d were effective, a clinical judgment needs to be made to decide the maintenance dose in the United States. The applicant has agreed to conduct a US maintenance dose-response study covering the US-approved dose range. Vortioxetine's adverse event profile is similar to that of other selective serotonin reuptake inhibitors (SSRIs). Nausea is the most common adverse event and is dose dependent. No dose adjustment is needed based on age, gender, or the presence of renal or mild to moderate hepatic impairment. The maximum recommended dose is 10 mg/d in known cytochrome P450 2D6 poor metabolizers. Vortioxetine is a new treatment for MDD, and its adverse event profile is similar to that of other SSRIs. © Copyright 2015 Physicians Postgraduate Press, Inc.

Interethnic variability of warfarin maintenance requirement is explained by VKORC1 genotype in an Asian population.

PubMed

Lee, Soo-Chin; Ng, Swee-Siang; Oldenburg, Johannes; Chong, Pei-Yi; Rost, Simone; Guo, Jia-Yi; Yap, Hui-Ling; Rankin, Sheila Clare; Khor, Hui-Boon; Yeo, Tiong-Cheng; Ng, Kheng-Siang; Soong, Richie; Goh, Boon-Cher

2006-03-01

Chinese and Malay subjects have been reported to require less maintenance warfarin than Indians that could not be accounted for by cytochrome P450 (CYP) 2C9 variants. Vitamin K epoxide reductase complex 1 (VKORC1) is the target enzyme of warfarin, and VKORC1 intronic variants and haplotypes have recently been shown to influence VKORC1 activity and warfarin requirements. We sequenced the coding regions of CYP2C9 and VKORC1 and inferred VKORC1 haplotype from 10 intronic variants in 147 Chinese, 85 Malay, and 43 Indian patients receiving maintenance warfarin. The mean weight-normalized warfarin dose was lower for Chinese and Malays than for Indians (0.058 +/- 0.025 mg/kg, 0.059 +/- 0.023 mg/kg, and 0.089 +/- 0.036 mg/kg, respectively; P < .001 for comparisons between Chinese and Malays with Indians). CYP2C9*2 and VKORC1 coding region variants were rare (<2%), whereas CYP2C9*3 associated with lower warfarin requirements was less common in Chinese and Malays (7% and 9%, respectively) than in Indians (18%) and could not account for their lower warfarin requirements. VKORC1 H1 and H7/H8/H9 haplotypes were associated with lower and higher warfarin requirements, respectively (0.050 +/- 0.019 mg/kg and 0.092 +/- 0.057 mg/kg, respectively; P < .001). VKORC1 H1 haplotype (requiring low warfarin doses) was common in Chinese (87%) and Malays (65%) but uncommon in Indians (12%), whereas H7, H8, and H9 haplotypes (requiring high warfarin doses) were rare in Chinese (9%), intermediate in Malays (30%), and common in Indians (82%). The interethnic difference in warfarin requirements became nonsignificant when adjusted for VKORC1 haplotype. Interethnic difference in VKORC1 haplotypes accounts for the difference in warfarin requirements between Chinese, Malays, and Indians, providing interesting insights into genetic variation between ethnogeographically distinct Asian groups.

Effect of smoking status on the efficacy of the SMART regimen in high risk asthma.

PubMed

Pilcher, Janine; Patel, Mitesh; Reddel, Helen K; Pritchard, Alison; Black, Peter; Shaw, Dominick; Holt, Shaun; Weatherall, Mark; Beasley, Richard

2016-07-01

The optimal management of people with asthma with a significant smoking history is uncertain. The aim of this study was to determine whether the efficacy/safety profile of single combination inhaled corticosteroid (ICS)/long acting beta-agonist (LABA) inhaler maintenance and reliever therapy is influenced by smoking status. We undertook secondary analyses from an open-label 24-week randomized study of 303 high risk adult asthma patients randomized to budesonide/formoterol 200/6-µg-metred dose inhaler for maintenance (two actuations twice daily) and either budesonide/formoterol 200/6-µg-metred dose inhaler one actuation ('single ICS/LABA maintenance and reliever therapy (SMART)' regimen) or salbutamol 100 µg 1-2 actuations for symptom relief ('Standard' regimen). Smoking status was classified in to three groups, as 'current', 'ex' or 'never', and a smoking/treatment interaction term tested for each outcome variable. The primary outcome variable was number of participants with at least one severe exacerbation. There were 59 current, 97 ex and 147 never smokers included in the analyses. The smoking status/treatment interaction term was not statistically significant for any of the outcome measures. With adjustment for smoking status, the number of participants with severe exacerbations was lower with the SMART regimen (OR 0.45, 95% CI: 0.26-0.77, P = 0.004; P value for interaction between smoking status and treatment 0.29). We conclude that the favourable safety/efficacy profile of the SMART regimen applies to patients with high risk asthma, irrespective of smoking status. © 2016 Asian Pacific Society of Respirology.

Intravenous iron administration strategies and anemia management in hemodialysis patients.

PubMed

Michels, Wieneke M; Jaar, Bernard G; Ephraim, Patti L; Liu, Yang; Miskulin, Dana C; Tangri, Navdeep; Crews, Deidra C; Scialla, Julia J; Shafi, Tariq; Sozio, Stephen M; Bandeen-Roche, Karen; Cook, Courtney J; Meyer, Klemens B; Boulware, L Ebony

2017-01-01

The effect of maintenance intravenous (IV) iron administration on subsequent achievement of anemia management goals and mortality among patients recently initiating hemodialysis is unclear. We performed an observational cohort study, in adult incident dialysis patients starting on hemodialysis. We defined IV administration strategies over a 12-week period following a patient's initiation of hemodialysis; all those receiving IV iron at regular intervals were considered maintenance, and all others were considered non-maintenance. We used multivariable models adjusting for demographics, clinical and treatment parameters, iron dose, measures of iron stores and pro-infectious and pro-inflammatory parameters to compare these strategies. The outcomes under study were patients' (i) achievement of hemoglobin (Hb) of 10-12 g/dL, (ii) more than 25% reduction in mean weekly erythropoietin stimulating agent (ESA) dose and (iii) mortality, ascertained over a period of 4 weeks following the iron administration period. Maintenance IV iron was administered to 4511 patients and non-maintenance iron to 8458 patients. Maintenance IV iron administration was not associated with a higher likelihood of achieving an Hb between 10 and 12 g/dL {adjusted odds ratio (OR) 1.01 [95% confidence interval (CI) 0.93-1.09]} compared with non-maintenance, but was associated with a higher odds of achieving a reduced ESA dose of 25% or more [OR 1.33 (95% CI 1.18-1.49)] and lower mortality [hazard ratio (HR) 0.73 (95% CI 0.62-0.86)]. Maintenance IV iron strategies were associated with reduced ESA utilization and improved early survival but not with the achievement of Hb targets. © The Author 2016. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

Comparative trial of low- and high-dose zonisamide as monotherapy for childhood epilepsy.

PubMed

Eun, So-Hee; Kim, Heung Dong; Eun, Baik-Lin; Lee, In Kyu; Chung, Hee Jung; Kim, Joon Sik; Kang, Hoon-Chul; Lee, Young-Mock; Suh, Eun Sook; Kim, Dong Wook; Eom, Soyong; Lee, Joon Soo; Moon, Han Ku

2011-09-01

To evaluate the effectiveness of zonisamide (ZNS) as monotherapy in children with newly diagnosed epilepsy. This randomized, multicenter trial included a 2-4-week titration and a 24-week maintenance phase after randomization to low-(3-4 mg/kg/day) or high-(6-8 mg/kg/day) dose groups as target maintenance dosages. The primary outcome measure was the seizure-free rate over 6 months, while a secondary measure was the change in cognition and behavior from screening to the end of the maintenance phase. Out of 125 patients enrolled, 90 (49 low-dose and 41 high-dose) completed the study. Forty-one patients (63.1%) in the low-dose group and 34(57.6%) in the high-dose group achieved 6 months' freedom from seizures (p=0.66). After treatment, the picture arrangement subtest improved in the low-dose group (p=0.047) while the vocabulary subtest worsened in the high-dose group (p=0.020). Comparing between the two groups, the vocabulary subtest in the high-dose group was significantly worse than that in the low-dose group (p=0.002). Social competence, somatic complaints, depression/anxiety and delinquent and aggressive behavior in the low-dose group were significantly improved (p<0.05). Moreover, total social competence, somatic complaints, delinquent behavior, externalizing, and total behavior problems were significantly more improved in the low-dose group than the high-dose group (p<0.05). ZNS is an effective monotherapy for newly diagnosed childhood epilepsy. Lower doses of ZNS have a similar efficacy and more beneficial neurocognitive effects compared to higher doses. When prescribing higher doses of ZNS, one must be aware of the possible manifestation of problems associated with language development, such as those affecting vocabulary acquisition. Copyright © 2011 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

Buspirone maintenance does not alter the reinforcing, subjective, and cardiovascular effects of intranasal methamphetamine.

PubMed

Reynolds, Anna R; Strickland, Justin C; Stoops, William W; Lile, Joshua A; Rush, Craig R

2017-12-01

Medications development efforts for methamphetamine-use disorder have targeted central monoamines because these systems are directly involved in the effects of methamphetamine. Buspirone is a dopamine autoreceptor and D3 receptor antagonist and partial agonist at serotonin 1A receptors, making it a logical candidate medication for methamphetamine-use disorder. Buspirone effects on abuse-related behaviors of methamphetamine have been mixed in clinical and preclinical studies. Experimental research using maintenance dosing, which models therapeutic use, is limited. This study evaluated the influence of buspirone maintenance on the reinforcing effects of methamphetamine using a self-administration procedure, which has predictive validity for clinical efficacy. The impact of buspirone maintenance on the subjective and cardiovascular response to methamphetamine was also determined. Eight research participants (1 female) reporting recent illicit stimulant use completed a placebo-controlled, crossover, double-blind protocol in which the pharmacodynamic effects of intranasal methamphetamine (0, 15, and 30mg) were assessed after at least 6days of buspirone (0 and 45mg/day) maintenance. Intranasal methamphetamine functioned as a reinforcer and produced prototypical stimulant-like subjective (e.g., increased ratings of Good Effects and Like Drug) and cardiovascular (e.g., elevated blood pressure) effects. These effects of methamphetamine were similar under buspirone and placebo maintenance conditions. Maintenance on buspirone was well tolerated and devoid of effects when administered alone. These data suggest that buspirone is unlikely to be an effective pharmacotherapy for methamphetamine-use disorder. Given the central role of monoamines in methamphetamine-use disorder, it is reasonable for future studies to continue to target these systems. Copyright © 2017 Elsevier B.V. All rights reserved.

Randomized study of intensified anthracycline doses for induction and recombinant interleukin-2 for maintenance in patients with acute myeloid leukemia age 50 to 70 years: results of the ALFA-9801 study.

PubMed

Pautas, Cecile; Merabet, Fatiha; Thomas, Xavier; Raffoux, Emmanuel; Gardin, Claude; Corm, Selim; Bourhis, Jean-Henri; Reman, Oumedaly; Turlure, Pascal; Contentin, Nathalie; de Revel, Thierry; Rousselot, Philippe; Preudhomme, Claude; Bordessoule, Dominique; Fenaux, Pierre; Terré, Christine; Michallet, Mauricette; Dombret, Hervé; Chevret, Sylvie; Castaigne, Sylvie

2010-02-10

PURPOSE In patients with acute myeloid leukemia (AML), induction chemotherapy is based on standard doses of anthracyclines and cytarabine. High doses of cytarabine have been reported as being too toxic for patients older than age 50 years, but few studies have evaluated intensified doses of anthracyclines. PATIENTS AND METHODS In this randomized Acute Leukemia French Association 9801 (ALFA-9801) study, high doses of daunorubicin (DNR; 80 mg/m(2)/d x 3 days) or idarubicin (IDA4; 12 mg/m(2)/d x 4 days) were compared with standard doses of idarubicin (IDA3; 12 mg/m(2)/d x 3 days) for remission induction in patients age 50 to 70 years, with an event-free survival (EFS) end point. After two consolidation courses based on intermediate doses of cytarabine, patients in continuous remission were randomly assigned to receive or not receive maintenance therapy with recombinant interleukin-2 (rIL-2; 5 x 10(6) U/m(2) x 5 days each month) for a total duration of 12 months. A total of 468 patients entered the study (median age, 60 years). Results Overall complete remission rate was 77% with significant differences among the three randomization arms (83%, 78%, and 70% in the IDA3, IDA4, and DNR arms, respectively; P = .04). However, no significant differences were observed in relapse incidence, EFS, or overall survival among the three arms. In the 161 patients randomly assigned for maintenance therapy, no difference in outcome was observed between the rIL-2 and the no further treatment arms. CONCLUSION Neither intensification of anthracycline doses nor maintenance with rIL-2 showed a significant impact on AML course, at least as scheduled in this trial.

Remanent dose rates around the collimators of the LHC beam cleaning insertions.

PubMed

Brugger, M; Roesler, S

2005-01-01

The LHC will require an extremely powerful and unprecedented collimation system. As approximately 30% of the LHC beam is lost in the cleaning insertions, these will become some of the most radioactive locations around the entire LHC ring. Thus, remanent dose rates to be expected during later repair or maintenance interventions must be considered in the design phase itself. As a consequence, the beam cleaning insertions form a unique test bed for a recently developed approach to calculate remanent dose rates. A set of simulations, different in complexity, is used in order to evaluate methods for the estimation of remanent dose rates. The scope, as well as the restrictions, of the omega-factor method are shown and compared with the explicit simulation approach. The latter is then used to calculate remanent dose rates in the beam cleaning insertions. Furthermore, a detailed example for maintenance dose planning is given.

Intravenous Iron Supplementation Practices and Short-Term Risk of Cardiovascular Events in Hemodialysis Patients

PubMed Central

Kshirsagar, Abhijit V.; Freburger, Janet K.; Ellis, Alan R.; Wang, Lily; Winkelmayer, Wolfgang C.; Brookhart, M. Alan

2013-01-01

Background & Objectives Intravenous iron supplementation is widespread in the hemodialysis population, but there is uncertainty about the safest dosing strategy. We compared the safety of different intravenous iron dosing practices on the risk of adverse cardiovascular outcomes in a large population of hemodialysis patients. Design settings, participants, & measurements A retrospective cohort was created from the clinical database of a large dialysis provider (years 2004-2008) merged with administrative data from the United States Renal Data System. Dosing comparisons were (1) bolus (consecutive doses ≥ 100 mg exceeding 600 mg during one month) versus maintenance (all other iron doses during the month); and (2) high (> 200 mg over 1 month) versus low dose (≤ 200 mg over 1 month). We established a 6-month baseline period (to identify potential confounders and effect modifiers), a one-month iron exposure period, and a three-month follow-up period. Outcomes were myocardial infarction, stroke, and death from cardiovascular disease. Results 117,050 patients contributed 776,203 unique iron exposure/follow-up periods. After adjustment, we found no significant associations of bolus dose versus maintenance, hazards ratio for composite outcome, 1.03 (95% C.I. 0.99, 1.07), or high dose versus low dose intravenous iron, hazards ratio for composite outcome, 0.99 (95% C.I. 0.96, 1.03). There were no consistent associations of either high or bolus dose versus low or maintenance respectively among pre-specified subgroups. Conclusions Strategies favoring large doses of intravenous iron were not associated with increased short-term cardiovascular morbidity and mortality. Investigation of the long-term safety of the various intravenous iron supplementation strategies may still be warranted. PMID:24223866

A Bayesian Model and Stochastic Exposure (Dose) Estimation for Relative Exposure Risk Comparison Involving Asbestos-Containing Dropped Ceiling Panel Installation and Maintenance Tasks.

PubMed

Boelter, Fred W; Xia, Yulin; Persky, Jacob D

2017-09-01

Assessing exposures to hazards in order to characterize risk is at the core of occupational hygiene. Our study examined dropped ceiling systems commonly used in schools and commercial buildings and lay-in ceiling panels that may have contained asbestos prior to the mid to late 1970s. However, most ceiling panels and tiles do not contain asbestos. Since asbestos risk relates to dose, we estimated the distribution of eight-hour TWA concentrations and one-year exposures (a one-year dose equivalent) to asbestos fibers (asbestos f/cc-years) for five groups of workers who may encounter dropped ceilings: specialists, generalists, maintenance workers, nonprofessional do-it-yourself (DIY) persons, and other tradespersons who are bystanders to ceiling work. Concentration data (asbestos f/cc) were obtained through two exposure assessment studies in the field and one chamber study. Bayesian and stochastic models were applied to estimate distributions of eight-hour TWAs and annual exposures (dose). The eight-hour TWAs for all work categories were below current and historic occupational exposure limits (OELs). Exposures to asbestos fibers from dropped ceiling work would be categorized as "highly controlled" for maintenance workers and "well controlled" for remaining work categories, according to the American Industrial Hygiene Association exposure control rating system. Annual exposures (dose) were found to be greatest for specialists, followed by maintenance workers, generalists, bystanders, and DIY. On a comparative basis, modeled dose and thus risk from dropped ceilings for all work categories were orders of magnitude lower than published exposures for other sources of banned friable asbestos-containing building material commonly encountered in construction trades. © 2016 The Authors Risk Analysis published by Wiley Periodicals, Inc. on behalf of Society for Risk Analysis.

Pharmacokinetic Dashboard-Recommended Dosing Is Different than Standard of Care Dosing in Infliximab-Treated Pediatric IBD Patients.

PubMed

Dubinsky, Marla C; Phan, Becky L; Singh, Namita; Rabizadeh, Shervin; Mould, Diane R

2017-01-01

Standard of care (SOC; combination of 5-10 mg/kg and an interval every 6-8 weeks) dosing of infliximab (IFX) is associated with significant loss of response. Dashboards using covariates that influence IFX pharmacokinetics (PK) may be a more precise way of optimizing anti-TNF dosing. We tested a prototype dashboard to compare forecasted dosing regimens with actual administered regimens and SOC. Fifty IBD patients completing IFX induction were monitored during maintenance (weeks 14-54). Clinical and laboratory data were collected at each infusion; serum was analyzed for IFX concentrations and anti-drug antibodies (ADA) at weeks 14 and 54 (Prometheus Labs, San Diego). Dosing was blinded to PK data. Dashboard-based assessments were conducted on de-identified clinical, laboratory, and PK data. Bayesian algorithms were used to forecast individualized troughs and determine optimal dosing to maintain target trough concentrations (3 μg/mL). Dashboard forecasted dosing post-week 14 was compared to actual administered dose and frequency and SOC. Using week 14 clinical data only, the dashboard recommended either a dose or an interval change (<0.5 mg/kg or <1 week difference) in 43/50 patients; only 44% recommended to have SOC dosing. When IFX14 concentration and ADA status were added to clinical data, dose and/or interval changes based on actual dosing were recommended in 48/50 (96%) patients; SOC dosing was recommended in only 11/50 (22%). Dashboard recommended SOC IFX dosing in a minority of patients. Dashboards will be an important tool to individualize IFX dosing to improve treatment durability.

Maintaining remission in ulcerative colitis – role of once daily extended-release mesalamine

PubMed Central

Oliveira, Lilliana; Cohen, Russell D

2011-01-01

The aminosalicylates (5-ASA; also referred to as mesalamine-based agents) are considered as first-line in the maintenance of remission of mild to moderate ulcerative colitis (UC). Traditionally these agents have required a large pill burden and multiple daily dosing regimens which may account for the low adherence rates, especially in patients in remission. Extended-release mesalamine is the first once daily mesalamine product approved by the Food and Drug Administration for the maintenance of UC remission. This review will examine the pharmacokinetics, dosing, efficacy, and safety data of extended-release mesalamine, and discuss the potential role of improving medication compliance and decreasing costs in UC maintenance. PMID:21448448

Maintaining remission in ulcerative colitis--role of once daily extended-release mesalamine.

PubMed

Oliveira, Lilliana; Cohen, Russell D

2011-02-27

The aminosalicylates (5-ASA; also referred to as mesalamine-based agents) are considered as first-line in the maintenance of remission of mild to moderate ulcerative colitis (UC). Traditionally these agents have required a large pill burden and multiple daily dosing regimens which may account for the low adherence rates, especially in patients in remission. Extended-release mesalamine is the first once daily mesalamine product approved by the Food and Drug Administration for the maintenance of UC remission. This review will examine the pharmacokinetics, dosing, efficacy, and safety data of extended-release mesalamine, and discuss the potential role of improving medication compliance and decreasing costs in UC maintenance.

The role of concomitant methotrexate dosage and maintenance over time in the therapy of rheumatoid arthritis patients treated with adalimumab or etanercept: retrospective analysis of a local registry.

PubMed

Favalli, Ennio Giulio; Becciolini, Andrea; Biggioggero, Martina; Bertoldi, Ilaria; Crotti, Chiara; Raimondo, Maria Gabriella; Marchesoni, Antonio

2018-01-01

To evaluate the pattern of prescription and maintenance over time of concomitant methotrexate (MTX), and its impact on a 2-year clinical response in a cohort of rheumatoid arthritis (RA) patients treated with a first-line tumor necrosis factor alpha inhibitor (TNFi). The study population included all RA patients receiving adalimumab or etanercept a as first-line biologic drug, extracted from a local registry. Enrolled patients were stratified into 3 subgroups according to baseline concomitant MTX: no MTX, low-dose MTX (≤10 mg/wk), and high-dose MTX (≥12.5 mg/wk). The 2-year persistence of the initial MTX regimen was computed by the Kaplan-Meier method, and a Cox proportional hazard model was developed to examine potential predictors of MTX withdrawal/change of dosage. European League Against Rheumatism remission and good-to-moderate response were evaluated according to baseline MTX regimen and MTX maintenance over time. A total of 330 patients (163 treated with adalimumab and 167 with etanercept) were included; 141 were prescribed TNFi without MTX and 112 received low-dose and 77 high-dose concomitant MTX. Male sex, younger age, and shorter mean disease duration were predictors of high-dose MTX use. Among MTX users (76.2% parenteral and 23.8% oral), initial MTX dose persisted over time in 79.9% at 1 year and 70.2% at 2 years. Fifty-one patients (27%) underwent MTX dose de-escalation/discontinuation because of intolerance/adverse events. The 2-year EULAR remission rate was higher in the patients receiving and maintaining high-dose MTX than in those receiving low-dose or no MTX (46.2% vs 29.5% and 23.4%, respectively; p =0.009). The same was true for good-to-moderate response rate (71.2% vs 52.6% and 50.4%, respectively; p =0.031). In a real-life setting, about one-third of RA patients treated with TNFis experienced dose reduction/discontinuation of concomitant MTX because of intolerance/adverse events over a 2-year follow-up period. Initial high-dose MTX and its maintenance over time are associated with better 2-year clinical response.

Dose reduction of risperidone and olanzapine and estimated dopamine D₂ receptor occupancy in stable patients with schizophrenia: findings from an open-label, randomized, controlled study.

PubMed

Takeuchi, Hiroyoshi; Suzuki, Takefumi; Bies, Robert R; Remington, Gary; Watanabe, Koichiro; Mimura, Masaru; Uchida, Hiroyuki

2014-11-01

While acute-phase antipsychotic response has been attributed to 65%-80% dopamine D₂ receptor blockade, the degree of occupancy for relapse prevention in the maintenance treatment of schizophrenia remains unknown. In this secondary study of an open-label, 28-week, randomized, controlled trial conducted between April 2009 and August 2011, clinically stable patients with schizophrenia (DSM-IV) treated with risperidone or olanzapine were randomly assigned to the reduction group (dose reduced by 50%) or maintenance group (dose kept constant). Plasma antipsychotic concentrations at peak and trough before and after dose reduction were estimated with population pharmacokinetic techniques, using 2 collected plasma samples. Corresponding dopamine D₂ occupancy levels were then estimated using the model we developed. Relapse was defined as worsening in 4 Positive and Negative Syndrome Scale-Positive subscale items: delusion, conceptual disorganization, hallucinatory behavior, and suspiciousness. Plasma antipsychotic concentrations were available for 16 and 15 patients in the reduction and maintenance groups, respectively. Estimated dopamine D₂ occupancy (mean ± SD) decreased following dose reduction from 75.6% ± 4.9% to 66.8% ± 6.4% at peak and 72.3% ± 5.7% to 62.0% ± 6.8% at trough. In the reduction group, 10 patients (62.5%) did not demonstrate continuous D₂ receptor blockade above 65% (ie, < 65% at trough) after dose reduction; furthermore, 7 patients (43.8%) did not achieve a threshold of 65% occupancy even at peak. Nonetheless, only 1 patient met our relapse criteria after dose reduction during the 6 months of the study. The results suggest that the therapeutic threshold regarding dopamine D₂ occupancy may be lower for those who are stable in antipsychotic maintenance versus acute-phase treatment. Positron emission tomography studies are warranted to further test our preliminary findings. UMIN Clinical Trials Registry identifier: UMIN000001834. © Copyright 2014 Physicians Postgraduate Press, Inc.

Methadone dose increase and abstinence reinforcement for treatment of continued heroin use during methadone maintenance.

PubMed

Preston, K L; Umbricht, A; Epstein, D H

2000-04-01

Although methadone maintenance is an effective therapy for heroin dependence, some patients continue to use heroin and may benefit from therapeutic modifications. This study evaluated a behavioral intervention, a pharmacological intervention, and a combination of both interventions. Throughout the study all patients received daily methadone hydrochloride maintenance (initially 50 mg/d orally) and weekly counseling. Following baseline treatment patients who continued to use heroin were randomly assigned to 1 of 4 interventions: (1) contingent vouchers for opiate-negative urine specimens (n = 29 patients); (2) methadone hydrochloride dose increase to 70 mg/d (n = 31 patients); (3) combined contingent vouchers and methadone dose increase (n = 32 patients); and (4) neither intervention (comparison standard; n = 28 patients). Methadone dose increases were double blind. Vouchers had monetary value and were exchangeable for goods and services. Groups not receiving contingent vouchers received matching vouchers independent of urine test results. Primary outcome measure was opiate-negative urine specimens (thrice weekly urinalysis). Contingent vouchers and a methadone dose increase each significantly increased the percentage of opiate-negative urine specimens during intervention. Contingent vouchers, with or without a methadone dose increase, increased the duration of sustained abstinence as assessed by urine screenings. Methadone dose increase, with or without contingent vouchers, reduced self-reported frequency of use and self-reported craving. In patients enrolled in a methadone-maintainence program who continued to use heroin, abstinence reinforcement and a methadone dose increase were each effective in reducing use. When combined, they did not dramatically enhance each other's effects on any 1 outcome measure, but they did seem to have complementary benefits.

The dose effects of short-term dronabinol (oral THC) maintenance in daily cannabis users.

PubMed

Vandrey, Ryan; Stitzer, Maxine L; Mintzer, Miriam Z; Huestis, Marilyn A; Murray, Jeannie A; Lee, Dayong

2013-02-01

Prior studies have separately examined the effects of dronabinol (oral THC) on cannabis withdrawal, cognitive performance, and the acute effects of smoked cannabis. A single study examining these clinically relevant domains would benefit the continued evaluation of dronabinol as a potential medication for the treatment of cannabis use disorders. Thirteen daily cannabis smokers completed a within-subject crossover study and received 0, 30, 60 and 120mg dronabinol per day for 5 consecutive days. Vital signs and subjective ratings of cannabis withdrawal, craving and sleep were obtained daily; outcomes under active dose conditions were compared to those obtained under placebo dosing. On the 5th day of medication maintenance, participants completed a comprehensive cognitive performance battery and then smoked five puffs of cannabis for subjective effects evaluation. Each dronabinol maintenance period occurred in a counterbalanced order and was separated by 9 days of ad libitum cannabis use. Dronabinol dose-dependently attenuated cannabis withdrawal and resulted in few adverse side effects or decrements in cognitive performance. Surprisingly, dronabinol did not alter the subjective effects of smoked cannabis, but cannabis-induced increases in heart rate were attenuated by the 60 and 120mg doses. Dronabinol's ability to dose-dependently suppress cannabis withdrawal may be therapeutically beneficial to individuals trying to stop cannabis use. The absence of gross cognitive impairment or side effects in this study supports safety of doses up to 120mg/day. Continued evaluation of dronabinol in targeted clinical studies of cannabis treatment, using an expanded range of doses, is warranted. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

The Dose Effects of Short-Term Dronabinol (Oral THC) Maintenance in Daily Cannabis Users

PubMed Central

Vandrey, Ryan; Stitzer, Maxine L.; Mintzer, Miriam Z.; Huestis, Marilyn A.; Murray, Jeannie A.; Lee, Dayong

2012-01-01

BACKGROUND Prior studies have separately examined the effects of dronabinol (oral THC) on cannabis withdrawal, cognitive performance, and the acute effects of smoked cannabis. A single study examining these clinically relevant domains would benefit the continued evaluation of dronabinol as a potential medication for the treatment of cannabis use disorders. METHODS Thirteen daily cannabis smokers completed a within-subject crossover study and received 0, 30, 60 and 120 mg dronabinol per day for 5 consecutive days. Vital signs and subjective ratings of cannabis withdrawal, craving and sleep were obtained daily; outcomes under active dose conditions were compared to those obtained under placebo dosing. On the 5th day of medication maintenance, participants completed a comprehensive cognitive performance battery and then smoked 5 puffs of cannabis for subjective effects evaluation. Each dronabinol maintenance period occurred in a counterbalanced order and was separated by 9 days of ad-libitum cannabis use. RESULTS Dronabinol dose-dependently attenuated cannabis withdrawal and resulted in few adverse side effects or decrements in cognitive performance. Surprisingly, dronabinol did not alter the subjective effects of smoked cannabis, but cannabis-induced increases in heart rate were attenuated by the 60 and 120 mg doses. CONCLUSIONS Dronabinol’s ability to dose-dependently suppress cannabis withdrawal may be therapeutically beneficial to individuals trying to stop cannabis use. The absence of gross cognitive impairment or side effects in this study supports safety of doses up to 120mg per day. Continued evaluation of dronabinol in targeted clinical studies of cannabis treatment, using an expanded range of doses, is warranted. PMID:22921474

[On Individualization of Therapeutic Doses of Optical Radiation according to Changes in Parameters of Blood Oxygenation].

PubMed

Zalesskaya, G A

2015-01-01

The effect of in vivo laser irradiation by optical radiation on blood from different patients is studied. The objects of research were three series of blood samples from patients whose treatment course included extracorporeal UV blood irradiation, intravenous laser blood irradiation and supra-venous blood laser irradiation. Before and after irradiation the results on optic oximetry and gas content of venous blood were compared. The results of positive and negative influence of blood irradiation on characteristics of an oxygen exchange in separate patients and on the maintenance of some products of metabolism are represented. It is shown that at the same power dose, their changes depend on individual, initial values of hemoglobin oxygen saturation of venous blood and its photoinduced changes which objectively reflect individual sensitivity of patients to the action of optical radiation on blood and can be used for assessment of the efficiency of phototherapy.

Association Between the Lower Extremity Deep Venous Thrombosis, the Warfarin Maintenance Dose, and CYP2C9*3, CYP2D6*10, and CYP3A5*3 Genetic Polymorphisms: A Case-Control Study.

PubMed

Ju, Shang; Gao, Yu; Cao, Xin; Zhang, Xiao-Fu; Yan, Cheng-Cheng; Liu, Feng-Tong

2017-09-01

This study explored the association between the CYP2C9*3/CYP2D6*10/CYP3A5*3 genetic polymorphisms with lower extremity deep venous thrombosis (LEDVT) and the warfarin maintenance dose. Five hundred thirty-six patients who were pathologically diagnosed with LEDVT after surgery were included in the LEDVT group. At the same time, 540 patients without LEDVT who underwent surgery were recruited as the control group. Patients were given warfarin at an initial dose of 2.5-3.0 mg. Blood samples were collected to detect the initial and stable international normalized ratio (INR) values. The warfarin maintenance dose was obtained if the INR remained within a range of 2.0-3.0 for 3 consecutive days. The genotype distribution and haplotype analysis of the CYP2C9*3/CYP2D6*10/CYP3A5*3 alleles were analyzed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) testing and SHEsis software, respectively. Logistic regression analysis was used to analyze the risk and protective factors for LEDVT. The A/G genotypes, G/G genotypes, and G allele of CYP3A5*3 in the LEDVT group were observed with increased frequency compared with the control group. The LEDVT group displayed a higher ACG haplotype frequency, and lower ACA and ATA haplotype frequencies than the control group. Age, diabetes, low-density lipoprotein, CYP3A5*3 and the ACG haplotype were independent risk factors for LEDVT. High-density lipoprotein and the ACA haplotype were independent protective factors for LEDVT. The genotype distributions of the CYP2C9*3, CYP2D6*10, and CYP3A5*3 genetic polymorphisms were associated with the warfarin maintenance dose. The CYP3A5*3 genetic polymorphism may be an important risk factor for LEDVT. Moreover, CYP2C9*3, CYP2D6*10, and CYP3A5*3 are associated with the warfarin maintenance dose.

Evaluation of the reinforcing and subjective effects of heroin in combination with dextromethorphan and quinidine

PubMed Central

Vosburg, Suzanne K.; Sullivan, Maria A.; Comer, Sandra D.

2015-01-01

Objective Studies have suggested that the N-methyl-d-aspartate antagonist dextromethorphan may be useful in the treatment of opioid dependence. Design This double-blinded, placebo-controlled inpatient study evaluated the effects of 0, 30, and 60 mg of dextromethorphan and quinidine (DMQ) on the reinforcing and subjective effects of heroin in recently detoxified heroin abusers. Participants Nine heroin-dependent participants were admitted and then detoxified from heroin over the course of several days. Interventions Participants were subsequently stabilized on 0, 30, or 60 mg of DMQ. Each dose of DMQ was administered for two consecutive weeks, and the effects of heroin (0, 12.5, and 50 mg) were studied under each DMQ maintenance dose condition. DMQ and heroin dose were administered in random order both within and between participants. Results Planned comparisons revealed statistically significant increases in progressive ratio breakpoint values and positive subjective ratings as a function of heroin dose. There were no consistent changes in any of the responses as a function of DMQ maintenance dose, other than a modest reduction in craving. Conclusions In summary, results from this study suggest that maintenance on dextromethorphan in combination with quinidine has a limited role in the treatment of opioid dependence. PMID:22320027

Caffeine Citrate Dosing Adjustments to Assure Stable Caffeine Concentrations in Preterm Neonates.

PubMed

Koch, Gilbert; Datta, Alexandre N; Jost, Kerstin; Schulzke, Sven M; van den Anker, John; Pfister, Marc

2017-12-01

To identify dosing strategies that will assure stable caffeine concentrations in preterm neonates despite changing caffeine clearance during the first 8 weeks of life. A 3-step simulation approach was used to compute caffeine doses that would achieve stable caffeine concentrations in the first 8 weeks after birth: (1) a mathematical weight change model was developed based on published weight distribution data; (2) a pharmacokinetic model was developed based on published models that accounts for individual body weight, postnatal, and gestational age on caffeine clearance and volume of distribution; and (3) caffeine concentrations were simulated for different dosing regimens. A standard dosing regimen of caffeine citrate (using a 20 mg/kg loading dose and 5 mg/kg/day maintenance dose) is associated with a maximal trough caffeine concentration of 15 mg/L after 1 week of treatment. However, trough concentrations subsequently exhibit a clinically relevant decrease because of increasing clearance. Model-based simulations indicate that an adjusted maintenance dose of 6 mg/kg/day in the second week, 7 mg/kg/day in the third to fourth week and 8 mg/kg/day in the fifth to eighth week assures stable caffeine concentrations with a target trough concentration of 15 mg/L. To assure stable caffeine concentrations during the first 8 weeks of life, the caffeine citrate maintenance dose needs to be increased by 1 mg/kg every 1-2 weeks. These simple adjustments are expected to maintain exposure to stable caffeine concentrations throughout this important developmental period and might enhance both the short- and long-term beneficial effects of caffeine treatment. Copyright © 2017 Elsevier Inc. All rights reserved.

A cluster-analytic profiling of heroin-dependent patients based on level, clinical adequacy, and patient-desired adjustment of buprenorphine dosage during buprenorphine-naloxone maintenance treatment in sixteen Spanish centers.

PubMed

Alcaraz, Saul; González-Saiz, Francisco; Trujols, Joan; Vergara-Moragues, Esperanza; Siñol, Núria; Pérez de Los Cobos, José

2018-06-01

Buprenorphine dosage is a crucial factor influencing outcomes of buprenorphine treatment for heroin use disorders. Therefore, the aim of the present study is to identify naturally occurring profiles of heroin-dependent patients regarding individualized management of buprenorphine dosage in clinical practice of buprenorphine-naloxone maintenance treatment. 316 patients receiving buprenorphine-naloxone maintenance treatment were surveyed at 16 Spanish centers during the stabilization phase of this treatment. Patients were grouped using cluster analysis based on three key indicators of buprenorphine dosage management: dose, adequacy according to physician, and adjustment according to patient. The clusters obtained were compared regarding different facets of patient clinical condition. Four clusters were identified and labeled as follows (buprenorphine average dose and percentage of participants in each cluster are given in brackets): "Clinically Adequate and Adjusted to Patient Desired Low Dosage" (2.60 mg/d, 37.05%); "Clinically Adequate and Adjusted to Patient Desired High Dosage" (10.71 mg/d, 29.18%); "Clinically Adequate and Patient Desired Reduction of Low Dosage" (3.38 mg/d, 20.0%); and "Clinically Inadequate and Adjusted to Patient Desired Moderate Dosage" (7.55 mg/d, 13.77%). Compared to patients from the other three clusters, participants in the latter cluster reported more frequent use of heroin and cocaine during last week, lower satisfaction with buprenorphine-naloxone as a medication, higher prevalence of buprenorphine-naloxone adverse effects and poorer psychological adjustment. Our results show notable differences between clusters of heroin-dependent patients regarding buprenorphine dosage management. We also identified a group of patients receiving clinically inadequate buprenorphine dosage, which was related to poorer clinical condition. Copyright © 2018 Elsevier B.V. All rights reserved.

Mycophenolate mofetil as maintenance therapy for childhood-onset systemic lupus erythematosus patients with severe lupus nephritis.

PubMed

Kizawa, Toshitaka; Nozawa, Tomo; Kikuchi, Masako; Nagahama, Kiyotaka; Okudela, Koji; Miyamae, Takako; Imagawa, Tomoyuki; Nakamura, Tomoko; Mori, Masaaki; Yokota, Shumpei; Tsutsumi, Hiroyuki

2015-03-01

We evaluated histological changes occurring in renal biopsy specimens, between the time before initial induction therapy and after 12 months' maintenance therapy, as well as changes in laboratory parameters, SLE disease activity (SLEDAI), and dosage of corticosteroid (CS) in childhood-onset systemic lupus erythematosus (SLE) patients treated with mycophenolate mofetil (MMF). A retrospective analysis was performed on nine patients diagnosed with childhood-onset SLE and lupus nephritis. They were treated with pulsed mPSL and intravenous cyclophosphamide as induction therapy and MMF (500-1500 mg/day) plus CS as maintenance therapy. Renal biopsy was performed before the initial induction therapy and after 12 months' maintenance therapy. Pathological findings at second biopsy were improved in eight of nine patients (89%). The findings of SLEDAI, urinalysis, and blood tests also showed improvement. CS doses could be tapered satisfactorily. Adverse events were observed in two patients. No patients treated with MMF experienced any disease flares during maintenance therapy. MMF as maintenance therapy might be useful in that not only the histological findings of lupus nephritis were improved, but also CS doses could be beneficially tapered. Nonetheless, this is a retrospective report of only nine cases and further prospective multicenter studies are necessary.

Adjunctive lacosamide for focal epilepsy: an open-label trial evaluating the impact of flexible titration and dosing on safety and seizure outcomes.

PubMed

Baulac, Michel; Coulbaut, Safia; Doty, Pamela; McShea, Cindy; De Backer, Marc; Bartolomei, Fabrice; Vlaicu, Mihaela

2017-06-01

To evaluate the safety and effectiveness of lacosamide in a real-life setting with the use of a flexible dose titration schedule and individualised maintenance doses up to the maximum approved dose of 400 mg/day. Adults with a diagnosis of focal seizures, with or without secondary generalization, were enrolled in this open-label Phase IV trial (NCT01235403). Lacosamide was initiated at 100 mg/day (50 mg bid) and uptitrated over a 12-week period to 200, 300 or 400 mg/day, based on safety and seizure control. Although dose increases were to be in increments of 100 mg/day, intermediate doses were permitted at each escalation step for one week for patients known to be particularly sensitive to starting new AEDs. After receiving a stable, effective dose for three weeks, patients entered the 12-week maintenance period. Primary outcomes were incidence of treatment-emergent adverse events (TEAEs) and withdrawal due to TEAEs. Seizure outcomes, all secondary, were median focal seizure frequency, ≥50% reduction in focal seizure frequency, and seizure freedom. One hundred patients with a mean age of 44 years were enrolled and 74 completed the trial. The incidence of TEAEs was 64.0% (n=100), with the most frequently reported (≥5% of patients) being dizziness, headache, and asthenia. Fourteen patients withdrew due to TEAEs, most frequently due to dizziness (six patients; 6.0%), vomiting (two patients; 2%), and tremor (two patients; 2%). Among patients with baseline and maintenance phase seizure data (n=75), median reduction in focal seizure frequency from baseline was 69.7% and the ≥50% responder rate was 69.3%. Among 74 patients who completed the maintenance phase, 21 (28.4%) were seizure-free. Flexible lacosamide dosing in this open-label trial was associated with a favourable tolerability and safety profile; the nature of the TEAEs was consistent with that observed in previous pivotal trials. Treatment with lacosamide was also associated with effective seizure control.

Time-Dependent Decline in Serum Phenytoin Concentration with Heightened Convulsive Seizure Risk by Prolonged Administration of Fosphenytoin in Japanese: A Retrospective Study.

PubMed

Ohno, Yuta; Niwa, Takashi; Hirai, Keita; Suzuki, Keiko; Yamada, Yuto; Hayashi, Yuichi; Hayashi, Hideki; Suzuki, Akio; Itoh, Yoshinori

2018-04-20

Because clinical data to confirm the safety and effectiveness of fosphenytoin, a prodrug of phenytoin, are insufficient, the length of administration of fosphenytoin is restricted. Nevertheless, some cases require fosphenytoin administration for more than a few days. The aim of this study was to retrospectively investigate the serum concentration of phenytoin in adult Japanese patients who received intravenous fosphenytoin therapy for more than 3 days. Patients injected with intravenous fosphenytoin for more than 3 days at Gifu University Hospital between January 2012 and September 2014 were enrolled. Individual pharmacokinetic parameters were predicted by Bayesian estimation using NONMEM software, and the maintenance dose of fosphenytoin required to maintain the therapeutic trough concentration (10-20 μg/mL) was calculated from the parameters. Among a total of 8 patients, the serum trough concentration of phenytoin decreased with each day after repeated injection of fosphenytoin. The incidence rate of significant convulsive seizures was increased time-dependently (0% on day 1, 12.5% on day 2, 25% on day 3, and 66.7% on day 4 and after). Phenytoin clearance showed a time-dependent increase. The maintenance dose of fosphenytoin required to maintain the therapeutic trough concentration was simulated to be 779.8 ± 316.8 mg/day, a dose that was markedly higher than the actual maintenance dose (414.1 ± 55.7 mg/day). Prolonged use of fosphenytoin for such patients as those with autoimmune-mediated encephalopathy accompanied with reflux disease and/or ileus time-dependently decreased the serum concentration of phenytoin and increased the risk of convulsion. Therefore, the maintenance dose should be increased to maintain the therapeutic serum concentration.

A review of protocols for 308 nm excimer laser phototherapy in psoriasis.

PubMed

Mudigonda, Tejaswi; Dabade, Tushar S; Feldman, Steven R

2012-01-01

308 nm excimer laser phototherapy is efficacious in the treatment of localized psoriasis. Different approaches regarding dose fluency, number of treatments, and maintenance have been utilized, and there is yet to be a consensus on standard protocol. To characterize treatment parameters for 308 nm excimer laser phototherapy. We performed a PubMed search for studies describing excimer laser treatment protocol with particular attention to dosage determination, dose adjustment, dose fluency, number of treatments, and maintenance. Seven prospective studies were found describing the excimer efficacy for psoriasis. All studies determined the initial treatment dose using either the minimal erythema dose (MED) or induration. Fluency ranged from 0.5 MED (low) to 16 MED (high); one study demonstrated that medium to high fluencies yielded better improvement in fewer number of treatments. Fluency adjustments during the course of treatment were important to minimize phototherapy-associated side effects. The use of higher fluencies was reported to result in higher occurrences of blistering. One study implemented a maintenance tapering of dose-frequency phase to better manage psoriasis flare-ups. The 308 nm excimer laser is an effective therapy for psoriasis regardless of the method used to determine initial dosage, dose fluency, or number of treatments. As its usage as a targeted monotherapy increases, future trials should consider evaluating and modifying these parameters to determine the most optimal management of localized psoriasis. Based on our reviewed studies, there is no consensus for a single excimer laser therapy protocol and as a result, patient preferences should continue to be an important consideration for phototherapy regimen planning.

Acinetobacter Prosthetic Joint Infection Treated with Debridement and High-Dose Tigecycline.

PubMed

Vila, Andrea; Pagella, Hugo; Amadio, Claudio; Leiva, Alejandro

2016-12-01

Prosthesis retention is not recommended for multidrug-resistant Acinetobacter prosthetic joint infection due to its high failure rate. Nevertheless, replacing the prosthesis implies high morbidity and prolonged hospitalization. Although tigecycline is not approved for the treatment of prosthetic joint infection due to multidrug resistant Acinetobacter baumannii, its appropriate use may preclude prosthesis exchange. Since the area under the curve divided by the minimum inhibitory concentration is the best pharmacodynamic predictor of its efficacy, we used tigecycline at high dose, in order to optimize its efficacy and achieve implant retention in 3 patients who refused prosthesis exchange. All patients with prosthetic joint infections treated at our Institution are prospectively registered in a database. Three patients with early prosthetic joint infection of total hip arthroplasty due to multidrug resistant A. baumannii were treated with debridement, antibiotics and implant retention, using a high maintenance dose of tigecycline (100 mg every 12 hours). The cases were retrospectively reviewed. All patients signed informed consent for receiving off-label use of tigecycline. Tigecycline was well tolerated, allowing its administration at high maintenance dose for a median of 40 days (range 30-60). Two patients were then switched to minocycline at standard doses for a median of 3.3 months in order to complete treatment. Currently, none of the patients showed relapse. Increasing the dose of tigecycline could be considered as a means to better attain pharmacodynamic targets in patients with severe or difficult-to-treat infections. Tigecycline at high maintenance dose might be useful when retention of the implant is attempted for treatment for prosthetic joint infections due to multidrug resistant Acinetobacter. Although this approach might be promising, off-label use of tigecycline should be interpreted cautiously until prospective data are available. Tigecycline is probably under-dosed for the treatment of implant and biofilm associated infections.

Once daily vs multiple daily mesalamine therapy for mild to moderate ulcerative colitis: a meta-analysis.

PubMed

Li, W; Zhang, Z-M; Jiang, X-L

2016-07-01

5-Aminosalicylic acid is the first-line drug for mild to moderate ulcerative colitis (UC). The most commonly used 5-aminosalicylic acid is mesalamine. Several systematic reviews have demonstrated that mesalamine is effective in inducing and maintaining remission. Efficacy, safety and adherence to once daily (OD) and multiple daily (MD) dosing of mesalamine for the induction and maintenance of remission in mild to moderate UC were systematically reviewed and compared. PubMed, Embase and the Cochrane Central Register of Controlled Trials were searched from inception to November 2014. Only randomized controlled trials were considered eligible. STATA software (version 12.0) was used to calculate the pooled risk ratios with 95% confidence interval. Seventeen randomized studies containing 5439 patients were identified. No significant differences were noted in comparisons between OD and MD dosing for maintenance and induction of remission. No significant differences were noted in rates of medication adherence or adverse events between OD and MD dosing. With regard to mesalamine suppository, no significant differences were noted for comparisons between dosing regimens and adverse events for induction of remission. OD dose of mesalamine is as effective and safe as MD doses for the induction and maintenance treatment of mild to moderate UC. OD mesalamine given as a suppository can attain the same effect and safety as MD mesalamine in inducing remission of mild to moderate ulcerative colitis. Colorectal Disease © 2016 The Association of Coloproctology of Great Britain and Ireland.

Occupational doses and ALARA - recent developments in Sweden

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

Godas, T.; Viktorsson, C.

1995-03-01

Sweden has traditionally experienced very slow doses to workers in the nuclear industry. However, this trend has since last year been broken mainly due to significant maintenance and repair work. This paper will describe occupational dose trends in Sweden and discuss actions that are being implemented to control this new situation.

Maintenance Management Update.

ERIC Educational Resources Information Center

Sternloff, Robert E.

1987-01-01

Current trends in park maintenance are overviewed, including maintenance impact statements, avoidance of cost through efficient use and national resource conservation, horticultural accomplishments that influence maintenance management, and vandalism prevention. (CB)

SLCO1B1 Polymorphisms are Associated With Drug Intolerance in Childhood Leukemia Maintenance Therapy.

PubMed

Eldem, İrem; Yavuz, Duygu; Cumaoğullari, Özge; İleri, Talia; Ünal İnce, Elif; Ertem, Mehmet; Doğanay Erdoğan, Beyza; Bindak, Recep; Özdağ, Hilal; Şatiroğlu-Tufan, N Lale; Uysal, L Zümrüt

2018-04-20

Therapy discontinuations and toxicities occur because of significant interindividual variations in 6-mercaptopurine (6-MP) and methotrexate (MTX) response during maintenance therapy of childhood acute lymphoblastic leukemia (ALL). 6-MP/MTX intolerance in some of the patients cannot be explained by thiopurine S-methyl transferase (TPMT) gene variants. In this study, we aimed to investigate candidate pharmacogenetic determinants of 6-MP and MTX intolerance in Turkish ALL children. In total, 48 children with ALL who had completed or were receiving maintenance therapy according to Children's Oncology Group (COG) protocols were enrolled. Fifteen single-nucleotide polymorphisms in 8 candidate genes that were related to drug toxicity or had a role in the 6-MP/MTX metabolism (TPMT, ITPA, MTHFR, IMPDH2, PACSIN2, SLCO1B1, ABCC4, and PYGL) were genotyped by competitive allele-specific PCR (KASP). Drug doses during maintenance therapy were modified according to the protocol. The median drug dose intensity was 50% (28% to 92%) for 6-MP and 58% (27% to 99%) for MTX in the first year of maintenance therapy, which were lower than that scheduled in all patients. Among the analyzed polymorphisms, variant alleles in SLCO1B1 rs4149056 and rs11045879 were found to be associated with lower 6-MP/MTX tolerance. SLCO1B1 rs4149056 and rs11045879 polymorphisms may be important genetic markers to individualize 6-MP/MTX doses.

Estimation of dynamic treatment strategies for maintenance therapy of children with acute lymphoblastic leukaemia: an application of history-adjusted marginal structural models.

PubMed

Rosthøj, S; Keiding, N; Schmiegelow, K

2012-02-28

Childhood acute lymphoblastic leukaemia is treated with long-term intensive chemotherapy. During the latter part of the treatment, the maintenance therapy, the patients receive oral doses of two cytostatics. The doses are tailored to blood counts measured on a weekly basis, and the treatment is therefore highly dynamic. In 1992-1996, the Nordic Society of Paediatric Haematology and Oncology (NOPHO) conducted a randomised study (NOPHO-ALL-92) to investigate the effect of a new and more sophisticated dynamic treatment strategy. Unexpectedly, the new strategy worsened the outcome for the girls, whereas there were no treatment differences for the boys. There are as yet no general guidelines for optimising the treatment. On basis of the data from this study, our goal is to formulate an alternative dosing strategy. We use recently developed methods proposed by van der Laan et al. to obtain statistical models that may be used in the guidance of how the physicians should assign the doses to the patients to obtain the target of the treatment. We present a possible strategy and discuss the reliability of this strategy. The implementation is complicated, and we touch upon the limitations of the methods in relation to the formulation of alternative dosing strategies for the maintenance therapy. Copyright © 2011 John Wiley & Sons, Ltd.

Phenytoin pharmacokinetics in critically ill trauma patients.

PubMed

Boucher, B A; Rodman, J H; Jaresko, G S; Rasmussen, S N; Watridge, C B; Fabian, T C

1988-12-01

Preliminary data have suggested that phenytoin systemic clearance may increase during initial therapy in critically ill patients. The objectives for this study were to model the time-variant phenytoin clearance and evaluate concomitant changes in protein binding and urinary metabolite elimination. Phenytoin was given as an intravenous loading dose of 15 mg/kg followed by an initial maintenance dose of 6 mg/kg/day in 10 adult critically ill trauma patients. Phenytoin bound and unbound plasma concentrations were determined in 10 patients and urinary excretion of the metabolite p-hydroxyphenyl phenylhydantoin (p-HPPH) was measured in seven patients for 7 to 14 days. A Michaelis-Menten one-compartment model incorporating a time-variant maximal velocity (Vmax) was sufficient to describe the data and superior to a conventional time-invariant Michaelis-Menten model. Vmax for the time-variant model was defined as V'max + Vmax delta (1 - e(-kindt)). Vmax infinity is the value for Vmax when t is large. The median values (ranges) for the parameters were Km = 4.8 (2.6 to 20) mg/L, Vmax infinity = 1348 (372 to 4741) mg/day, and kind = 0.0115 (0.0045 to 0.132) hr-1. Phenytoin free fraction increased in a majority of patients during the study period, with a binding ratio inversely related to albumin. Measured urinary p-HPPH data were consistent with the proposed model. A loading and constant maintenance dose of phenytoin frequently yielded a substantial, clinically significant fall in plasma concentrations with a pattern of apparently increasing clearance that may be a consequence of changes in protein binding, induction of metabolism, or the influence of stress on hepatic metabolic capacity.

High-dose Versus Low-dose Tranexamic Acid to Reduce Transfusion Requirements in Pediatric Scoliosis Surgery.

PubMed

Johnson, Daniel J; Johnson, Christine C; Goobie, Susan M; Nami, Nina; Wetzler, Joshua A; Sponseller, Paul D; Frank, Steven M

2017-12-01

Our objective was to quantify blood loss and transfusion requirements for high-dose and low-dose tranexamic acid (TXA) dosing regimens in pediatric patients undergoing spinal fusion for correction of idiopathic scoliosis. Previous investigators have established the efficacy of TXA in pediatric scoliosis surgery; however, the dosing regimens vary widely and the optimal dose has not been established. We retrospectively analyzed electronic medical records for 116 patients who underwent spinal fusion surgery for idiopathic scoliosis by a single surgeon and were treated with TXA. In total, 72 patients received a 10 mg/kg loading dose with a 1 mg/kg/h maintenance dose (low-dose) and 44 patients received 50 mg/kg loading dose with a 5 mg/kg/h maintenance dose (high-dose). Estimated blood loss and transfusion requirements were compared between dosing groups. Patient characteristics were nearly identical between the 2 groups. Compared with the low-dose TXA group, the high-dose TXA group had decreased estimated blood loss (695 vs. 968 mL, P=0.01), and a decrease in both intraoperative (0.3 vs. 0.9 units, P=0.01) and whole hospitalization (0.4 vs. 1.0 units, P=0.04) red blood cell transfusion requirements. The higher-dose TXA was associated with decreased intraoperative (P=0.01), and whole hospital transfusion (P=0.01) requirements, even after risk-adjustment for potential confounding variables. High-dose TXA is more effective than low-dose TXA in reducing blood loss and transfusion requirements in pediatric idiopathic scoliosis patients undergoing surgery. Level-III, retrospective cohort study.

[Is Herceptin(®) (trastuzumab) by subcutaneous a mini revolution? Pharmaco-economic study].

PubMed

Lieutenant, Vincent; Toulza, Émilie; Pommier, Martine; Lortal-Canguilhem, Barbara

2015-03-01

Herceptin(®) injected by intravenous (IV) is one of the key treatment of breast cancer HER2+. The improvement of galenic form allowed a new way of administration, the sub-cutaneous way (SC), authorized by EMEA in 2013. This new way enables a 5-minute infusion, a fixed dose and a fixed volume of preparation. On 2012, saving-time and financial impacts were calculated by extrapolation of the IV way in a cancer treatment center. The study showed a preparing time-saving of 7.5min/loading dose and of 6.5min/maintenance dose, and a nurse time-saving of 4.5min/loading dose and 4.25min/maintenance dose. Moreover, it can be added a saving of consumable of 13,31€ per injection in case of monotherapy. The SC leads to a new adaptation and reorganization in the preparation of monoclonal antibodies and day hospitals. Copyright © 2015 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

Efficacy and safety of once-daily, extended-release hydrocodone in individuals previously receiving hydrocodone/acetaminophen combination therapy for chronic pain.

PubMed

Bartoli, Adrian; Michna, Edward; He, Ellie; Wen, Warren

2015-01-01

Hydrocodone/acetaminophen combination analgesics are frequently prescribed for chronic pain management; however, acetaminophen presents potential hepatotoxicity to patients and thus dose limitations. These opioid medications are also widely abused. Once-daily, single-entity hydrocodone (Hysingla™ ER tablets [HYD]) is a novel formulation with abuse-deterrent properties for the management of chronic pain and represents a suitable option for those patients receiving analgesics containing the same opioid analgesic, hydrocodone. This post-hoc analysis evaluated the efficacy and safety of HYD in patients whose primary pre-study analgesic was hydrocodone/acetaminophen analgesics (23-31% of the study populations). Data were analyzed from two Phase III trials, a 12-week randomized, placebo-controlled trial (RCT) and an open-label, 52-week trial. In both trials, a dose-titration period with HYD was followed by respective periods of fixed-dose double-blind (randomized controlled trial [RCT]) or open-label, flexible-dose maintenance treatment. Pain intensity was assessed using a numerical rating scale (0-10, 0 = no pain). For the RCT, primary and sensitivity analyses of pain scores used different approaches to handle missing data. Safety data for both studies were summarized. In the RCT, the mean baseline pain score was 7.3. Pain relief was greater with HYD than placebo during double-blind treatment. In the open-label, flexible-dose trial, the majority of patients were maintained on their titrated dose. Mean baseline pain score was 6.3, about 57% of patients completed the 1-year maintenance period, and mean pain scores were between 3.6 and 4.1 during the maintenance period. Use of supplemental pain medication decreased or was maintained during the maintenance treatment with HYD. Adverse events in both trials were typical of those associated with opioid analgesics. In patients whose primary pretrial analgesic was hydrocodone/acetaminophen combination tablets, single-entity HYD was effective in reducing pain intensity and in maintaining analgesia over time without need for continued dose increase. HYD's safety and tolerability profiles were similar to other opioid analgesics.

21 CFR 522.2005 - Propofol injection.

Code of Federal Regulations, 2010 CFR

2010-04-01

... indicated for use as an anesthetic as follows: As a single injection to provide general anesthesia for procedures lasting up to 5 minutes; for induction and maintenance of general anesthesia using incremental doses to effect; for induction of general anesthesia where maintenance is provided by inhalant...

Early and late benefits of prasugrel in patients with acute coronary syndromes undergoing percutaneous coronary intervention: a TRITON-TIMI 38 (TRial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet InhibitioN with Prasugrel-Thrombolysis In Myocardial Infarction) analysis.

PubMed

Antman, Elliott M; Wiviott, Stephen D; Murphy, Sabina A; Voitk, Juri; Hasin, Yonathan; Widimsky, Petr; Chandna, Harish; Macias, William; McCabe, Carolyn H; Braunwald, Eugene

2008-05-27

We evaluated the relative contributions of the loading and maintenance doses of prasugrel on events in a TRITON-TIMI 38 (TRial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet InhibitioN with Prasugrel-Thrombolysis In Myocardial Infarction) analysis. Prasugrel is superior to clopidogrel in preventing ischemic events in patients with an acute coronary syndrome who are undergoing percutaneous coronary intervention, but it is associated with an increased risk of major bleeding. Landmark analyses for efficacy, safety, and net clinical benefit were performed from randomization to day 3 and from day 3 to the end of the trial. Significant reductions in ischemic events, including myocardial infarction, stent thrombosis, and urgent target vessel revascularization, were observed with the use of prasugrel both during the first 3 days and from 3 days to the end of the trial. Thrombolysis In Myocardial Infarction major non-coronary artery bypass graft bleeding was similar to clopidogrel during the first 3 days but was significantly greater with the use of prasugrel from 3 days to the end of the study. Net clinical benefit significantly favored prasugrel both early and late in the trial. Both the loading dose and maintenance dose of prasugrel were superior to clopidogrel for the reduction of ischemic events. This result emphasizes the importance of maintaining high levels of inhibition of platelet aggregation via P2Y(12) receptor inhibition, not only for the prevention of periprocedural ischemic events but also during long-term follow-up. The excess major bleeding observed with the use of prasugrel occurred predominantly during the maintenance phase. Approaches to reduce the relative excess of bleeding with prasugrel should focus on the maintenance dose (e.g., reduction in maintenance dose in previously reported high-risk subgroups, such as the elderly and those patients with low body weight). (A Comparison of CS-747 and Clopidogrel in Acute Coronary Syndrome Subjects Who Are to Undergo Percutaneous Coronary Intervention; NCT00097591).

Once daily oral mesalamine compared to conventional dosing for induction and maintenance of remission in ulcerative colitis: a systematic review and meta-analysis.

PubMed

Feagan, Brian G; MacDonald, John K

2012-09-01

We systematically reviewed and compared the efficacy and safety of once daily (OD) mesalamine to conventional dosing for induction and maintenance of remission in ulcerative colitis (UC). A literature search to January 2012 identified all applicable randomized trials. Study quality was evaluated using the Cochrane risk of bias tool. The GRADE criteria were used to assess the overall quality of the evidence. Studies were subgrouped by formulation for meta-analysis. Eleven studies that evaluated 4070 patients were identified. The risk of bias was low for most factors, although five studies were single-blind and one was open-label. No difference was observed between the dosing strategies in the proportion of patients with clinical remission (relative risk [RR] 0.95; 95% confidence interval [CI] 0.82-1.10), clinical improvement (RR 0.87 95% CI 0.68-1.10), or relapse at 6 (RR 1.10; 95% CI 0.83-1.46) or 12 months (RR 0.92; 95% CI 0.83-1.03). Subgroup analyses showed no important differences in efficacy. No significant difference was demonstrated in rates of medication adherence or adverse events between OD and conventional dosing. OD mesalamine appears to be as effective and safe as conventional dosing for both the treatment of mild to moderately active UC and for maintenance of remission in quiescent UC. The failure to demonstrate a superior rate of adherence to OD dosing may be due to the high rate of adherence observed in the clinical trials environment. Future research should assess the value of OD dosing in community settings. Copyright © 2012 Crohn's & Colitis Foundation of America, Inc.

Exposure of infants to budesonide through breast milk of asthmatic mothers.

PubMed

Fält, Anette; Bengtsson, Thomas; Kennedy, Britt-Marie; Gyllenberg, Ann; Lindberg, Bengt; Thorsson, Lars; Stråndgarden, Kerstin

2007-10-01

Maintenance treatment with inhaled corticosteroids is often required for asthmatic nursing women. Data on the transfer of inhaled corticosteroids from plasma to breast milk and the subsequent exposure of the breast-feeding infant has been unavailable. We sought to assess budesonide concentrations in milk and plasma of asthmatic nursing women receiving maintenance treatment with the Pulmicort Turbuhaler and estimate the exposure of their breast-fed infants. Milk and plasma samples were collected up to 8 hours after dosing from 8 mothers receiving budesonide maintenance treatment (200 or 400 microg twice daily). Pharmacokinetic parameters were calculated from budesonide milk and plasma concentrations. Infant exposure was estimated based on average milk budesonide concentrations. A single blood sample was obtained from 5 infants close to expected infant maximum concentration. Budesonide concentrations in milk reflected those in maternal plasma, supporting passive diffusion of budesonide between plasma and milk, and was always lower than that in plasma. The mean milk/plasma ratio was 0.46. The estimated daily infant dose was 0.3% of the daily maternal dose for both dose levels, and the average plasma concentration in infants was estimated to be 1/600th of the concentrations observed in maternal plasma, assuming complete infant oral bioavailability. Budesonide concentrations in infant plasma samples were all less than the limit of quantification. Maintenance treatment with inhaled budesonide (200 or 400 microg twice daily) in asthmatic nursing women results in negligible systemic exposure to budesonide in breast-fed infants. These data support continued use of inhaled budesonide during breast-feeding.

Influence of Herbicide Triasulfuron on Soil Microbial Community in an Unamended Soil and a Soil Amended with Organic Residues

PubMed Central

Pose-Juan, Eva; Igual, José M.; Sánchez-Martín, María J.; Rodríguez-Cruz, M. S.

2017-01-01

The effect of organic amendments and pesticides on a soil microbial community has garnered considerable interest due to the involvement of microorganisms in numerous soil conservation and maintenance reactions. The aim of this work was to assess the influence on a soil microbial community of the simultaneous application of the herbicide triasulfuron at three doses (2, 10, and 50 mg kg-1), with an organic amendment [sewage sludge (SS) or green compost (GC)]. Dissipation kinetics, soil microbial biomass, dehydrogenase activity (DHA) and respiration, and the profile of phospholipid fatty acids (PLFAs) extracted from the soil, were determined in unamended (S) soil and amended (S+SS and S+GC) ones. Triasulfuron dissipation followed the single first-order kinetics model. Half-life (DT50) values were higher in the amended soils than in the unamended one for the 10 and 50 mg kg-1 doses. The dissipation rates were lower in the S+GC soil for the three herbicide doses applied. In general, soil biomass, DHA and respiration values increased in SS- and GC-amended soils compared to the unamended one. DHA values decreased (S and S+SS) or increased (S+GC) with the incubation time of soil with herbicide at the different doses applied. Respiration values increased with the herbicide doses applied and decreased with the incubation time, although maximum values were obtained for soils treated with the highest dose after 70 days of incubation. PLFA analysis indicated different effects of triasulfuron on the soil microbial community structure depending on the organic amendments. While the increasing triasulfuron doses resulted in deeper alterations in the S soil, the time after triasulfuron application was the most important variation in the S+SS and S+GC soils. The overall results indicate that the soil amendment has an effect on herbicide dissipation rate and the soil microbial community. Initially, a high dose of triasulfuron had detrimental effects on the soil microbial community, which is important in the case of the long-term use of this compound. PMID:28337188

Thalidomide treatment in cutaneous lesions of systemic lupus erythematosus: a multicenter study in China.

PubMed

Wang, Dandan; Chen, Haifeng; Wang, Shiying; Zou, Yaohong; Li, Jing; Pan, Jieping; Wang, Xiangdang; Ren, Tianli; Zhang, Yu; Chen, Zhiwei; Feng, Xuebing; Sun, Lingyun

2016-06-01

Thalidomide is effective for treating severe cutaneous lupus patients. The aim of this study was to observe the optimum effective and maintenance doses of thalidomide to maximize clinical benefit and minimize side effects for patients with cutaneous lupus in China. Sixty-nine patients with lupus rash from eight hospitals in China were enrolled and treated with different doses of thalidomide. We started the dose of thalidomide at 25 mg daily and gradually increased administration dose once a week until erythema was markedly improved. The effective and maintenance doses were documented. The size of skin lesions was noted once a week. Systemic lupus erythematosus disease activity index (SLEDAI) score, levels of erythrocyte sedimentation rate (ESR), and serum TNF-α were measured before and after treatment. The remission rates were evaluated weekly until 8 weeks. Sixty-eight percent of patients showed an effective dose of 50 mg daily; another 13, 10, and 9 % of patients had an effective dose of 100, 75, and 25 mg daily, respectively. The maintenance dose was 50 mg daily for 71 % of the patients, and 100, 75, and 25 mg daily for 9, 14, and 6 % of the patients. SLEDAI score and serum ESR levels significantly decreased 4 weeks after thalidomide treatment. At the end of the fourth week, the rates of complete remission, partial remission, and no response were 56 % (n = 39), 41 % (n = 28), and 3 % (n = 2). At the eighth week, the rate of total remission rose up to 100 %. The most common side effects were drowsiness and constipation. No peripheral neuropathy was observed in these patients. Thalidomide at a dose of 50 mg daily may offer a better benefit to risk ratio in the treatment of Chinese cutaneous lupus patients.

[Definition of parameters of the condition of oxidizing stress in smooth muscle cells under influence of exogenous nitroso-glutatyon in vitro].

PubMed

Kapilevich, L V; Nosarev, A V; D'iakova, E Iu; Andrushkevich, V V; Nasedkina, A K; Nosareva, O L; Davlet'iarova, K V; Ogorodova, L M; Kovalev, I V; Baskakov, M B; Medvedev, M A

2007-08-01

Influence of exogenous nitroso-glutatyon on intensity of oxidizing processes in smooth muscles of colon and bronchial tubes in intact and atopic sensitised porpoises (guinea pigs) was studied. In sensitised porpoises, antioxidant protection has been initially reduced against the background of increased maintenance of products of oxidizing that reflects a picture of oxidizing damage and can be associated with an inflammatory process. In incubation with nitroso-glutatyon, a decrease in activities of syperoxiddismutase and catalase is marked and, in sensitised animals, this effect has been expressed to a lesser degree. Syperoxiddismutase and catalase are antioxidant for the enzymes participating in protection of cells from free-radical damage. A dose-dependence decrease in activity catalase and syperoxiddismutase is defined by a parity of the enzymes participating in disintegration of nitrosoglutatyon and the enzymes which have kept antioxidant activity.

A Randomized, Placebo-Controlled Study of High-Dose Baclofen in Alcohol-Dependent Patients-The ALPADIR Study.

PubMed

Reynaud, Michel; Aubin, Henri-Jean; Trinquet, Francoise; Zakine, Benjamin; Dano, Corinne; Dematteis, Maurice; Trojak, Benoit; Paille, Francois; Detilleux, Michel

2017-07-01

Alcohol dependence is a major public health issue with a need for new pharmacological treatments. The ALPADIR study assessed the efficacy and safety of baclofen at the target dose of 180 mg/day for the maintenance of abstinence and the reduction in alcohol consumption in alcohol-dependent patients. Three hundred and twenty adult patients (158 baclofen and 162 placebo) were randomized after alcohol detoxification. After a 7-week titration, the maintenance dose was provided for 17 weeks, then progressively decreased over 2 weeks before stopping. The percentage of abstinent patients during 20 consecutive weeks (primary endpoint) was low (baclofen: 11.9%; placebo: 10.5%) and not significantly different between groups (OR 1.20; 95%CI: 0.58 to 2.50; P = 0.618). A reduction in alcohol consumption was observed from month 1 in both groups, but the difference of 10.9 g/day at month 6 between groups, in favour of baclofen, was not statistically significant (P = 0.095). In a subgroup of patients with high drinking risk level at baseline, the reduction was greater with a difference at month 6 of 15.6 g/day between groups in favour of baclofen (P = 0.089). The craving assessed with Obsessive-Compulsive Drinking Scale significantly decreased in the baclofen group (P = 0.017). No major safety concern was observed. This study did not demonstrate the superiority of baclofen in the maintenance of abstinence at the target dose of 180 mg/day. A tendency towards a reduction in alcohol consumption and a significantly decreased craving were observed in favour of baclofen. Baclofen was assessed versus placebo for maintenance of abstinence and reduction in alcohol consumption in alcohol-dependent patients. This study did not demonstrate the superiority of baclofen in the maintenance of abstinence. A tendency towards a reduction in alcohol consumption and a significantly decreased craving were observed in favour of baclofen. © The Author 2017. Medical Council on Alcohol and Oxford University Press. All rights reserved.

Initial Results of a Phase I Dose-Escalation Trial of Concurrent and Maintenance Erlotinib and Reirradiation for Recurrent and New Primary Head-and-Neck Cancer

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

Rusthoven, Kyle E.; Feigenberg, Steven J.; Raben, David

2010-11-15

Purpose: To present the first report of a Phase I trial evaluating concurrent and maintenance erlotinib and reirradiation in patients with recurrent or secondary primary head-and-neck cancer (HNC). Methods and Materials: Patients with recurrent or new primary HNC with an interval of at least 6 months since prior radiation were eligible. Patients were treated in 3 sequential cohorts: Cohort I, 100 mg of erlotinib daily with reirradiation at 61.6 Gy in 28 fractions; Cohort II, 150 mg of erlotinib with 61.6 Gy in 28 fractions; and Cohort III, 150 mg of erlotinib with 66 Gy in 30 fractions. Maintenance erlotinibmore » started immediately after reirradiation at 150 mg daily and was continued for 2 years or until disease progression or dose-limiting toxicity. Dose-limiting toxicities were defined as any Grade 4 or 5 toxicity or a toxicity-related delay in radiation therapy of greater than 7 days. Results: Fourteen patients were accrued, 3 to Cohort I, 4 to Cohort II, and 7 to Cohort III. Thirteen patients were evaluable for toxicity. Median follow-up was 8.4 months overall and 15.1 months for surviving patients. One patient had a dose-limiting toxicity in Cohort III. This patient declined initial percutaneous endoscopic gastrostomy tube placement, was hospitalized with Grade 3 dysphagia and aspiration, and required a delay in radiation therapy of greater than 7 days. No Grade 4 acute toxicity was observed. Acute Grade 3 toxicity occurred in 9 of 13 patients. No erlotinib-related toxicity of Grade 3 or greater was observed during maintenance therapy. One patient had Grade 5 carotid hemorrhage 6 months after reirradiation, and another patient had Grade 3 osteoradionecrosis. Conclusions: Reirradiation (66 Gy in 2.2 Gy fractions) with concurrent and maintenance erlotinib (150 mg daily) for recurrent or new primary HNC is feasible.« less

Contribution of VKORC1 and CYP2C9 polymorphisms in the interethnic variability of warfarin dose in Malaysian populations.

PubMed

Gan, Gin Gin; Phipps, Maude E; Lee, Michael M T; Lu, Liang S; Subramaniam, Rajallectchumy Y; Bee, Ping C; Chang, Sean H

2011-06-01

Within the Asian populations, Indian patients had been reported to require higher warfarin dose compared with the Chinese and Malay patients, and this could not entirely be explained by cytochrome P450 (CYP)2C9 gene variants. Genetic variants of vitamin K epoxide oxidase reductase complex subunit 1 (VKORC1) has been well established as one of key determinants in the different responses of warfarin amongst patients. Adult patients who attended an anticoagulation clinic with stable INR were recruited. VKORC1 and CYP2C9 genotype were sequenced, and clinical characteristics were assessed. A total of 91 Malays, 96 Chinese, and 46 Indian patients were recruited. The mean age was 55 years and 51.5% were males. The mean dose of warfarin for all patients was 3.7 mg, and the mean daily dose of warfarin was significantly higher in Indians compared with the Chinese and Malay patients, 4.9 versus 3.5 and 3.3 mg, respectively (p < 0.001). VKORC1 GG genotype was more commonly seen in Indian patients. The mean warfarin dose in patients with GG genotype required a significant higher warfarin dose compared with those with AG and AA genotype (4.9 vs. 3.7 vs. 3.1 mg, respectively; p < 0.001). CYP2C9*2 and *3 is associated with a lower maintenance dose, 2.9 versus 3.7 mg in CYP2C9*1; p < 0.01. In multivariate analysis, age, ethnic groups, and genotypes had a significant influence on the required warfarin dose. In conclusion, VKORC1 and CYP2C9 polymorphism contribute to the difference dose requirement amongst the patients but other additional possible factors may play a role in the Indian race.

Population Genetic-Based Pharmacokinetic Modeling of Methadone and its Relationship with the QTc Interval in Opioid-Dependent Patients.

PubMed

Csajka, Chantal; Crettol, Séverine; Guidi, Monia; Eap, Chin B

2016-12-01

Methadone is a μ-opioid agonist widely used for the treatment of pain, and for detoxification or maintenance treatment in opioid addiction. It has been shown to exhibit large pharmacokinetic variability and concentration-QTc relationships. In this study we investigated the relative influence of genetic polymorphism and other variables on the dose concentration-QTc relationship. A population model for methadone enantiomers in 251 opioid-dependent patients was developed using non-linear mixed effect modeling (NONMEM ® ). Various models were tested to characterize the pharmacokinetics of (R)- and (S)-methadone and the pharmacokinetic-pharmacodynamic relationship, while including demographics, physiological conditions, co-medications, and genetic variants as covariates. Model-based simulations were performed to assess the relative increase in QTc with dose upon stratification according to genetic polymorphisms involved in methadone disposition. A two-compartment model with first-order absorption and lag time provided the best model fit for (R)- and (S)-methadone pharmacokinetics. (S)-methadone clearance was influenced by cytochrome P450 (CYP) 2B6 activity, ABCB1 3435C>T, and α-1 acid glycoprotein level, while (R)-methadone clearance was influenced by CYP2B6 activity, POR*28, and CYP3A4*22. A linear model described the methadone concentration-QTc relationship, with a mean QTc increase of 9.9 ms and 19.2 ms per 1000 ng/ml of (R)- and (S)-methadone, respectively. Simulations with different methadone doses up to 240 mg/day showed that <8 % of patients presented with a QTc interval above 450 ms; however, this might reach 12 to 18 % for (R)- and (S)-methadone, respectively, in patients with a genetic status associated with a decreased methadone elimination at doses exceeding 240 mg/day. Risk factor assessment, electrocardiogram monitoring, and therapeutic drug monitoring are beneficial to optimize treatment in methadone patients, especially for those who have low levels despite high methadone doses, or who are at risk of overdosing.

Language Maintenance at a Distance: The Daily Russian "Vitamin."

ERIC Educational Resources Information Center

Valentine, Susan M.; Supinski, Stanley B.; Sutherland, Richard L.

This study addressed how to maintain "use or lose" language skills among Department of Defense linguists. The study, which involved over 300 linguists at 61 installations worldwide, supported the Air Force strategy of global engagement by regularly providing pedagogically sound language maintenance materials in small doses and…

What Predicts Exercise Maintenance and Well-Being? Examining The Influence of Health-Related Psychographic Factors and Social Media Communication.

PubMed

Zhou, Xin; Krishnan, Archana

2018-01-26

Habitual exercising is an important precursor to both physical and psychological well-being. There is, thus, a strong interest in identifying key factors that can best motivate individuals to sustain regular exercise regimen. In addition to the importance of psychographic factors, social media use may act as external motivator by allowing users to interact and communicate about exercise. In this study, we examined the influence of health consciousness, health-oriented beliefs, intrinsic motivation, as willingness to communicate about health on social media, social media activity on exercise, and online social support on exercise maintenance and well-being on a sample of 532 American adults. Employing structural equation modeling, we found that health-oriented beliefs mediated the effect of health consciousness on intrinsic motivation which in turn was a significant predictor of exercise maintenance. Exercise maintenance significantly predicted both physical and psychological well-being. Extrinsic motivators, as measured by willingness to communicate about health on social media, social media activity on exercise, and online social support did not however significantly influence exercise maintenance. These findings have implications for the design and implementation of exercise-promoting interventions by identifying underlying factors that influence exercise maintenance.

Prevalence and Safety of Intravenous Immunoglobulin Administration During Maintenance Chemotherapy in Children with Acute Lymphoblastic Leukemia in First Complete Remission: A Health Maintenance Organization Perspective.

PubMed

Van Winkle, Patrick; Burchette, Raoul; Kim, Raymond; Raghunathan, Rukmani; Qureshi, Naveen

2018-04-09

Children with acute lymphoblastic leukemia (ALL) in first complete remission (CR1) experience hypogammaglobulinemia and are at risk of sepsis during maintenance chemotherapy. Intravenous immunoglobulin (IVIG) has been used to try to circumvent this risk, but no data exist regarding its safety and prevalence in a health maintenance organization. To evaluate the prevalence and safety of IVIG in children with ALL in CR1 during maintenance chemotherapy. A multicenter, retrospective cohort study of consecutive children with ALL in CR1 during maintenance chemotherapy from 2008 to 2014. Groups treated with or without IVIG were compared using nonparametric statistics. Multivariate logistic regression involved all variables available before maintenance therapy began. One hundred eighteen patients were included (53% males), aged 9 months to 19 years. Thirty of 31 patients (97%) who had immunoglobulins analyzed before IVIG were hypogammaglobulinemic. Thirty-six patients (30%) received IVIG during maintenance chemotherapy. Patients received an average of 10.5 IVIG doses (range = 1-31). Ninety-seven percent of doses were administered without a transfusion reaction. Other factors associated with IVIG use were prior double-delayed intensification (odds ratio = 5.36, 95% confidence interval = 1.3-27.49, p = 0.026) and episodes of bacteremia or fungemia before maintenance chemotherapy (odds ratio = 3.04, 95% confidence interval = 1.25-7.51, p = 0.015). Use of IVIG in children with ALL in CR1 with hypogammaglobulinemia occurred in approximately 30% of patients and was well tolerated. Administration of IVIG significantly correlated with a history of double-delayed intensification and prior bacteremia or fungemia.

Methadone dose at the time of release from prison significantly influences retention in treatment: implications from a pilot study of HIV-infected prisoners transitioning to the community in Malaysia.

PubMed

Wickersham, Jeffrey A; Zahari, Muhammad Muhsin; Azar, Marwan M; Kamarulzaman, Adeeba; Altice, Frederick L

2013-09-01

To evaluate the impact of methadone dose on post-release retention in treatment among HIV-infected prisoners initiating methadone maintenance treatment (MMT) within prison. Thirty HIV-infected prisoners meeting DSM-IV pre-incarceration criteria for opioid dependence were enrolled in a prison-based, pre-release MMT program in Klang Valley, Malaysia; 3 died before release from prison leaving 27 evaluable participants. Beginning 4 months before release, standardized methadone initiation and dose escalation procedures began with 5mg daily for the first week and 5mg/daily increases weekly until 80 mg/day or craving was satisfied. Participants were followed for 12 months post-release at a MMT clinic within 25 kilometers of the prison. Kaplan-Meier survival analysis was used to evaluate the impact of methadone dose on post-release retention in treatment. Methadone dose ≥80 mg/day at the time of release was significantly associated with retention in treatment. After 12 months of release, only 21.4% of participants on <80 mg were retained at 12 months compared to 61.5% of those on ≥80 mg (Log Rank χ(2)=(1,26) 7.6, p<0.01). Higher doses of MMT at time of release are associated with greater retention on MMT after release to the community. Important attention should be given to monitoring and optimizing MMT doses to address cravings and side effects prior to community re-entry from prisons. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Methadone Dose at the Time of Release from Prison Significantly Influences Retention in Treatment: Implications From a Pilot Study of HIV-Infected Prisoners Transitioning to the Community in Malaysia

PubMed Central

Wickersham, Jeffrey A.; Muhsin Zahari, Muhammad; Azar, Marwan M.; Kamarulzaman, Adeeba; Altice, Frederick L.

2013-01-01

Objective To evaluate the impact of methadone dose on post-release retention in treatment among HIV-infected prisoners initiating methadone maintenance treatment (MMT) within prison. Methods Thirty HIV-infected prisoners meeting DSM-IV pre-incarceration criteria for opioid dependence were enrolled in a prison-based, pre-release MMT program in Klang Valley, Malaysia; 3 died before release from prison leaving 27 evaluable participants. Beginning 4 months before release, standardized methadone initiation and dose escalation procedures began with 5mg daily for the first week and 5mg/daily increases weekly until 80 mg/day or craving was satisfied. Participants were followed for 12 months post-release at a MMT clinic within 25 kilometers of the prison. Kaplan-Meier survival analysis was used to evaluate the impact of methadone dose on post-release retention in treatment. Findings Methadone dose ≥80 mg/day at the time of release was significantly associated with retention in treatment. After 12 months of release, only 21.4% of participants on <80mg were retained at 12 months compared to 61.5% of those on ≥80mg (Log Rank χ2=(1,26) 7.6, p <0.01). Conclusions Higher doses of MMT at time of release are associated with greater retention on MMT after release to the community. Important attention should be given to monitoring and optimizing MMT doses to address cravings and side effects prior to community re-entry from prisons. PMID:23414931

Dose reduction of risperidone and olanzapine can improve cognitive function and negative symptoms in stable schizophrenic patients: A single-blinded, 52-week, randomized controlled study.

PubMed

Zhou, Yanling; Li, Guannan; Li, Dan; Cui, Hongmei; Ning, Yuping

2018-05-01

The long-term effects of dose reduction of atypical antipsychotics on cognitive function and symptomatology in stable patients with schizophrenia remain unclear. We sought to determine the change in cognitive function and symptomatology after reducing risperidone or olanzapine dosage in stable schizophrenic patients. Seventy-five stabilized schizophrenic patients prescribed risperidone (≥4 mg/day) or olanzapine (≥10 mg/day) were randomly divided into a dose-reduction group ( n=37) and a maintenance group ( n=38). For the dose-reduction group, the dose of antipsychotics was reduced by 50%; for the maintenance group, the dose remained unchanged throughout the whole study. The Positive and Negative Syndrome Scale, Negative Symptom Assessment-16, Rating Scale for Extrapyramidal Side Effects, and Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery were measured at baseline, 12, 28, and 52 weeks. Linear mixed models were performed to compare the Positive and Negative Syndrome Scale, Negative Symptom Assessment-16, Rating Scale for Extrapyramidal Side Effects and MATRICS Consensus Cognitive Battery scores between groups. The linear mixed model showed significant time by group interactions on the Positive and Negative Syndrome Scale negative symptoms, Negative Symptom Assessment-16, Rating Scale for Extrapyramidal Side Effects, speed of processing, attention/vigilance, working memory and total score of MATRICS Consensus Cognitive Battery (all p<0.05). Post hoc analyses showed significant improvement in Positive and Negative Syndrome Scale negative subscale, Negative Symptom Assessment-16, Rating Scale for Extrapyramidal Side Effects, speed of processing, working memory and total score of MATRICS Consensus Cognitive Battery for the dose reduction group compared with those for the maintenance group (all p<0.05). This study indicated that a risperidone or olanzapine dose reduction of 50% may not lead to more severe symptomatology but can improve speed of processing, working memory and negative symptoms in patients with stabilized schizophrenia.

Vitamin D3 Loading Is Superior to Conventional Supplementation After Weight Loss Surgery in Vitamin D-Deficient Morbidly Obese Patients: a Double-Blind Randomized Placebo-Controlled Trial.

PubMed

Luger, Maria; Kruschitz, Renate; Kienbacher, Christian; Traussnigg, Stefan; Langer, Felix B; Prager, Gerhard; Schindler, Karin; Kallay, Enikö; Hoppichler, Friedrich; Trauner, Michael; Krebs, Michael; Marculescu, Rodrig; Ludvik, Bernhard

2017-05-01

Bariatric patients often suffer from vitamin D deficiency (VDD), and both, morbid obesity and VDD, are related to non-alcoholic fatty liver disease. However, limited data are available regarding best strategies for treating VDD, particularly, in bariatric patients undergoing omega-loop gastric bypass (OLGB). Therefore, we examined the efficacy and safety of a forced vitamin D dosing regimen and intervention effects in liver fibrotic patients. In this double-blind, randomized, placebo-controlled trial, 50 vitamin D-deficient patients undergoing OLGB were randomly assigned to receive, in the first month postoperatively, oral vitamin D 3 (≤3 doses of 100,000 IU; intervention group) or placebo as loading dose (control group) with subsequent maintenance dose (3420 IU/day) in both groups until 6-month visit. Compared with control group, higher increase of 25(OH)D (67.9 (21.1) vs. 55.7 nmol/L (21.1); p = 0.049) with lower prevalence of secondary hyperparathyroidism (10 vs. 24 %; p = 0.045) was observed in intervention group. No (serious) adverse events related to study medication were found. The loading dose regimen was more effective in increasing 25(OH)D in patients with significant liver fibrosis while this was not the case for conventional supplementation (placebo with maintenance dose) (71.5 (20.5) vs. 22.5 nmol/L (13.8); p = 0.022; n = 14). Our findings indicate that a high vitamin D 3 loading dose, in the first month postoperatively, with subsequent maintenance dose is effective and safe in achieving higher vitamin D concentrations in OLGB patients. Unexpectedly, it is more effective in patients with significant liver fibrosis which is of potentially high clinical relevance and requires further investigation.

Genetic polymorphisms are associated with variations in warfarin maintenance dose in Han Chinese patients with venous thromboembolism.

PubMed

Zhang, Wei; Zhang, Wei-Juan; Zhu, Jin; Kong, Fan-Cui; Li, Yan-Yan; Wang, He-Yao; Yang, Yuan-Hua; Wang, Chen

2012-02-01

Warfarin is a clinical anticoagulant that requires periodic monitoring because it is associated with adverse outcomes. Personalized medicine, which is based on pharmacogenetics, holds great promise in solving these types of problems. It aims to provide the tools and knowledge to tailor drug therapy to an individual patient, with the potential of increasing safety and efficacy of medications. In the present study we analyzed genotypes of 14 SNPs for seven genes using DNA from 297 Han Chinese venous thromboembolism patients treated with warfarin. Multiple regression analyses revealed that CYP2C9 genotype (p = 0.001), VKORC1 genotype (p < 0.001), age (p < 0.01) and weight (p < 0.001) were all associated with warfarin dose requirements, which can explain 37.4% of the variability of warfarin dose among Han Chinese patients. Meanwhile, in the validation cohort, the predicted warfarin daily dose was calculated using the best model with a 64.5% predicted dose being acceptable (-1 mg/day ≤Δwarfarin dose ≤1 mg/day). We developed a pharmacogenetic dose algorithm for warfarin treatment that uses genotypes from two genes (VKORC1 and CYP2C9) and clinical variables to predict therapeutic maintenance doses in Chinese patients with venous thromboembolism. The validity of the dosing algorithm was confirmed in a cohort of venous thromboembolism patients on warfarin therapy.

Maintenance therapy of childhood acute lymphoblastic leukemia revisited-Should drug doses be adjusted by white blood cell, neutrophil, or lymphocyte counts?

PubMed

Schmiegelow, Kjeld; Nersting, Jacob; Nielsen, Stine Nygaard; Heyman, Mats; Wesenberg, Finn; Kristinsson, Jon; Vettenranta, Kim; Schrøeder, Henrik; Weinshilboum, Richard; Jensen, Katrine Lykke; Grell, Kathrine; Rosthoej, Susanne

2016-12-01

6-Mercaptopurine (6MP) and methotrexate (MTX) based maintenance therapy is a critical phase of childhood acute lymphoblastic leukemia treatment. Wide interindividual variations in drug disposition warrant frequent doses adjustments, but there is a lack of international consensus on dose adjustment guidelines. To identify relapse predictors, we collected 28,255 data sets on drug doses and blood counts (median: 47/patient) and analyzed erythrocyte (Ery) levels of cytotoxic 6MP/MTX metabolites in 9,182 blood samples (median: 14 samples/patient) from 532 children on MTX/6MP maintenance therapy targeted to a white blood cell count (WBC) of 1.5-3.5 × 10 9 /l. After a median follow-up of 13.8 years for patients in remission, stepwise Cox regression analysis did not find age, average doses of 6MP and MTX, hemoglobin, absolute lymphocyte counts, thrombocyte counts, or Ery levels of 6-thioguanine nucleotides or MTX (including its polyglutamates) to be significant relapse predictors. The parameters significantly associated with risk of relapse (N = 83) were male sex (hazard ratio [HR] 2.0 [1.3-3.1], P = 0.003), WBC at diagnosis (HR = 1.04 per 10 × 10 9 /l rise [1.00-1.09], P = 0.048), the absolute neutrophil count (ANC; HR = 1.7 per 10 9 /l rise [1.3-2.4], P = 0.0007), and Ery thiopurine methyltransferase activity (HR = 2.7 per IU/ml rise [1.1-6.7], P = 0.03). WBC was significantly related to ANC (Spearman correlation coefficient, r s  = 0.77; P < 0.001), and only a borderline significant risk factor for relapse (HR = 1.28 [95% CI: 1.00-1.64], P = 0.046) when ANC was excluded from the Cox model. This study indicates that a low neutrophil count is likely to be the best hematological target for dose adjustments of maintenance therapy. © 2016 Wiley Periodicals, Inc.

Summary of anti-malarial prophylactic efficacy of tafenoquine from three placebo-controlled studies of residents of malaria-endemic countries.

PubMed

Dow, Geoffrey S; Liu, Jun; Lin, Gina; Hetzell, Brian; Thieling, Sarah; McCarthy, William F; Tang, Douglas; Smith, Bryan

2015-11-26

Tafenoquine is a long half-life primaquine analog being developed for malaria prophylaxis. The US Army recently performed a unified analysis of efficacy in preparation for a regulatory submission, utilizing legacy data from three placebo-controlled studies conducted in the late 1990s and early 2000s. The subjects were residents of Africa who were naturally exposed to Plasmodium falciparum for 12-26 weeks. The prophylactic efficacy of tafenoquine and mefloquine (included in some studies as a comparator) was calculated using incidence density among subjects who had completed the three-day loading doses of study drug, had at least one maintenance dose and had at least one blood smear assessed during the prophylactic period. The three placebo-controlled studies were analysed separately and then in two pooled analyses: one for tafenoquine versus placebo (three studies) and one for tafenoquine and mefloquine versus placebo (two studies). The pooled protective efficacy (PE) of a tafenoquine regimen with three daily loading doses plus weekly maintenance at 200-mg for 10 weeks or longer (referred to as 200-mg weekly hereafter) relative to placebo in three placebo-controlled studies was 93.1 % [95 % confidence interval (CI) 89.1-95.6 %; total N = 492]. The pooled PEs of regimens of tafenoquine 200-mg weekly and mefloquine 250-mg weekly relative to placebo in two placebo-controlled studies (total N = 519) were 93.5 % (95 % CI 88.6-96.2 %) and 94.5 % (95 % CI 88.7-97.3 %), respectively. Three daily loading plus weekly maintenance doses of 50- and 100-mg, but not 25-mg, exhibited similar PEs. The PEs of tafenoquine regimens of a three-day loading dose at 400-mg with and without follow-up weekly maintenance doses at 400-mg were 93.7 % (95 % CI 85.4-97.3 %) and 81.0 % (95 % CI 66.8-89.1 %), respectively. Tafenoquine provided the same level of prophylactic efficacy as mefloquine in residents of Africa. These data support the prophylactic efficacy of tafenoquine and mefloquine that has already been demonstrated in the intended malaria naive population.

Commentary on "Optimal schedule of bacillus Calmette-Guérin for non-muscle-invasive bladder cancer: A meta-analysis of comparative studies." Zhu S, Tang Y, Li K, Shang Z, Jiang N, Nian X, Sun L, Niu Y, Department of Urology Tianjin Institute of Urology, 2nd Hospital of Tianjin Medical University, People's Republic of China.: BMC Cancer 2013; 13:332. doi:10.1186/1471-2407-13-332.

PubMed

See, William A

2014-11-01

To explore the necessity of maintenance, efficacy of low-dose and superiority of various combination therapies of Bacillus Calmette-Guérin (BCG) in treatment of superficial bladder cancer (BCa). Comprehensive searches of electronic databases (PubMed, Embase, and the Cochrane Library), were performed, then a systematic review and cumulative meta-analysis of 21 randomized, controlled trials (RCTs) and 9 retrospective comparative studies were carried out according to, predefined inclusion criteria. Significantly better recurrence-free survivals (RFS) were observed respectively in patients who received BCG maintenance, standard-dose and BCG plus epirubicin therapy comparing to those received induction, low-dose and BCG alone. BCG maintenance therapy was also associated with significantly better progression-free survival (PFS), but there were more incidences of adverse events. Pooled results showed no remarkable advantage of BCG combined with Mitomycin C or with interferon α-2b in improving oncologic outcomes. Sensitivity-analyses stratified by study-design and tumor stage led to very similar overall results and often to a decrease of the between-study heterogeneity. Our data confirmed that non-RCT only affected strength rather than direction of the overall results. All patients with superficial BCa should be encouraged to accept BCG maintenance therapy with standard-dose if well tolerated. Patients can benefit from BCG combined with epirubicin but not from BCG combined with Mitomycin C or interferon α-2b. Copyright © 2014 Elsevier Inc. All rights reserved.

Systematic review with network meta-analysis: comparative efficacy and safety of budesonide and mesalazine (mesalamine) for Crohn's disease.

PubMed

Moja, L; Danese, S; Fiorino, G; Del Giovane, C; Bonovas, S

2015-06-01

Budesonide and mesalazine (mesalamine) are commonly used in the medical management of patients with mild to moderate Crohn's disease. To assess their comparative efficacy and harm using the methodology of network meta-analysis. A comprehensive search of Medline, Embase, the Cochrane Library and ClinicalTrials.gov, through October 2014, was performed to identify randomised controlled trials (RCTs) that recruited adult patients with active or quiescent Crohn's disease, and compared budesonide or mesalazine with placebo, or against each other, or different dosing strategies of one drug. Twenty-five RCTs were combined using Bayesian network meta-analysis. Budesonide 9 mg/day, or at higher doses (15 or 18 mg/day), was shown superior to placebo for induction of remission [odds ratio (OR), 2.93; 95% credible interval (CrI), 1.52-5.39, and OR, 3.28; CrI, 1.46-7.55 respectively] and ranks at the top of the hierarchy of the competing treatments. For maintenance of remission, budesonide 6 mg/day demonstrated superiority over placebo (OR, 1.69; CrI, 1.05-2.75), being also at the best ranking position among all compared treatment strategies. No other comparisons (i.e. different doses of mesalazine vs. placebo or budesonide, for induction or maintenance of remission) reached significance. The occurrence of withdrawals due to adverse events was not shown different between budesonide, mesalazine and placebo, in both the induction and maintenance phases. Budesonide, at the doses of 9 mg/day, or higher, for induction of remission in active mild or moderate Crohn's disease, and at 6 mg/day for maintenance of remission, appears to be the best treatment choice. © 2015 John Wiley & Sons Ltd.

Genome-wide association study of therapeutic opioid dosing identifies a novel locus upstream of OPRM1

PubMed Central

Smith, Andrew H.; Jensen, Kevin P.; Li, Jin; Nunez, Yaira; Farrer, Lindsay A.; Hakonarson, Hakon; Cook-Sather, Scott D.; Kranzler, Henry R.; Gelernter, Joel

2017-01-01

Opioids are very effective analgesics, but they are also highly addictive. Methadone is used to treat opioid dependence (OD), acting as a selective agonist at the μ-opioid receptor encoded by the gene OPRM1. Determining the optimal methadone maintenance dose is time-consuming; currently, no biomarkers are available to guide treatment. In methadone-treated OD subjects drawn from a case and control sample, we conducted a genome-wide association study (GWAS) of usual daily methadone dose. In African-American (AA) OD subjects (n = 383), we identified a genome-wide significant association between therapeutic methadone dose (mean = 68.0 mg, standard deviation (SD) = 30.1 mg) and rs73568641 (P = 2.8 × 10−8), the nearest gene (306 kilobases) being OPRM1. Each minor (C) allele corresponded to an additional ~20 mg/day of oral methadone, an effect specific to AAs. In European-Americans (EAs) (n = 1,027), no genome-wide significant associations with methadone dose (mean = 77.8 mg, SD = 33.9 mg) were observed. In an independent set of opioid-naïve AA children being treated for surgical pain, rs73568641-C was associated with a higher required dose of morphine (n = 241, P = 3.9 × 10−2). Similarly, independent genomic loci previously shown to associate with higher opioid analgesic dose were associated with higher methadone dose in the OD sample (AA and EA: n = 1,410, genetic score P = 1.3 × 10−3). The present results in AAs indicate that genetic variants influencing opioid sensitivity across different clinical settings could contribute to precision pharmacotherapy for pain and addiction. PMID:28115739

Retrospective Analysis of Dose Titration and Serum Testosterone Level Assessments in Patients Treated With Topical Testosterone.

PubMed

Muram, David; Kaltenboeck, Anna; Boytsov, Natalie; Hayes-Larson, Eleanor; Ivanova, Jasmina; Birnbaum, Howard G; Swindle, Ralph

2015-11-01

Patterns of care following topical testosterone agent (TTA) initiation are poorly understood. This study aimed to characterize care following TTA initiation and compare results between patients with and without a serum testosterone (T) assay within 30 days before and including TTA initiation. Adult men (N=4,146) initiating TTAs from January 1, 2011, to March 31, 2012, were identified from a commercially insured database. Patients were included if they initiated at recommended starting dose (RSD) and had ≥12 and ≥6 months of continuous eligibility preinitiation (baseline) and postinitiation (study period), respectively. Patients were stratified by preinitiation T assay. Maintenance dose attainment month was determined using unadjusted generalized estimating equations regression to compare dose relative to RSD month by month. Outcomes included maintenance dose attainment month, time to stopping of index TTA refills or a claim for nonindex testosterone replacement therapy (TRT), and proportion of patients with study period T assay or diagnosis of hypogonadism (HG) or another low testosterone condition, and were compared using chi-square and Wilcoxon rank-sum tests for categorical and continuous variables, respectively. Maintenance dose was attained in Month 4 postinitiation, at 115.2% of RSD. Approximately 46% of patients had a preinitiation T assay; these men were more likely to receive a diagnosis of HG or another low testosterone condition, to have a follow-up T assay, to continue treatment by filling a nonindex TRT, and less likely to stop refilling treatment with their index TTA. Differences in care following TTA initiation suggest that preinitiation T assays (i.e., guideline-based care) may be helpful in ensuring treatment benefits. © The Author(s) 2014.

A placebo-controlled, double-blind, dose-escalation study to assess the safety, tolerability and pharmacokinetics/pharmacodynamics of single and multiple intravenous infusions of AZD9773 in patients with severe sepsis and septic shock

PubMed Central

2012-01-01

Introduction Tumor necrosis factor-alpha (TNF-α), an early mediator in the systemic inflammatory response to infection, is a potential therapeutic target in sepsis. The primary objective of this study was to determine the safety and tolerability of AZD9773, an ovine, polyclonal, anti-human TNF-α Fab preparation, in patients with severe sepsis. Secondary outcomes related to pharmacokinetic (PK) and pharmacodynamic (PD) parameters. Methods In this double-blind, placebo-controlled, multicenter Phase IIa study, patients were sequentially enrolled into five escalating-dose cohorts (single doses of 50 or 250 units/kg; multiple doses of 250 units/kg loading and 50 units/kg maintenance, 500 units/kg loading and 100 units/kg maintenance, or 750 units/kg loading and 250 units/kg maintenance). In each cohort, patients were randomized 2:1 to receive AZD9773 or placebo. Results Seventy patients received AZD9773 (n = 47) or placebo (n = 23). Baseline characteristics were similar across cohorts. Mean baseline APACHE score was 25.9. PK data demonstrated an approximately proportional increase in concentration with increasing dose and a terminal half-life of 20 hours. For the multiple-dose cohorts, serum TNF-α concentrations decreased to near-undetectable levels within two hours of commencing AZD9773 infusion. This suppression was maintained in most patients for the duration of treatment. AZD9773 was well tolerated. Most adverse events were of mild-to-moderate intensity and considered by the reporting investigator as unrelated to study treatment. Conclusions The safety, PK and PD data support the continued evaluation of AZD9773 in larger Phase IIb/III studies. PMID:22340283

Effect of Two Different Doses of Dexmedetomidine on Stress Response in Laparoscopic Pyeloplasty: A Randomized Prospective Controlled Study.

PubMed

Shamim, Rafat; Srivastava, Shashi; Rastogi, Amit; Kishore, Kamal; Srivastava, Aneesh

2017-01-01

Clonidine, opioids, β-blockers, and dexmedetomidine have been tried to attenuate stress responses during laparoscopic surgery. We evaluated the efficacy of dexmedetomidine in two different doses in attenuating stress responses on patients undergoing laparoscopic pyeloplasty. Ninety patients were assigned to one of the three groups: Group A, Group B, and Group C. Group B received dexmedetomidine 1 mcg/kg as loading dose, followed by 0.7 mcg/kg/h for maintenance; Group C received dexmedetomidine 0.7 mcg/kg as a loading dose, followed by 0.5 mcg/kg/h for maintenance. Group A received normal saline. Stress responses were assessed by the variations in heart rate (HR), mean arterial pressure (MAP), blood glucose levels, and serum cortisol levels. One-way analysis of variance test was applied. Multiple comparisons between groups were done with post hoc Bonferroni test. The HR and MAP were found to be higher in Group A. The difference was statistically significant ( P < 0.05) during intubation, carbon dioxide insufflation, and extubation when compared with Groups B and C. Blood glucose levels at postintubation and at extubation were higher in Group A and statistically significant ( P < 0.05) when compared with Groups B and C. Serum cortisol levels at postintubation, during midsurgery, and 2 h after extubation were higher in Group A and statistically significant ( P < 0.05) when compared with Groups B and C. However, HR, MAP, blood glucose levels, and serum cortisol levels were similar in dexmedetomidine groups. Dexmedetomidine decreases stress response and provides good condition for maintenance of anesthesia. Dexmedetomidine when used in lower dose in Group C decreases stress response comparable to higher dose in Group B.

A phase III study of the efficacy and safety of a novel iron-based phosphate binder in dialysis patients.

PubMed

Floege, Jürgen; Covic, Adrian C; Ketteler, Markus; Rastogi, Anjay; Chong, Edward M F; Gaillard, Sylvain; Lisk, Laura J; Sprague, Stuart M

2014-09-01

Efficacy of PA21 (sucroferric oxyhydroxide), a novel calcium-free polynuclear iron(III)-oxyhydroxide phosphate binder, was compared with that of sevelamer carbonate in an open-label, randomized, active-controlled phase III study. Seven hundred and seven hemo- and peritoneal dialysis patients with hyperphosphatemia received PA21 1.0-3.0 g per day and 348 received sevelamer 4.8-14.4 g per day for an 8-week dose titration, followed by 4 weeks without dose change, and then 12 weeks maintenance. Serum phosphorus reductions at week 12 were -0.71 mmol/l (PA21) and -0.79 mmol/l (sevelamer), demonstrating non-inferiority of, on average, three tablets of PA21 vs. eight of sevelamer. Efficacy was maintained to week 24. Non-adherence was 15.1% (PA21) vs. 21.3% (sevelamer). The percentage of patients that reported at least one treatment-emergent adverse event was 83.2% with PA21 and 76.1% with sevelamer. A higher proportion of patients withdrew owing to treatment-emergent adverse events with PA21 (15.7%) vs. sevelamer (6.6%). Mild, transient diarrhea, discolored feces, and hyperphosphatemia were more frequent with PA21; nausea and constipation were more frequent with sevelamer. After 24 weeks, 99 hemodialysis patients on PA21 were re-randomized into a 3-week superiority analysis of PA21 maintenance dose in 50 patients vs. low dose (250 mg per day (ineffective control)) in 49 patients. The PA21 maintenance dose was superior to the low dose in maintaining serum phosphorus control. Thus, PA21 was effective in lowering serum phosphorus in dialysis patients, with similar efficacy to sevelamer carbonate, a lower pill burden, and better adherence.

Sirolimus and everolimus clearance in maintenance kidney and liver transplant recipients: Diagnostic efficiency of the concentration/dose ratio for the prediction of trough steady-state concentrations

PubMed Central

Bouzas, Lorena; Hermida, Jesús

2010-01-01

Objectives Therapeutic monitoring of sirolimus and everolimus is necessary in order to minimize adverse side-effects and to ensure effective immunosuppression. A sirolimus-dosing model using the concentration/dose ratio has been previously proposed for kidney transplant patients, and the aim of our study was the evaluation of this single model for the prediction of trough sirolimus and everolimus concentrations. Methods Trough steady-state sirolimus concentrations were determined in several blood samples from each of 7 kidney and 9 liver maintenance transplant recipients, and everolimus concentrations from 20 kidney, 17 liver, and 3 kidney/liver maintenance transplant recipients. Predicted sirolimus and everolimus concentrations (Css), corresponding to the doses (D), were calculated using the measured concentrations (Css0) and corresponding doses (D0) on starting the study: Css = (Css0)(D)/D0. Results The diagnostic efficiency of the predicting model for the correct classification as subtherapeutic, therapeutic, and supratherapeutic values with respect to the experimentally obtained concentrations was 91.3% for sirolimus and 81.4% for everolimus in the kidney transplant patients. In the liver transplant patients the efficiency was 69.2% for sirolimus and 72.6% for everolimus, and in the kidney/liver transplant recipients the efficiency for everolimus was 67.9%. Conclusions The model has an acceptable diagnostic efficiency (>80%) for the prediction of sirolimus and everolimus concentrations in kidney transplant recipients, but not in liver transplant recipients. However, considering the wide ranges found for the prediction error of sirolimus and everolimus concentrations, the clinical relevance of this dosing model is weak. PMID:19943816

Weight and the vitamin K expoxide reductase 1 genotype primarily contribute to the warfarin dosing in pediatric patients with Kawasaki disease.

PubMed

Wang, Zhouping; Zhang, Li; Huang, Ping; Gu, Xiaoqiong; Xie, Xiaofei; Wang, Yanfei; Li, Wei; Zeng, Qiyi

2018-05-08

Warfarin therapy is recommended in children with giant coronary artery aneurysms (GCAAs) after Kawasaki disease (KD). Large individual variability makes it difficult to predict the warfarin dose. Polymorphisms in the vitamin K expoxide reductase 1 (VKORC1) and cytochrome P4502C9 (CYP2C9) genes have been reported to influence the warfarin dose. We investigated the effects of the VKORC1 and CYP2C9 genotypes on the warfarin dose in pediatric patients with giant CAAs after KD. We attempted to create a dosing algorithm. The clinical and genetic data of patients were documented. VKORC1 (rs 9923231) and CYP2C9 *3 (rs 1057910) were genotyped using TaqMan real-time polymerase chain reaction. A linear regression analysis was performed to evaluate the contribution of clinical and genetic factors to the warfarin maintenance dose. Forty-seven patients were enrolled. Patients with the CT or CC genotype of VKORC1 had a relatively higher warfarin dose than did those with the TT genotype (p < 0.05). Three patients with CYP2C9*1/*3 had a lower warfarin dose than did those with the wild CYP2C9*1/*1 genotype, but the difference did not reach significance (p > 0.05). Weight and the VKORC1 genotype predominantly contributed to the warfarin dose, with 33.0% and 11.2% of variability, respectively. The observed warfarin dose was correlated with the predicted dose based on the algorithm used in our study (r = 0.45, p < 0.01). Weight and the VKORC1 genotype primarily determined the warfarin dose in Chinese pediatric patients with KD. Further studies are warranted to verify the findings of our study. Copyright © 2018 Elsevier Ltd. All rights reserved.

[Influence of venom immunotherapy on anxiety level of being re-stung].

PubMed

Sacha, Małgorzata; Czarnobilska, Ewa; Stobiecki, Marcin; Dyga, Wojciech

2012-01-01

Hymenoptera venom allergy is related to higher risk of potential life -threatening anaphylactic reactions, which leads to anxiety and decreased quality of life. The aim of this paper was: 1) estimation of fear level of being re-stung among venom allergy adults treated with venom specific immunotherapy (VIT)--before and during treatment; 2) estimation of expectation of outcome of VIT as compared to level of anxiety of being re-strug, in the Visual Analogue Scale--VAS score; 3) identification of factors influencing changes in the fear level among patients during VIT. The study group comprised 42 patients (18 women, 24 men) in the mean age 42.6 years, with bee or vespid allergy, who had been qualified to the VIT treatment with Alutard SQ. Visual Analogue Scale--VAS and the Expectation of Outcome Questionnaire were used. The demographic data were collected. The VAS score before VIT for insect venom allergic patients was 8.8 (SD = 0.9). It decreased after achieving maintenance dose to 3.1 (SD = 1.6) and was significantly lower in men (p < 0.05). Score achieved in the Expectation of Outcome Questionnaire was for each question 2.2 (SD = 1.5) and there was correlation with VAS score during VIT. The patients with insect venom allergy, who undergo a serious allergic reaction (SR) as a result of being stung and who are qualified to VIT, have a high level of anxiety of being re-stung. Achieving the maintenance dose of VIT, results in a significant decrease of anxiety level in women and men, significantly so in men. There is a significant correlation between VAS score and the Expectation of Outcome Questionnaire results during VIT. Both VAS for anxiety level and the Expectation of Outcome Questionnaire can be simple, easily available and useful instruments helping to estimate quality of life. VIT significantly decreases the patients level of anxiety of being restung and improves their quality of life.

Pediatric Fluid and Electrolyte Therapy

PubMed Central

Meyers, Rachel S.

2009-01-01

Managing fluids and electrolytes in children is an important skill for pharmacists, who can play an important role in monitoring therapy. Fluid therapy is divided into maintenance, deficit, and replacement requirements. The Holliday-Segar equation remains the standard method for calculating maintenance fluid requirements. Accounting for deficits when determining the fluid infusion rate is an important factor in treating dehydrated patients; deficit fluid is generally administered over the first 24 hours of hospitalization. Maintenance electrolyte requirements must be taken into account, with particular attention paid to sodium requirements, as recent evidence suggests that sodium needs in hospitalized children are higher than originally thought. Fluid therapy can also have an impact on drug therapy. Hydration status can affect the dose needed to achieve therapeutic concentrations, and dehydrated patients may be at risk for toxicity if standard doses of drugs with high volumes of distribution are used. Monitoring fluid and electrolyte therapy is an important role of the pediatric pharmacist. PMID:23055905

Sugammadex and Ideal Body Weight in Bariatric Surgery

PubMed Central

Alessandri, Francesco; Wefki Abdelgawwad Shousha, Ahmed Abdelgawwad; Sabba, Antonio; Cutolo, Alessandra

2013-01-01

Background. The obese patients have differences in body composition, drug distribution, and metabolism. Sugammadex at T 2 recovery in a dose of 2 mg kg−1 of real body weight (RBW) can completely reverse the NMB block; in our study we investigated the safety and efficacy of Sugammadex dose based on their ideal body weight (IBW). Methods. 40 patients of both sexes undergoing laparoscopic bariatric surgery were enrolled divided into 2 groups according to the dose of Sugammadex: the first received a dose of 2 mg kg−1 of IBW and the second received a dose of 2 mg kg−1 of RBW. Both were anesthetized with doses calculated according to the IBW: fentanyl 2 μg kg−1, propofol 3 mg kg−1, rocuronium 0,6 mg kg−1, oxygen, air, and desflurane (6–8%). Maintenance doses of rocuronium were 1/4 of the intubation dose. Sugammadex was administrated at T 2 recovery. Results. The durations of intubation and maintenance doses of rocuronium were similar in both groups. In IBW group, the T 4/T 1 value of 0.9 was reached in 151 ± 44 seconds and in 121 ± 55 seconds in RBW group (P = 0.07). Discussion. Recovery times to T 4/T 1 of 0.9 are surprisingly similar in both groups without observing any postoperative residual curarization. Conclusion. Sugammadex doses calculated according to the IBW are certainly safe for a rapid recovery and absence of PORC. PMID:23840203

Morphine reduces social cohesion in rats.

PubMed

Panksepp, J; Najam, N; Soares, F

1979-08-01

The effect of low (1 mg/kg) doses of morphine on maintenance of physical proximity were evaluated in paired rats observed in a 4 square foot test arena. Morphine reliably reduced proximity maintenance time, and this was apparently not due to sedation, since the effect was unmodified by doses of amphetamine which substantially increased motor activity. The effects of naloxone were inconsistent on this measure of social motivation. In general, the results are consistent with the theoretical proposition that a brain neurochemical change which might lead to social attraction is the activation of endogenous opioid systems. When opiate activity is exogenously sustained, animals exhibit a subnormal tendency to be gregarious.

Excimer laser therapy and narrowband ultraviolet B therapy for exfoliative cheilitis.

PubMed

Bhatia, Bhavnit K; Bahr, Brooks A; Murase, Jenny E

2015-06-01

Exfoliative cheilitis is a condition of unknown etiology characterized by hyperkeratosis and scaling of vermilion epithelium with cyclic desquamation. It remains largely refractory to treatment, including corticosteroid therapy, antibiotics, antifungals, and immunosuppressants. We sought to evaluate the safety and efficacy of excimer laser therapy and narrowband ultraviolet B therapy in female patients with refractory exfoliative cheilitis. We reviewed the medical records of two female patients who had been treated unsuccessfully for exfoliative cheilitis. We implemented excimer laser therapy, followed by hand-held narrowband UVB treatments for maintenance therapy, and followed them for clinical improvement and adverse effects. Both patients experienced significant clinical improvement with minimal adverse effects with excimer laser therapy 600-700 mJ/cm 2 twice weekly for several months. The most common adverse effects were bleeding and burning, which occurred at higher doses. The hand-held narrowband UVB unit was also an effective maintenance tool. Limitations include small sample size and lack of standardization of starting dose and dose increments. Excimer laser therapy is a well-tolerated and effective treatment for refractory exfoliative cheilitis with twice weekly laser treatments of up to 700 mJ/cm 2 . Transitioning to the hand-held narrowband UVB device was also an effective maintenance strategy.

The combination of fluticasone furoate and vilanterol trifenatate in the management of asthma: clinical trial evidence and experience

PubMed Central

Albertson, Timothy E.; Richards, John R.; Zeki, Amir A.

2015-01-01

The treatment of persistent asthma has been aided by the recent approval of new medications. The combined inhaled corticosteroid (ICS)/long-acting β2 agonist (LABA) powder inhaler fluticasone furoate (FF)/vilanterol trifenatate (VI) is one of these new agents, which was recently approved as a maintenance therapy for persistent asthma. This once-daily ICS/LABA inhaler has previously been approved and used in chronic obstructive pulmonary disease as a maintenance therapy. Both FF and VI individually have been shown to have efficacy in the treatment of persistent asthma; the combination of FF/VI at the dose of 100/25 μg daily improves trough peak expiratory flows and forced expiratory volume in 1 s. It also reduces the frequency of asthma exacerbations in patients with persistent asthma. The once-daily dosing is well tolerated, with limited clinically significant adverse events; the once-daily inhaled dosing regimen should also improve medication adherence. The data supporting the use of the FF/VI inhaler in persistent asthma are reviewed. The dry powder inhaler of FF/VI (100/25 μg) is an effective and well tolerated once-daily maintenance treatment for patients with persistent asthma. PMID:26668137

Influence of CYP3A5 genetic variation on everolimus maintenance dosing after cardiac transplantation.

PubMed

Lesche, Dorothea; Sigurdardottir, Vilborg; Setoud, Raschid; Englberger, Lars; Fiedler, Georg M; Largiadèr, Carlo R; Mohacsi, Paul; Sistonen, Johanna

2015-12-01

Everolimus (ERL) has become an alternative to calcineurin inhibitors (CNIs) due to its renal-sparing properties, especially in heart transplant (HTx) recipients with kidney dysfunction. However, ERL dosing is challenging due to its narrow therapeutic window combined with high interindividual pharmacokinetic variability. Our aim was to evaluate the effect of clinical and genetic factors on ERL dosing in a pilot cohort of 37 HTx recipients. Variants in CYP3A5, CYP3A4, CYP2C8, POR, NR1I2, and ABCB1 were genotyped, and clinical data were retrieved from patient charts. While ERL trough concentration (C0 ) was within the targeted range for most patients, over 30-fold variability in the dose-adjusted ERL C0 was observed. Regression analysis revealed a significant effect of the non-functional CYP3A5*3 variant on the dose-adjusted ERL C0 (p = 0.031). ERL dose requirement was 0.02 mg/kg/d higher in patients with CYP3A5*1/*3 genotype compared to patients with CYP3A5*3/*3 to reach the targeted C0 (p = 0.041). ERL therapy substantially improved estimated glomerular filtration rate (28.6 ± 6.6 mL/min/1.73 m(2)) in patients with baseline kidney dysfunction. Everolimus pharmacokinetics in HTx recipients is highly variable. Our preliminary data on patients on a CNI-free therapy regimen suggest that CYP3A5 genetic variation may contribute to this variability. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

[Effectiveness of the maintenance operations on the air conditioning systems of a university building in relation to the microbiological quality of the air indoor].

PubMed

De Filippis, Patrizia; Spinaci, Anna; Coia, Maura; Maggi, Oriana; Panà, Augusto

2003-01-01

The microbiological quality of the air indoor is influenced from various factors and one of the most important is represented from the maintenance of the conditioning systems. In this study it has been estimated the effectiveness of an intervention of cleaning and maintenance on the systems of conditioning of an university building executing sampling before and after such intervention. The two results were confronted and it is observed as the maintenance of the air conditioners has influenced on the quality of the air indoor.

Sympathetic nervous system influences on the kidney. Role in hypertension.

PubMed

DiBona, G F

1989-03-01

Efferent renal sympathetic nerve activity (ERSNA) is elevated in human essential hypertension as well as several forms of experimental hypertension in animals. In addition, bilateral complete renal denervation delays the development and/or attenuates the magnitude of the hypertension in several different forms of experimental hypertension in animals. Efferent renal sympathetic nerve activity is known to have dose-dependent effects on renal blood flow and glomerular filtration rate, renal tubular sodium and water reabsorption, and renin secretion rate that are capable of contributing, singly or in combination, to the development, maintenance, and exacerbation of the hypertensive state. Of the many factors known to influence the central nervous system integrative regulation of ERSNA, two environmental factors, dietary sodium intake and environmental stress, are capable of significant interaction. This resultant increase in ERSNA and subsequent renal functional alterations can participate in the hypertensive process. This is especially evident in the presence of an underlying genetic predisposition to the development of hypertension. Thus, interactions between environmental and genetic influences can produce alterations in the sympathetic neural control of renal function that play an important role in hypertension.

Evidence of validity and reliability of the Opiate Dosage Adequacy Scale (ODAS) in a sample of heroin addicted patients in buprenorphine/naloxone maintenance treatment.

PubMed

González-Saiz, Francisco; Lozano Rojas, Oscar; Trujols, Joan; Alcaraz, Saul; Siñol, Núria; Pérez de Los Cobos, José

2018-02-01

The Opiate Dosage Adequacy Scale (ODAS) is a clinical tool to individually measure the "adequacy" of opioid doses in patients on maintenance treatment. The aim of this paper is to provide evidence for the validity and reliability of the ODAS in a sample of patients in buprenorphine/naloxone (B/N) maintenance treatment. Cross-sectional study of a convenience sample of B/N-treated patients (n = 316) from four Autonomous Communities in Spain. Participants completed a battery of instruments to assess the following: buprenorphine dose adequacy; heroin dependence severity; psychological adjustment; and patient-desired adjustment of buprenorphine dose. Exploratory Factor Analysis identified four factors from the ODAS that together account for 85.4% of the total variance: "Heroin craving and use"; "Overmedication"; "Objective opiate withdrawal symptoms (OWS)" and 'Subjective OWS'. Compared to patients with an "inadequate" B/N dose (ODAS), patients with "adequate" doses had less heroin use in the last week (0.01 vs. 0.40; t = -2.73; p < 0.01, 95% CI: -0.67, -0.10), less severe heroin dependence (2.20 vs. 5.26, t = -5.14, p < 0.001; 95% CI: -4.23, -1.88), less psychological distress (3.00 vs. 6.31, t = -4.37, p < 0.001; 95% CI: -4.80, -1.81), and greater satisfaction with their doses (42.1% vs. 13.6%, χ 2  = 14.44, p < 0.01). Cronbach's alpha coefficient was 0.76 (0.81, 0.92, 0.94, and 0.93, respectively, for the four factor dimensions). These findings support the validity and reliability of the ODAS as a tool to measure and assess buprenorphine dose adequacy in the context of an opioid dependency treatment program. Copyright © 2017 Elsevier B.V. All rights reserved.

Randomized double-blind assessment of the ONSET and OFFSET of the antiplatelet effects of ticagrelor versus clopidogrel in patients with stable coronary artery disease: the ONSET/OFFSET study.

PubMed

Gurbel, Paul A; Bliden, Kevin P; Butler, Kathleen; Tantry, Udaya S; Gesheff, Tania; Wei, Cheryl; Teng, Renli; Antonino, Mark J; Patil, Shankar B; Karunakaran, Arun; Kereiakes, Dean J; Parris, Cordel; Purdy, Drew; Wilson, Vance; Ledley, Gary S; Storey, Robert F

2009-12-22

Ticagrelor is the first reversibly binding oral P2Y(12) receptor antagonist. This is the first study to compare the onset and offset of platelet inhibition (IPA) with ticagrelor using the PLATO (PLATelet inhibition and patient Outcomes) trial loading dose (180 mg) with a high loading dose (600 mg) of clopidogrel. In a multicenter, randomized, double-blind study, 123 patients with stable coronary artery disease who were taking aspirin therapy (75 to 100 mg/d) received ticagrelor (180-mg load, 90-mg BID maintenance dose [n=57]), clopidogrel (600-mg load, 75-mg/d maintenance dose [n=54]), or placebo (n=12) for 6 weeks. Greater IPA (20 micromol/L ADP, final extent) occurred with ticagrelor than with clopidogrel at 0.5, 1, 2, 4, 8, and 24 hours after loading and at 6 weeks (P<0.0001 for all); by 2 hours after loading, a greater proportion of patients achieved >50% IPA (98% versus 31%, P<0.0001) and >70% IPA (90% versus 16%, P<0.0001) in the ticagrelor group than in the clopidogrel group, respectively. A faster offset occurred with ticagrelor than with clopidogrel (4-to-72-hour slope [% IPA/h] -1.04 versus -0.48, P<0.0001). At 24 hours after the last dose, mean IPA was 58% for ticagrelor versus 52% for clopidogrel (P=NS). IPA for ticagrelor on day 3 after the last dose was comparable to clopidogrel at day 5; IPA on day 5 for ticagrelor was similar to clopidogrel on day 7 and did not differ from placebo (P=NS). Ticagrelor achieved more rapid and greater platelet inhibition than high-loading-dose clopidogrel; this was sustained during the maintenance phase and was faster in offset after drug discontinuation.

42 CFR 2.34 - Disclosures to prevent multiple enrollments in detoxification and maintenance treatment programs.

Code of Federal Regulations, 2013 CFR

2013-10-01

..., DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL PROVISIONS CONFIDENTIALITY OF ALCOHOL AND DRUG ABUSE PATIENT... means the dispensing of a narcotic drug in decreasing doses to an individual in order to reduce or... narcotic drug. Maintenance treatment means the dispensing of a narcotic drug in the treatment of an...

42 CFR 2.34 - Disclosures to prevent multiple enrollments in detoxification and maintenance treatment programs.

Code of Federal Regulations, 2011 CFR

2011-10-01

..., DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL PROVISIONS CONFIDENTIALITY OF ALCOHOL AND DRUG ABUSE PATIENT... means the dispensing of a narcotic drug in decreasing doses to an individual in order to reduce or... narcotic drug. Maintenance treatment means the dispensing of a narcotic drug in the treatment of an...

42 CFR 2.34 - Disclosures to prevent multiple enrollments in detoxification and maintenance treatment programs.

Code of Federal Regulations, 2012 CFR

2012-10-01

..., DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL PROVISIONS CONFIDENTIALITY OF ALCOHOL AND DRUG ABUSE PATIENT... means the dispensing of a narcotic drug in decreasing doses to an individual in order to reduce or... narcotic drug. Maintenance treatment means the dispensing of a narcotic drug in the treatment of an...

42 CFR 2.34 - Disclosures to prevent multiple enrollments in detoxification and maintenance treatment programs.

Code of Federal Regulations, 2014 CFR

2014-10-01

..., DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL PROVISIONS CONFIDENTIALITY OF ALCOHOL AND DRUG ABUSE PATIENT... means the dispensing of a narcotic drug in decreasing doses to an individual in order to reduce or... narcotic drug. Maintenance treatment means the dispensing of a narcotic drug in the treatment of an...

Hedonic sensitivity to low-dose ketamine is modulated by gonadal hormones in a sex-dependent manner

PubMed Central

Saland, Samantha K.; Schoepfer, Kristin J.; Kabbaj, Mohamed

2016-01-01

We recently reported a greater sensitivity of female rats to rapid antidepressant-like effects of ketamine compared to male rats, and that ovarian-derived estradiol (E2) and progesterone (P4) are essential for this response. However, to what extent testosterone may also contribute, and whether duration of response to ketamine is modulated in a sex- and hormone-dependent manner remains unclear. To explore this, we systematically investigated the influence of testosterone, estradiol and progesterone on initiation and maintenance of hedonic response to low-dose ketamine (2.5 mg/kg) in intact and gonadectomized male and female rats. Ketamine induced a sustained increase in sucrose preference of female, but not male, rats in an E2P4-dependent manner. Whereas testosterone failed to alter male treatment response, concurrent administration of P4 alone in intact males enhanced hedonic response low-dose ketamine. Treatment responsiveness in female rats only was associated with greater hippocampal BDNF levels, but not activation of key downstream signaling effectors. We provide novel evidence supporting activational roles for ovarian-, but not testicular-, derived hormones in mediating hedonic sensitivity to low-dose ketamine in female and male rats, respectively. Organizational differences may, in part, account for the persistence of sex differences following gonadectomy and selective involvement of BDNF in treatment response. PMID:26888470

Initiatives to improve prescribing efficiency for drugs to treat Parkinson's disease in Croatia: influence and future directions.

PubMed

Brkicic, Ljiljana Sovic; Godman, Brian; Voncina, Luka; Sovic, Slavica; Relja, Maja

2012-06-01

Parkinson's disease (PD) is the second most common neurological disease affecting older adults. Consequently, this disease should be a focus among payers, with increasing utilization of newer premium-priced patent-protected add-on therapies to stabilize or even improve motor function over time. However, expenditure can be moderated by reforms. Consequently, there is a need to assess the influence of these reforms on the prescribing efficiency for drugs to treat PD in Croatia before proposing additional measures. Prescribing efficiency is defined as increasing the use of add-on therapies for similar expenditure. An observational retrospective study of the Croatian Institute for Health Insurance database of drugs to treat patients with PD in Croatia from 2000 to 2010 was carried out, with utilization measured in defined daily doses (defined as the average maintenance dose of a drug when used in its major indication in adults). The study years were chosen to reflect recent reforms. Only reimbursed expenditure is measured from a health insurance perspective. Utilization of drugs to treat PD increased by 218% between 2000 and 2010. Reimbursed expenditure increased by 360%, principally driven by increasing utilization of premium-priced patent-protected add-on therapies, including ropinirole and pramipexole. However, following recent reforms, reducing expenditure/defined daily dose for the different drugs, as well as overall expenditure, stabilized reimbursed expenditure between 2005 and 2010. Treatment of PD is complex, and add-on therapies are needed to improve care. Reimbursed expenditure should now fall following stabilization, despite increasing volumes, as successive add-on therapies lose their patents, further increasing prescribing efficiency.

Respirators, internal dose, and Oyster Creek

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

Michal, R.

1996-06-01

This article looks at the experience of Oyster Creek in relaxing the requirements for the use of respirators in all facets of plant maintenance, on the overall dose received by plant maintenance personnel. For Roger Shaw, director of radiological controls for three years at GPU Nuclear Corporation`s Oyster Creek nuclear plant the correct dose balance is determined on a job-by-job basis: Does the job require a respirator, which is an effective means of decreasing worker inhalation of airborne radioactive particles? Will wearing a respirator slow down a worker, consequently increasing whole body radiation exposure by prolonging the time spent inmore » fields of high external radiation? How does respiratory protection affect worker safety and to what degree? While changes to the Nuclear Regulatory Commission`s 10CFR20 have updated the radiation protection requirements for the nuclear industry, certain of the revisions have been directed specifically at reducing worker dose, Shaw said. {open_quotes}It basically delineates that dose is dose,{close_quotes} Shaw said, {open_quotes}regardless of whether it is acquired externally or internally.{close_quotes} The revision of Part 20 changed the industry`s attitude toward internal dose, which had always been viewed negatively. {open_quotes}Internal dose was always seen as preventable by wearing respirators and by using engineering techniques such as ventilation control and decontamination,{close_quotes} Shaw said, {open_quotes}whereas external dose, although reduced where practical, was seen as a fact of the job.{close_quotes}« less

Reduced tyrosine kinase inhibitor dose is predicted to be as effective as standard dose in chronic myeloid leukemia: A simulation study based on phase 3 trial data.

PubMed

Fassoni, Artur C; Baldow, Christoph; Roeder, Ingo; Glauche, Ingmar

2018-06-28

Continuing tyrosine kinase inhibitor mediated targeting of the BCR-ABL1 oncoprotein is the standard therapy for chronic myeloid leukemia and allows for a sustained disease control in the majority of patients. While therapy cessation for patients appeared as a safe option for about half of the optimally responding patients, a systematic assessment of long-term tyrosine kinase inhibitor dose de-escalation is missing. We use a mathematical model to analyze and consistently describe biphasic treatment responses from tyrosine kinase inhibitor treated patients from two independent clinical phase-3 trials. Scale estimates reveal that drug efficiency determines the initial response while the long-term behavior is limited by the rare activation of leukemic stem cells. We use this mathematical framework to investigate the influence of different dosing regimens on the treatment outcome. We provide strong evidence suggesting that tyrosine kinase inhibitor dose de-escalation (at least 50%) does not lead to a reduction of long-term treatment efficiency for most patients, which have already achieved sustained remission, and maintains the secondary decline of BCR-ABL1 levels. We demonstrate that continuous BCR-ABL1 monitoring provides patient-specific predictions of an optimal reduced dose not decreasing the anti-leukemic effect on residual leukemic stem cells. Our results are consistent with the interim results of the DESTINY trial and provide clinically testable predictions. Our results suggest that dose halving should be considered as a long-term treatment option for well-responding chronic myeloid leukemia patients under continuing maintenance therapy with tyrosine kinase inhibitors. We emphasize the clinical potential of this approach to reduce treatment-related side-effects and therapy costs. Copyright © 2018, Ferrata Storti Foundation.

The comparative short-term effectiveness of iron dosing and formulations in US hemodialysis patients.

PubMed

Kshirsagar, Abhijit V; Freburger, Janet K; Ellis, Alan R; Wang, Lily; Winkelmayer, Wolfgang C; Brookhart, M Alan

2013-06-01

Intravenous iron is used widely in hemodialysis, yet there are limited data on the effectiveness of contemporary dosing strategies or formulation type. We conducted a retrospective cohort study using data from the clinical database of a large dialysis provider (years 2004-2008) merged with administrative data from the US Renal Data System to compare the effects of intravenous iron use on anemia management. Dosing comparisons were bolus (consecutive doses ≥100 mg exceeding 600 mg during 1 month) versus maintenance (all other iron doses during the month); and high (>200 mg over 1 month) versus low dose (≤200 mg over 1 month). Formulation comparison was administration of ferric gluconate versus iron sucrose over 1 month. Outcomes were hemoglobin, epoetin dose, transferrin saturation, and serum ferritin during 6 weeks of follow-up. We identified 117,050 patients for the dosing comparison, and 66,207 patients for the formulation comparison. Bolus dosing was associated with higher average adjusted hemoglobin (+0.23 g/dL; 95% confidence interval [CI], 0.21-0.26), transferrin saturation (+3.31%; 95% CI, 2.99-3.63), serum ferritin (+151 μg/L; 95% CI, 134.9-168.7), and lower average epoetin dose (-464 units; 95% CI, -583 to -343) compared with maintenance. Similar trends were observed with high-dose iron versus low-dose. Iron sucrose was associated with higher adjusted average hemoglobin (+0.16 g/dL; 95% CI, 0.12-0.19) versus ferric gluconate. Strategies favoring large doses of intravenous iron or iron sucrose lead to improved measures of anemia management. These potential benefits should be weighed against risks, which currently remain incompletely characterized. Copyright © 2013 Elsevier Inc. All rights reserved.

The long-term effects of switching from active intravenous bisphosphonate treatment to low-dose maintenance therapy in children with osteogenesis imperfecta.

PubMed

Biggin, Andrew; Zheng, Linda; Briody, Julie N; Coorey, Craig P; Munns, Craig F

2015-01-01

Intravenous bisphosphonate therapy is the first-line treatment in moderate-to-severe osteogenesis imperfecta (OI), but there are varied treatment protocols with little data on long-term efficacy. This study evaluates the clinical outcomes when transitioning from active bisphosphonate treatment to maintenance therapy. A retrospective review was conducted on 17 patients before treatment, following active treatment (zoledronate 0.05 mg/kg 6-monthly or pamidronate 6-9 mg/kg/year) and after establishment on maintenance treatment for more than 2 years (zoledronate 0.025 mg/kg 6-monthly or pamidronate <4 mg/kg/year). There was a significant reduction in mean fracture rate from 1.5 ± 1.1 fractures/year at baseline to 0.7 ± 0.7 fractures/year on active treatment. Z-scores for lumbar spine bone mineral density, bone mineral content, volumetric bone mineral density and bone mineral content for lean tissue mass increased during active treatment. These improvements were maintained during the period of maintenance treatment. Vertebral height improved in fractured thoracic vertebrae from pre-treatment to active therapy and improved further during maintenance treatment. Metacarpal cortical thickness and relative cortical area also increased over the treatment periods. Maintenance intravenous bisphosphonate therapy preserved the beneficial effects of active treatment at the doses stated above. Further studies are required to determine the optimal bisphosphonate treatment regimen in the management of children with OI. © 2015 S. Karger AG, Basel.

Indoor Air Quality Management for Operations and Maintenance Personnel

DTIC Science & Technology

1991-09-01

short-lived radioisotopes collectively referred to as radon " daughters ." The first four of these daughters-polonium- 218, lead-214, bismuth-214, and...that can damage cells, increasing the risk of lung cancer. The radiation dose from inhaled radon daughters makes up about half the total dose from

Maintenance on naltrexone+amphetamine decreases cocaine-vs.-food choice in male rhesus monkeys.

PubMed

Moerke, Megan J; Banks, Matthew L; Cheng, Kejun; Rice, Kenner C; Negus, S Stevens

2017-12-01

Cocaine use disorder remains a significant public health issue for which there are no FDA-approved pharmacotherapies. Amphetamine maintenance reduces cocaine use in preclinical and clinical studies, but the mechanism of this effect is unknown. Previous studies indicate a role for endogenous opioid release and subsequent opioid receptor activation in some amphetamine effects; therefore, the current study examined the role of mu-opioid receptor activation in d-amphetamine treatment effects in an assay of cocaine-vs-food choice. Adult male rhesus monkeys with double-lumen intravenous catheters responded for concurrently available food pellets and cocaine injections (0-0.1mg/kg/injection) during daily sessions. Cocaine choice and overall reinforcement rates were evaluated during 7-day treatments with saline or test drugs. During saline treatment, cocaine maintained a dose-dependent increase in cocaine-vs.-food choice. The mu-opioid receptor agonist morphine (0.032-0.32mg/kg/h) dose-dependently increased cocaine choice and decreased rates of reinforcement. A dose of the mu-selective opioid receptor antagonist naltrexone (0.0032mg/kg/h) that completely blocked morphine effects had no effect on cocaine choice when it was administered alone, but it enhanced the effectiveness of a threshold dose of 0.032mg/kg/h amphetamine to decrease cocaine choice without also enhancing nonselective behavioral disruption by this dose of amphetamine. Conversely, the kappa-selective opioid antagonist norbinalorphimine did not enhance amphetamine effects on cocaine choice. These results suggest that amphetamine maintenance produces mu opioid-receptor mediated effects that oppose its anti-cocaine effects. Co-administration of naltrexone may selectively enhance amphetamine potency to decrease cocaine choice without increasing amphetamine potency to produce general behavioral disruption. Copyright © 2017 Elsevier B.V. All rights reserved.

High-dose methotrexate and rituximab with deferred radiotherapy for newly diagnosed primary B-cell CNS lymphoma.

PubMed

Chamberlain, Marc C; Johnston, Sandra K

2010-07-01

We conducted a prospective Phase II study of high-dose methotrexate (HD-MTX) and rituximab with deferred whole brain radiotherapy in patients with newly diagnosed B-cell primary central nervous system lymphoma with a primary objective of evaluating progression-free survival (PFS). Forty patients (25 men; 15 women), ages 18-93 years (median 61.5), were treated. All patients received biweekly HD-MTX/rituximab (8 g/m(2)/dose; 375 mg/m(2)/dose) for 4-6 cycles (induction) and following best radiographic response, with every 4 weeks HD-MTX (8 g/m(2)/dose) for 4 cycles (maintenance). Neurological and neuroradiographic evaluation were performed every 4 weeks during induction therapy and every 8 weeks during maintenance therapy. All patients were evaluable. A total of 303 cycles of HD-MTX (median 8 cycles; range 4-10) was administered. HD-MTX/rituximab-related toxicity included 16 grade 3 adverse events in 13 patients (32.5%). Following induction, 8 patients (20%) demonstrated progressive disease and discontinued therapy; 32 patients (80%) demonstrated a partial (8/40; 20%) or complete (24/40; 60%) radiographic response. At the conclusion of maintenance therapy (6-10 months of total therapy), 28 patients (70%) demonstrated either a partial (1/28) or complete (27/28) response. Overall, survival of these 28 patients ranged from 11 to 80 months (median 33.5). Survival in the entire cohort ranged from 6 to 80 months with an estimated median of 29 months. Overall, PFS ranged from 2 to 80 months (median 21.0). HD-MTX/rituximab and deferred radiotherapy demonstrated similar or better efficacy similar to other HD-MTX-only regimens and reduced time on therapy on average to 6 months.

High-dose methotrexate and rituximab with deferred radiotherapy for newly diagnosed primary B-cell CNS lymphoma

PubMed Central

Chamberlain, Marc C.; Johnston, Sandra K.

2010-01-01

We conducted a prospective Phase II study of high-dose methotrexate (HD-MTX) and rituximab with deferred whole brain radiotherapy in patients with newly diagnosed B-cell primary central nervous system lymphoma with a primary objective of evaluating progression-free survival (PFS). Forty patients (25 men; 15 women), ages 18–93 years (median 61.5), were treated. All patients received biweekly HD-MTX/rituximab (8 g/m2/dose; 375 mg/m2/dose) for 4–6 cycles (induction) and following best radiographic response, with every 4 weeks HD-MTX (8 g/m2/dose) for 4 cycles (maintenance). Neurological and neuroradiographic evaluation were performed every 4 weeks during induction therapy and every 8 weeks during maintenance therapy. All patients were evaluable. A total of 303 cycles of HD-MTX (median 8 cycles; range 4–10) was administered. HD-MTX/rituximab-related toxicity included 16 grade 3 adverse events in 13 patients (32.5%). Following induction, 8 patients (20%) demonstrated progressive disease and discontinued therapy; 32 patients (80%) demonstrated a partial (8/40; 20%) or complete (24/40; 60%) radiographic response. At the conclusion of maintenance therapy (6–10 months of total therapy), 28 patients (70%) demonstrated either a partial (1/28) or complete (27/28) response. Overall, survival of these 28 patients ranged from 11 to 80 months (median 33.5). Survival in the entire cohort ranged from 6 to 80 months with an estimated median of 29 months. Overall, PFS ranged from 2 to 80 months (median 21.0). HD-MTX/rituximab and deferred radiotherapy demonstrated similar or better efficacy similar to other HD-MTX-only regimens and reduced time on therapy on average to 6 months. PMID:20511181

Six-month, open-label study of hydrocodone extended release formulated with abuse-deterrence technology: Safety, maintenance of analgesia, and abuse potential.

PubMed

Hale, Martin E; Ma, Yuju; Malamut, Richard

2016-01-01

To evaluate long-term safety, maintenance of analgesia, and aberrant drug-related behaviors of hydrocodone extended release (ER) formulated with CIMA® Abuse-Deterrence Technology. Phase 3, multicenter, open-label extension. Fifty-six US centers. Adults with chronic low back pain completing a 12-week placebocontrolled study of abuse-deterrent hydrocodone ER were eligible. One hundred eighty-two patients enrolled and received ≥1 dose of study drug, 170 entered openlabel treatment, and 136 completed the study. Patients receiving hydrocodone ER in the 12-week, placebo-controlled study continued their previous dose unless adjustment was needed; those previously receiving placebo (n=78) underwent dose titration/adjustment to an analgesic dose (15-90 mg every 12 hours). Patients received 22 weeks of open-label treatment. adverse events (AEs). Maintenance of analgesia: worst pain intensity (WPI) and average pain intensity (API) at each study visit. Aberrant drug behavior: study drug loss and diversion. AEs were reported for 65/182 (36 percent) patients during dose titration/ adjustment and 88/170 (52 percent) during open-label treatment. No treatmentrelated serious AEs were reported. There were no clinically meaningful trends in other safety assessments, including physical examinations and pure tone audiometry. One patient receiving hydrocodone ER 30 mg twice daily experienced a severe AE of neurosensory deafness that was considered treatment related. Mean WPI and API remained steady throughout open-label treatment. Six (3 percent) patients reported medication loss, and 5 (3 percent) reported diversion. Abuse-deterrent hydrocodone ER was generally well tolerated in patients with chronic low back pain, maintained efficacy, and was associated with low rates of loss and diversion.

Therapeutic drug monitoring of vedolizumab in inflammatory bowel disease: current data and future directions.

PubMed

Ward, Mark G; Sparrow, Miles P; Roblin, Xavier

2018-01-01

The introduction of vedolizumab, a lymphocyte adhesion inhibitor, has expanded the relatively limited therapeutic armamentarium available for Crohn's disease and ulcerative colitis. Despite its effectiveness, both primary nonresponse and secondary loss of response to vedolizumab do occur, as is observed with the use of anti-tumour necrosis factor (TNF) therapy. Further, in a proportion, onset of efficacy may be relatively slow. A large body of data support an exposure-response relationship with anti-TNF drug levels, which has led to therapeutic drug monitoring becoming incorporated into everyday clinical management. The influence of patient and disease factors on the pharmacokinetics of anti-TNF levels, including immunogenicity, has also been examined. The role of therapeutic drug monitoring with vedolizumab is less clear. This review summarizes the available evidence on the pharmacokinetics and pharmacodynamics of vedolizumab in inflammatory bowel disease and how drug levels, immunogenicity and other factors influence clinical outcomes. Vedolizumab clearance is increased with very high body weight and hypoalbuminaemia, but is not influenced by the addition of an immunomodulator. Immunogenicity is uncommon. α4β7 receptor saturation occurs at low serum vedolizumab drug levels, and measuring it alone is insufficient to predict clinical outcomes. Using quartile analysis of vedolizumab drug levels, there appears to be a modest exposure-response relationship during induction. Drug levels at week 6 of approximately >20 μg/ml have been shown to be associated with improved clinical outcomes, including subsequent mucosal healing rates during maintenance and avoiding the need to dose escalate due to lack of response. There are currently insufficient data to support the routine use of therapeutic drug monitoring during maintenance therapy. Further studies to elucidate the role of therapeutic drug monitoring of vedolizumab are needed.

A randomized trail using motivational interviewing for maintenance of blood pressure improvements in a community-engaged lifestyle intervention: HUB City Steps

USDA-ARS?s Scientific Manuscript database

Background: Little is known about the effective dose of motivational interviewing for maintaining intervention-induced health outcome improvements. Purpose: To compare effects of two doses of motivational interviewing for maintaining blood pressure improvements in a community-engaged lifestyle int...

Long-term mesalamine maintenance in ulcerative colitis: which is more important? Adherence or daily dose.

PubMed

Khan, Nabeel; Abbas, Ali M; Koleva, Yordanka N; Bazzano, Lydia A

2013-05-01

There are limited data about the long-term follow-up of patients with ulcerative colitis (UC) maintained on high versus low doses of mesalamine. We evaluated the best long-term average daily dose that would keep the disease in remission. Nationwide ulcerative colitis data were obtained from the Veterans Affairs health care system for the period 2001 to 2011. Those who started mesalamine maintenance during this period were included. Average daily dose and the level of adherence were assessed for the period between the first mesalamine dispense and the date of first flare defined as the first filling of 40 mg/day or more of oral prednisone or any dose of intravenous steroids. Patients with ulcerative colitis maintained on an average daily dose 2.4 to 2.8 g/day (low dose) were compared with 4.4 to 4.8 g/day (high dose). Adherence was assessed using continuous single interval medication availability indicator. We included 4452 patients with a median follow-up of 6 years. There was no significant reduction in the risk of flares when comparing high versus low average mesalamine dose among patients with high [hazard ratio = 0.96, P = 0.8)] and medium (hazard ratio = 0.74, P = 0.17) adherence. However, there was a significant reduction in the risk of flares with high dose of mesalamine among patients with low adherence (hazard ratio = 0.28, P = 0.003). Our data show that when starting a patient on mesalamine, there is no difference in the long-term flare risk between low versus high average daily dose as long as the patients have a high to moderate level of adherence.

The effect of switching from oral low-dose aripiprazole to aripiprazole once-monthly 300 mg on the quality of life in three patients with schizophrenia.

PubMed

Suzuki, Hidenobu; Hibino, Hiroyuki; Inoue, Yuichi; Matsumoto, Hideo; Mikami, Katsunaka

2017-01-01

Schizophrenia is a chronic disease that requires long-term management with antipsychotics; however, an important barrier to the success of long-term treatment is drug noncompliance, which increases the risk of recurrence and hospitalization. Second-generation long-acting injectable antipsychotics have improved drug adherence, and the pharmacological effects of the drugs, and therefore, have become useful treatment options. We report on three schizophrenia patients who switched from oral low-dose aripiprazole to aripiprazole once-monthly 300 mg. We examined the efficacy and safety of aripiprazole once-monthly 300 mg, as well as its influence on quality of life, from baseline to 20 weeks after aripiprazole once-monthly 300 mg treatment. Aripiprazole once-monthly 300 mg did not exacerbate the depressive and negative symptoms, and extrapyramidal symptoms were improved, which may have helped improve the quality of life. The results suggest the efficacy of aripiprazole once-monthly 300 mg in maintenance treatment for schizophrenia when mental symptoms are stable.

Once-daily MMX(®) mesalamine for endoscopic maintenance of remission of ulcerative colitis.

PubMed

D'Haens, Geert; Sandborn, William J; Barrett, Karen; Hodgson, Ian; Streck, Paul

2012-07-01

Treatment with mesalamine to maintain endoscopic remission (mucosal healing) of ulcerative colitis (UC) has been shown to reduce the risk of relapse and is the recommended first-line maintenance therapy. To improve treatment adherence, a mesalamine formulation that can be administered once-daily, MMX(®) mesalamine (Lialda; Shire Pharmaceuticals LLC, Wayne, PA), was developed. This study was conducted to determine the efficacy and safety of once-daily MMX mesalamine compared with twice-daily delayed-release mesalamine (Asacol; Warner Chilcott, Dublin, Ireland) for maintaining endoscopic remission in patients with UC. A multicenter, randomized, double-blind, 6-month, active-control trial was conducted to assess the non-inferiority of once-daily MMX mesalamine 2.4 g/day compared with twice-daily delayed-release mesalamine at a total daily dose of 1.6 g/day in patients with UC in endoscopic remission. The primary end point was maintenance of endoscopic remission at month 6 in the per-protocol (PP) population. Overall, 826 patients were randomized and dosed. The primary objective (non-inferiority) was met. At month 6, 83.7 and 77.8% of patients receiving MMX mesalamine in the PP and intent-to-treat (ITT) populations, respectively, had maintained endoscopic remission compared with 81.5% (PP) and 76.9% (ITT) of patients receiving delayed-release mesalamine (95% confidence interval for difference: -3.9%, 8.1% (PP); -5.0%, 6.9% (ITT)). Time to relapse was not significantly different between the two treatment groups (log-rank test, P=0.5116 (PP); P=0.5455 (ITT)). The proportion of patients with adverse events was 37.1 and 36.0% in patients receiving MMX mesalamine and delayed-release mesalamine, respectively. Once-daily dosing of MMX mesalamine 2.4 g/day was shown to be well tolerated and non-inferior to twice-daily dosing with delayed-release mesalamine 1.6 g/day for maintenance of endoscopic remission in patients with UC.

The efficacy of alfaxalone for immersion anesthesia in koi carp (Cyprinus carpio).

PubMed

Minter, Larry J; Bailey, Kate M; Harms, Craig A; Lewbart, Gregory A; Posner, Lysa P

2014-07-01

To characterize the physiologic and behavioral effects of a single induction dose and two maintenance doses of alfaxalone delivered by water immersion in the anesthesia of koi (Cyprinus carpio). Prospective, within-subject complete crossover design. Six adult koi (Cyprinus carpio) with a median body weight of 344.5 g (range 292.0-405.0 g). Koi were immersed in water containing 10 mg L(-1) alfaxalone until immobile and then maintained with alfaxalone at either 1 or 2.5 mg L(-1) via a recirculating water system. Times for anesthetic induction and recovery periods were recorded. Physiologic and blood gas parameters were evaluated before, during and after the anesthetic trial. Response to noxious stimuli was also assessed. Median anesthesia induction time for all fish was 5.4 minutes. Median recovery time was 11.8 and 26.4 minutes in the 1.0 and 2.5 mg L(-1) doses, respectively, which were significantly different (p = 0.04). Cessation of opercular movement occurred in 0/6 and 4/6 fish exposed to 1.0 and 2.5 mg L(-1) dose respectively. No difference was observed in median heart rate over the duration of the anesthetic events. Response to noxious stimulation was 4/6 and 0/6 in the 1.0 and 2.5 mg L(-1) doses respectively. Oxygenation and ventilation did not change during the experiment, but there was a significant decrease in blood pH along with an increase in blood lactate concentration. Administration of alfaxalone, via water immersion, as an induction and maintenance anesthesia agent provided rapid and reliable anesthesia of koi with no mortality. The maintenance dose of 2.5 mg L(-1) was sufficient to prevent response to noxious stimuli but was associated with a clinically relevant depression in opercular rate. © 2014 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia.

Oral 5-aminosalicylic acid for maintenance of remission in ulcerative colitis.

PubMed

Wang, Yongjun; Parker, Claire E; Feagan, Brian G; MacDonald, John K

2016-05-09

Oral 5-aminosalicylic (5-ASA) preparations were intended to avoid the adverse effects of sulfasalazine (SASP) while maintaining its therapeutic benefits. Previously, it was found that 5-ASA drugs were more effective than placebo but had a statistically significant therapeutic inferiority relative to SASP. This updated review includes more recent studies and evaluates the effectiveness, dose-responsiveness, and safety of 5-ASA preparations used for maintenance of remission in quiescent ulcerative colitis. The primary objectives were to assess the efficacy, dose-responsiveness and safety of oral 5-ASA compared to placebo, SASP, or 5-ASA comparators for maintenance of remission in quiescent ulcerative colitis. A secondary objective was to compare the efficacy and safety of once daily dosing of oral 5-ASA with conventional (two or three times daily) dosing regimens. A literature search for relevant studies (inception to 9 July 2015) was performed using MEDLINE, EMBASE and the Cochrane Library. Review articles and conference proceedings were also searched to identify additional studies. Studies were accepted for analysis if they were randomized controlled trials with a minimum treatment duration of six months. Studies of oral 5-ASA therapy for treatment of patients with quiescent ulcerative colitis compared with placebo, SASP or other 5-ASA formulations were considered for inclusion. Studies that compared once daily 5-ASA treatment with conventional dosing of 5-ASA and 5-ASA dose ranging studies were also considered for inclusion. The primary outcome was the failure to maintain clinical or endoscopic remission. Secondary outcomes included adherence, adverse events, withdrawals due to adverse events, and withdrawals or exclusions after entry. Trials were separated into five comparison groups: 5-ASA versus placebo, 5-ASA versus sulfasalazine, once daily dosing versus conventional dosing, 5-ASA versus comparator 5-ASA formulation, and 5-ASA dose-ranging. Placebo-controlled trials were subgrouped by dosage. Once daily versus conventional dosing studies were subgrouped by formulation. 5-ASA-controlled trials were subgrouped by common 5-ASA comparators (e.g. Asacol and Salofalk). Dose-ranging studies were subgrouped by 5-ASA formulation. We calculated the risk ratio (RR) and 95% confidence intervals (95% CI) for each outcome. Data were analyzed on an intention-to-treat basis. Forty-one studies (8928 patients) were included. The majority of included studies were rated as low risk of bias. Ten studies were rated at high risk of bias. Seven of these studies were single-blind and three studies were open-label. However, two open-label studies and four of the single-blind studies utilized investigator performed endoscopy as an endpoint, which may protect against bias. 5-ASA was significantly superior to placebo for maintenance of clinical or endoscopic remission. Forty-one per cent of 5-ASA patients relapsed compared to 58% of placebo patients (7 studies, 1298 patients; RR 0.69, 95% CI 0.62 to 0.77). There was a trend towards greater efficacy with higher doses of 5-ASA with a statistically significant benefit for the 1 to 1.9 g/day (RR 0.65; 95% CI 0.56 to 0.76) and the > 2 g/day subgroups (RR 0.73, 95% CI 0.60 to 0.89). SASP was significantly superior to 5-ASA for maintenance of remission. Forty-eight per cent of 5-ASA patients relapsed compared to 43% of SASP patients (12 studies, 1655 patients; RR 1.14, 95% CI 1.03 to 1.27). A GRADE analysis indicated that the overall quality of the evidence for the primary outcome for the placebo and SASP-controlled studies was high. No statistically significant differences in efficacy or adherence were found between once daily and conventionally dosed 5-ASA. Twenty-nine per cent of once daily patients relapsed over 12 months compared to 31% of conventionally dosed patients (8 studies, 3127 patients; RR 0.91, 95% CI 0.82 to 1.01). Eleven per cent of patients in the once daily group failed to adhere to their medication regimen compared to 9% of patients in the conventional dosing group (6 studies, 1462 patients; RR 1.22, 95% CI 0.91 to 1.64). There does not appear to be any difference in efficacy among the various 5-ASA formulations. Forty-four per cent of patients in the 5-ASA group relapsed compared to 41% of patients in the 5-ASA comparator group (6 studies, 707 patients; RR 1.08, 95% CI 0.91 to 1.28). A pooled analysis of two studies showed no statistically significant difference in efficacy between Balsalazide 6 g and 3 g/day. Twenty-three per cent of patients in the 6 g/day group relapsed compared to 33% of patients in the 3 g/day group (216 patients; RR 0.76; 95% CI 0.45 to 2.79). One study found Balsalazide 4 g to be superior to 2 g/day. Thirty-seven per cent of patients in the 4 g/day Balsalazide group relapsed compared to 55% of patients in the 2 g/day group (133 patients; RR 0.66; 95% CI 0.45 to 0.97). One study found a statistically significant difference between Salofalk granules 3 g and 1.5 g/day. Twenty-five per cent of patients in the Salofalk 3 g/day group relapsed compared to 39% of patients in the 1.5 g/day group (429 patients; RR 0.65; 95% CI 0.49 to 0.86). Common adverse events included flatulence, abdominal pain, nausea, diarrhea, headache, dyspepsia, and nasopharyngitis. There were no statistically significant differences in the incidence of adverse events between 5-ASA and placebo, 5-ASA and SASP, once daily and conventionally dosed 5-ASA, 5-ASA and comparator 5-ASA formulations and 5-ASA dose ranging studies. The trials that compared 5-ASA and SASP may have been biased in favour of SASP because most trials enrolled patients known to be tolerant to SASP which may have minimized SASP-related adverse events. 5-ASA was superior to placebo for maintenance therapy in ulcerative colitis. However, 5-ASA had a statistically significant therapeutic inferiority relative to SASP. Oral 5-ASA administered once daily is as effective and safe as conventional dosing for maintenance of remission in quiescent ulcerative colitis. There does not appear to be any difference in efficacy or safety between the various formulations of 5-ASA. Patients with extensive ulcerative colitis or with frequent relapses may benefit from a higher dose of maintenance therapy. High dose therapy appears to be as safe as low dose and is not associated with a higher incidence of adverse events.

Space-type radiation induces multimodal responses in the mouse gut microbiome and metabolome.

PubMed

Casero, David; Gill, Kirandeep; Sridharan, Vijayalakshmi; Koturbash, Igor; Nelson, Gregory; Hauer-Jensen, Martin; Boerma, Marjan; Braun, Jonathan; Cheema, Amrita K

2017-08-18

Space travel is associated with continuous low dose rate exposure to high linear energy transfer (LET) radiation. Pathophysiological manifestations after low dose radiation exposure are strongly influenced by non-cytocidal radiation effects, including changes in the microbiome and host gene expression. Although the importance of the gut microbiome in the maintenance of human health is well established, little is known about the role of radiation in altering the microbiome during deep-space travel. Using a mouse model for exposure to high LET radiation, we observed substantial changes in the composition and functional potential of the gut microbiome. These were accompanied by changes in the abundance of multiple metabolites, which were related to the enzymatic activity of the predicted metagenome by means of metabolic network modeling. There was a complex dynamic in microbial and metabolic composition at different radiation doses, suggestive of transient, dose-dependent interactions between microbial ecology and signals from the host's cellular damage repair processes. The observed radiation-induced changes in microbiota diversity and composition were analyzed at the functional level. A constitutive change in activity was found for several pathways dominated by microbiome-specific enzymatic reactions like carbohydrate digestion and absorption and lipopolysaccharide biosynthesis, while the activity in other radiation-responsive pathways like phosphatidylinositol signaling could be linked to dose-dependent changes in the abundance of specific taxa. The implication of microbiome-mediated pathophysiology after low dose ionizing radiation may be an unappreciated biologic hazard of space travel and deserves experimental validation. This study provides a conceptual and analytical basis of further investigations to increase our understanding of the chronic effects of space radiation on human health, and points to potential new targets for intervention in adverse radiation effects.

ABCB1 haplotype and OPRM1 118A > G genotype interaction in methadone maintenance treatment pharmacogenetics

PubMed Central

Barratt, Daniel T; Coller, Janet K; Hallinan, Richard; Byrne, Andrew; White, Jason M; Foster, David JR; Somogyi, Andrew A

2012-01-01

Background: Genetic variability in ABCB1, encoding the P-glycoprotein efflux transporter, has been linked to altered methadone maintenance treatment dose requirements. However, subsequent studies have indicated that additional environmental or genetic factors may confound ABCB1 pharmacogenetics in different methadone maintenance treatment settings. There is evidence that genetic variability in OPRM1, encoding the mu opioid receptor, and ABCB1 may interact to affect morphine response in opposite ways. This study aimed to examine whether a similar gene-gene interaction occurs for methadone in methadone maintenance treatment. Methods: Opioid-dependent subjects (n = 119) maintained on methadone (15–300 mg/day) were genotyped for five single nucleotide polymorphisms of ABCB1 (61A > G; 1199G > A; 1236C > T; 2677G > T; 3435C > T), as well as for the OPRM1 118A > G single nucleotide polymorphism. Subjects’ methadone doses and trough plasma (R)-methadone concentrations (Ctrough) were compared between ABCB1 haplotypes (with and without controlling for OPRM1 genotype), and between OPRM1 genotypes (with and without controlling for ABCB1 haplotype). Results: Among wild-type OPRM1 subjects, an ABCB1 variant haplotype group (subjects with a wild-type and 61A:1199G:1236C:2677T:3435T haplotype combination, or homozygous for the 61A:1199G:1236C:2677T:3435T haplotype) had significantly lower doses (median ± standard deviation 35 ± 5 versus 180 ± 65 mg/day, P < 0.01) and Ctrough (78 ± 22 versus 177 ± 97 ng/mL, P < 0.05) than ABCB1 wild-type subjects. Among subjects with the most common ABCB1 haplotype combination (wild-type with 61A:1199G:1236T:2677T:3435T), the OPRM1 118 A/G genotype was associated with a significantly higher Ctrough than 118 A/A (250 ± 126 versus 108 ± 36 ng/mL, P = 0.016). No ABCB1 haplotype group or OPRM1 genotype was associated with dose or Ctrough without taking into account confounding genetic variability at the other locus. Therefore, two interacting pharmacogenetic determinants of methadone maintenance treatment response were identified, ie, ABCB1, where variants are associated with lower methadone requirements, and OPRM1, where the variant is associated with higher methadone requirements. Conclusion: These opposing pharmacogenetic effects therefore need to be considered in combination when assessing methadone maintenance treatment pharmacogenetics. PMID:23226062

5-Azacitidine Monotherapy Followed by Related Haploidentical Hematopoietic Stem Cell Transplantation Achieves Durable Remission in a Pediatric Patient With Acute Undifferentiated Leukemia Refractory to High-Dose Chemotherapy.

PubMed

Polishchuk, Veronika; Khazal, Sajad; Berulava, Giorgi; Roth, Michael; Mahadeo, Kris M

2016-06-01

Patients with acute leukemias of undifferentiated lineage (AUL) generally have guarded prognosis. Here, we describe the first reported pediatric patient with AUL refractory to high-dose chemotherapy who achieved clinical remission with ALL maintenance therapy and 5-azacitidine. His induction remission was followed by consolidation with reduced toxicity haploidentical hematopoietic stem cell transplant (HSCT). At 9 months post-HSCT, the patient is alive and in remission. This combination therapy of remission induction with ALL maintenance therapy and 5-azacitidine and consolidation with reduced toxicity haploidentical HSCT is novel and promising for patients who lack conventional donors and are not candidates for myeloablative therapy. © 2016 Wiley Periodicals, Inc.

Conflict, negative emotion, and reports of partners' relationship maintenance in same-sex couples.

PubMed

Ogolsky, Brian G; Gray, Christine R

2016-03-01

The literature on relationship maintenance has focused primarily on the beneficial outcomes of maintenance, and, as a result, little is known about relational processes that may interfere with reports of partners' maintenance. The authors examine how daily conflict influences individuals' reports of their partners' maintenance, and how a constructive communication style buffers this influence by reducing negative emotion on conflict days. In a daily diary study of 98 same-sex couples in romantic relationships, they found that the negative association between conflict and reports of a partner's relationship maintenance was mediated by negative emotion. That is, there was an indirect effect by which daily conflict was associated with higher levels of daily negative emotion, which was associated with reports of lower levels of partners' relationship maintenance. This indirect effect was moderated by couples' overall level of constructive communication such that higher levels diminished the degree to which couples experienced negative emotion on days with episodes of relational conflict. The authors discuss results in the context of interpersonal theory and provide implications for clinicians and practitioners. (c) 2016 APA, all rights reserved).

A Randomized Trial Using Motivational Interviewing for Maintenance of Blood Pressure Improvements in a Community-Engaged Lifestyle Intervention: HUB City Steps

ERIC Educational Resources Information Center

Landry, Alicia; Madson, Michael; Thomson, Jessica; Zoellner, Jamie; Connell, Carol; Yadrick, Kathleen

2015-01-01

Little is known about the effective dose of motivational interviewing for maintaining intervention-induced health outcome improvements. The purpose of this study was to compare effects of two doses of motivational interviewing for maintaining blood pressure improvements in a community-engaged lifestyle intervention conducted with…

Selenium Reduces Early Signs of Tumor Necrosis Factor Alpha-Induced Meniscal Tissue Degradation.

PubMed

Häfelein, Klaus; Preuße-Prange, Andrea; Behrendt, Peter; Kurz, Bodo

2017-05-01

Meniscal integrity is a prerequisite for sustained knee joint health and prevention of meniscal degeneration is a main research goal. Cartilage-protective effects of selenium have been described, but little is known about the impact on the meniscus. We therefore investigated the influence of sodium selenite on meniscal explants under tumor necrosis factor-alpha (TNFα)-stimulated proinflammatory conditions. Meniscal explant disks (3 mm diameter × 1 mm thickness) were isolated from 2-year-old cattle and incubated with TNFα (10 ng/ml) and sodium selenite (low dose, LoD 6.7 ng/ml as being found in Insulin-Transferrin-Selenium medium supplements, ITS; medium-dose, MeD 40 ng/ml described as physiological synovial concentration; high dose, HiD 100 ng/ml described as optimal serum concentration). After 3 days of culture glycosaminoglycan (GAG) release (DMMB assay), nitric oxide (NO) production (Griess assay), gene expression of matrix-degrading enzymes (quantitative RT-PCR), and apoptosis rate were determined. TNFα led to a significant raise of GAG release and NO production. LoD and MeD selenite significantly reduced the TNFα-induced GAG release (by 83, 55 %, respectively), NO production (by 59, 40 %, respectively), and apoptosis (by 68, 39 %, respectively). LoD and MeD selenite showed a tendency to reduce the TNFα-mediated increase of inducible NO-synthase (iNOS) levels, LoD selenite furthermore matrix metalloproteinase (MMP)-3 transcription levels and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-4 levels. LoD and less pronounced MeD selenite show a substantial impact on the early meniscal inflammatory response. To our knowledge this is the first study showing the protective influence of selenium on meniscal tissue maintenance. To understand the superior potency of low-dose selenium on molecular level future studies are needed.

Efficacy and Safety of a Colistin Loading Dose, High-Dose Maintenance Regimen in Critically Ill Patients With Multidrug-Resistant Gram-Negative Pneumonia.

PubMed

Elefritz, Jessica L; Bauer, Karri A; Jones, Christian; Mangino, Julie E; Porter, Kyle; Murphy, Claire V

2017-09-01

Emergence of multidrug-resistant (MDR) gram-negative (GN) pathogens and lack of novel antibiotics have increased the use of colistin, despite unknown optimal dosing. This study aimed to evaluate the safety and efficacy of a colistin loading dose, high-dose (LDHD) maintenance regimen in patients with MDR-GN pneumonia. A retrospective cohort analysis was performed comparing critically ill patients with MDR-GN pneumonia pre- and postimplementation of a colistin LDHD guideline with a primary outcome of clinical cure. Safety was assessed using incidence of acute kidney injury (AKI) based on RIFLE (risk, injury, failure, loss, end-stage renal disease) criteria. Seventy-two patients met the inclusion criteria (42 preimplementation and 30 postimplementation). Clinical cure was achieved in 23 (55%) patients in the preimplementation group and 20 (67%) patients in the postimplementation group ( P = .31). AKI occurred in 50% of the patients during the preimplementation period and 58% during the postimplementation period ( P = .59) with no difference in initiation rates of renal replacement therapy. The increased clinical cure rate after implementation of the colistin LDHD guideline did not reach statistical significance. The LDHD guideline, however, was not associated with an increased incidence of AKI, despite higher intravenous colistin doses. Opportunity exists to optimize colistin dosage while balancing toxicity, but larger studies are warranted.

Description and Results of the Air Force Research and Development Program for the Improvement of Maintenance Efficiency.

ERIC Educational Resources Information Center

Foley, John P., Jr.

An overview of the Air Force's Research and Development Program for the Improvement of Maintenance Efficiency is provided. First described are the steps found in any detailed task analysis, a process which results in the complete specification of each task involved in an overall maintenance effort. The factors influencing maintenance effectiveness…

Can we safely administer the recommended dose of phenobarbital in very low birth weight infants?

PubMed

Oztekin, Osman; Kalay, Salih; Tezel, Gonul; Akcakus, Mustafa; Oygur, Nihal

2013-08-01

We investigated whether the recommended phenobarbital loading dose of 15-20 mg/kg with maintenance of 3-4 mg/kg/day can safely be administered to very low birth weight preterm newborns with seizures. Twenty-four convulsive preterms of <1,500 g were enrolled in the study. Phenobarbital was administered intravenously with a loading dose of 15 mg/kg in approximately 10-15 min. After 24 h, the maintenance dose of 3 mg/kg/day was administered as a single injection. Blood samples were obtained 2, 24, 48, 72, and 96 h after the phenobarbital loading dose was administered, immediately before the next phenobarbital dose was injected. None of the cases had plasma phenobarbital concentrations above the therapeutic upper limit of 40 μg/mL on the 2nd hour; one case (4.7%), on the 24th; 11 cases (45.8%), on the 48th; 15 cases (62.5%), on the 72nd; and 17 cases (70.8%), on the 96th hour. A negative correlation was detected between the serum concentrations of phenobarbital and gestational age on the 72th (p, 0.036; r, -0.608) and 96th hour (p, 0.043; r, -0.769). We suggest that particular attention should be done while administering phenobarbital in preterms, as blood levels of phenobarbital are higher than the reference ranges that those are often reached with the recommended doses in these groups of babies.

Predicting the neurobehavioral side effects of dexamethasone in pediatric acute lymphoblastic leukemia.

PubMed

Warris, Lidewij T; van den Akker, Erica L T; Aarsen, Femke K; Bierings, Marc B; van den Bos, Cor; Tissing, Wim J E; Sassen, Sebastiaan D T; Veening, Margreet A; Zwaan, Christian M; Pieters, Rob; van den Heuvel-Eibrink, Marry M

2016-10-01

Although dexamethasone is an effective treatment for acute lymphoblastic leukemia (ALL), it can induce a variety of serious neurobehavioral side effects. We hypothesized that these side effects are influenced by glucocorticoid sensitivity at the tissue level. We therefore prospectively studied whether we could predict the occurrence of these side effects using the very low-dose dexamethasone suppression test (DST) or by measuring trough levels of dexamethasone. Fifty pediatric patients (3-16 years of age) with acute lymphoblastic leukemia (ALL) were initially included during the maintenance phase (with dexamethasone) of the Dutch ALL treatment protocol. As a marker of glucocorticoid sensitivity, the salivary very low-dose DST was used. A post-dexamethasone cortisol level <2.0nmol/L was considered a hypersensitive response. The neurobehavioral endpoints consisted of questionnaires regarding psychosocial and sleeping problems administered before and during the course of dexamethasone (6mg/m(2)), and dexamethasone trough levels were measured during dexamethasone treatment. Patients with a hypersensitive response to dexamethasone had more behavioral problems (N=11), sleeping problems, and/or somnolence (N=12) (P<0.05 for all three endpoints). The positive predictive values of the DST for psychosocial problems and sleeping problems were 50% and 30%, respectively. Dexamethasone levels were not associated with neurobehavioral side effects. We conclude that neither the very low-dose DST nor measuring dexamethasone trough levels can accurately predict dexamethasone-induced neurobehavioral side effects. However, patients with glucocorticoid hypersensitivity experienced significantly more symptoms associated with dexamethasone-induced depression. Future studies should elucidate further the mechanisms by which neurobehavioral side effects are influenced by glucocorticoid sensitivity. Copyright © 2016 Elsevier Ltd. All rights reserved.

Value of information of repair times for offshore wind farm maintenance planning

NASA Astrophysics Data System (ADS)

Seyr, Helene; Muskulus, Michael

2016-09-01

A large contribution to the total cost of energy in offshore wind farms is due to maintenance costs. In recent years research has focused therefore on lowering the maintenance costs using different approaches. Decision support models for scheduling the maintenance exist already, dealing with different factors influencing the scheduling. Our contribution deals with the uncertainty in the repair times. Given the mean repair times for different turbine components we make some assumptions regarding the underlying repair time distribution. We compare the results of a decision support model for the mean times to repair and those repair time distributions. Additionally, distributions with the same mean but different variances are compared under the same conditions. The value of lowering the uncertainty in the repair time is calculated and we find that using distributions significantly decreases the availability, when scheduling maintenance for multiple turbines in a wind park. Having detailed information about the repair time distribution may influence the results of maintenance modeling and might help identify cost factors.

Maintenance dose conversion between oral risperidone and paliperidone palmitate 1 month: Practical guidance based on pharmacokinetic simulations.

PubMed

Russu, Alberto; Kern Sliwa, Jennifer; Ravenstijn, Paulien; Singh, Arun; Mathews, Maju; Kim, Edward; Gopal, Srihari

2018-06-01

We assessed the dosage strengths of paliperidone palmitate 1-month (PP1M) long-acting injectable resulting in similar steady-state (SS) exposures to the dosage strengths of oral risperidone using pharmacokinetic (PK) simulations. Population PK simulations of SS PK were performed using the PK models of oral risperidone and PP1M. The concentrations of active moiety (risperidone + paliperidone) from risperidone were compared to paliperidone concentrations resulting from PP1M administration. Similarity was assessed via graphical evaluation of median and 90% prediction intervals of SS PK profiles over 28 days. Oral risperidone doses of 1, 2, 3, 4, and 6 mg/d are expected to result in similar SS PK as PP1M doses of 25, 50, 75, 100, and 150 mg eq. (which correspond to 39, 78, 117, 156, and 234 mg of paliperidone palmitate) respectively (ie 25-fold dose conversion factor from oral risperidone to PP1M). This study provides clinicians with a practical guidance to establish suitable maintenance dose levels of PP1M and oral risperidone when transitioning patients from one formulation to another. © 2018 The Authors. International Journal of Clinical Practice Published by John Wiley & Sons Ltd.

Digoxin: placental transfer, effects on the fetus, and therapeutic use in the newborn.

PubMed

Soyka, L F

1975-03-01

Digoxin rapidly crosses the placenta and reaches equilibrium, with maternal and fetal sera having equal concentrations. Virtually nothing is known about the effects of transplacentally administered digoxin on the fetus. Toxicity has been reported in the fetus of a woman ingesting a huge overdose of digitoxin; the same result would be anticipated with digoxin poisoning. Serum levels in pregnant women receiving the standard dose of 0.25 mg tend to be subnormal and certain patients may require a small increase in dose during the last trimester. While the full-term neonate appears to tolerate relatively high doses and the resultant high serum levels, there is no compelling evidence that such doses are necessary or even useful. Since toxicity can and does occur in neonates, especially during administration of loading (digitalizing) doses, it is recommended that maintenance doses of 0.01 mg per kg per day be used routinely. If the full inotropic effect is needed immediately, a loading dose of 0.03 mg per kg may be employed. Maintenance therapy is then begun on the following day. Without a loading dose cumulation occurs for about 3 days; after 5 or so days, serum levels will equal those found after use of a loading dose followed by maintenance therapy. Results of a single study suggest that the daily dose should be divided and given every 12 hours. After about 1 week of therapy, the serum level should be determined and the dose modified to maintain a serum level of 1 to 2 ng per ml. If the therapeutic effect is less than desired, a cautions increase in dose to as high as 0.02 mg per kg per day or to that dose which produces serum levels up to 3 ng per ml can be tried. Certain infants appear to tolerate serum levels of 3.5 to 4 ng per ml but such infants must be closely monitored. There are no data which indicate that a greater inotropic response will occur at these high serum levels, though this point has not been definitively investigated, and is the highest priority question for research. The intramuscular route should be researved for the unusual situation. Vomiting should be considered an early sign of toxicity and may act as a "safety valve." When adminstered in solution (as in the elixir or solution for intravenous use), oral digoxin is rapidly absorbed an an inotropic response is found within minutes, reaching a peak within hours, so that little is gained by parenteral administration. If an inotropic effect is urgently needed, intravenous administration of ouabain will give an immediate response.

The Influence of Academic Culture on Quality Management System ISO 9001 Maintenance within Malaysian Universities

ERIC Educational Resources Information Center

Basir, Siti Arni; Davies, John; Douglas, Jacqueline; Douglas, Alexander

2017-01-01

This study investigates the influence of the elements of academic culture on quality management system ISO 9001 maintenance within Malaysian universities. There is a dearth of empirical studies on maintaining ISO 9001, particularly in the higher education context. From the literature review, academic culture was classified according to four…

Dose reduction and cost-benefit analysis at Japan`s Tokai No. 2 Plant

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

Humamoto, Hisao; Suzuki, Seishiro; Taniguchi, Kazufumi

1995-03-01

In the Tokai No. 2 power plant of the Japan Atomic Power Company, about 80% of the annual dose equivalent is received during periodic maintenance outages. A project group for dose reduction was organized at the company`s headquarters in 1986; in 1988, they proposed a five-year program to reduce by half the collective dose of 4 person-Sv per normal outage work. To achieve the target dose value, some dose-reduction measures were undertaken, namely, permanent radiation shielding, decontamination, automatic, operating machines, and ALARA organization. As the result, the collective dose from normal outage work was 1.6 person-Sv in 1992, which wasmore » less than the initial target value.« less

On tolerability and safety of a maintenance treatment with 6-thioguanine in azathioprine or 6-mercaptopurine intolerant IBD patients

PubMed Central

de Boer, Nanne KH; Derijks, Luc JJ; Gilissen, Lennard PL; Hommes, Daniel W; Engels, Leopold GJB; de Boer, Sybrand Y; den Hartog, Gijsbertus; Hooymans, Piet M; Mäkelburg, Anja BU; Westerveld, Barend D; Naber, Anton HJ; Mulder, Chris JJ; de Jong, Dirk J

2005-01-01

AIM: To determine the tolerability and safety profile of a low-dose maintenance therapy with 6-TG in azathioprine (AZA) or 6-mercaptopurine (6-MP) intolerant inflammatory bowel disease (IBD) patients over a treatment period of at least 1 year. METHODS: Database analysis. RESULTS: Twenty out of ninety-five (21%) patients discontinued 6-TG (mean dose 24.6 mg; mean 6-TGN level 540 pmol/8×108 RBC) within 1 year. Reasons for discontinuation were GI complaints (31%), malaise (15%) and hepatotoxicity (15%). Hematological events occurred in three patients, one discontinued treatment. In the 6-TG-tolerant group, 9% (7/75) could be classified as hepatotoxicity. An abdominal ultrasound was performed in 54% of patients, one patient had splenomegaly. CONCLUSION: The majority of AZA or 6-MP-intolerant IBD patients (79%) is able to tolerate maintenance treatment with 6-TG (dosages between 0.3 and 0.4 mg/kg per d). 6-TG may still be considered as an escape maintenance immunosuppressant in this difficult to treat group of patients, taking into account potential toxicity and efficacy of other alternatives. The recently reported hepatotoxicity is worrisome and 6-TG should therefore be administered only in prospective trials. PMID:16222751

Opioid Detoxification and Naltrexone Induction Strategies: Recommendations for Clinical Practice

PubMed Central

Sigmon, Stacey C.; Bisaga, Adam; Nunes, Edward V.; O'Connor, Patrick G.; Kosten, Thomas; Woody, George

2015-01-01

Background Opioid dependence is a significant public health problem associated with high risk for relapse if treatment is not ongoing. While maintenance on opioid agonists (i.e., methadone, buprenorphine) often produces favorable outcomes, detoxification followed by treatment with the μ-opioid receptor antagonist naltrexone may offer a potentially useful alternative to agonist maintenance for some patients. Method Treatment approaches for making this transition are described here based on a literature review and solicitation of opinions from several expert clinicians and scientists regarding patient selection, level of care, and detoxification strategies. Conclusion Among the current detoxification regimens, the available clinical and scientific data suggest that the best approach may be using an initial 2–4 mg dose of buprenorphine combined with clonidine, other ancillary medications, and progressively increasing doses of oral naltrexone over 3–5 days up to the target dose of naltrexone. However, more research is needed to empirically validate the best approach for making this transition. PMID:22404717

A Grounded Theory Study of Aircraft Maintenance Technician Decision-Making

NASA Astrophysics Data System (ADS)

Norcross, Robert

Aircraft maintenance technician decision-making and actions have resulted in aircraft system errors causing aircraft incidents and accidents. Aircraft accident investigators and researchers examined the factors that influence aircraft maintenance technician errors and categorized the types of errors in an attempt to prevent similar occurrences. New aircraft technology introduced to improve aviation safety and efficiency incur failures that have no information contained in the aircraft maintenance manuals. According to the Federal Aviation Administration, aircraft maintenance technicians must use only approved aircraft maintenance documents to repair, modify, and service aircraft. This qualitative research used a grounded theory approach to explore the decision-making processes and actions taken by aircraft maintenance technicians when confronted with an aircraft problem not contained in the aircraft maintenance manuals. The target population for the research was Federal Aviation Administration licensed aircraft and power plant mechanics from across the United States. Nonprobability purposeful sampling was used to obtain aircraft maintenance technicians with the experience sought in the study problem. The sample population recruitment yielded 19 participants for eight focus group sessions to obtain opinions, perceptions, and experiences related to the study problem. All data collected was entered into the Atlas ti qualitative analysis software. The emergence of Aircraft Maintenance Technician decision-making themes regarding Aircraft Maintenance Manual content, Aircraft Maintenance Technician experience, and legal implications of not following Aircraft Maintenance Manuals surfaced. Conclusions from this study suggest Aircraft Maintenance Technician decision-making were influenced by experience, gaps in the Aircraft Maintenance Manuals, reliance on others, realizing the impact of decisions concerning aircraft airworthiness, management pressures, and legal concerns related to decision-making. Recommendations included an in-depth systematic review of the Aircraft Maintenance Manuals, development of a Federal Aviation Administration approved standardized Aircraft Maintenance Technician decision-making flow diagram, and implementation of risk based decision-making training. The benefit of this study is to save the airline industry revenue by preventing poor decision-making practices that result in inefficient maintenance actions and aircraft incidents and accidents.

Nitrous oxide-induced slow and delta oscillations

PubMed Central

Pavone, Kara J.; Akeju, Oluwaseun; Sampson, Aaron; Ling, Kelly; Purdon, Patrick L.; Brown, Emery N.

2015-01-01

Objectives Switching from maintenance of general anesthesia with an ether anesthetic to maintenance with high-dose (concentration > 50% and total gas flow rate > 4 liters per minute) nitrous oxide is a common practice used to facilitate emergence from general anesthesia. The transition from the ether anesthetic to nitrous oxide is associated with a switch in the putative mechanisms and sites of anesthetic action. We investigated whether there is an electroencephalogram (EEG) marker of this transition. Methods We retrospectively studied the ether anesthetic to nitrous oxide transition in 19 patients with EEG monitoring receiving sevoflurane, oxygen and air for general anesthesia maintenance. Results Following the transition to nitrous oxide, the alpha (8 to 12 Hz) oscillations associated with sevoflurane dissipated within 3 to 12 minutes (median 6 minutes) and were replaced by highly coherent large-amplitude slow-delta (0.1 to 4 Hz) oscillations that persisted for 2 to 12 minutes (median 3 minutes). Conclusions Administration of high-dose nitrous oxide is associated with transient, large amplitude slow-delta oscillations. Significance We postulate that these slow-delta oscillations may result from nitrous oxide-induced blockade of major excitatory inputs (NMDA glutamate projections) from the brainstem (parabrachial nucleus and medial pontine reticular formation) to the thalamus and cortex. This EEG signature of high-dose nitrous oxide may offer new insights into brain states during general anesthesia. PMID:26118489

Multi-Matrix System (MMX®) mesalamine for the treatment of mild-to-moderate ulcerative colitis.

PubMed

Horst, Sara N; Kane, Sunanda

2012-10-01

Ulcerative colitis (UC) is an inflammatory disease of the colon characterized by periods of active disease and remission. The pathogenesis of this disease is likely a complex interaction of genetic predisposition, environmental factors, and immune system dysregulation, and is not completely understood. A Multi-MatriX (MMX®) system formulation of mesalamine, MMX mesalamine (SPD476; Lialda®; Mesavancol®; Mezavant®), allows for high-dose, once-daily dosing for patients with mild-to-moderate UC. Mesalamine is a topically active agent with anti-inflammatory properties. Available literature regarding MMX mesalamine is extensively reviewed in this article, covering its chemical makeup, mechanism of action, pharmaceutics and pharmacokinetics, clinical efficacy, and safety and tolerability. A dose of 2.4 and 4.8 g was used in large Phase III clinical trials and was efficacious for induction of clinical and endoscopic remission in UC. MMX mesalamine was also efficacious in large multicenter maintenance studies for the maintenance of clinical and endoscopic remission. The introduction of the first once-daily mesalamine has given practitioners and patients more flexibility in dosing administration, which will ultimately lead to higher satisfaction and improved clinical outcomes.

Neurosteroid Modulators of GABAA Receptors Differentially Modulate Ethanol Intake Patterns in Male C57BL/6J Mice

PubMed Central

Ford, Matthew M.; Nickel, Jeffrey D.; Phillips, Tamara J.; Finn, Deborah A.

2006-01-01

Background Allopregnanolone (ALLO) and structurally related endogenous neurosteroids are potent modulators of GABAA receptor function at physiologically relevant concentrations. Accumulating evidence implicates a modulatory role for ALLO in behavioral processes underlying ethanol self-administration, discrimination and reinstatement. The purpose of this study was to evaluate the impact of exogenous neurosteroid challenges with the agonist ALLO and the partial agonist/antagonist epipregnanolone (EPI) on the microarchitecture of ethanol drinking patterns. Methods Male C57BL/6J mice were initiated to consume an unsweetened 10% v/v ethanol solution (10E) by a saccharin fading procedure during daily 2-hour limited access sessions beginning 1 hour after dark phase onset. Cumulative lick responses were recorded for 10E and water using lickometer circuits. After establishing 10E intake baselines, mice were habituated to vehicle injection (VEH; 20% w/v β-cyclodextrin; i.p.), and then were treated with either VEH or neurosteroid immediately prior to the drinking session. Each mouse received a series of ALLO doses (3.2, 10, 17 and 24 mg/kg) alone and EPI doses (0.15, 1, 3 and 10 mg/kg) alone in a counterbalanced within-group design. Results The GABAA receptor positive modulator, ALLO, dose-dependently modulated overall ethanol intake throughout the 2-hr session with the 3.2 mg/kg dose eliciting a significant increase whereas the 24 mg/kg dose produced a significant suppression of ethanol intake versus vehicle pretreatment. ALLO-evoked alterations in intake corresponded with a significant, dose-dependent alterations in bout frequency and inter-bout interval. ALLO also elicited robust, dose-dependent elevations in 10E licks during the initial 5-minutes of access, but subsequently resulted in a dose-dependent suppression of 10E licks during session minutes 20–80. In contrast, the partial agonist/antagonist neurosteroid, EPI, exhibited no influence on any consumption parameter evaluated. Conclusions The present findings suggest that GABAA receptor-active neurosteroids may modulate the regulatory processes that govern the onset, maintenance, and termination of drinking episodes. The differential influence of ALLO and EPI on ethanol intake patterns may reflect an alteration in GABAergic inhibitory tone that is likely due to each neurosteroid’s pharmacological profile at GABAA receptors. Manipulation of endogenous ALLO may prove a useful strategy for diminishing excessive intake and protecting against the loss of regulatory control over drinking. PMID:16205363

Developmental Differences in the Influence of Distractors on Maintenance in Spatial Working Memory

ERIC Educational Resources Information Center

Schutte, Anne R.; Keiser, Brian A.; Beattie, Heidi L.

2017-01-01

This study examined whether attention to a location plays a role in the maintenance of locations in spatial working memory in young children as it does in adults. This study was the first to investigate whether distractors presented during the delay of a spatial working-memory task influenced young children's memory responses. Across 2…

How to select among available options for the treatment of multiple myeloma.

PubMed

Harousseau, J L

2012-09-01

The introduction of novel agents (thalidomide, bortezomib and lenalidomide) in the frontline therapy of multiple myeloma has markedly improved the outcome both in younger patients who are candidates for high-dose therapy plus autologous stem-cell transplantation (HDT/ASCT) and in elderly patients. In the HDT/ASCT paradigm, novel agents may be used as induction therapy or after HDT/ASCT as consolidation and/or maintenance therapy. It is now possible to achieve up to 70% complete plus very good partial remission after HDT/ASCT and 70% 3-year progression-free survival (PFS). However long-term non-intensive therapy may also yield high response rates and prolonged PFS. Randomized trials comparing these two strategies are underway. In elderly patients, six randomized studies show the benefit of adding thalidomide to melphalan-prednisone (MP). a large randomized trial has also shown that the combination of bortezomib-MP is superior to MP for all parameters measuring the response and outcome. Finally, the role of maintenance is currently evaluated and a randomized trial shows that low-dose lenalidomide maintenance prolongs PFS.

Spotlight on fluticasone furoate/vilanterol trifenatate for the once-daily treatment of asthma: design, development and place in therapy

PubMed Central

Albertson, Timothy E; Bullick, Samuel W; Schivo, Michael; Sutter, Mark E

2016-01-01

The use of inhaled corticosteroids (ICSs) plays a key role in the treatment of asthmatic patients, and international guidelines have designated ICSs as an early maintenance therapy in controlling asthma symptoms. When asthmatic patients remain symptomatic on ICSs, one common option is to add a long-acting beta2 agonist (LABA) to the maintenance treatment. Fixed combination inhalers that contain both an ICS and a LABA have been popular for both chronic obstructive pulmonary disease (COPD) and asthma. Historically, these inhalers have been dosed twice daily. However, currently, there is a once-daily combination therapy with the ICS fluticasone furoate (FF) and the LABA vilanterol trifenatate (VI) with indications for use in both COPD and asthma. This dry powder inhaler (DPI) comes in two doses of FF (100 or 200 μg) both combined with VI (25 μg). This article reviews the clinical trial data for FF, VI and FF/VI combination inhalers and documents the efficacy and safety of once-daily inhaled maintenance therapy by DPI in asthmatic patients. PMID:28008228

Frequency, predictors, and economic impact of upward dose adjustment of infliximab in managed care patients with rheumatoid arthritis.

PubMed

Ollendorf, Daniel A; Massarotti, Elena; Birbara, Charles; Burgess, Somali Misra

2005-06-01

To examine dosing patterns and costs among rheumatoid arthritis (RA) patients newly treated with infliximab in a large national health care claims database. Using data from a proprietary database of pharmacy and medical claims for 75 U.S. health plans, RA patients newly treated with infliximab between June 2000 and June 2002 were selected and assigned an .index date. based on the first infusion. A pretreatment period of 6 months was created; patients were also followed for a minimum of 6 months after the initial infusion. Follow-up was allowed to vary beyond this minimum 6 months in order to preserve all available patient data. A maintenance number of infliximab vials was determined as of the second infusion; patients with 1 subsequent increase in vials used or 2 intervals between infusions of <49 days were considered to have had an upward dose adjustment. Differences (i.e., between those with upward dose adjustment and those with no upward dose) in patient characteristics were examined using descriptive statistics. In addition, time to upward dose adjustment and factors influencing its likelihood were analyzed using Kaplan-Meier and Cox proportional hazards techniques. Finally, differences in RA-related and unrelated costs (medication, outpatient, inpatient, and total, expressed in 2003 dollars) were examined using Wilcoxon rank-sum tests and were also stratified by a number of patient characteristics found to differ between the 2 groups. A total of 1,236 patients met all study entry criteria and were included in these analyses. One or more upward dose adjustments were experienced by 61.7% (N=762) of patients during an average of 15 months of follow-up (median =13 months, range=6 to 31 months). The majority (63.3%) of upward dose adjustments were due to increases in the number of billed vials. Median time to upward dose adjustment was 254 days and declined steadily based on year of initiation (from 330 days in 2000 to 224 days in 2002). Factors significantly influencing upward dose adjustment included pretreatment use of leflunomide, comorbid Crohn.s disease, and pretreatment liver function testing. During followup, patients in the upward dose adjustment group used a mean (SD) of 30.28 (20.90) vials of infliximab, compared with 15.90 (14.28) among those not adjusting dose (P<0.001). Annualized (i.e., standardized to a 365-day rate) RA-related costs were higher by more than 50% among patients with upward dose adjustment (SD $22,283 [$20,517] versus $14,425 [$10,828] for those without upward dose adjustment; P<0.001); differences were driven almost entirely by the costs of infliximab itself ($16,336 [$9,490] versus $9,573 [$6,790], P<0.001). In a cohort of managed care members with RA, upward dose adjustment with infliximab was frequent and appeared to occur earlier in the drug therapy in 2002 compared with 2000. Upward dose adjustment was associated with significant increases in drug treatment costs; therefore, payers and providers should consider the impact of current dosing trends when monitoring the use of biologics for autoimmune diseases.

P15.05 High-dose methotrexate based immuno-chemotherapy with maintenance chemotherapy with High-dose methotrexate and deferred radiotherapy for elderly primary CNS lymphoma patients

PubMed Central

Mishima, K.; Miyake, Y.

2017-01-01

Abstract Introduction: High-dose methotrexate (HD-MTX)-based chemotherapy with whole brain irradiation (WBRT) improves the prognosis of PCNSL. However, the high neurotoxicity rates observed, especially in the elderly, raised interest in chemotherapy-only treatments. Withholding radiotherapy substantially decreases the risk of neurotoxicity, however, disease control may be compromised. Therefore, developing novel treatment for the elderly patients is crucial. To assess the efficacy and toxicity of induction immunochemotherapy with rituximab (RIT) and HD-MTX, maintenance chemotherapy with HD-MTX and deferred WBRT in the treatment of elderly PCNSL patients, we conducted a retrospective analysis. Materials and Methods: Newly diagnosed elderly PCNSL patients (median age: 74 years) received biweekly RIT/ HD-MTX (375 mg/m2/dose; 3.5g/m2/dose) for 6 cycles followed by monthly RIT/MTX for 2 cycles (induction) and then were treated differently according to radiological response. With CR patents, HD-MTX was continued with every 3 months (maintenance) for 2 years. For PD patients, immunochemotherapy was interrupted and WBRT initiated immediately. Patients with PR and SD were treated with alternative chemotherapy with temozolomide and/or stereotactic radiotherapy or WBRT. Results: Twenty-eight patients were treated with the RIT/HD-MTX regimen. In 26 patients suitable for radiographic evaluation, 61.5% (16/26) had a CR, 23.1% (6/26) had a PR, 3.8 % (1/26) had a SD and 11.5% (3/26) had a PD. The median PFS was 24.6 months and median OS was 28.2 months for the entire cohort. Grade III-IV toxicities were observed in 8 of 28 patients and included neutropenia in 17.9%, thrombocytopenia in 3.6%, pneumonia in 10.7%, elevation of aminotransferases in 3.6%, and hyponatremia in 3.6%. Patients achieving a CR after induction immunochemotherapy (n=16) had a significantly longer OS (65.8 months) and PFS (52.4 months) than patients with less than CR (n=10) (OS: 13.9 months; PFS: 9.3 months) (P<.0001). Conclusions: The RIT/HD-MTX regimen and maintenance chemotherapy with HD-MTX seems to play a favorable role in elderly PCNSL patients with mild toxicity.

VKORC1 polymorphisms and warfarin maintenance dose in population of Sakha (Yakuts).

PubMed

Chertovskikh, Y V; Malova, E U; Maksimova, N R; Popova, N V; Sychev, D A

2015-01-01

Vitamin K antagonists are effective in the prevention and treatment of thromboembolic disorders. Warfarin is one of the most widely prescribed vitamin K antagonists in the world [1, 2]. It has a narrow therapeutic range and a given dose may result in a large inter-individual variation of response. Insufficient dose may fail to prevent thromboembolism, while an overdose increases the risk of bleeding. Patient-specific factors (e.g., age, body size, race, concurrent diseases, and medications) explain some of the variability in warfarin dosage, but genetic factors influencing warfarin response explain a significantly higher proportion of this variability [3]. Molecular analysis of the gene that encodes the target enzyme vitamin K epoxide reductase complex 1 (VKORC1) strongly suggests that its genetic variations greatly affect the individual response to oral anticoagulants [4-7]. To evaluate effects of VKORC1 polymorphisms on warfarin dose excess anticoagulation (INR >4.0) in the population of Sakha (S) patients. 53 patients (29-women, 24-men) with atrial fibrillation (68%), congestive heart failure (60%), hypertension (49%) and cardiac valve replacement (26%) were recruited. The age range was 26-80 years, with a mean age of 62.87 ± 12.57 years.International normalized ratio and plasma warfarin concentrations were determined. Genotyping was carried out by RT-PCR (real-time PCR). The three genetic polymorphisms of the gene VKORC1 G3673A (rs9923231) were studied: normal (GG), heterozygous (GA) and homozygous (AA). Fisher exact probability test and chi-square test (with Yates correction) were applied to compare data among the AA and GG + GA groups; also Mann-Whitney test was used. The median maintenance daily dose of warfarin among AA carriers was 3.0 mg/day [1.25-7.5 mg], while in GG and GA patients it was 3.13 mg/day [1.88-7.92 mg]. The mean daily warfarin dosage was higher in GG and GA genotype carriers 4.05 mg/day (SD ± 1.7) than in patients with AA genotype 3.13 (SD ± 1.5). Differences are of borderline significance (p = 0.054). Of the 41 patients who required warfarin doses of less than 5 mg, 28 (63%) were found to be AA carriers and 14 (37%) were GG, GA carriers. Differences were not quite significant (p = 0.072). Among 31 homozygous polymorphism carriers 2 (4%) patients developed overanticoagulation (INR >4.0), while among 22 normal and heterozygous polymorphisms carriers only 3 (6%) patients developed overanticoagulation (INR >4.0). Differences were not statistically significant (p = 0.36). No significant association between VKORC1 polymorphisms and the frequency of excess anticoagulation (INR >4.0) was found. This may be explained by the number of cases included. AA polymorphisms compared to other polymorphisms shows borderline difference in the warfarin dose. The results can be used for the development of a pharmacogenetic-guided warfarin dosing algorithm.

Maintenance treatment for opioid dependence with slow-release oral morphine: a randomized cross-over, non-inferiority study versus methadone

PubMed Central

Beck, Thilo; Haasen, Christian; Verthein, Uwe; Walcher, Stephan; Schuler, Christoph; Backmund, Markus; Ruckes, Christian; Reimer, Jens

2014-01-01

Aims To compare the efficacy of slow-release oral morphine (SROM) and methadone as maintenance medication for opioid dependence in patients previously treated with methadone. Design Prospective, multiple-dose, open label, randomized, non-inferiority, cross-over study over two 11-week periods. Methadone treatment was switched to SROM with flexible dosing and vice versa according to period and sequence of treatment. Setting Fourteen out-patient addiction treatment centres in Switzerland and Germany. Participants Adults with opioid dependence in methadone maintenance programmes (dose ≥50 mg/day) for ≥26 weeks. Measurements The efficacy end-point was the proportion of heroin-positive urine samples per patient and period of treatment. Each week, two urine samples were collected, randomly selected and analysed for 6-monoacetyl-morphine and 6-acetylcodeine. Non-inferiority was concluded if the two-sided 95% confidence interval (CI) in the difference of proportions of positive urine samples was below the predefined boundary of 10%. Findings One hundred and fifty-seven patients fulfilled criteria to form the per protocol population. The proportion of heroin-positive urine samples under SROM treatment (0.20) was non-inferior to the proportion under methadone treatment (0.15) (least-squares mean difference 0.05; 95% CI = 0.02, 0.08; P > 0.01). The 95% CI fell within the 10% non-inferiority margin, confirming the non-inferiority of SROM to methadone. A dose-dependent effect was shown for SROM (i.e. decreasing proportions of heroin-positive urine samples with increasing SROM doses). Retention in treatment showed no significant differences between treatments (period 1/period 2: SROM: 88.7%/82.1%, methadone: 91.1%/88.0%; period 1: P = 0.50, period 2: P = 0.19). Overall, safety outcomes were similar between the two groups. Conclusions Slow-release oral morphine appears to be at least as effective as methadone in treating people with opioid use disorder. PMID:24304412

High-dose buprenorphine: perioperative precautions and management strategies.

PubMed

Roberts, D M; Meyer-Witting, M

2005-02-01

Buprenorphine has been in clinical use in anaesthesia for several decades. Recently, the high-dose sublingual formulation (Subutex, Reckitt Benckiser, Slough, U.K.) has been increasingly used as maintenance therapy in opioid dependence, as an alternative to methadone and other pharmacological therapies. Buprenorphine has unique pharmacological properties making it well suited for use as a maintenance therapy in opioid dependence. However, these same properties may cause difficulty in the perioperative management of pain. Buprenorphine is a partial opioid agonist, attenuating the effects of supplemental illicit or therapeutic opioid agonists. As a result of its high receptor affinity, supplemental opioids do not readily displace buprenorphine from the opioid receptor in standard doses. High-dose buprenorphine has an extended duration of action that prolongs both of these effects. The perioperative management of patients stabilized on high-dose buprenorphine and undergoing surgery requires consideration of the likely analgesic requirements. Where possible the buprenorphine should be continued. Pain management should focus on maximizing non-opioid analgesia, local anaesthesia and non-pharmacological techniques. Where pain may not be adequately relieved by these methods, the addition of a full opioid agonist such as fentanyl or morphine at appropriate doses should be considered, accompanied by close monitoring in a high dependency unit. In situations where this regimen is unlikely to be effective, preoperative conversion to morphine or methadone may be an option. Where available, liaison with a hospital-based alcohol and drug service should always be considered.

APD125, a Selective Serotonin 5-HT2A Receptor Inverse Agonist, Significantly Improves Sleep Maintenance in Primary Insomnia

PubMed Central

Rosenberg, Russell; Seiden, David J.; Hull, Steven G.; Erman, Milton; Schwartz, Howard; Anderson, Christen; Prosser, Warren; Shanahan, William; Sanchez, Matilde; Chuang, Emil; Roth, Thomas

2008-01-01

Introduction: Insomnia is a condition affecting 10% to 15% of the adult population and is characterized by difficulty falling asleep, difficulty staying asleep, or nonrestorative sleep, accompanied by daytime impairment or distress. This study evaluates APD125, a selective inverse agonist of the 5-HT2A receptor, for treatment of chronic insomnia, with particular emphasis on sleep maintenance. In phase 1 studies, APD125 improved sleep maintenance and was well tolerated. Methodology: Adult subjects (n = 173) with DSM-IV defined primary insomnia were randomized into a multicenter, double-blind, placebo-controlled, 3-way crossover study to compare 2 doses of APD125 (10 mg and 40 mg) with placebo. Each treatment period was 7 days with a 7- to 9-day washout period between treatments. Polysomnographic recordings were performed at the initial 2 screening nights and at nights (N) 1/2 and N 6/7 of each treatment period. Results: APD125 was associated with significant improvements in key sleep maintenance parameters measured by PSG. Wake time after sleep onset decreased (SEM) by 52.5 (3.2) min (10 mg) and 53.5 (3.5) min (40 mg) from baseline to N 1/2 vs. 37.8 (3.4) min for placebo, (P < 0.0001 for both doses vs placebo), and by 51.7 (3.4) min (P = 0.01) and 48.0 (3.6) min (P = 0.2) at N 6/7 vs. 44.0 (3.8) min for placebo. Significant APD125 effects on wake time during sleep were also seen (P < 0.0001 N 1/2, P < 0.001 N 6/7). The number of arousals and number of awakenings decreased significantly with APD125 treatment compared to placebo. Slow wave sleep showed a statistically significant dose-dependent increase. There was no significant decrease in latency to persistent sleep. No serious adverse events were reported, and no meaningful differences in adverse event profiles were observed between either dose of APD125 and placebo. APD125 was not associated with next-day psychomotor impairment as measured by Digit Span, Digit Symbol Copy, and Digit Symbol Coding Tests. Conclusions: APD125 produced statistically significant improvements in objective parameters of sleep maintenance and sleep consolidation and was well tolerated in adults with primary chronic insomnia. Citation: Rosenberg R; Seiden DJ; Hull SG; Erman M; Schwartz H; Anderson C; Prosser W; Shanahan W; Sanchez M; Chuang E; Roth T. APD125, a selective serotonin 5-HT2A receptor inverse agonist, significantly improves sleep maintenance in primary insomnia. SLEEP 2008;31(12):1663–1671. PMID:19090322

Efficacy and Tolerability of High-Dose Escitalopram in Posttraumatic Stress Disorder.

PubMed

Qi, Wei; Gevonden, Martin; Shalev, Arieh

2017-02-01

Open-label trials suggest that escitalopram (up to 20 mg/d) is an effective treatment for some, but not all posttraumatic stress disorder (PTSD) patients. Higher doses of escitalopram effectively reduced major depression symptoms in patients who had not responded to regular doses. The current study examines the efficacy, tolerability, and adherence to high-dose escitalopram in PTSD. Forty-five PTSD patients received 12 weeks of gradually increasing doses of escitalopram reaching 40 mg daily at 4 weeks. Among those, 12 participants received regular doses of antidepressants at study onset including escitalopram (n = 7). The Clinician-Administered PTSD Scale (CAPS) evaluated PTSD symptoms severity before treatment, at 3 months (upon treatment termination), and at 6 months (maintenance effect). A 20% reduction in CAPS scores was deemed clinically significant. Adverse events and medication adherence were monitored at each clinical session. Linear mixed-models analysis showed a significant reduction of mean CAPS scores (11.5 ± 18.1 points) at 3 months and maintenance of gains by 6 months (F2,34.56 = 8.15, P = 0.001). Eleven participants (34.3%) showed clinically significant improvement at 3 months. Only 9 participants (20%) left the study. There were no serious adverse events and few mild ones with only 2 adverse events (diarrhea, 11.1%; drowsiness, 11.1%) reported by more than 10% of participants. High doses of escitalopram are tolerable and well adhered to in PTSD. Their beneficial effect at a group level is due to a particularly good response in a subset of patients.Variability in prior pharmacological treatment precludes a definite attribution of the results to high doses of escitalopram.

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.

Efficacy of budesonide/formoterol maintenance and reliever therapy compared with higher-dose budesonide as step-up from low-dose inhaled corticosteroid treatment.

PubMed

Jenkins, Christine R; Eriksson, Göran; Bateman, Eric D; Reddel, Helen K; Sears, Malcolm R; Lindberg, Magnus; O'Byrne, Paul M

2017-04-20

Asthma management may involve a step up in treatment when symptoms are not well controlled. We examined whether budesonide/formoterol maintenance and reliever therapy (MRT) is as effective as higher, fixed-dose budesonide plus as-needed terbutaline in patients requiring step-up from Step 2 treatment (low-dose inhaled corticosteroids), stratified by baseline reliever use. A post-hoc analysis utilized data from three clinical trials of 6-12 months' duration. Patients aged ≥12 years with symptomatic asthma uncontrolled despite Step 2 treatment were included. Severe exacerbation rate, lung function and reliever use were analysed, stratified by baseline reliever use (<1, 1-2 and >2 occasions/day). Overall, 1239 patients were included. Reductions in severe exacerbation rate with budesonide/formoterol MRT versus fixed-dose budesonide were similar across baseline reliever use levels, and were statistically significant in patients using 1-2 (42%, p = 0.01) and >2 (39%, p = 0.02) reliever occasions/day, but not <1 reliever occasion/day (35%, p = 0.11). Both treatments significantly increased mean FEV 1 from baseline; improvements were significantly greater for budesonide/formoterol MRT in all reliever use groups. Reductions in reliever use from baseline were significantly greater with budesonide/formoterol MRT versus fixed-dose budesonide in patients using 1-2 and >2 reliever occasions/day (-0.33 and -0.74 occasions/day, respectively). Treatment benefit with budesonide/formoterol MRT versus higher, fixed-dose budesonide plus short-acting β 2 -agonist was found in Step 2 patients with relatively low reliever use, supporting the proposal that budesonide/formoterol MRT may be useful when asthma is uncontrolled with low-dose inhaled corticosteroid.

Promoting Abstinence from Cocaine and Heroin with a Methadone Dose Increase and a Novel Contingency

PubMed Central

Schmittner, John; Umbricht, Annie; Schroeder, Jennifer R.; Moolchan, Eric T.; Preston, Kenzie L.

2010-01-01

To test whether a combination of contingency management and methadone dose increase would promote abstinence from heroin and cocaine, we conducted a randomized controlled trial using a 2 X 3 (Dose X Contingency) factorial design in which dose assignment was double-blind. Participants were 252 heroin- and cocaine-abusing outpatients on methadone maintenance. They were randomly assigned to methadone dose (70 or 100 mg/day, double blind) and voucher condition (noncontingent, contingent on cocaine-negative urines, or “split”). The “split” contingency was a novel contingency that reinforced abstinence from either drug while doubly reinforcing simultaneous abstinence from both: the total value of incentives was “split” between drugs to contain costs. The main outcome measures were percentages of urine specimens negative for heroin, cocaine, and both simultaneously; these were monitored during a 5-week baseline of standard treatment (to determine study eligibility), a 12-week intervention, and a 10-week maintenance phase (to examine intervention effects in return-to-baseline conditions). DSM-IV criteria for ongoing drug dependence were assessed at study exit. Urine-screen results showed that the methadone dose increase reduced heroin use but not cocaine use. The Split 100mg group was the only group to achieve a longer duration of simultaneous negatives than its same-dose Noncontingent control group. The frequency of DSM-IV opiate and cocaine dependence diagnoses decreased in the active intervention groups. For a split contingency to promote simultaneous abstinence from cocaine and heroin, a relatively high dose of methadone appears necessary but not sufficient; an increase in overall incentive amount may also be required. PMID:19101098

[Effect of dexmedetomidine on emergence agitation after general anesthesia in children undergoing odontotherapy in day-surgery operating room].

PubMed

Lin, Luo; Yueming, Zhang; Meisheng, Li; Jiexue, Wang; Yang, Ji

2017-12-01

To study the effectiveness of dexmedetomidine used for general anesthesia maintenance in children undergoing odontotherapy in day-surgery operating room in reducing the incidence of emergence agitation (EA). Eighty children undergoing odontotherapy and under general anesthesia in day-surgery operating room were randomized into two groups, group A (n=40) and group B (n=40). Each patient in group A was administered with a bolus dose of dexmedetomidine (1.0 μg·kg⁻¹, saline diluted to 10 mL) pump-infused after intubation and a maintenance dose of 0.1-0.4 mL·(kg·h)⁻¹ followed-up until 45 min before the end of operation. Each patient in group B was administered with a bolus dose of normal saline 10 mL pump-infused after intubation and maintenance dose of 0.1-0.4 mL·(kg·h)⁻¹ followed-up until 45 min before the end of operation. Gender, age, weight, physical status according to the American Society of Anesthesiologists, perioperative heart rate (HR), mean arterial pressure (MAP), pulse oxygen saturation (SpO₂), sufentanil dosage, duration of surgery, time of extubation, time of regaining consciousness, and time to reach modified Aldrete's score≥12 were recorded. Behavior in postanesthesia care unit was rated on the four-point agitation scale. Compared with group B, decreases were observed in HR and MAP at the beginning of operation, in 10 and 30 min, 1 and 2 h after the beginning of operation, and after extubation of group A (P<0.05). Sufentanil dosage and incidence of EA during recovery of group A were also lower than those of group B (P<0.05). Time to regain consciousness and time to reach modified Aldrete's score≥12 of group A were longer than those of group B (P<0.05). No statistical difference was observed between other indexes of the two groups. As an anesthetic used for general anesthesia maintenance in children undergoing odontotherapy in day-surgery operating room, dexmedetomidine results in low incidence of EA during recovery and more stable vital signs.

A randomized 2×2 factorial trial, part 1: single-dose rabbit antithymocyte globulin induction may improve renal transplantation outcomes.

PubMed

Stevens, R Brian; Foster, Kirk W; Miles, Clifford D; Lane, James T; Kalil, Andre C; Florescu, Diana F; Sandoz, John P; Rigley, Theodore H; Nielsen, Kathleen J; Skorupa, Jill Y; Kellogg, Anna M; Malik, Tamer; Wrenshall, Lucile E

2015-01-01

We conducted a randomized and unblinded 2 × 2 sequential-factorial trial, composed of an induction arm (part 1) comparing single-dose (SD) versus divided-dose rabbit antithymocyte globulin (rATG), and a maintenance arm (part 2) comparing tacrolimus minimization versus withdrawal. We report the long-term safety and efficacy of SD-rATG induction in the context of early steroid withdrawal and tacrolimus minimization or withdrawal. Patients (n=180) received 6 mg/kg rATG, SD or four alternate-day doses (1.5 mg/kg/dose), with early steroid withdrawal and tacrolimus or sirolimus maintenance. After 6 months targeted maintenance levels were tacrolimus, 2 to 4 ng/mL and sirolimus, 4 to 6 ng/mL or, if calcineurin inhibitor-withdrawn, sirolimus 8 to 12 ng/mL with mycophenolate mofetil 2 g two times per day. Primary endpoints were renal function (abbreviated modification of diet in renal disease) and chronic graft histopathology (Banff). Secondary endpoints included patient survival, graft survival, biopsy-proven rejection, and infectious or noninfectious complications. Follow-up averaged longer than 4 years. Tacrolimus or sirolimus and mycophenolate mofetil exposure was identical between groups. The SD-rATG associated with improved renal function (2-36 months; P<0.001) in deceased donor recipients. The SD-rATG associated with quicker lymphocyte, CD4 T cell, and CD4-CD8 recovery and fewer infections. Cox multivariate hazard modeling showed divided-dose-rATG (P=0.019), deceased donor (P=0.003), serious infection (P=0.0.018), and lower lymphocyte count (P=0.001) associated with increased mortality. Patients with all four covariates showed a 27-fold increased likelihood of death (P=0.00002). Chronic graft histopathology, rejection rates, and death-censored graft survival were not significantly different between groups. The SD-rATG induction improves the 3-year renal function in recipients of deceased donor kidneys. This benefit, along with possibly improved patient survival and fewer infections suggest that how rATG is administered may impact its efficacy and safety.

Low-dose budesonide for maintenance of clinical remission in collagenous colitis: a randomised, placebo-controlled, 12-month trial

PubMed Central

Münch, Andreas; Bohr, Johan; Miehlke, Stephan; Benoni, Cecilia; Olesen, Martin; Öst, Åke; Strandberg, Lars; Hellström, Per M; Hertervig, Erik; Armerding, Peter; Stehlik, Jiri; Lindberg, Greger; Björk, Jan; Lapidus, Annika; Löfberg, Robert; Bonderup, Ole; Avnström, Sören; Rössle, Martin; Dilger, Karin; Mueller, Ralph; Greinwald, Roland; Tysk, Curt; Ström, Magnus

2016-01-01

Objective This 1-year study aimed to assess low-dose budesonide therapy for maintenance of clinical remission in patients with collagenous colitis. Design A prospective, randomised, placebo-controlled study beginning with an 8-week open-label induction phase in which patients with histologically confirmed active collagenous colitis received budesonide (Budenofalk, 9 mg/day initially, tapered to 4.5 mg/day), after which 92 patients in clinical remission were randomised to budesonide (mean dose 4.5 mg/day; Budenofalk 3 mg capsules, two or one capsule on alternate days) or placebo in a 12-month double-blind phase with 6 months treatment-free follow-up. Primary endpoint was clinical remission throughout the double-blind phase. Results Clinical remission during open-label treatment was achieved by 84.5% (93/110 patients). The median time to remission was 10.5 days (95% CI (9.0 to 14.0 days)). The maintenance of clinical remission at 1 year was achieved by 61.4% (27/44 patients) in the budesonide group versus 16.7% (8/48 patients) receiving placebo (treatment difference 44.5% in favour of budesonide; 95% CI (26.9% to 62.7%), p<0.001). Health-related quality of life was maintained during the 12-month double-blind phase in budesonide-treated patients. During treatment-free follow-up, 82.1% (23/28 patients) formerly receiving budesonide relapsed after study drug discontinuation. Low-dose budesonide over 1 year resulted in few suspected adverse drug reactions (7/44 patients), all non-serious. Conclusions Budesonide at a mean dose of 4.5 mg/day maintained clinical remission for at least 1 year in the majority of patients with collagenous colitis and preserved health-related quality of life without safety concerns. Treatment extension with low-dose budesonide beyond 1 year may be beneficial given the high relapse rate after budesonide discontinuation. Trial registration numbers http://www.clinicaltrials.gov (NCT01278082) and http://www.clinicaltrialsregister.eu (EudraCT: 2007-001315-31). PMID:25425655

The local and systemic side-effects of venom and inhaled-allergen subcutaneous immunotherapy.

PubMed

Adamic, Katja; Zidarn, Mihaela; Bajrovic, Nissera; Erzen, Renato; Kopac, Peter; Music, Ema

2009-01-01

Although immunotherapy is effective in allergic rhinitis, conjunctivitis, asthma and stinging insect hypersensitivity, it carries a risk of anaphylactic reactions. In a 4-year retrospective survey, we investigated 1257 adult patients who had received venom or inhaled-allergen subcutaneous immunotherapy. The dose-increase phase was performed as the 2-day rush protocol for venom immunotherapy and the 6-week protocol for inhaled-allergen immunotherapy. A total of 904 patients received venom immunotherapy and 353 patients inhaled-allergen immunotherapy. The prevalence of systemic reactions was 13.6%. The frequency of systemic reactions was higher during the maintenance phase than in the dose-increase phase (9.6% vs. 5.9%) and was highest in both phases of treatment with honeybee venom (P < 0.001). The majority of systemic reactions were mild. Five (0.4%) patients had reaction with a fall of blood pressure and were treated with adrenaline. There was no fatal outcome. The systemic side-effects during the dose-increase phase of venom immunotherapy occurred at a median dose of 46 microg (range 2-100 microg). Large local reactions occurred in 13.9% of patients without any significant difference between the allergens. We have shown that systemic reactions are not rare even during maintenance phase in patients with a well tolerated dose-increase phase of treatment. The most prominent risk factor for systemic reactions was immunotherapy with honeybee extract.

Durability of treatment response to zolpidem with three different maintenance regimens: a preliminary study.

PubMed

Perlis, Michael; Grandner, Michael; Zee, Jarcy; Bremer, Erin; Whinnery, Julia; Barilla, Holly; Andalia, Priscilla; Gehrman, Phil; Morales, Knashawn; Thase, Michael; Bootzin, Richard; Ader, Robert

2015-09-01

At present, there is no consensus regarding how to medically manage chronic insomnia in the long term. The unstated standard of practice is for patients to use hypnotics intermittently. The present study aimed to compare a partial reinforcement strategy with nightly and intermittent dosing strategies for its potential as a maintenance therapy. A mixed model was used in the study. One between-subjects factor: group (n = 4). One repeated-measures factor: time (12 weekly assessments). A total of 74 subjects with chronic Insomnia were treated with 10 mg zolpidem for 4 weeks. Treatment respondents were randomized to nightly dosing with 10 mg or 5 mg (QHS-10 and QHS-5), intermittent dosing with 10 mg (IDS-10 [3-5 days weekly]), or partial reinforcement dosing with 10 mg (PRS-10 [nightly pill use with 50% active medication and 50% placebos]) for 12 weeks. It was found, in compliant subjects (n = 55), that all four strategies evaluated maintained treatment response over time (ie, prevented or delayed relapse). For the subjects that remained in remission, the subjects in the intermittent dosing group (IDS-10) group exhibited poorer sleep continuity. While best considered a preliminary study, the present findings suggest that the partial reinforcement strategy may be a viable means toward maintaining treatment gains over time with less active medication. Copyright © 2015. Published by Elsevier B.V.

Durability of treatment response to zolpidem with three different maintenance regimens: a preliminary study

PubMed Central

Perlis, Michael; Grandner, Michael; Zee, Jarcy; Bremer, Erin; Whinnery, Julia; Barilla, Holly; Andalia, Priscilla; Gehrman, Phil; Morales, Knashawn; Thase, Michael; Bootzin, Richard; Ader, Robert

2015-01-01

Background and aim At present, there is no consensus regarding how to medically manage chronic insomnia in the long term. The unstated standard of practice is for patients to use hypnotics intermittently. The present study aimed to compare a partial reinforcement strategy with nightly and intermittent dosing strategies for its potential as a maintenance therapy. Methods A mixed model was used in the study. One between-subjects factor: group (n = 4). One repeated-measures factor: time (12 weekly assessments). A total of 74 subjects with chronic Insomnia were treated with 10 mg zolpidem for 4 weeks. Treatment respondents were randomized to nightly dosing with 10 mg or 5 mg (QHS-10 and QHS-5), intermittent dosing with 10 mg (IDS-10 [3–5 days weekly]), or partial reinforcement dosing with 10 mg (PRS-10 [nightly pill use with 50% active medication and 50% placebos]) for 12 weeks. Results It was found, in compliant subjects (n = 55), that all four strategies evaluated maintained treatment response over time (ie, prevented or delayed relapse). For the subjects that remained in remission, the subjects in the intermittent dosing group (IDS-10) group exhibited poorer sleep continuity. Conclusions While best considered a preliminary study, the present findings suggest that the partial reinforcement strategy may be a viable means toward maintaining treatment gains over time with less active medication. PMID:26298795

Maintenance ECT as a therapeutic approach to medication-refractory epilepsy in an adult with mental retardation: case report and review of literature.

PubMed

Shah, Nilesh; Pande, Nikhil; Bhat, Tushar; Murke, Mukund; Andrade, Chittaranjan

2012-06-01

Electroconvulsive therapy (ECT) raises the seizure threshold. This physiological change may benefit patients with seizure disorders. Whereas ECT has recently been used to terminate medication-refractory status epilepticus, there is little current literature on its planned administration as a specific maintenance treatment for medication-refractory epilepsy. We used maintenance ECT to treat an 18-year-old man with a long-standing generalized tonic-clonic seizure disorder who had shown poor response to several antiepileptic drugs administered in combination with antiepileptic medication compliance confirmed through drug level monitoring. A total of 52 ECTs were administered across nearly 20 months at a mean frequency of once in nearly 12 days. From the very outset, ECT dramatically decreased the frequency of spontaneous seizures from approximately 6 to 24 per week at baseline to approximately 1 to 2 per week after ECT initiation. The efficacy of maintenance ECT in spontaneous seizure prophylaxis was greater when the ECT treatment interval was narrower. Improvement with ECT was associated with improved behavior and improved psychosocial functioning on clinical report. No cognitive or other adverse effects were reported or clinically ascertained. The ECT charge administered at the last 10 treatment sessions was 1434 millicoulombs. This is probably the highest electrical stimulus dose recorded in literature. Maintenance ECT may reduce the frequency of breakthrough seizures in patients with seizure disorder that is inadequately responsive to antiepileptic medication regimes. Very high ECT seizure thresholds may be observed when many antiepileptic drugs are concurrently administered in high doses.

ALARA and planning of interventions

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

Rocaboy, A.

1995-03-01

The implementation of ALARA programs implies integration of radiation protection criterion at all stages of outage management. Within the framework of its ALARA policy, Electricide de France (EDF) has given an incentive to all of its nuclear power plants to develop {open_quotes}good practices{close_quotes} in this domain, and to exchange their experience by the way of a national feed back file. Among the developments in the field of outage organization, some plants have focused on the planning stage of activities because of its influence on the radiological conditions of interventions and on the good succession of tasks within the radiological controlledmore » areas. This paper presents the experience of Chinon nuclear power plant. At Chinon, we are pursuing this goal through careful outage planning. We want the ALARA program during outages to be part of the overall maintenance task planning. This planning includes the provision of the availability of every safety-related component, and of the variations of water levels in hthereactor and steam generators to take advantage of the shield created by the water. We have developed a computerized data base with the exact position of all the components in the reactor building in order to avoid unnecessary interactions between different tasks performed in the same room. A common language between Operation and Maintenance had been established over the past years, using {open_quotes}Milestones and Corridors{close_quotes}. A real time dose rate counting system enables the Radiation Protection (RP) Department to do an accurate and efficient follow up during the outage for all the {open_quotes}ALARA{close_quotes} maintenance tasks.« less

Clinical Study on Prospective Efficacy of All-Trans Acid, Realgar-Indigo Naturalis Formula Combined with Chemotherapy as Maintenance Treatment of Acute Promyelocytic Leukemia

PubMed Central

Lu-Qun, Wang; Hao, Li; Xiao-Peng, He; Fang-Lin, Li; Ling-Ling, Wang; Xue-Liang, Chen; Ming, Hou

2014-01-01

Objectives. To test the efficiency and safety of sequential application of retinoic acid (ATRA), Realgar-Indigo naturalis formula (RIF) and chemotherapy (CT) were used as the maintenance treatment in patients with acute promyelocytic leukemia (APL). Methods. This was a retrospective study of 98 patients with newly diagnosed APL who accepted two different maintenance treatments. After remission induction and consolidation chemotherapy according to their Sanz scores, patients received two different kinds of maintenance scheme. The first regimen was using ATRA, RIF, and standard dose of CT sequentially (ATRA/RIF/CT regimen), while the second one was using ATRA and low dose of chemotherapy with methotrexate (MTX) plus 6-mercaptopurine (6-MP) alternately (ATRA/CTlow regimen). The OS, DFS, relapse rate, minimal residual disease, and adverse reactions in two groups were monitored and evaluated. Results. ATRA/RIF/CT regimen could effectively reduce the chance of relapse in different risk stratification of patients, but there was no significant difference in 5-year DFS rate and OS rate between the two groups. Besides, the patients in the experimental group suffered less severe adverse reactions than those in the control group. Conclusions. The repeated sequential therapeutic regimen to APL with ATRA, RIF, and chemotherapy is worth popularizing for its high effectiveness and low toxicity. PMID:24963332

Clinical study on prospective efficacy of all-trans Acid, realgar-indigo naturalis formula combined with chemotherapy as maintenance treatment of acute promyelocytic leukemia.

PubMed

Xiang-Xin, Li; Lu-Qun, Wang; Hao, Li; Xiao-Peng, He; Fang-Lin, Li; Ling-Ling, Wang; Xue-Liang, Chen; Ming, Hou

2014-01-01

Objectives. To test the efficiency and safety of sequential application of retinoic acid (ATRA), Realgar-Indigo naturalis formula (RIF) and chemotherapy (CT) were used as the maintenance treatment in patients with acute promyelocytic leukemia (APL). Methods. This was a retrospective study of 98 patients with newly diagnosed APL who accepted two different maintenance treatments. After remission induction and consolidation chemotherapy according to their Sanz scores, patients received two different kinds of maintenance scheme. The first regimen was using ATRA, RIF, and standard dose of CT sequentially (ATRA/RIF/CT regimen), while the second one was using ATRA and low dose of chemotherapy with methotrexate (MTX) plus 6-mercaptopurine (6-MP) alternately (ATRA/CTlow regimen). The OS, DFS, relapse rate, minimal residual disease, and adverse reactions in two groups were monitored and evaluated. Results. ATRA/RIF/CT regimen could effectively reduce the chance of relapse in different risk stratification of patients, but there was no significant difference in 5-year DFS rate and OS rate between the two groups. Besides, the patients in the experimental group suffered less severe adverse reactions than those in the control group. Conclusions. The repeated sequential therapeutic regimen to APL with ATRA, RIF, and chemotherapy is worth popularizing for its high effectiveness and low toxicity.

10 CFR 35.12 - Application for license, amendment, or renewal.

Code of Federal Regulations, 2010 CFR

2010-01-01

... precautions and instructions; (ii) Methodology for measurement of dosages or doses to be administered to patients or human research subjects; and (iii) Calibration, maintenance, and repair of instruments and...

Visuospatial abilities and fine motor experiences influence acquisition and maintenance of fundamentals of laparoscopic surgery (FLS) task performance.

PubMed

Harrington, Cuan M; Dicker, Patrick; Traynor, Oscar; Kavanagh, Dara O

2018-05-18

Minimally invasive surgery poses a unique learning curve due to the requirement for non-intuitive psychomotor skills. The fundamentals of laparoscopic surgery (FLS) program trains and certifies residents in such skills. However, innate predictors of FLS performance and maintenance remain to be described. This single-centre observational study aimed to assess for candidate factors influencing the acquisition and maintenance of FLS performance amongst a surgically naïve cohort. Laparoscopically naïve medical students were recruited from pre-clinical university grades. Participants completed five visuospatial/psychomotor tests and a questionnaire surveying non-surgical experiences and personality traits. Individuals completed baseline assessments of FLS standard tasks followed by an intensive training course over week one and two on inanimate box trainers. A post-training assessment was performed in week three to evaluate acquisition. Participants were withdrawn from exposure and retested at four 1-month intervals to assess maintenance requirements. Forty-nine participants enrolled with 35 (71.4%) and 33 (67.3%) completing acquisition and maintenance phases, respectively. Mean age of participants was 19.3 (± 1.2) years with 68.6% female predominance. Participants demonstrated significant improvements in all five tasks during the acquisition (p < 0.05) period and maintenance of skills with task exposure at 1-month intervals. Significant predictors of skill acquisition included: card rotations for intracorporeal knot (p = 0.027) and combined tasks (p = 0.028) and cube comparisons for extracorporeal knot (p = 0.040). During skill maintenance: Card rotations predicted performance across all tasks (p < 0.05), Cube comparisons for tasks 1/2/4/5 (p < 0.05), PicSOR for peg transfer (p = 0.017) and grooved pegboard for peg transfer (p = 0.023) and ligating-loop (p = 0.038) tasks. Musical instrument experience demonstrated associations with skill acquisition in peg transfer (p = 0.042) and intracorporeal knot (p = 0.034) while video gaming predicted performance in these tasks (p < 0.05) during the maintenance phase. A sporting background or competitive personality did not influence skill performance. Multiple visuospatial abilities and non-surgical experiences positively influenced FLS performance during skill acquisition and/or maintenance. Further consideration to these individual factors may facilitate selection of more technically adaptable surgical residents.

Methadone continuation versus forced withdrawal on incarceration in a combined US prison and jail: a randomised, open-label trial.

PubMed

Rich, Josiah D; McKenzie, Michelle; Larney, Sarah; Wong, John B; Tran, Liem; Clarke, Jennifer; Noska, Amanda; Reddy, Manasa; Zaller, Nickolas

2015-07-25

Methadone is an effective treatment for opioid dependence. When people who are receiving methadone maintenance treatment for opioid dependence are incarcerated in prison or jail, most US correctional facilities discontinue their methadone treatment, either gradually, or more often, abruptly. This discontinuation can cause uncomfortable symptoms of withdrawal and renders prisoners susceptible to relapse and overdose on release. We aimed to study the effect of forced withdrawal from methadone upon incarceration on individuals' risk behaviours and engagement with post-release treatment programmes. In this randomised, open-label trial, we randomly assigned (1:1) inmates of the Rhode Island Department of Corrections (RI, USA) who were enrolled in a methadone maintenance-treatment programme in the community at the time of arrest and wanted to remain on methadone treatment during incarceration and on release, to either continuation of their methadone treatment or to usual care--forced tapered withdrawal from methadone. Participants could be included in the study only if their incarceration would be more than 1 week but less than 6 months. We did the random assignments with a computer-generated random permutation, and urn randomisation procedures to stratify participants by sex and race. Participants in the continued-methadone group were maintained on their methadone dose at the time of their incarceration (with dose adjustments as clinically indicated). Patients in the forced-withdrawal group followed the institution's standard withdrawal protocol of receiving methadone for 1 week at the dose at the time of their incarceration, then a tapered withdrawal regimen (for those on a starting dose >100 mg, the dose was reduced by 5 mg per day to 100 mg, then reduced by 3 mg per day to 0 mg; for those on a starting dose >100 mg, the dose was reduced by 3 mg per day to 0 mg). The main outcomes were engagement with a methadone maintenance-treatment clinic after release from incarceration and time to engagement with methadone maintenance treatment, by intention-to-treat and as-treated analyses, which we established in a follow-up interview with the participants at 1 month after their release from incarceration. Our study paid for 10 weeks of methadone treatment after release if participants needed financial help. This trial is registered with ClinicalTrials.gov, number NCT01874964. Between June 14, 2011, and April 3, 2013, we randomly assigned 283 prisoners to our study, 142 to continued methadone treatment, and 141 to forced withdrawal from methadone. Of these, 60 were excluded because they did not fit the eligibility criteria, leaving 114 in the continued-methadone group and 109 in the forced-withdrawal group (usual care). Participants assigned to continued methadone were more than twice as likely than forced-withdrawal participants to return to a community methadone clinic within 1 month of release (106 [96%] of 110 in the continued-methadone group compared with 68 [78%] of 87 in the forced-withdrawal group; adjusted hazard ratio [HR] 2·04, 95% CI 1·48-2·80). We noted no differences in serious adverse events between groups. For the continued-methadone and forced-withdrawal groups, the number of deaths were one and zero, non-fatal overdoses were one and two, admissions to hospital were one and four; and emergency-room visits were 11 and 16, respectively. Although our study had several limitations--eg, it only included participants incarcerated for fewer than 6 months, we showed that forced withdrawal from methadone on incarceration reduced the likelihood of prisoners re-engaging in methadone maintenance after their release. Continuation of methadone maintenance during incarceration could contribute to greater treatment engagement after release, which could in turn reduce the risk of death from overdose and risk behaviours. National Institute on Drug Abuse and the Lifespan/Tufts/Brown Center for AIDS Research from the National Institutes of Health. Copyright © 2015 Elsevier Ltd. All rights reserved.

Methadone continuation versus forced withdrawal on incarceration in a combined US prison and jail: a randomised, open-label trial

PubMed Central

Rich, Josiah D; McKenzie, Michelle; Larney, Sarah; Wong, John B; Tran, Liem; Clarke, Jennifer; Noska, Amanda; Reddy, Manasa; Zaller, Nickolas

2015-01-01

Summary Background Methadone is an effective treatment for opioid dependence. When people who are receiving methadone maintenance treatment for opioid dependence are incarcerated in prison or jail, most US correctional facilities discontinue their methadone treatment, either gradually, or more often, abruptly. This discontinuation can cause uncomfortable symptoms of withdrawal and renders prisoners susceptible to relapse and overdose on release. We aimed to study the effect of forced withdrawal from methadone upon incarceration on individuals’ risk behaviours and engagement with post-release treatment programmes. Methods In this randomised, open-label trial, we randomly assigned (1:1) inmates of the Rhode Island Department of Corrections (RI, USA) who were enrolled in a methadone maintenance-treatment programme in the community at the time of arrest and wanted to remain on methadone treatment during incarceration and on release, to either continuation of their methadone treatment or to usual care—forced tapered withdrawal from methadone. Participants could be included in the study only if their incarceration would be more than 1 week but less than 6 months. We did the random assignments with a computer-generated random permutation, and urn randomisation procedures to stratify participants by sex and race. Participants in the continued-methadone group were maintained on their methadone dose at the time of their incarceration (with dose adjustments as clinically indicated). Patients in the forced-withdrawal group followed the institution’s standard withdrawal protocol of receiving methadone for 1 week at the dose at the time of their incarceration, then a tapered withdrawal regimen (for those on a starting dose >100 mg, the dose was reduced by 5 mg per day to 100 mg, then reduced by 3 mg per day to 0 mg; for those on a starting dose ≤100 mg, the dose was reduced by 3 mg per day to 0 mg). The main outcomes were engagement with a methadone maintenance-treatment clinic after release from incarceration and time to engagement with methadone maintenance treatment, by intention-to-treat and as-treated analyses, which we established in a follow-up interview with the participants at 1 month after their release from incarceration. Our study paid for 10 weeks of methadone treatment after release if participants needed financial help. This trial is registered with ClinicalTrials.gov, number NCT01874964. Findings Between June 14, 2011, and April 3, 2013, we randomly assigned 283 prisoners to our study, 142 to continued methadone treatment, and 141 to forced withdrawal from methadone. Of these, 60 were excluded because they did not fit the eligibility criteria, leaving 114 in the continued-methadone group and 109 in the forced-withdrawal group (usual care). Participants assigned to continued methadone were more than twice as likely than forced-withdrawal participants to return to a community methadone clinic within 1 month of release (106 [96%] of 110 in the continued-methadone group compared with 68 [78%] of 87 in the forced-withdrawal group; adjusted hazard ratio [HR] 2·04, 95% CI 1·48–2·80). We noted no differences in serious adverse events between groups. For the continued-methadone and forced-withdrawal groups, the number of deaths were one and zero, non-fatal overdoses were one and two, admissions to hospital were one and four; and emergency-room visits were 11 and 16, respectively. Interpretation Although our study had several limitations—eg, it only included participants incarcerated for fewer than 6 months, we showed that forced withdrawal from methadone on incarceration reduced the likelihood of prisoners re-engaging in methadone maintenance after their release. Continuation of methadone maintenance during incarceration could contribute to greater treatment engagement after release, which could in turn reduce the risk of death from overdose and risk behaviours. PMID:26028120

Rigorous-two-Steps scheme of TRIPOLI-4® Monte Carlo code validation for shutdown dose rate calculation

NASA Astrophysics Data System (ADS)

Jaboulay, Jean-Charles; Brun, Emeric; Hugot, François-Xavier; Huynh, Tan-Dat; Malouch, Fadhel; Mancusi, Davide; Tsilanizara, Aime

2017-09-01

After fission or fusion reactor shutdown the activated structure emits decay photons. For maintenance operations the radiation dose map must be established in the reactor building. Several calculation schemes have been developed to calculate the shutdown dose rate. These schemes are widely developed in fusion application and more precisely for the ITER tokamak. This paper presents the rigorous-two-steps scheme implemented at CEA. It is based on the TRIPOLI-4® Monte Carlo code and the inventory code MENDEL. The ITER shutdown dose rate benchmark has been carried out, results are in a good agreement with the other participant.

Aripiprazole long-acting injectable formulations for schizophrenia: aripiprazole monohydrate and aripiprazole lauroxil.

PubMed

Citrome, Leslie

2016-01-01

Aripiprazole monohydrate (AM) and aripiprazole lauroxil (AL) are two different long-acting injectable formulations of aripiprazole. AM 400 mg administered once monthly demonstrated efficacy in an acute, double-blind, placebo-controlled, randomized clinical trial, as well as in a double-blind, placebo-controlled, randomized-withdrawal maintenance study, and in two non-inferiority maintenance studies. AL is a prodrug of aripiprazole and available in 441 mg, 662 mg or 882 mg strengths. AL 441 mg and 882 mg administered once monthly demonstrated efficacy in an acute, double-blind, placebo-controlled, randomized clinical trial. The pharmacokinetic profile of AL also led to approval of dosing intervals of every 6 weeks for the 882 mg dose. The overall tolerability profiles of both products are consistent with what is known about oral aripiprazole.

Low dose oral pH modified release budesonide for maintenance of steroid induced remission in Crohn's disease

PubMed Central

Gross, V; Andus, T; Ecker, K; Raedler, A; Loeschke, K; Plauth, M; Rasenack, J; Weber, A; Gierend, M; Ewe, K; Scholmerich, J; Budesonide, S

1998-01-01

Background—The relapse rate after steroid induced remission in Crohn's disease is high. 
Aims—To test whether oral pH modified release budesonide (3 × 1 mg/day) reduces the relapse rate and to identify patient subgroups with an increased risk of relapse. 
Methods—In a multicentre, randomised, double blind study, 179 patients with steroid induced remission of Crohn's disease received either 3 × 1 mg budesonide (n=84) or placebo (n=95) for one year. The primary study aim was the maintenance of remission of Crohn's disease for one year. 
Results—Patient characteristics at study entry were similar for both groups. The relapse rate was 67% (56/84) in the budesonide group and 65% (62/95) in the placebo group. The relapse curves in both groups were similar. The mean time to relapse was 93.5days in the budesonide group and 67.0 days in the placebo group. No prognostic factors allowing prediction of an increased risk for relapse or definition of patient subgroups who derived benefit from low dose budesonide were found. Drug related side effects were mild and no different between the budesonide and the placebo group. 
Conclusion—Oral pH modified release budesonide at a dose of 3 × 1 mg/day is not effective for maintaining steroid induced remission in Crohn's disease. 

 Keywords: budesonide; Crohn's disease; maintenance of remission PMID:9616309

How to Improve Adherence to Life-saving Heart Failure Treatments with Potassium Binders

PubMed Central

2017-01-01

Medications that affect the renin–angiotensin–aldosterone system (RAAS) form the mainstay of current heart failure (HF) therapy in patients with reduced ejection fraction. Concerns about the risk of hyperkalaemia have created a significant barrier to optimal RAAS inhibitor therapy in patients with HF, however, and many patients are discontinuing or receiving suboptimal doses of these lifesaving therapies. This has serious health and economic implications due to adverse renal and cardiovascular events. There is therefore an important unmet need for novel therapeutic options for the long-term management of patients with, and at risk for, hyperkalaemia. Two new potassium-binding agents, patiromer and ZS-9, have been shown to be effective and safe for the treatment of hyperkalaemia, as well as the maintenance of normokalaemia, without dose reduction or discontinuation of RAAS inhibitors. In addition, the fast onset of ZS-9 action suggests that it may be useful in the treatment of acute hyperkalaemia. These agents may allow for dose optimisation of RAAS inhibitors for the long-term maintenance and protection of the renal and cardiovascular system. PMID:28785473

Maintenance treatment of recurrent ovarian cancer: Is it ready for prime time?

PubMed

DiSilvestro, Paul; Alvarez Secord, Angeles

2018-06-05

Approximately 1% of women in the United States will be diagnosed with epithelial ovarian cancer (EOC) during their lifetime. It is most likely to present at a more advanced stage, requiring aggressive therapeutic measures, and most women will succumb to this illness. Due to advancements in therapy, the oncology community has begun to shift its focus to molecular targeted agents, alternative dosing schedules, and maintenance therapy. Women who achieve a response to initial adjuvant chemotherapy may be candidates for maintenance therapy, with the goal of inducing a lasting remission or prolonging the disease-free interval before recurrence. The rationale for maintenance therapy is to delay disease progression by eliminating residual, slowly-dying cancerous cells, or impeding cell turnover. This review discusses the goals of maintenance therapy for EOC with antiangiogenic agents or poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors, and reviews clinical studies that have demonstrated improvements in survival outcomes. The side-effect profiles for PARP inhibitors and the implications for preserving quality of life during maintenance therapy will also be discussed. Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

Bugs in Your Rugs? Carpet Maintenance and Indoor Air Quality.

ERIC Educational Resources Information Center

Schmidt, Edward A.

1994-01-01

This article, the second in a three-part series of articles that discuss indoor air quality (IAQ) issues affecting schools, looks at the effects of carpet maintenance and environmental influences on IAQ. (MLF)

Allopregnanolone influences the consummatory processes that govern ethanol drinking in C57BL/6J mice

PubMed Central

Ford, Matthew M.; Mark, Gregory P.; Nickel, Jeffrey D.; Phillips, Tamara J.; Finn, Deborah A.

2007-01-01

Although systemic allopregnanolone (ALLO; a positive modulator of GABAA receptors) has been shown to enhance ethanol-reinforced responding and to modulate drinking patterns in rodents, the effects of centrally administered ALLO on ethanol intake are not known. The current work examined the effects of intracranial ALLO on operant ethanol self-administration in food- and water-satiated mice, with a procedure designed to estimate ALLO’s influence on appetitive versus consummatory processes. Male C57BL/6J (B6) mice were trained to press an ethanol-appropriate lever by being reinforced with 30-min of continuous access to a 10% ethanol solution. Following surgical implantation of a guide cannula aimed at the lateral ventricle and subsequent habituation to vehicle infusions, ALLO (50–400 ng; ICV) was delivered immediately prior to session start. ALLO doses of 100 and 400 ng were further evaluated for their effects on locomotor behavior within activity chambers. ALLO selectively modulated ethanol intake patterns associated with the onset and maintenance of self-administration, while leaving appetitive (i.e., ethanol seeking) measures unaltered. The effects of ALLO on drinking patterns were dissociable from changes in locomotor behavior, as evidenced by the absence of ALLO’s influence on response frequency and horizontal distance traveled. These findings support the premise that manipulations in brain ALLO levels may influence the regulatory processes governing ethanol consumption. PMID:17376546

Influence of Herpes Simplex Virus 1 Latency-Associated Transcripts on the Establishment and Maintenance of Latency in the ROSA26R Reporter Mouse Model

PubMed Central

Nicoll, M. P.; Proença, J. T.; Connor, V.

2012-01-01

Herpes simplex virus 1 (HSV-1) can establish life-long latent infection in sensory neurons, from which periodic reactivation can occur. During latency, viral gene expression is largely restricted to the latency-associated transcripts (LATs). While not essential for any phase of latency, to date the LATs have been shown to increase the efficiency of both establishment and reactivation of latency in small-animal models. We sought to investigate the role of LAT expression in the frequency of latency establishment within the ROSA26R reporter mouse model utilizing Cre recombinase-encoding recombinant viruses harboring deletions of the core LAT promoter (LAP) region. HSV-1 LAT expression was observed to influence the number of latently infected neurons in trigeminal but not dorsal root ganglia. Furthermore, the relative frequencies of latency establishment of LAT-positive and LAT-negative viruses are influenced by the inoculum dose following infection of the mouse whisker pads. Finally, analysis of the infected cell population at two latent time points revealed a relative loss of latently infected cells in the absence of LAT expression. We conclude that the HSV-1 LATs facilitate the long-term stability of the latent cell population within the infected host and that interpretation of LAT establishment phenotypes is influenced by infection methodology. PMID:22696655

Nonclinical Safety and Toxicokinetics of MnTnBuOE-2-PyP5+ (BMX-001).

PubMed

Gad, Shayne Cox; Sullivan, Dexter W; Spasojevic, Ivan; Mujer, Cesar V; Spainhour, Charles B; Crapo, James D

2016-07-01

BMX-001, a manganese porphyrin that has anti-inflammatory, antioxidant, and antitumor properties, is being developed as a potential therapeutic for high-grade glioma (HGG) and head and neck (H&N) cancer. An IND has been opened for BMX-001 in the treatment of HGG (NCT02655601) and another is in preparation for H&N. The safety of BMX-001 has been evaluated in a battery of nonclinical Good Laboratory Practice (GLP)-compliant studies. Systemic toxicity has been evaluated using the intended cGMP product administered subcutaneously for periods of up to 5 weeks in both the mouse and the monkey and included toxicokinetic evaluations to characterize systemic exposure and tissue distribution and clearance of BMX-001. In additional GLP studies, BMX-001 was not irritating to the skin or eye and caused no changes in cardiac rate or rhythm or blood pressure. Mixed results for genotoxicity were seen with the weight of evidence indicating that BMX-001 poses no genotoxic risk in humans. In systemic mouse and monkey studies, loading/maintenance dose no observed adverse effect levels were 12/2 mg/kg/dose and 6/2 mg/kg/dose, respectively, with maintenance doses administered every 3 days after the initial loading dose. Systemic data were used to determine a Food and Drug Administration-approved safe starting dose for the initial clinical study in patients with HGG. BMX-001 was detected in analyzed tissues, including the brain, persisting well past the short plasma clearance period. The highest levels of BMX-001 were seen in the liver and kidneys, with amounts in these tissues returning to close to undetectable levels after a 2-week cessation of dosing. © The Author(s) 2016.

A Prospective, Randomized, Open-Label, Blinded, Endpoint Study Exploring Platelet Response to Half-Dose Prasugrel and Ticagrelor in Patients with the Acute Coronary Syndrome: HOPE-TAILOR Study.

PubMed

Jin, Cai De; Kim, Moo Hyun; Bang, Junghee; Serebruany, Victor

The optimal dosing of novel oral P2Y12 receptor platelet inhibitors such as prasugrel or ticagrelor is unclear and especially challenging in East Asians. We hypothesize that half-dose prasugrel and ticagrelor may be sufficient for long-term maintenance management in Korean patients with the acute coronary syndrome (ACS) compared with conventional dosages. HOPE-TAILOR (Half Dose of Prasugrel and Ticagrelor in Platelet Response after Acute Coronary Syndromes) is a prospective, randomized, open-label, blinded, endpoint (PROBE) single-center, clinical trial. A total of 100 patients with ACS undergoing drug-eluting stent implantation will be randomly assigned to prasugrel, ticagrelor, or clopidogrel, and the patients in each treatment group will receive 1-month therapy with 100 mg q.d. aspirin plus prasugrel 10 mg q.d., ticagrelor 90 mg b.i.d., or clopidogrel 75 mg q.d., followed by half-dose prasugrel 5 mg q.d. or ticagrelor 45 mg b.i.d. for maintenance treatment but without clopidogrel dose reduction. The primary endpoint will be optimal platelet reactivity 3 months after coronary intervention, defined by VerifyNow Analyzer (PRU: 85-208) and vasodilator-stimulated phosphoprotein P2Y12 flow cytometry assay (platelet reactivity indices: 16-50%). Clinical outcomes will also be assessed, including major efficacy (composite of cardiac death, nonfatal myocardial infarction, repeat revascularization, or stroke) and safety (bleeding ≥2 according to the Bleeding Academic Research Consortium). HOPE-TAILOR is a prospective, randomized, open-label, blinded, endpoint study to explore the efficacy and safety of novel P2Y12 receptor inhibitors administered orally at half the dose in Korean patients with ACS. The results will be available late in 2017. © 2017 S. Karger AG, Basel.

Efficacy of granulocyte colony stimulating factor as a secondary prophylaxis along with full-dose chemotherapy following a prior cycle of febrile neutropenia.

PubMed

Gupta, Seema; Singh, Pankaj K; Bhatt, Madan L B; Pant, Mohan C; Gupta, Rajeev; Negi, Mahendra P S

2010-10-01

Secondary prophylaxis with recombinant human granulocyte colony stimulating factor (G-CSF) is recommended where patients have experienced febrile neutropenia in an earlier chemotherapy cycle and for whom the maintenance of chemotherapy dose intensity is important; or where febrile neutropenia has not occurred but prolonged neutropenia is causing excessive dose delay or reduction, where maintenance of dose intensity is important. The objective of this study was to determine the efficacy and feasibility of G-CSF as secondary prophylaxis when used along with full dose moderately myelotoxic chemotherapy following a prior cycle with febrile-neutropenia. Fifty-two patients aged 22-75 years with febrile neutropenia that required intravenous antibiotics following moderately myelotoxic chemotherapy were included. These patients received the next cycle of the same chemotherapy regime without dose modification but with support of filgrastim 24 h after completion of chemotherapy (300 μg/day/subcutaneously (s.c.) for weight < 60 kg, 480 μg/day/s.c. for weight > 60 kg, for at least 10 consecutive days), patients in whom neutropenia was associated with a life-threatening infection and those who developed prolonged myelosuppression were excluded. The use of the hematopoietic growth factor G-CSF was shown to shorten the neutrophil recovery time, resulting in significant reduction of incidence of febrile neutropenia, hospitalization and use of broad spectrum antibiotics. There was no drug related death or adverse events associated with either cycle. In conclusion, recombinant human G-CSF is effective and relatively safe as a secondary prophylaxis with full dose chemotherapy in patients who develop febrile neutropenia following prior cycles of moderately myelotoxic chemotherapy.

The impact of benzodiazepine use on methadone maintenance treatment outcomes.

PubMed

Brands, Bruna; Blake, Joan; Marsh, David C; Sproule, Beth; Jeyapalan, Renuka; Li, Selina

2008-01-01

The purposes of this study were to examine predictors of benzodiazepine use among methadone maintenance treatment patients, to determine whether baseline benzodiazepine use influenced ongoing use during methadone maintenance treatment, and to assess the effect of ongoing benzodiazepine use on treatment outcomes (i.e., opioid and cocaine use and treatment retention). A retrospective chart review of 172 methadone maintenance treatment patients (mean age = 34.6 years; standard deviation = 8.5 years; 64% male) from January 1997 to December 1999 was conducted. At baseline, 29% were "non-users" (past year) of benzodiazepine, 36% were "occasional users," and 35% were "regular/problem users." Regular/problem users were more likely to have started opioid use with prescription opioids, experienced more overdoses, and reported psychiatric comorbidity. Being female, more years of opioid use, and a history of psychiatric treatment were significant predictors of baseline benzodiazepine use. Ongoing benzodiazepine users were more likely to have opioid-positive and cocaine-positive urine screens during methadone maintenance treatment. Only ongoing cocaine use was negatively related to retention. Benzodiazepine use by methadone maintenance treatment patients is associated with a more complex clinical picture and may negatively influence treatment outcomes.

A phase I/II study of sunitinib and intensive chemotherapy in patients over 60 years of age with acute myeloid leukaemia and activating FLT3 mutations.

PubMed

Fiedler, Walter; Kayser, Sabine; Kebenko, Maxim; Janning, Melanie; Krauter, Jürgen; Schittenhelm, Marcus; Götze, Katharina; Weber, Daniela; Göhring, Gudrun; Teleanu, Veronica; Thol, Felicitas; Heuser, Michael; Döhner, Konstanze; Ganser, Arnold; Döhner, Hartmut; Schlenk, Richard F

2015-06-01

Acute myeloid leukaemia (AML) with FLT3 mutation has a dismal prognosis in elderly patients. Treatment with a combination of FLT3 inhibitors and standard chemotherapy has not been extensively studied. Therefore, we instigated a phase I/II clinical trial of chemotherapy with cytosine arabinoside (Ara-C)/daunorubicin induction (7+3) followed by three cycles of intermediate-dose Ara-C consolidation in 22 AML patients with activating FLT3 mutations. Sunitinib was added at predefined dose levels and as maintenance therapy for 2 years. At dose level 1, sunitinib 25 mg daily continuously from day 1 onwards resulted in two cases with dose-limiting toxicity (DLT), prolonged haemotoxicity and hand-foot syndrome. At dose level -1, sunitinib 25 mg was restricted to days 1-7 of each chemotherapy cycle. One DLT was observed in six evaluable patients. Six additional patients were treated in an extension phase. Thirteen of 22 patients (59%; 8/14 with FLT3-internal tandem duplication and 5/8 with FLT3-tyrosine kinase domain) achieved a complete remission/complete remission with incomplete blood count recovery. For the 17 patients included at the lower dose level, median overall, relapse-free and event-free survival were 1·6, 1·0 and 0·4 years, respectively. Four out of five analysed patients with relapse during maintenance therapy lost their initial FLT3 mutation, suggesting outgrowth of FLT3 wild-type subclones. © 2015 John Wiley & Sons Ltd.

Epidural analgesia practices for labour: results of a 2005 national survey in Ireland.

PubMed

Fanning, Rebecca A; Briggs, Liam P; Carey, Michael F

2009-03-01

The last 25 years have seen changes in the management of epidural analgesia for labour, including the advent of low-dose epidural analgesia, the development of new local anaesthetic agents, various regimes for maintaining epidural analgesia and the practice of combined spinal-epidural analgesia. We conducted a survey of Irish obstetric anaesthetists to obtain information regarding the conduct and management of obstetric epidural analgesia in Ireland in 2005. The specific objective of this survey was to discover whether new developments in obstetric anaesthesia have been incorporated into clinical practice. A postal survey was sent to all anaesthetists with a clinical commitment for obstetric anaesthesia in the sites approved for training by the College of Anaesthetists, Ireland. Fifty-three per cent of anaesthetists surveyed responded. The majority of anaesthetists (98%) use low-dose epidural analgesia for the maintenance of analgesia. Only 11% use it for test-dosing and 32% for the induction of analgesia. The combined spinal-epidural analgesia method is used by 49%, but two-thirds of those who use it perform fewer than five per month. Patient-controlled epidural analgesia was in use at only one site. It appears that Irish obstetric anaesthetists have adopted the low-dose epidural analgesia trend for the maintenance of labour analgesia. This practice is not as widespread, however, for test dosing, the induction of analgesia dose or in the administration of intermittent epidural boluses to maintain analgesia when higher concentrations are used. Since its introduction in 2000, levobupivacaine has become the most popular local anaesthetic agent.

Dexamethasone and High-Dose Methotrexate Improve Outcome for Children and Young Adults With High-Risk B-Acute Lymphoblastic Leukemia: A Report From Children’s Oncology Group Study AALL0232

PubMed Central

Devidas, Meenakshi; Chen, Si; Salzer, Wanda L.; Raetz, Elizabeth A.; Loh, Mignon L.; Mattano, Leonard A.; Cole, Catherine; Eicher, Alisa; Haugan, Maureen; Sorenson, Mark; Heerema, Nyla A.; Carroll, Andrew A.; Gastier-Foster, Julie M.; Borowitz, Michael J.; Wood, Brent L.; Willman, Cheryl L.; Winick, Naomi J.; Hunger, Stephen P.; Carroll, William L.

2016-01-01

Purpose Survival for children and young adults with high-risk B-acute lymphoblastic leukemia has improved significantly, but 20% to 25% of patients are not cured. Children’s Oncology Group study AALL0232 tested two interventions to improve survival. Patients and Methods Between January 2004 and January 2011, AALL0232 enrolled 3,154 participants 1 to 30 years old with newly diagnosed high-risk B-acute lymphoblastic leukemia. By using a 2 × 2 factorial design, 2,914 participants were randomly assigned to receive dexamethasone (14 days) versus prednisone (28 days) during induction and high-dose methotrexate versus Capizzi escalating-dose methotrexate plus pegaspargase during interim maintenance 1. Results Planned interim monitoring showed the superiority of the high-dose methotrexate regimens, which exceeded the predefined boundary and led to cessation of enrollment in January 2011. At that time, participants randomly assigned to high-dose methotrexate during interim maintenance 1 versus those randomly assigned to Capizzi methotrexate had a 5-year event-free survival (EFS) of 82% versus 75.4% (P = .006). Mature final data showed 5-year EFS rates of 79.6% for high-dose methotrexate and 75.2% for Capizzi methotrexate (P = .008). High-dose methotrexate decreased both marrow and CNS recurrences. Patients 1 to 9 years old who received dexamethasone and high-dose methotrexate had a superior outcome compared with those who received the other three regimens (5-year EFS, 91.2% v 83.2%, 80.8%, and 82.1%; P = .015). Older participants derived no benefit from dexamethasone during induction and experienced excess rates of osteonecrosis. Conclusion High-dose methotrexate is superior to Capizzi methotrexate for the treatment of high-risk B-acute lymphoblastic leukemia, with no increase in acute toxicity. Dexamethasone given during induction benefited younger children but provided no benefit and was associated with a higher risk of osteonecrosis among participants 10 years and older. PMID:27114587

Dosimetric evaluation of intrafractional tumor motion by means of a robot driven phantom

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

Richter, Anne; Wilbert, Juergen; Flentje, Michael

2011-10-15

Purpose: The aim of the work was to investigate the influence of intrafractional tumor motion to the accumulated (absorbed) dose. The accumulated dose was determined by means of calculations and measurements with a robot driven motion phantom. Methods: Different motion scenarios and compensation techniques were realized in a phantom study to investigate the influence of motion on image acquisition, dose calculation, and dose measurement. The influence of motion on the accumulated dose was calculated by employing two methods (a model based and a voxel based method). Results: Tumor motion resulted in a blurring of steep dose gradients and a reductionmore » of dose at the periphery of the target. A systematic variation of motion parameters allowed the determination of the main influence parameters on the accumulated dose. The key parameters with the greatest influence on dose were the mean amplitude and the pattern of motion. Investigations on necessary safety margins to compensate for dose reduction have shown that smaller safety margins are sufficient, if the developed concept with optimized margins (OPT concept) was used instead of the standard internal target volume (ITV) concept. Both calculation methods were a reasonable approximation of the measured dose with the voxel based method being in better agreement with the measurements. Conclusions: Further evaluation of available systems and algorithms for dose accumulation are needed to create guidelines for the verification of the accumulated dose.« less

A maintenance time prediction method considering ergonomics through virtual reality simulation.

PubMed

Zhou, Dong; Zhou, Xin-Xin; Guo, Zi-Yue; Lv, Chuan

2016-01-01

Maintenance time is a critical quantitative index in maintainability prediction. An efficient maintenance time measurement methodology plays an important role in early stage of the maintainability design. While traditional way to measure the maintenance time ignores the differences between line production and maintenance action. This paper proposes a corrective MOD method considering several important ergonomics factors to predict the maintenance time. With the help of the DELMIA analysis tools, the influence coefficient of several factors are discussed to correct the MOD value and the designers can measure maintenance time by calculating the sum of the corrective MOD time of each maintenance therbligs. Finally a case study is introduced, by maintaining the virtual prototype of APU motor starter in DELMIA, designer obtains the actual maintenance time by the proposed method, and the result verifies the effectiveness and accuracy of the proposed method.

Phase III, randomised, multicentre trial of maintenance immunotherapy with low-dose interleukin-2 and interferon-alpha for metastatic renal cell cancer.

PubMed

Passalacqua, Rodolfo; Buzio, Carlo; Buti, Sebastiano; Porta, Camillo; Labianca, Roberto; Pezzuolo, Debora; Camisa, Roberta; Sabbatini, Roberto; Benecchi, Luigi; Messina, Caterina; Cengarle, Rita; Vaglio, Augusto; Dalla Chiesa, Matteo; Tomasello, Gianluca; Caminiti, Caterina

2010-04-01

This is the first phase III randomised trial to evaluate maintenance immunotherapy in metastatic renal cell cancer (mRCC). Patients were randomised to receive treatment with a 4-week cycle of subcutaneous low doses IL-2 + IFN in months 1, 3 and 5, and then every 3 months until the first documented disease progression (arm A, suspension), or the same regimen, with chronic maintenance of immunotherapy, regardless of tumour response, until death or intolerable toxicity (arm B, maintenance). The primary endpoint was overall survival (OS); secondary endpoints were time from first progression to death (TFPTD) and tolerability. One hundred and eighty-three patients were enrolled between January 1998 and November 2003. After a median follow-up of 53.9 months, response rate, median OS and median TFPTD were 14.7% (6.3% CR) versus 11.3% (5.5% CR), 14 versus 14 months, 6 versus 5 months, in arms A and B, respectively with no significant differences between the groups. Cox regression analysis showed that the use of chemotherapy after first progression (HR 0.54; 95% CI 0.35-0.86; p = 0.008), PS = 0 (HR 0.53; 95% CI 0.35-0.81; p = 0.001) and female gender (HR 0.63; 95% CI 0.41-0.98; p = 0.038) were significantly associated with a longer TFPTD; treatment arm was not significant (HR 0.88; 95% CI 0.60-1.31; p = 0.54). Toxicity was mainly limited to WHO grades 1 or 2. Chronic maintenance immunotherapy after disease progression is feasible, but does not significantly increase OS or the TFPTD.

Efficacy and Safety of Brexpiprazole (OPC-34712) as Maintenance Treatment in Adults with Schizophrenia: a Randomized, Double-Blind, Placebo-Controlled Study.

PubMed

Fleischhacker, W Wolfgang; Hobart, Mary; Ouyang, John; Forbes, Andy; Pfister, Stephanie; McQuade, Robert D; Carson, William H; Sanchez, Raymond; Nyilas, Margareta; Weiller, Emmanuelle

2017-01-01

Brexpiprazole has previously demonstrated efficacy in acute schizophrenia trials. The objective of this trial was to assess the efficacy, safety, and tolerability of maintenance treatment with brexpiprazole in adults with schizophrenia. Patients with an acute exacerbation of psychotic symptoms were converted to brexpiprazole (1-4mg/d) over 1 to 4 weeks and entered a single-blind stabilization phase. Those patients who met stability criteria for 12 weeks were randomized 1:1 to double-blind maintenance treatment with either brexpiprazole (at their stabilization dose) or placebo for up to 52 weeks. The primary efficacy endpoint was the time from randomization to impending relapse. Safety and tolerability were also assessed. A total of 524 patients were enrolled, 202 of whom were stabilized on brexpiprazole and randomized to brexpiprazole (n=97) or placebo (n=105). Efficacy was demonstrated at a prespecified interim analysis (conducted after 45 events), and so the trial was terminated early. The final analysis showed that time to impending relapse was statistically significantly delayed with brexpiprazole treatment compared with placebo (P<.0001, log-rank test). The hazard ratio for the final analysis was 0.292 (95% confidence interval: 0.156, 0.548); mean dose at last visit, 3.6mg. The proportion of patients meeting the criteria for impending relapse was 13.5% with brexpiprazole and 38.5% with placebo (P<.0001). During the maintenance phase, the incidence of adverse events was comparable to placebo. or patients with schizophrenia already stabilized on brexpiprazole, maintenance treatment with brexpiprazole was efficacious, with a favorable safety profile. © The Author 2016. Published by Oxford University Press on behalf of CINP.

Switch maintenance chemotherapy using S-1 with or without bevacizumab in patients with advanced non-small cell lung cancer: a phase II study.

PubMed

Niho, Seiji; Ohe, Yuichiro; Ohmatsu, Hironobu; Umemura, Shigeki; Matsumoto, Shingo; Yoh, Kiyotaka; Goto, Koichi

2017-06-01

We conducted this single-institute; prospective, non-randomized parallel two-arm phase II study to evaluate the efficacy and safety of switch maintenance chemotherapy with S-1 after induction therapy with a platinum-based regimen in patients with advanced non-small cell lung cancer (NSCLC). Patients not showing disease progression after induction platinum-based chemotherapy received S-1 at the dose of 40mg/m 2 twice daily for 14 consecutive days, every three weeks, with or without bevacizumab (Bev) at the dose of 15mg/kg. In cases where the induction chemotherapy regimen contained Bev, Bev was used as continuation maintenance chemotherapy where appropriate. The efficacy/toxicity of switch maintenance chemotherapy with S-1 and S-1+Bev was evaluated separately. The primary end point of this study was the treatment success rate at three months after the start of S-1 treatment. Between July 2010 and January 2014, 79 patients were enrolled, of which 78 were found to be eligible for inclusion in this study. The treatment success rate at three months was 28.2% (90% confidence interval (CI), 7.1-17.1%) in the S-1 group and 64.1% (90% CI, 50.0-76.8%) in the S-1+Bev group. The primary endpoint was met in the S-1+Bev group. The median PFS and OS were 2.6 months and 11.0 months in the S-1 group, and 4.6 months and 19.9 months in the S-1+Bev group, respectively. The most common grade three toxicity was neutropenia (10% incidence in the S-1+Bev group). There were no cases of febrile neutropenia. Switch maintenance chemotherapy with S-1 in combination with continuation maintenance chemotherapy with bevacizumab yielded modest efficacy with mild and acceptable toxicities. Copyright © 2017. Published by Elsevier B.V.

Designing Interventions that Last: A Classification of Environmental Behaviors in Relation to the Activities, Costs, and Effort Involved for Adoption and Maintenance

PubMed Central

Moore, Harriet E.; Boldero, Jennifer

2017-01-01

Policy makers draw on behavioral research to design interventions that promote the voluntary adoption of environmental behavior in societies. Many environmental behaviors will only be effective if they are maintained over the long-term. In the context of climate change and concerns about future water security, behaviors that involve reducing energy consumption and improving water quality must be continued indefinitely to mitigate global warming and preserve scarce resources. Previous reviews of environmental behavior have focused exclusively on factors related to adoption. This review investigates the factors that influence both adoption and maintenance, and presents a classification of environmental behaviors in terms of the activities, costs, and effort required for both adoption and maintenance. Three categories of behavior are suggested. One-off behaviors involve performing an activity once, such as purchasing an energy efficient washing machine, or signing a petition. Continuous behaviors involve the performance of the same set of behaviors for adoption and for maintenance, such as curbside recycling. Dynamic behaviors involve the performance of different behaviors for adoption and maintenance, such as revegetation. Behaviors can also be classified into four categories related to cost and effort: those that involve little cost and effort for adoption and maintenance, those that involve moderate cost and effort for adoption and maintenance, those that involve a high cost or effort for adoption and less for maintenance, and those that involve less cost or effort for adoption and a higher amount for maintenance. In order to design interventions that last, policy makers should consider the factors that influence the maintenance as well as the adoption of environmental behaviors. PMID:29163265

Understanding the impact of diet and nutrition on symptoms of Tourette syndrome: A scoping review.

PubMed

Ludlow, Amanda K; Rogers, Samantha L

2018-03-01

Anecdotal reports frequently suggest some dietary involvement in the maintenance of tics in children with Tourette syndrome (TS). This scoping review aimed to (1) understand the possible influence of diet as a trigger of tics and (2) map out the existing studies documenting dietary interventions in children with TS. Current evidence suggests no single diet to benefit individuals with TS. However, reports from parents of children with TS suggest that certain allergens in food may exacerbate tic-related symptoms. For example, an increase in tics has been related to the consumption of caffeine and refined sugar. Moreover, oligoantigenic diets and sugar-free diets have been identified as significantly reducing tics. More research is urgently needed to develop more accurate guidance for parents and children with TS, as many have reported using dietary and nutritional supplements, despite the lack of evidence detailing any benefits, side effects and recommended doses.

The Effect of Rapacuronium or Succinylcholine on the Duration of Action of Rocuronium

DTIC Science & Technology

2001-10-01

of the pre-determined rocuronium dose, supramaximal TOF sequence was evoked every 12 seconds to the anterior branch of the recurrent laryngeal nerve ...Paragraph™ Nerve Stimulator was used to observe the neuromuscular response (return of the second twitch) during the first maintenance dose of...of the train-of-four (TOF) twitch response is 62 seconds at the laryngeal muscles and 96 seconds at the adductor pollicis muscle. Similar to

Effects of maintenance operations on track buckling potential

DOT National Transportation Integrated Search

2003-05-04

This paper presents the results of buckling analyses based on data from recent tests determining the influence of track maintenance and consolidation on track lateral resistance. The buckling analyses were performed using the USDOT/Volpe "CWR-SAFE" m...

Effect of the implementation of the fluvial performance standard on maintenance of bridges and culverts.

DOT National Transportation Integrated Search

2013-08-01

The objective of this project was to determine what factors influence maintenance cost of Oregon Department of Transportation (ODOT) stream-crossing structures. Data acquired for the project included structure characteristics, stream characteristics,...

Could pharmacogenetic data explain part of the interindividual sensitivity to methadone-induced respiratory depression?

PubMed Central

Crettol, Séverine; Monnat, Martine; Eap, Chin B

2007-01-01

In this issue of Critical Care, Megarbane and colleagues present a case report of methadone-induced respiratory depression and conduct a toxicokinetic/toxicodynamic evaluation. An opioid-dependent patient receiving methadone maintenance treatment (daily dose 70 mg) was found unconscious after ingesting 240 mg methadone and 2 mg flunitrazepam. Significant improvement in consciousness was achieved after an intravenous bolus of 0.3 mg naloxone followed by a continuous infusion of naloxone at 0.3 mg/hour. In patients receiving methadone maintenance treatment, an occasional intake of two to four times the usual daily dose of methadone is not an exceptional occurrence. However, few such patients experience episodes of life-threatening respiratory depression. Here, we discuss whether recent pharmacogenetic data could help us to understand interindividual variability in sensitivity to respiratory depression and, ultimately, to predict which patients are most likely to be affected. PMID:17338832

The effect of low versus high approach-motivated positive affect on the balance between maintenance and flexibility.

PubMed

Liu, Liting; Xu, Baihua

2016-05-27

Successful goal-directed behavior in a constantly changing environment requires a balance between maintenance and flexibility. Although some studies have found that positive affect influences this balance differently than neutral affect, one recent study found that motivational intensity of positive affective states influences this balance in a cognitive set-shifting paradigm. However, working memory updating and set shifting are interrelated but distinct components of cognitive control. The present study examined the effect of low versus high approach-motivated positive affect on the balance between maintenance and flexibility in working memory. A simple cuing paradigm (the AX Continuous Performance Task) was employed, and neutral affect and high and low approach-motivated positive affect were induced using affective pictures. The results revealed that, relative to neutral affect, low approach-motivated positive affect attenuated maintenance and increased flexibility, whereas high approach-motivated positive affect promoted maintenance and decreased flexibility. These findings offer further evidence that the effects of positive affect on cognitive control are modulated by approach motivational intensity. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Dermal Exposure to Jet Fuel JP-8 Significantly Contributes to the Production of Urinary Naphthols in Fuel-Cell Maintenance Workers

PubMed Central

Chao, Yi-Chun E.; Kupper, Lawrence L.; Serdar, Berrin; Egeghy, Peter P.; Rappaport, Stephen M.; Nylander-French, Leena A.

2006-01-01

Jet propulsion fuel 8 (JP-8) is the major jet fuel used worldwide and has been recognized as a major source of chemical exposure, both inhalation and dermal, for fuel-cell maintenance workers. We investigated the contributions of dermal and inhalation exposure to JP-8 to the total body dose of U.S. Air Force fuel-cell maintenance workers using naphthalene as a surrogate for JP-8 exposure. Dermal, breathing zone, and exhaled breath measurements of naphthalene were obtained using tape-strip sampling, passive monitoring, and glass bulbs, respectively. Levels of urinary 1- and 2-naphthols were determined in urine samples and used as biomarkers of JP-8 exposure. Multiple linear regression analyses were conducted to investigate the relative contributions of dermal and inhalation exposure to JP-8, and demographic and work-related covariates, to the levels of urinary naphthols. Our results show that both inhalation exposure and smoking significantly contributed to urinary 1-naphthol levels. The contribution of dermal exposure was significantly associated with levels of urinary 2-naphthol but not with urinary 1-naphthol among fuel-cell maintenance workers who wore supplied-air respirators. We conclude that dermal exposure to JP-8 significantly contributes to the systemic dose and affects the levels of urinary naphthalene metabolites. Future work on dermal xenobiotic metabolism and toxicokinetic studies are warranted in order to gain additional knowledge on naphthalene metabolism in the skin and the contribution to systemic exposure. PMID:16451852

Dermal exposure to jet fuel JP-8 significantly contributes to the production of urinary naphthols in fuel-cell maintenance workers.

PubMed

Chao, Yi-Chun E; Kupper, Lawrence L; Serdar, Berrin; Egeghy, Peter P; Rappaport, Stephen M; Nylander-French, Leena A

2006-02-01

Jet propulsion fuel 8 (JP-8) is the major jet fuel used worldwide and has been recognized as a major source of chemical exposure, both inhalation and dermal, for fuel-cell maintenance workers. We investigated the contributions of dermal and inhalation exposure to JP-8 to the total body dose of U.S. Air Force fuel-cell maintenance workers using naphthalene as a surrogate for JP-8 exposure. Dermal, breathing zone, and exhaled breath measurements of naphthalene were obtained using tape-strip sampling, passive monitoring, and glass bulbs, respectively. Levels of urinary 1- and 2-naphthols were determined in urine samples and used as biomarkers of JP-8 exposure. Multiple linear regression analyses were conducted to investigate the relative contributions of dermal and inhalation exposure to JP-8, and demographic and work-related covariates, to the levels of urinary naphthols. Our results show that both inhalation exposure and smoking significantly contributed to urinary 1-naphthol levels. The contribution of dermal exposure was significantly associated with levels of urinary 2-naphthol but not with urinary 1-naphthol among fuel-cell maintenance workers who wore supplied-air respirators. We conclude that dermal exposure to JP-8 significantly contributes to the systemic dose and affects the levels of urinary naphthalene metabolites. Future work on dermal xenobiotic metabolism and toxicokinetic studies are warranted in order to gain additional knowledge on naphthalene metabolism in the skin and the contribution to systemic exposure.

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.

Pharmacokinetics and clinical effect of phenobarbital in children with severe falciparum malaria and convulsions

PubMed Central

Kokwaro, Gilbert O; Ogutu, Bernhards R; Muchohi, Simon N; Otieno, Godfrey O; Newton, Charles R J C

2003-01-01

Aims Phenobarbital is commonly used to treat status epilepticus in resource-poor countries. Although a dose of 20 mg kg−1 is recommended, this dose, administered intramuscularly (i.m.) for prophylaxis, is associated with an increase in mortality in children with cerebral malaria. We evaluated a 15-mg kg−1 intravenous (i.v.) dose of phenobarbital to determine its pharmacokinetics and clinical effects in children with severe falciparum malaria and status epilepticus. Methods Twelve children (M/F: 11/1), aged 7–62 months, received a loading dose of phenobarbital (15 mg kg−1) as an i.v. infusion over 20 min and maintenance dose of 5 mg kg−1 at 24 and 48 h later. The duration of convulsions and their recurrence were recorded. Vital signs were monitored. Plasma and cerebrospinal fluid (CSF) phenobarbital concentrations were measured with an Abbott TDx FLx® fluorescence polarisation immunoassay analyser (Abbott Laboratories, Diagnostic Division, Abbott Park, IL, USA). Simulations were performed to predict the optimum dosage regimen that would maintain plasma phenobarbital concentrations between 15 and 20 mg l−1 for 72 h. Results All the children achieved plasma concentrations above 15 mg l−1 by the end of the infusion. Mean (95% confidence interval or median and range for Cmax) pharmacokinetic parameters were: area under curve [AUC (0, ∞) ]: 4259 (3169, 5448) mg l−1.h, t½: 82.9 (62, 103) h, CL: 5.8 (4.4, 7.3) ml kg−1 h−1, Vss: 0.8 (0.7, 0.9) l kg −1, CSF: plasma phenobarbital concentration ratio: 0.7 (0.5, 0.8; n = 6) and Cmax: 19.9 (17.9–27.9) mg l−1. Eight of the children had their convulsions controlled and none of them had recurrence of convulsions. Simulations suggested that a loading dose of 15 mg kg−1 followed by two maintenance doses of 2.5 mg kg−1 at 24 h and 48 h would maintain plasma phenobarbital concentrations between 16.4 and 20 mg l−1 for 72 h. Conclusions Phenobarbital, given as an i.v. loading dose, 15 mg kg−1, achieves maximum plasma concentrations of greater than 15 mg l−1 with good clinical effect and no significant adverse events in children with severe falciparum malaria. A maintenance dose of 2.5 mg kg−1 at 24 h and 48 h was predicted to be sufficient to maintain concentrations of 15–20 mg l−1 for 72 h, and may be a suitable regimen for treatment of convulsions in these children. PMID:12968992

Influence of genetic polymorphisms on the effect of high- and standard-dose clopidogrel after percutaneous coronary intervention: the GIFT (Genotype Information and Functional Testing) study.

PubMed

Price, Matthew J; Murray, Sarah S; Angiolillo, Dominick J; Lillie, Elizabeth; Smith, Erin N; Tisch, Rebecca L; Schork, Nicholas J; Teirstein, Paul S; Topol, Eric J

2012-05-29

This study sought to evaluate the influence of single nucleotide polymorphisms (SNPs) on the pharmacodynamic effect of high- or standard-dose clopidogrel after percutaneous coronary intervention (PCI). There is a lack of prospective, multicenter data regarding the effect of different genetic variants on clopidogrel pharmacodynamics over time in patients undergoing PCI. The GRAVITAS (Gauging Responsiveness with A VerifyNow assay-Impact on Thrombosis And Safety) trial screened patients with platelet function testing after PCI and randomly assigned those with high on-treatment reactivity (OTR) to either high- or standard-dose clopidogrel; a cohort of patients without high OTR were also followed. DNA samples obtained from 1,028 patients were genotyped for 41 SNPs in 17 genes related to platelet reactivity. After adjusting for clinical characteristics, the associations between the SNPs and OTR using linear regression were evaluated. CYP2C19*2 was significantly associated with OTR at 12 to 24 h (R(2) = 0.07, p = 2.2 × 10(-15)), 30 days (R(2) = 0.10, p = 1.3 × 10(-7)), and 6 months after PCI (R(2) = 0.07, p = 1.9 × 10(-11)), whereas PON1, ABCB1 3435 C→T, and other candidate SNPs were not. Carriers of 1 and 2 reduced-function CYP2C19 alleles were significantly more likely to display persistently high OTR at 30 days and 6 months, irrespective of treatment assignment. The portion of the risk of persistently high OTR at 30 days attributable to reduced-function CYP2C19 allele carriage was 5.2% in the patients randomly assigned to high-dose clopidogrel. CYP2C19, but not PON1 or ABCB1, is a significant determinant of the pharmacodynamic effects of clopidogrel, both early and late after PCI. In patients with high OTR identified by platelet function testing, the CYP2C19 genotype provides limited incremental information regarding the risk of persistently high reactivity with clopidogrel 150-mg maintenance dosing. (Genotype Information and Functional Testing Study [GIFT]; NCT00992420). Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

[Radon risk in healthcare facilities: environmental monitoring and effective dose].

PubMed

Cammarota, B; Cascone, Maria Teresa; De Paola, L; Schillirò, F; Del Prete, U

2009-01-01

Radon, the second cause of lung cancer after smoking (WHO- IARC), is a natural, radioactive gas, which originates from the soil and pollutes indoor air, especially in closed or underground spaces. The purpose of this study was to determine the concentration of radon gas, its effective dose, and the measurement of microclimatic degrees C; U.R. % and air velocity in non-academic intensive care units of public hospitals in the Naples area. The annual average concentrations of radon gas were detected with EIC type ionization electret chambers, type LLT with exposure over four 3-month periods. The concentrations varied for all health facilities between 186 and 1191 Bq/m3. Overall, the effective dose of exposure to radon gas of 3mSv/a recommended by Italian legislation was never exceeded. The concentration of radon gas showed a decreasing trend starting from the areas below ground level to those on higher floors; such concentrations were also influenced by natural and artificial ventilation of the rooms, building materials used for walls, and by the state of maintenance and improvements of the building (insulation of floors and walls). The data obtained confirmed the increased concentration of radionuclides in the yellow tuff of volcanic origin in the Campania Region and the resulting rate of release of radon gas, whereas the reinforced concrete structure (a hospital located on the hillside), which had the lowest values, proved to provide good insulation against penetration and accumulation of radon gas.

Osmotic Release Oral System Methylphenidate Versus Atomoxetine for the Treatment of Attention-Deficit/Hyperactivity Disorder in Chinese Youth: 8-Week Comparative Efficacy and 1-Year Follow-Up.

PubMed

Su, Yi; Yang, Li; Stein, Mark A; Cao, Qingjiu; Wang, Yufeng

2016-05-01

The purpose of this study was to compare the short-term efficacy, tolerability, and 1-year adherence in Chinese children and adolescents with attention-deficit/hyperactivity disorder (ADHD) treated with either osmotic release oral system methylphenidate (OROS MPH) or atomoxetine (ATX). Children and adolescents meeting Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) criteria for ADHD were randomly assigned to receive either OROS MPH (n = 119) or ATX (n = 118). Participants underwent a 1-4 week dose titration period to determine optimal dose, and then were maintained on that dose for 4 weeks (maintenance period). Assessment for efficacy was conducted every week over the titration period and at the end of the maintenance period. The primary efficacy measure was the investigator-rated total ADHD Rating Scale-IV (ADHD-RS-IV) score. Response was further classified as remission (ADHD-RS-IV [18 or 9 items] average score ≤1), robust improvement (ADHD-RS-IV ≥40% decrease in total score), or improvement (≥ 25% decrease in total score) at the end of maintenance period. Medication adherence (taking medication at least 5 days in 1 week) and reasons for nonadherence were evaluated every week over the titration period, at the end of maintenance period, and then at 3, 6, and 12 months. At the end of maintenance period, both OROS MPH and ATX were associated with significant and similar reductions from baseline in ADHD symptoms. Percentages achieving remission, robust improvement, and improvement were comparable for OROS MPH and ATX treatment (35.3% vs. 37.1%, 45.4% vs. 44.8%, 65.5% vs. 66.4%). Medication use decreased over time for both treatments; however, at end of maintenance period, 3 month, 6 month, and 1 year follow-ups, subjects in the OROS MPH group were more likely to be compliant with treatment (74.8%, 50.4%, 38.7%, and 21.8% for OROS MPH vs. 52.5%, 33.9%, 12.7%, and 3.4% for ATX) ( p < 0.05). The most common reasons for nonadherence were adverse events and lack of efficacy. Both OROS MPH and ATX resulted in similar reductions in ADHD symptoms in Chinese children and adolescents with ADHD. Long-term adherence with medication was poor in general, although somewhat better with OROS MPH than with ATX. ClinicalTrials.gov , Identifier: NCT01065259.

Identification of novel variants associated with warfarin stable dosage by use of a two-stage extreme phenotype strategy.

PubMed

Luo, Z; Li, X; Zhu, M; Tang, J; Li, Z; Zhou, X; Song, G; Liu, Z; Zhou, H; Zhang, W

2017-01-01

Essentials Required warfarin doses for mechanical heart valves vary greatly. A two-stage extreme phenotype design was used to identify novel warfarin dose associated mutation. We identified a group of variants significantly associated with extreme warfarin dose. Four novel identified mutations account for 2.2% of warfarin dose discrepancies. Background The variation among patients in warfarin response complicates the management of warfarin therapy, and an improper therapeutic dose usually results in serious adverse events. Objective To use a two-stage extreme phenotype strategy in order to discover novel warfarin dose-associated mutations in heart valve replacement patients. Patients/method A total of 1617 stable-dose patients were enrolled and divided randomly into two cohorts. Stage I patients were genotyped into three groups on the basis of VKORC1-1639G>A and CYP2C9*3 polymorphisms; only patients with the therapeutic dose at the upper or lower 5% of each genotype group were selected as extreme-dose patients for resequencing of the targeted regions. Evaluation of the accuracy of the sequence data and the potential value of the stage I-identified significant mutations were conducted in a validation cohort of 420 subjects. Results A group of mutations were found to be significantly associated with the extreme warfarin dose. The validation work finally identified four novel mutations, i.e. DNMT3A rs2304429 (24.74%), CYP1A1 rs3826041 (47.35%), STX1B rs72800847 (7.01%), and NQO1 rs10517 (36.11%), which independently and significantly contributed to the overall variability in the warfarin dose. After addition of these four mutations, the estimated regression equation was able to account for 56.2% (R 2 Adj = 0.562) of the overall variability in the warfarin maintenance dose, with a predictive accuracy of 62.4%. Conclusion Our study provides evidence linking genetic variations in STX1B, DNMT3A and CYP1A1 to warfarin maintenance dose. The newly identified mutations together account for 2.2% of warfarin dose discrepancy. © 2016 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals, Inc. on behalf of International Society on Thrombosis and Haemostasis.

Advanced sensors and applications : commercial motor vehicle tire pressure monitoring and maintenance.

DOT National Transportation Integrated Search

2014-02-01

This study evaluated the costs and benefits of tire pressure monitoring and maintenance systems for commercial : fleets by conducting a yearlong field test. Specifically, the studys goal was to determine whether these systems : could influence mai...

A Randomized 2×2 Factorial Trial, Part 1: Single-Dose Rabbit Antithymocyte Globulin Induction May Improve Renal Transplantation Outcomes

PubMed Central

Stevens, R. Brian; Foster, Kirk W.; Miles, Clifford D.; Lane, James T.; Kalil, Andre C.; Florescu, Diana F.; Sandoz, John P.; Rigley, Theodore H.; Nielsen, Kathleen J.; Skorupa, Jill Y.; Kellogg, Anna M.; Malik, Tamer; Wrenshall, Lucile E.

2015-01-01

Background We conducted a randomized and unblinded 2×2 sequential-factorial trial, composed of an induction arm (part 1) comparing single-dose (SD) versus divided-dose rabbit antithymocyte globulin (rATG), and a maintenance arm (part 2) comparing tacrolimus minimization versus withdrawal. We report the long-term safety and efficacy of SD-rATG induction in the context of early steroid withdrawal and tacrolimus minimization or withdrawal. Methods Patients (n=180) received 6 mg/kg rATG, SD or four alternate-day doses (1.5 mg/kg/dose), with early steroid withdrawal and tacrolimus or sirolimus maintenance. After 6 months targeted maintenance levels were tacrolimus, 2 to 4 ng/mL and sirolimus, 4 to 6 ng/mL or, if calcineurin inhibitor–withdrawn, sirolimus 8 to 12 ng/mL with mycophenolate mofetil 2 g two times per day. Primary endpoints were renal function (abbreviated modification of diet in renal disease) and chronic graft histopathology (Banff). Secondary endpoints included patient survival, graft survival, biopsy-proven rejection, and infectious or noninfectious complications. Results Follow-up averaged longer than 4 years. Tacrolimus or sirolimus and mycophenolate mofetil exposure was identical between groups. The SD-rATG associated with improved renal function (2-36 months; P<0.001) in deceased donor recipients. The SD-rATG associated with quicker lymphocyte, CD4 T cell, and CD4-CD8 recovery and fewer infections. Cox multivariate hazard modeling showed divided-dose–rATG (P=0.019), deceased donor (P=0.003), serious infection (P=0.0.018), and lower lymphocyte count (P=0.001) associated with increased mortality. Patients with all four covariates showed a 27-fold increased likelihood of death (P=0.00002). Chronic graft histopathology, rejection rates, and death-censored graft survival were not significantly different between groups. Conclusion The SD-rATG induction improves the 3-year renal function in recipients of deceased donor kidneys. This benefit, along with possibly improved patient survival and fewer infections suggest that how rATG is administered may impact its efficacy and safety. PMID:25083614

The effect of low-dose dexmedetomidine on hemodynamics and anesthetic requirement during bis-spectral index-guided total intravenous anesthesia.

PubMed

Park, Hee Yeon; Kim, Jong Yeop; Cho, Sang Hyun; Lee, Dongchul; Kwak, Hyun Jeong

2016-08-01

The purpose of this study was to evaluate the effects of low-dose dexmedetomidine on hemodynamics and anesthetic requirements during propofol and remifentanil anesthesia for laparoscopic cholecystectomy. Thirty adult patients were randomly allocated to receive dexmedetomidine infusion of 0.3 μg/kg/h (dexmedetomidine group, n = 15) or comparable volumes of saline infusion (control group, n = 15). Target controlled infusion of propofol and remifentanil was used for anesthetic induction and maintenance, and adjusted in order to maintain a bispectral index of 40-55 and hemodynamic stability. We measured hemodynamics and recorded total and mean infused dosages of propofol and remifentanil. For anesthesia induction and maintenance, mean infused doses of propofol (121 ± 27 vs. 144 ± 29 μg/kg/min, P = 0.04) and remifentanil (118 ± 27 vs. 150 ± 36 ng/kg/min, P = 0.01) were lower in the dexmedetomidine group than in the control group, respectively. The dexmedetomidine group required 16 % less propofol and 23 % less remifentanil. During anesthetic induction and maintenance, the dexmedetomidine group required fewer total doses of propofol (9.6 ± 2.3 vs. 12.4 ± 3.3 mg/kg, P = 0.01) and remifentanil (9.6 ± 3.4 vs. 12.7 ± 2.6 μg/kg, P = 0.01). The change in mean arterial pressure over time differed between the groups (P < 0.05). Significantly lower mean arterial pressure was observed in the dexmedetomidine group than in the control group at immediately and 5 min after pneumoperitoneum. The time to extubation after completion of drug administration did not differ between the groups (P = 0.25). This study demonstrated that a low-dose dexmedetomidine infusion of 0.3 μg/kg/h reduced propofol and remifentanil requirements as well as hemodynamic change by pneumoperitoneum without delayed recovery during propofol-remifentanil anesthesia for laparoscopic cholecystectomy.

TH-AB-BRA-06: MOSFET-Based Dosimetry in An MR Image-Guided Radiation Therapy System: Comparison with and Without a Static 0.3T Magnetic Field

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

Cammin, J; Curcuru, A; Li, H

Purpose: To compare depth-dose and surface-dose measurements without and with the magnetic field in a 0.3T MR image-guided Co-60 treatment unit using MOSFET dosimeters. Methods: MOSFET dosimeters (Best Medical Canada, model TN-502RDH-10) were placed in a solid water phantom at 5cm depth with 8cm backscatter (with the MOSFET wires in different orientations to the couch long axis) and also on the surface of an 8cm solid water phantom. The phantoms were placed in an MR image-guided Co-60 treatment machine at an SAD of 105cm to the MOSFETs. Dose measurements were performed between 50 and 200cGy at 5cm depth in amore » 10.5cm × 10.5cm radiation field without the magnetic field (during a machine maintenance period) and with the nominal magnetic field of 0.3T. The dose linearity was measured at 5cm depth with an orthogonal field and the angular dose dependence was measured on the surface with an orthogonal field and oblique fields at +60 degrees and −60 degrees. Results: The measured MOSFET readings at 5cm depth were linear with dose with slopes of (2.97 +/− 0.01) mV/cGy and (3.01 +/− 0.02) mV/cGy without and with the magnetic field, respectively. No statistically significant difference was found. The surface dose measurements, however, were lower by 6.4% for the AP field (2.3 σ) with magnetic field, 4.9% for the −60 degree field (1.4 σ), and 0.4% different for the +60 degree field (0.2 σ). Conclusion: There is no statistically significant difference in the dose at depth without and with the magnetic field and different orientations of the MOSFET wires. There is a statistically significant difference for the surface dose due to the influence of the magnetic field on secondary electrons from head-scatter and the build-up region in certain field orientations. Clinical surface-dose dosimetry in a magnetic field should apply asymmetric angle-dependent corrections.« less

Maintaining close relationships: gratitude as a motivator and a detector of maintenance behavior.

PubMed

Kubacka, Kaska E; Finkenauer, Catrin; Rusbult, Caryl E; Keijsers, Loes

2011-10-01

This research examined the dual function of gratitude for relationship maintenance in close relationships. In a longitudinal study among married couples, the authors tested the dyadic effects of gratitude over three time points for approximately 4 years following marriage. They found that feelings of gratitude toward a partner stem from the partner's relationship maintenance behaviors, partly because such behaviors create the perception of responsiveness to one's needs. In turn, gratitude motivates partners to engage in relationship maintenance. Hence, the present model emphasizes that gratitude between close partners (a) originates from partners' relationship maintenance behaviors and the perception of a partner's responsiveness and (b) promotes a partner's reciprocal maintenance behaviors. Thus, the authors' findings add credence to their model, in that gratitude contributes to a reciprocal process of relationship maintenance, whereby each partner's maintenance behaviors, perceptions of responsiveness, and feelings of gratitude feed back on and influence the other's behaviors, perceptions, and feelings.

Population-Level Density Dependence Influences the Origin and Maintenance of Parental Care

PubMed Central

Reyes, Elijah; Thrasher, Patsy; Bonsall, Michael B.; Klug, Hope

2016-01-01

Parental care is a defining feature of animal breeding systems. We now know that both basic life-history characteristics and ecological factors influence the evolution of care. However, relatively little is known about how these factors interact to influence the origin and maintenance of care. Here, we expand upon previous work and explore the relationship between basic life-history characteristics (stage-specific rates of mortality and maturation) and the fitness benefits associated with the origin and the maintenance of parental care for two broad ecological scenarios: the scenario in which egg survival is density dependent and the case in which adult survival is density dependent. Our findings suggest that high offspring need is likely critical in driving the origin, but not the maintenance, of parental care regardless of whether density dependence acts on egg or adult survival. In general, parental care is more likely to result in greater fitness benefits when baseline adult mortality is low if 1) egg survival is density dependent or 2) adult mortality is density dependent and mutant density is relatively high. When density dependence acts on egg mortality, low rates of egg maturation and high egg densities are less likely to lead to strong fitness benefits of care. However, when density dependence acts on adult mortality, high levels of egg maturation and increasing adult densities are less likely to maintain care. Juvenile survival has relatively little, if any, effect on the origin and maintenance of egg-only care. More generally, our results suggest that the evolution of parental care will be influenced by an organism’s entire life history characteristics, the stage at which density dependence acts, and whether care is originating or being maintained. PMID:27093056

Low-dose budesonide for maintenance of clinical remission in collagenous colitis: a randomised, placebo-controlled, 12-month trial.

PubMed

Münch, Andreas; Bohr, Johan; Miehlke, Stephan; Benoni, Cecilia; Olesen, Martin; Öst, Åke; Strandberg, Lars; Hellström, Per M; Hertervig, Erik; Armerding, Peter; Stehlik, Jiri; Lindberg, Greger; Björk, Jan; Lapidus, Annika; Löfberg, Robert; Bonderup, Ole; Avnström, Sören; Rössle, Martin; Dilger, Karin; Mueller, Ralph; Greinwald, Roland; Tysk, Curt; Ström, Magnus

2016-01-01

This 1-year study aimed to assess low-dose budesonide therapy for maintenance of clinical remission in patients with collagenous colitis. A prospective, randomised, placebo-controlled study beginning with an 8-week open-label induction phase in which patients with histologically confirmed active collagenous colitis received budesonide (Budenofalk, 9 mg/day initially, tapered to 4.5 mg/day), after which 92 patients in clinical remission were randomised to budesonide (mean dose 4.5 mg/day; Budenofalk 3 mg capsules, two or one capsule on alternate days) or placebo in a 12-month double-blind phase with 6 months treatment-free follow-up. Primary endpoint was clinical remission throughout the double-blind phase. Clinical remission during open-label treatment was achieved by 84.5% (93/110 patients). The median time to remission was 10.5 days (95% CI (9.0 to 14.0 days)). The maintenance of clinical remission at 1 year was achieved by 61.4% (27/44 patients) in the budesonide group versus 16.7% (8/48 patients) receiving placebo (treatment difference 44.5% in favour of budesonide; 95% CI (26.9% to 62.7%), p<0.001). Health-related quality of life was maintained during the 12-month double-blind phase in budesonide-treated patients. During treatment-free follow-up, 82.1% (23/28 patients) formerly receiving budesonide relapsed after study drug discontinuation. Low-dose budesonide over 1 year resulted in few suspected adverse drug reactions (7/44 patients), all non-serious. Budesonide at a mean dose of 4.5 mg/day maintained clinical remission for at least 1 year in the majority of patients with collagenous colitis and preserved health-related quality of life without safety concerns. Treatment extension with low-dose budesonide beyond 1 year may be beneficial given the high relapse rate after budesonide discontinuation. http://www.clinicaltrials.gov (NCT01278082) and http://www.clinicaltrialsregister.eu (EudraCT: 2007-001315-31). Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Characterizing Potentially Inappropriate Prescribing of Proton Pump Inhibitors in Older People in Primary Care in Ireland from 1997 to 2012.

PubMed

Moriarty, Frank; Bennett, Kathleen; Cahir, Caitriona; Fahey, Tom

2016-12-01

To characterize prescribing of proton pump inhibitors (PPIs) and medicines that increase gastrointestinal bleeding risk (ulcerogenic) in older people from 1997 to 2012 and assess factors associated with maximal-dose prescribing in long-term PPI users. Repeated cross-sectional study of pharmacy claims data. Eastern Health Board region of Ireland. Individuals aged 65 and older from a means-tested health plan in 1997, 2002, 2007, and 2012 (range 78,489-133,884 individuals). PPI prescribing prevalence was determined per study year, categorized according to duration (≤8 or >8 weeks), dosage (maximal or maintenance), and co-prescribed drugs. Logistic regression in long-term PPI users was used to determine whether age, sex, polypharmacy, and ulcerogenic medicine use were associated with being prescribed a maximal dose rather than a maintenance dose. Adjusted odds ratios (ORs) with 95% confidence intervals (CIs) are presented. Half of this older population received a PPI in 2007 and 2012. Long-term use (>8 weeks) of maximal doses rose from 0.8% of individuals in 1997 to 23.6% in 2012. Although some ulcerogenic medicines and polypharmacy were significantly associated with maximal PPI doses, any nonsteroidal anti-inflammatory drug use was significantly associated with lower odds of maximal PPI dose (adjusted OR = 0.87, 95% CI = 0.85-0.89), as were aspirin use and older age. Adjusting for medication and demographic factors, odds of being prescribed a maximal PPI dose were significantly higher in 2012 than in 1997 (adjusted OR = 6.30, 95% CI = 5.76-6.88). Long-term maximal-dose PPI prescribing is highly prevalent in older adults and is not consistently associated with gastrointestinal bleeding risk factors. Interventions involving prescribers and patients may promote appropriate PPI use, reducing costs and adverse effects of PPI overprescribing. © 2016, Copyright the Authors Journal compilation © 2016, The American Geriatrics Society.

Update on the cardiovascular profile of fingolimod in the therapy of relapsing-remitting multiple sclerosis (MS).

PubMed

Meissner, Axel; Limmroth, Volker

2016-07-01

Fingolimod (FTY720) has been approved as the first oral representative of the class of sphingosine-1-phosphate (S1P) receptor modulators for the treatment of relapsing-remitting multiple sclerosis (MS). Besides inducing vaso-relaxation, fingolimod can also influence electrical conduction in the myocardium and vascular endothelium by having a transient negative chronotropic effect on the sinus node. Cardiac safety and tolerability of fingolimod in the cardiac sense were reviewed by analysing the data collected from the FREEDOMS and TRANSFORMS studies -both relevant studies for marketing authorisation, from their extension studies, as well as the clinical data collected from a practice-related MS patient cohort with cardiovascular risk factors and corresponding co-medication (FIRST study). The safety analyses on file gave no indication of any increased cardiovascular risk. The 2-3mmHg increase in blood pressure observed after the first dose of fingolimod has no therapeutic consequences. The first dose of 0.5mg fingolimod resulted in an average decrease in heart rate of 7-8beats/min. The onset of effect occurred approximately 1-2h after the first dose and the nadir was reached after approximately 4-5h. This negative chronotropic effect returned to normal after internalisation of the S1P1 receptors on maintenance therapy. There were no indications that patients with cardiac risk factors required closer observation beyond the monitoring recommended by the EMA following the first dose of fingolimod. Case study observations from the routine clinical setting show that patients accept this method of monitoring, which they assess as being a positive aspect of attentive medical care and concern. Copyright © 2016 Elsevier B.V. All rights reserved.

Methadone Treatment for HIV Prevention—Feasibility, Retention, and Predictors of Attrition in Dar es Salaam, Tanzania: A Retrospective Cohort Study

PubMed Central

Lambdin, Barrot H.; Masao, Frank; Chang, Olivia; Kaduri, Pamela; Mbwambo, Jessie; Magimba, Ayoub; Sabuni, Norman; Bruce, R. Douglas

2014-01-01

Background. People who inject drugs (PWID) in Dar es Salaam, Tanzania, have an estimated human immunodeficiency virus (HIV) prevalence of 42%–50% compared with 6.9% among the general population. Extensive evidence supports methadone maintenance to lower morbidity, mortality, and transmission of HIV and other infectious diseases among PWID. In 2011, the Tanzanian government launched the first publicly funded methadone clinic on the mainland of sub-Saharan Africa at Muhimbili National Hospital. Methods. We conducted a retrospective cohort study of methadone-naive patients enrolling into methadone maintenance treatment. Kaplan-Meier survival curves were constructed to assess retention probability. Proportional hazards regression models were used to evaluate the association of characteristics with attrition from the methadone program. Results. Overall, 629 PWID enrolled into methadone treatment during the study. At 12 months, the proportion of clients retained in care was 57% (95% confidence interval [CI], 53%–62%). Compared with those receiving a low dose (<40 mg), clients receiving a medium (40–85 mg) (adjusted hazard ratio [aHR], 0.50 [95% CI, .37–.68]) and high (>85 mg) (aHR, 0.41 [95% CI, .29–.59]) dose of methadone had a lower likelihood of attrition, adjusting for other characteristics. Older clients (aHR, 0.53 per 10 years [95% CI, .42–.69]) and female clients (aHR, 0.50 [95% CI, .28–.90]) had a significantly lower likelihood of attrition, whereas clients who reported a history of sexual abuse (aHR, 2.84 [95% CI, 1.24–6.51]) had a significantly higher likelihood of attrition. Conclusions. Patient retention in methadone maintenance is comparable to estimates from programs in North America, Europe, and Asia. Future implementation strategies should focus on higher doses and flexible dosing strategies to optimize program retention and strengthened efforts for clients at higher risk of attrition. PMID:24855149

Preliminary study of the role of gastrointestinal endocrine cells in the maintenance of villous structure following X-irradiation

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

Wyatt, M.G.; Hume, S.P.; Carr, K.E.

The mechanism of gastrointestinal villous damage following ionizing irradiation is complex. Various compartments within the gastrointestinal tract have in turn been considered important for the maintenance of normal villous structure. To date, however, evidence for a single overriding regulator of epithelial well-being is lacking. In this study, the role of the gastro-intestinal (enteroendocrine) cells is explored and comparison made between endocrine cell number and villous structure. Experiments were organized using both control and irradiated groups of mice. Two time points (1 and 3 days) and three radiation doses (6, 10 and 18Gy) were employed. A simple method for endocrine cellmore » identification and subsequent quantification is described. Endocrine cell number was then compared with villous surface detail, as seen with a scanning electron microscope (SEM). Results indicated a decrease in the endocrine cell number at all three radiation doses. Whereas at low doses endocrine cell recovery occurred between 1 and 3 days, at medium and high doses further decline was noticed. A similar pattern was seen when considering villous surface structure. It is suggested that both scanning electron microscopy and endocrine cell number provide a more sensitive indicator of gastrointestinal radiation damage than do current crypt counting techniques. In addition, a link between endocrine cell number and villous structure is proposed.« less

A placebo-controlled trial of dextromethorphan as an adjunct in opioid-dependent patients undergoing methadone maintenance treatment.

PubMed

Lee, Sheng-Yu; Chen, Shiou-Lan; Chang, Yun-Hsuan; Chu, Chun-Hsien; Chen, Shih-Heng; Chen, Po See; Huang, San-Yuan; Tzeng, Nian-Sheng; Wang, Liang-Jen; Lee, I Hui; Wang, Tzu-Yun; Chen, Kao Chin; Yang, Yen Kuang; Hong, Jau-Shyong; Lu, Ru-Band

2015-02-25

Low-dose dextromethorphan (DM) might have anti-inflammatory and neurotrophic effects mechanistically remote from an NMDA receptor. In a randomized, double-blind, controlled 12 week study, we investigated whether add-on dextromethorphan reduced cytokine levels and benefitted opioid-dependent patients undergoing methadone maintenance therapy (MMT). Patients were randomly assigned to a group: DM60 (60mg/day dextromethorphan; n = 65), DM120 (120mg/day dextromethorphan; n = 65), or placebo (n = 66). Primary outcomes were the methadone dose required, plasma morphine level, and retention in treatment. Plasma tumor necrosis factor (TNF)-α, C-reactive protein, interleukin (IL)-6, IL-8, transforming growth factor-β1, and brain-derived neurotrophic factor (BDNF) levels were examined during weeks 0, 1, 4, 8, and 12. Multiple linear regressions with generalized estimating equation methods were used to examine the therapeutic effect. After 12 weeks, the DM60 group had significantly longer treatment retention and lower plasma morphine levels than did the placebo group. Plasma TNF-α was significantly decreased in the DM60 group compared to the placebo group. However, changes in plasma cytokine levels, BDNF levels, and the methadone dose required in the three groups were not significantly different. We provide evidence-decreased concomitant heroin use-of low-dose add-on DM's efficacy for treating opioid-dependent patients undergoing MMT. © The Author 2015. Published by Oxford University Press on behalf of CINP.

A Placebo-Controlled Trial of Dextromethorphan as an Adjunct in Opioid-Dependent Patients Undergoing Methadone Maintenance Treatment

PubMed Central

Lee, Sheng-Yu; Chen, Shiou-Lan; Chang, Yun-Hsuan; Chu, Chun-Hsien; Chen, Shih-Heng; Chen, Po See; Huang, San-Yuan; Tzeng, Nian-Sheng; Wang, Liang-Jen; Lee, I Hui; Wang, Tzu-Yun; Chen, Kao Chin; Yang, Yen Kuang; Hong, Jau-Shyong

2015-01-01

Background: Low-dose dextromethorphan (DM) might have anti-inflammatory and neurotrophic effects mechanistically remote from an NMDA receptor. In a randomized, double-blind, controlled 12 week study, we investigated whether add-on dextromethorphan reduced cytokine levels and benefitted opioid-dependent patients undergoing methadone maintenance therapy (MMT). Methods: Patients were randomly assigned to a group: DM60 (60mg/day dextromethorphan; n = 65), DM120 (120mg/day dextromethorphan; n = 65), or placebo (n = 66). Primary outcomes were the methadone dose required, plasma morphine level, and retention in treatment. Plasma tumor necrosis factor (TNF)-α, C-reactive protein, interleukin (IL)-6, IL-8, transforming growth factor–β1, and brain-derived neurotrophic factor (BDNF) levels were examined during weeks 0, 1, 4, 8, and 12. Multiple linear regressions with generalized estimating equation methods were used to examine the therapeutic effect. Results: After 12 weeks, the DM60 group had significantly longer treatment retention and lower plasma morphine levels than did the placebo group. Plasma TNF-α was significantly decreased in the DM60 group compared to the placebo group. However, changes in plasma cytokine levels, BDNF levels, and the methadone dose required in the three groups were not significantly different. Conclusions: We provide evidence—decreased concomitant heroin use—of low-dose add-on DM’s efficacy for treating opioid-dependent patients undergoing MMT. PMID:25716777

Albuminuria after renal transplantation: maintenance with sirolimus/low-dose tacrolimus vs. mycophenolate mofetil/high-dose tacrolimus.

PubMed

Miles, Clifford D; Skorupa, Jill Y; Sandoz, John P; Rigley, Theodore H; Nielsen, Kathleen J; Stevens, R Brian

2011-01-01

Maintenance immunosuppression with sirolimus (SRL) in renal transplantation has been associated with proteinuria. We report long-term outcomes of kidney transplant recipients maintained on steroid-free regimens, either SRL with low-dose tacrolimus (SRL/L-Tac) or mycophenolate mofetil (MMF) with high-dose tacrolimus (MMF/H-Tac). We conducted a case-matched study of 50 patients receiving MMF/H-Tac, matched 1:2 with 100 patients maintained on SRL/L-Tac. All patients were induced with rabbit antithymocyte globulin followed by early steroid withdrawal. Comparisons were made of patient and graft survival, graft function, acute rejection, and albuminuria. There were no significant differences between the SRL/L-Tac and MMF/H-Tac groups for patient survival, graft survival, occurrence of acute rejection, or graft function. There was no difference in the proportion of patients with albumin/creatinine ratio (ACR) ≥300 μg/mg (19% vs. 20%), but more patients in the SRL group were receiving renin-angiotensin system blocking agents (72% vs. 53%, p = 0.04). Only flushing the donor kidney with histidine-tryptophan-ketoglutarate solution (vs. UW solution) was predictive of albuminuria. Long-term outcomes are similar at our center for kidney transplant patients receiving either SRL/L-Tac or MMF/H-Tac. Although the occurrence of albuminuria was not different, significantly more SRL-treated patients were receiving antiproteinuric medications. © 2010 John Wiley & Sons A/S.

Platelet Aggregation Inhibitory Effects and Pharmacokinetics of Prasugrel Used in Combination With Aspirin in Healthy Japanese Subjects.

PubMed

Umemura, Kazuo; Ikeda, Yasuhiko; Matsushima, Nobuko; Kondo, Kazunao

2017-07-01

We evaluated the pharmacokinetics and pharmacodynamics of prasugrel used in combination with aspirin in healthy Japanese subjects. All subjects received aspirin 100 mg/day. Subsequently, in the single-administration study, 23 subjects also received prasugrel 20 or 30 mg, and in the multiple-administration study, 20 subjects received a loading dose of prasugrel 20 or 30 mg on day 1, followed by a maintenance dose of prasugrel 5 or 7.5 mg/day, respectively, on days 2-5. In both studies, the plasma concentration of the active metabolite of prasugrel, R-138727, reached a maximum 0.5 hours after administration and rapidly decreased within 4 hours. In the single-administration study, the inhibitory effect on adenosine diphosphate-induced platelet aggregation was significantly higher in the prasugrel 20- and 30-mg groups than in the placebo group at all times (1-144 hours) after administration. In the multiple-administration study, a similar antiplatelet effect was found after both the loading dose and the maintenance dose and was maintained for 3-6 days after the last administration. There were study drug-related adverse events; however, all were mild, and none was clinically significant. © 2016 The Authors. Clinical Pharmacology in Drug Development Published by Wiley Periodicals, Inc. on behalf of The American College of Clinical Pharmacology.

Favipiravir Pharmacokinetics in Nonhuman Primates and Insights for Future Efficacy Studies of Hemorrhagic Fever Viruses.

PubMed

Madelain, Vincent; Guedj, Jérémie; Mentré, France; Nguyen, Thi Huyen Tram; Jacquot, Frédéric; Oestereich, Lisa; Kadota, Takumi; Yamada, Koichi; Taburet, Anne-Marie; de Lamballerie, Xavier; Raoul, Hervé

2017-01-01

Favipiravir is an RNA polymerase inhibitor that showed strong antiviral efficacy in vitro and in small-animal models of several viruses responsible for hemorrhagic fever (HF), including Ebola virus. The aim of this work was to characterize the complex pharmacokinetics of favipiravir in nonhuman primates (NHPs) in order to guide future efficacy studies of favipiravir in large-animal models. Four different studies were conducted in 30 uninfected cynomolgus macaques of Chinese (n = 17) or Mauritian (n = 13) origin treated with intravenous favipiravir for 7 to 14 days with maintenance doses of 60 to 180 mg/kg of body weight twice a day (BID). A pharmacokinetic model was developed to predict the plasma concentrations obtained with different dosing regimens, and the model predictions were compared to the 50% effective concentration (EC 50 ) of favipiravir against several viruses. Favipiravir pharmacokinetics were described by a model accounting for concentration-dependent aldehyde oxidase inhibition. The enzyme-dependent elimination rate increased over time and was higher in NHPs of Mauritian origin than in those of Chinese origin. Maintenance doses of 100 and 120 mg/kg BID in Chinese and Mauritian NHPs, respectively, are predicted to achieve median trough plasma free concentrations above the EC 50 for Lassa and Marburg viruses until day 7. For Ebola virus, higher doses are required. After day 7, a 20% dose increase is needed to compensate for the increase in drug clearance over time. These results will help rationalize the choice of dosing regimens in future studies evaluating the antiviral effect of favipiravir in NHPs and support its development against a variety of HF viruses. Copyright © 2016 American Society for Microbiology.

Challenging the FDA black box warning for high aspirin dose with ticagrelor in patients with diabetes.

PubMed

DiNicolantonio, James J; Serebruany, Victor L

2013-03-01

Ticagrelor, a novel reversible antiplatelet agent, has a Food and Drug Administration (FDA) black box warning to avoid maintenance doses of aspirin (ASA) >100 mg/daily. This restriction is based on the hypothesis that ASA doses >100 mg somehow decreased ticagrelor's benefit in the Platelet Inhibition and Patient Outcomes (PLATO) U.S. cohort. However, these data are highly postrandomized, come from a very small subgroup in PLATO (57% of patients in the U.S. site), and make no biological sense. Moreover, the ticagrelor-ASA interaction was not significant by any multivariate Cox regression analyses. The Complete Response Review for ticagrelor indicates that for U.S. PLATO patients, an ASA dose >300 mg was not a significant interaction for vascular outcomes. In the ticagrelor-ASA >300 mg cohort, all-cause and vascular mortality were not significantly increased (hazard ratio [HR] 1.27 [95% CI 0.84-1.93], P = 0.262 and 1.39 [0.87-2.2], P = 0.170), respectively. Furthermore, for major adverse cardiovascular events (MACEs), 30-day all-cause mortality, and 30-day vascular mortality, the strongest interaction is the diabetes-ASA interaction. That is, patients who had diabetes had significantly fewer MACEs through study end (0.49 [0.34-0.63], P < 0.0001), significantly less 30-day all-cause mortality (0.33 [0.20-0.56], P < 0.0001), and significantly less 30-day vascular mortality (0.35 [0.22-0.55], P < 0.0001), respectively, when given high-dose (300-325 mg) ASA, regardless of treatment (clopidogrel or ticagrelor) assignment. The black box warning for the use of maintenance ASA doses >100 mg with ticagrelor is inappropriate for patients with diabetes and not evidence based.

Analysis of Railroad Track Maintenance Expenditures for Class I Railroads 1962-1977

DOT National Transportation Integrated Search

1982-02-01

This study investigates the decision-making process for railroad track maintenance (T/M) expenditures. The objectives are to (1) describe how Federal track safety standards have influenced this process and (2) try to predict the impact of changes in ...

Conditioning of the vacuum system of the TPS storage ring without baking in situ

NASA Astrophysics Data System (ADS)

Chan, C. K.; Chang, C. C.; Shueh, C.; Yang, I. C.; Wu, L. H.; Chen, B. Y.; Cheng, C. M.; Huang, Y. T.; Chuang, J. Y.; Cheng, Y. T.; Hsiao, Y. M.; Sheng, Albert

2017-04-01

To shorten the machine downtime, a maintenance procedure without baking in situ has been developed and applied to maintain and to upgrade the vacuum system of the TPS storage ring. The data of photon-stimulated desorption (PSD) reveal no obvious discrepancy between baking and not baking the vacuum system in situ. A beam-conditioning dose of extent only 11.8 A h is required to recover quickly the dynamic pressure of an unbaked vacuum system to its pre-intervention value according to the TPS maintenance experience.

Mechanisms of lower maintenance dose of tacrolimus in obese patients.

PubMed

Sawamoto, Kazuki; Huong, Tran T; Sugimoto, Natsumi; Mizutani, Yuka; Sai, Yoshimichi; Miyamoto, Ken-ichi

2014-01-01

A retrospective analysis suggested that blood tacrolimus concentrations were consistent among patients with a body mass index (BMI) that was lean (<18.5), normal (≥ 18.5 and <25) or overweight/obese (≥ 25). The average maintenance dose of tacrolimus in patients with BMI ≥ 25 was significantly lower compared with that in patients with a BMI of less than 25. Lean and obese Zucker rats fed a normal diet were given tacrolimus intravenously or orally. The blood concentrations of tacrolimus in obese rats were significantly higher than those in lean rats after administration via both routes. The moment analysis has suggested that CLtot and Vdss of tacrolimus were not significantly different between lean and obese rats. The bioavailability was higher in obese rats, compared with that in lean rats. The protein expression of Cyp3a2 in the liver was significantly decreased in obese rats, compared with lean rats, while P-gp in the small intestine was also significantly decreased in obese rats. These results suggested that the steady-state trough concentration of tacrolimus in obese patients was well maintained by a relatively low dose compared with that in normal and lean patients, presumably due to increased bioavailability.

Clozapine Titration for People in Early Psychosis: A Chart Review and Treatment Guideline.

PubMed

Ballon, Jacob S; Ashfaq, Hera; Noordsy, Douglas L

2018-06-01

The use of clozapine, particularly in young people, is often limited by early treatment-emergent adverse effects including drowsiness and lethargy. Concerns about adverse effects, medication adherence, and the need for blood monitoring often impede the use of clozapine in this population, leading to repeated trials of less effective medications. Current clozapine dosing recommendations are based on people further in the course of their illness and thus reflect different responsiveness and sensitivities to antipsychotic medication. As such, there is a need for evidence-based guidelines for titration and dosing of clozapine among people in early psychosis. We performed a chart review of 14 people treated with clozapine within our early psychosis team. Data regarding dose titration, response, time to discontinuation, symptom severity, weight gain, and other adverse effects were gathered at clozapine initiation, 3 months, and last available visit on clozapine. People treated with slow titration within their first year of psychosis onset achieved sustained response at very low maintenance doses (mean dose = 81 mg/d, mean duration of treatment = 200 weeks) compared with slow titration with longer duration of illness (mean dose = 350 mg/d, mean duration of treatment = 68 weeks) or standard dose titration in early psychosis (mean dose = 112 mg/d, mean duration of treatment = 38 weeks). The most common adverse effects in all groups were weight gain and sedation, with the groups requiring higher mean doses reporting a broader range of adverse effects. There was no apparent difference in the clinical global impression for severity or improvement between the slow titration and standard titration groups in people with early psychosis. These observations are synthesized into a proposed treatment guideline for use of clozapine among people in early psychosis. We describe development of a slow titration approach to initiating clozapine among people in early psychosis. This approach resulted in clinical response at remarkably low maintenance doses of clozapine among people within their first year of illness, but not in those with longer duration of symptoms. Slow titration also led to good tolerability and acceptance of clozapine treatment for some patients.

Comparing paediatric intravenous phenytoin doses using physiologically based pharmacokinetic (PBPK) modelling software.

PubMed

Batchelor, Hannah; Appleton, Richard; Hawcutt, Daniel B

2015-12-01

To use a physiologically based pharmacokinetic (PBPK) modelling system to predict the serum levels achieved by two different intravenous loading doses of phenytoin. A phenytoin pharmacokinetic model was used in the Simcyp population-based ADME simulator, simulating 100 children age 2-10 years receiving intravenous phenytoin (18 and 20mg/kg). Visual checks were used to evaluate the predictive performance of the candidate model. Loading with doses of 18 mg/kg, blood levels were sub-therapeutic in 22/100 (concentration at 2h post infusion (C2h) <10 μg/mL), therapeutic in 62/100 (C2h 10-20 μg/mL), and supra-therapeutic in 16/100 (C2h>20 μg/mL). Loading with 20mg/kg, the percentages were 15, 59, and 26, respectively. Increasing from 18 to 20 mg/kg increased the mean C2h from 16.0 to 17.9 μg/mL, and the mean AUC from 145 to 162 μg/mL/h. A C2h>30 μg/mL was predicted in 4% and 8% of children in the 18 and 20 mg/kg doses, with 3% predicted to have a C2h>40 μg/mL following either dose. For maintenance doses, a 1st dose of 2.5 or 5mg/kg (intravenous) given at 12h (after either 18 or 20 mg/kg loading) gives the highest percentages of 10-20 μg/mL serum concentrations. For sub-therapeutic concentrations following intravenous loading (20 mg/kg), a 1st maintenance dose (intravenous) of 10mg/kg will achieve therapeutic concentrations in 93%. Use of PBPK modelling suggests that children receiving the 20 mg/kg intravenous loading dose are at slightly increased risk of supra-therapeutic blood levels. Ideally, therapeutic drug monitoring is required to monitor serum concentrations, although the dose regime suggested by the BNFc appear appropriate. Copyright © 2015 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

Inhaled Combined Budesonide-Formoterol as Needed in Mild Asthma.

PubMed

O'Byrne, Paul M; FitzGerald, J Mark; Bateman, Eric D; Barnes, Peter J; Zhong, Nanshan; Keen, Christina; Jorup, Carin; Lamarca, Rosa; Ivanov, Stefan; Reddel, Helen K

2018-05-17

In patients with mild asthma, as-needed use of an inhaled glucocorticoid plus a fast-acting β 2 -agonist may be an alternative to conventional treatment strategies. We conducted a 52-week, double-blind trial involving patients 12 years of age or older with mild asthma. Patients were randomly assigned to one of three regimens: twice-daily placebo plus terbutaline (0.5 mg) used as needed (terbutaline group), twice-daily placebo plus budesonide-formoterol (200 μg of budesonide and 6 μg of formoterol) used as needed (budesonide-formoterol group), or twice-daily budesonide (200 μg) plus terbutaline used as needed (budesonide maintenance group). The primary objective was to investigate the superiority of as-needed budesonide-formoterol to as-needed terbutaline with regard to electronically recorded weeks with well-controlled asthma. A total of 3849 patients underwent randomization, and 3836 (1277 in the terbutaline group, 1277 in the budesonide-formoterol group, and 1282 in the budesonide maintenance group) were included in the full analysis and safety data sets. With respect to the mean percentage of weeks with well-controlled asthma per patient, budesonide-formoterol was superior to terbutaline (34.4% vs. 31.1% of weeks; odds ratio, 1.14; 95% confidence interval [CI], 1.00 to 1.30; P=0.046) but inferior to budesonide maintenance therapy (34.4% and 44.4%, respectively; odds ratio, 0.64; 95% CI, 0.57 to 0.73). The annual rate of severe exacerbations was 0.20 with terbutaline, 0.07 with budesonide-formoterol, and 0.09 with budesonide maintenance therapy; the rate ratio was 0.36 (95% CI, 0.27 to 0.49) for budesonide-formoterol versus terbutaline and 0.83 (95% CI, 0.59 to 1.16) for budesonide-formoterol versus budesonide maintenance therapy. The rate of adherence in the budesonide maintenance group was 78.9%. The median metered daily dose of inhaled glucocorticoid in the budesonide-formoterol group (57 μg) was 17% of the dose in the budesonide maintenance group (340 μg). In patients with mild asthma, as-needed budesonide-formoterol provided superior asthma-symptom control to as-needed terbutaline, assessed according to electronically recorded weeks with well-controlled asthma, but was inferior to budesonide maintenance therapy. Exacerbation rates with the two budesonide-containing regimens were similar and were lower than the rate with terbutaline. Budesonide-formoterol used as needed resulted in substantially lower glucocorticoid exposure than budesonide maintenance therapy. (Funded by AstraZeneca; SYGMA 1 ClinicalTrials.gov number, NCT02149199 .).

Diet-induced obesity does not impact the generation and maintenance of primary memory CD8 T cells.

PubMed

Khan, Shaniya H; Hemann, Emily A; Legge, Kevin L; Norian, Lyse A; Badovinac, Vladimir P

2014-12-15

The extent to which obesity compromises the differentiation and maintenance of protective memory CD8 T cell responses and renders obese individuals susceptible to infection remains unknown. In this study, we show that diet-induced obesity did not impact the maintenance of pre-existing memory CD8 T cells, including acquisition of a long-term memory phenotype (i.e., CD27(hi), CD62L(hi), KLRG1(lo)) and function (i.e., cytokine production, secondary expansion, and memory CD8 T cell-mediated protection). Additionally, obesity did not influence the differentiation and maintenance of newly evoked memory CD8 T cell responses in inbred and outbred hosts generated in response to different types of systemic (LCMV, L. monocytogenes) and/or localized (influenza virus) infections. Interestingly, the rate of naive-to-memory CD8 T cell differentiation after a peptide-coated dendritic cell immunization was similar in lean and obese hosts, suggesting that obesity-associated inflammation, unlike pathogen- or adjuvant-induced inflammation, did not influence the development of endogenous memory CD8 T cell responses. Therefore, our studies reveal that the obese environment does not influence the development or maintenance of memory CD8 T cell responses that are either primed before or after obesity is established, a surprising notion with important implications for future studies aiming to elucidate the role obesity plays in host susceptibility to infections. Copyright © 2014 by The American Association of Immunologists, Inc.

Immobilization of grizzly bears (Ursus arctos) with dexmedetomidine, tiletamine, and zolazepam.

PubMed

Teisberg, Justin E; Farley, Sean D; Nelson, O Lynne; Hilderbrand, Grant V; Madel, Michael J; Owen, Patricia A; Erlenbach, Joy A; Robbins, Charles T

2014-01-01

Safe and effective immobilization of grizzly bears (Ursus arctos) is essential for research and management. Fast induction of anesthesia, maintenance of healthy vital rates, and predictable recoveries are priorities. From September 2010 to May 2012, we investigated these attributes in captive and wild grizzly bears anesthetized with a combination of a reversible α2 agonist (dexmedetomidine [dexM], the dextrorotatory enantiomer of medetomidine) and a nonreversible N-methyl-d-aspartate (NMDA) agonist and tranquilizer (tiletamine and zolazepam [TZ], respectively). A smaller-than-expected dose of the combination (1.23 mg tiletamine, 1.23 mg zolazepam, and 6.04 µg dexmedetomidine per kg bear) produced reliable, fast ataxia (3.7 ± 0.5 min, x̄±SE) and workable anesthesia (8.1 ± 0.6 min) in captive adult grizzly bears. For wild bears darted from a helicopter, a dose of 2.06 mg tiletamine, 2.06 mg zolazepam, and 10.1 µg dexmedetomidine/kg produced ataxia in 2.5 ± 0.3 min and anesthesia in 5.5 ± 1.0 min. Contrary to published accounts of bear anesthesia with medetomidine, tiletamine, and zolazepam, this combination did not cause hypoxemia or hypoventilation, although mild bradycardia (<50 beats per min) occurred in most bears during the active season. With captive bears, effective dose rates during hibernation were approximately half those during the active season. The time to first signs of recovery after the initial injection of dexMTZ was influenced by heart rate (P<0.001) and drug dose (P<0.001). Intravenous (IV) injection of the reversal agent, atipamezole, significantly decreased recovery time (i.e., standing on all four feet and reacting to the surrounding environment) relative to intramuscular injection. Recovery times (25 ± 8 min) following IV injections of the recommended dose of atipamezole (10 µg/µg of dexmedetomidine) and half that dose (5 µg/µg) did not differ. However, we recommend use of the full dose based on the appearance of a more complete recovery. Field trials confirmed that the dexMTZ + atipamezole protocol is safe, reliable, and predictable when administered to wild grizzly bears, especially during helicopter capture operations.

Light qualities and dose influence ascorbate pool size in detached oat leaves.

PubMed

Mastropasqua, Linda; Borraccino, Giuseppe; Bianco, Laura; Paciolla, Costantino

2012-02-01

In this work, we studied the mechanism of light influence on AsA pool size in Avena sativa L. under the effects of low intensity light at different wavelengths. Exposure to low intensity light of oat leaf segments incubated in water or in l-galactono-1,4-lactone (GL), resulted in an increase in AsA content compared with the dark control. This increase was due to modulation of l-galactono-1,4-lactone dehydrogenase (GLDH; EC 1.3.2.3) light-dependent activity and was dependent on the size of the endogenous GL pool. Both blue and red light were effective in increasing AsA, and this increase depended on both exposure time and light intensity. Protein biosynthesis, photosynthesis and calcium were involved in controlling the level of light-dependent AsA. We suggest that multiple checkpoints correlated to the presence of light underlie the ascorbate pool size. The presence of a light-activated switch for the maintenance of an adequate AsA level seems to be necessary for the various tasks of scavenging reactive oxygen species, in response to the dark-light cycle which plants experience under natural conditions. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Sympathetic neural control of the kidney in hypertension.

PubMed

DiBona, G F

1992-01-01

Efferent renal sympathetic nerve activity is elevated in human essential hypertension as well as in several forms of experimental hypertension in animals. In addition, bilateral complete renal denervation delays the development and/or attenuates the magnitude of the hypertension in several different forms of experimental hypertension in animals. Efferent renal sympathetic nerve activity is known to have dose-dependent effects on renal blood flow, the glomerular filtration rate, renal tubular sodium and water reabsorption, and the renin secretion rate, which are capable of contributing, singly or in combination, to the development, maintenance, and exacerbation of the hypertensive state. Of the many factors known to influence the central nervous system integrative regulation of efferent renal sympathetic nerve activity, two environmental factors, a high dietary sodium intake and environmental stress, are capable of significant interaction. This resultant increase in efferent renal sympathetic nerve activity and subsequent renal functional alterations can participate in the hypertensive process. This is especially evident in the presence of an underlying genetic predisposition to the development of hypertension. Thus, interactions between environmental and genetic influences can produce alterations in the sympathetic neural control of renal function that play an important role in hypertension.

Effective treatment of etanercept and phototherapy-resistant psoriasis using the excimer laser.

PubMed

Park, Kelly K; Swan, James; Koo, John

2012-03-15

Treatment of moderate-to-severe plaque psoriasis often requires the use of phototherapy or systemic therapy, which includes immunosuppressants, retinoids, and biologic agents. Although biologic use is becoming increasingly popular, it is not uncommon for patients to experience treatment failure. We describe a patient who had a suboptimal response to etanercept monotherapy after twelve weeks of induction dosing (50 mg twice weekly), as well as to a combination of etanercept (50 mg once weekly-maintenance dosing) and narrowband ultraviolet B (NB-UVB) phototherapy three times weekly for an additional twelve weeks. Noticeable improvement was noted after the addition of NB-UVB and the patient's promising response to phototherapy influenced further management. Etanercept and NB-UVB were discontinued and the patient was initiated on excimer laser treatments twice weekly. After 4 weeks, the patient had a 75 percent reduction in Psoriasis Area Severity Index (PASI) score and after 7 weeks had over 95 percent clearance of psoriasis. The unique properties of the excimer laser may account for its clinical efficacy in our patient as well as in other cases of recalcitrant psoriasis. We propose that the excimer laser be considered in cases of biologic or conventional phototherapy failure in addition to being a standard treatment option or adjunct for the treatment of psoriasis.

Modification of pharmacokinetics of norfloxacin following oral administration of curcumin in rabbits

PubMed Central

Pavithra, B. H.; Jayakumar, K.

2009-01-01

Investigation was carried out in adult New Zealand white rabbits to study the influence of curcumin pre-treatment on pharmacokinetic disposition of norfloxacin following single oral administration. Sixteen rabbits were divided into two groups of eight each consisting of either sex. Animals in group-I were administered norfloxacin (100 mg/kg body weight p.o), while animals in group-II received similar dose of norfloxacin after pre-treatment with curcumin (60 mg/kg body weight per day, 3 days, p.o). Blood samples were drawn from the marginal ear vein into heparin-coated vials at 0 (zero time), 5, 10, 15, 30 min and 1, 2, 4, 6, 12 and 24 h post-treatment. Plasma norfloxacin concentrations were determined by high performance liquid chromatography. The plasma concentration-time profile of norfloxacin was adequately described by a one-compartment open model. The pharmacokinetic data revealed that curcumin-treated animals had significantly (p ≤ 0.05) higher area under the plasma concentration-time curve and area under the first moment of plasma drug concentration-time curve. Prior treatment of curcumin significantly (p ≤ 0.05) increased elimination half-life and volume of distribution of norfloxacin. Further treatment with curcumin reduced loading and maintenance doses by 26% and 24% respectively. PMID:19934593

The future prospects of pharmacogenetics in oral anticoagulation therapy

PubMed Central

Kamali, Farhad; Pirmohamed, Munir

2006-01-01

Coumarins are the mainstay of oral anticoagulation for the treatment and prophylaxis of thromboembolic disorders. They have a narrow therapeutic index and regular monitoring is therefore required to avoid serious adverse effects. There is wide interindividual variability in dosage requirements, which makes anticoagulation response unpredictable. Current dosing titrations are haphazard and inconvenient and poor initial control leads to morbidity, and occasional mortality, because of bleeding and further thromboembolism. Recent discoveries have helped to characterize the factors that contribute to the interindividual variability in responses to coumarins. Patient and environmental factors that affect anticoagulation response to coumarins include age, body size, dietary vitamin K status, concurrent disease and drug interactions. More recently, single nucleotide polymorphisms in the 2C9 isoform of cytochrome P450 (CYP2C9) and vitamin K epoxide reductase (VKOR) have been shown to make significant contributions to the variability in coumarin dosage requirements. Polymorphisms in other genes that mediate the actions of coumarins may also contribute to this variability. Racial and cultural differences influence dosage requirements, which can be explained, at least in part, by genetic and dietary factors. Incorporation of genetic and environmental factors could help in the prediction of more individualized loading and maintenance doses for safer anticoagulation therapy. PMID:16722840

Fludarabine and rituximab with escalating doses of lenalidomide followed by lenalidomide/rituximab maintenance in previously untreated chronic lymphocytic leukaemia (CLL): the REVLIRIT CLL-5 AGMT phase I/II study.

PubMed

Egle, Alexander; Steurer, Michael; Melchardt, Thomas; Weiss, Lukas; Gassner, Franz Josef; Zaborsky, Nadja; Geisberger, Roland; Catakovic, Kemal; Hartmann, Tanja Nicole; Pleyer, Lisa; Voskova, Daniela; Thaler, Josef; Lang, Alois; Girschikofsky, Michael; Petzer, Andreas; Greil, Richard

2018-06-04

Despite recent advances, chemoimmunotherapy remains a standard for fit previously untreated chronic lymphocytic leukaemia patients. Lenalidomide had activity in early monotherapy trials, but tumour lysis and flare proved major obstacles in its development. We combined lenalidomide in increasing doses with six cycles of fludarabine and rituximab (FR), followed by lenalidomide/rituximab maintenance. In 45 chemo-naive patients, included in this trial, individual tolerability of the combination was highly divergent and no systematic toxicity determining a maximum tolerated dose was found. Grade 3/4 neutropenia (71%) was high, but only 7% experienced grade 3 infections. No tumour lysis or flare > grade 2 was observed, but skin toxicity proved dose-limiting in nine patients (20%). Overall and complete response rates after induction were 89 and 44% by intention-to-treat, respectively. At a median follow-up of 78.7 months, median progression-free survival (PFS) was 60.3 months. Minimal residual disease and immunoglobulin variable region heavy chain mutation state predicted PFS and TP53 mutation most strongly predicted OS. Baseline clinical factors did not predict tolerance to the immunomodulatory drug lenalidomide, but pretreatment immunophenotypes of T cells showed exhausted memory CD4 cells to predict early dose-limiting non-haematologic events. Overall, combining lenalidomide with FR was feasible and effective, but individual changes in the immune system seemed associated with limiting side effects. clinicaltrials.gov (NCT00738829) and EU Clinical Trials Register ( www.clinicaltrialsregister.eu , 2008-001430-27).

Model-Informed Drug Development for Ixazomib, an Oral Proteasome Inhibitor.

PubMed

Gupta, Neeraj; Hanley, Michael J; Diderichsen, Paul M; Yang, Huyuan; Ke, Alice; Teng, Zhaoyang; Labotka, Richard; Berg, Deborah; Patel, Chirag; Liu, Guohui; van de Velde, Helgi; Venkatakrishnan, Karthik

2018-02-15

Model-informed drug development (MIDD) was central to the development of the oral proteasome inhibitor ixazomib, facilitating internal decisions (switch from body surface area (BSA)-based to fixed dosing, inclusive phase III trials, portfolio prioritization of ixazomib-based combinations, phase III dose for maintenance treatment), regulatory review (model-informed QT analysis, benefit-risk of 4 mg dose), and product labeling (absolute bioavailability and intrinsic/extrinsic factors). This review discusses the impact of MIDD in enabling patient-centric therapeutic optimization during the development of ixazomib. © 2017 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

An intelligent healthcare management system: a new approach in work-order prioritization for medical equipment maintenance requests.

PubMed

Hamdi, Naser; Oweis, Rami; Abu Zraiq, Hamzeh; Abu Sammour, Denis

2012-04-01

The effective maintenance management of medical technology influences the quality of care delivered and the profitability of healthcare facilities. Medical equipment maintenance in Jordan lacks an objective prioritization system; consequently, the system is not sensitive to the impact of equipment downtime on patient morbidity and mortality. The current work presents a novel software system (EQUIMEDCOMP) that is designed to achieve valuable improvements in the maintenance management of medical technology. This work-order prioritization model sorts medical maintenance requests by calculating a priority index for each request. Model performance was assessed by utilizing maintenance requests from several Jordanian hospitals. The system proved highly efficient in minimizing equipment downtime based on healthcare delivery capacity, and, consequently, patient outcome. Additionally, a preventive maintenance optimization module and an equipment quality control system are incorporated. The system is, therefore, expected to improve the reliability of medical equipment and significantly improve safety and cost-efficiency.

The activity of the inosine triphosphate pyrophosphatase affects toxicity of 6-mercaptopurine during maintenance therapy for acute lymphoblastic leukemia in Japanese children.

PubMed

Tanaka, Yoichi; Manabe, Atsushi; Nakadate, Hisaya; Kondoh, Kensuke; Nakamura, Kozue; Koh, Katsuyoshi; Utano, Tomoyuki; Kikuchi, Akira; Komiyama, Takako

2012-05-01

The association between inosine triphosphate pyrophosphatase (ITPA) activity and toxicity of 6-mercaptopurine (6-MP) was retrospectively evaluated in 65 Japanese children with acute lymphoblastic leukemia (ALL). Patients with an ITPA activity of less than 126 μmol/h/gHb presented with hepatotoxicity more frequently than those with higher ITPA activity (p<0.01). The average 6-MP dose during maintenance therapy administered to two patients with the ITPA deficiency was lower than that given to the other patients. Measuring ITPA activity is important for ensuring the safety of maintenance therapy for Asians with ALL because thiopurine S-methyl transferase mutations are rare in the Asian population. Copyright © 2011 Elsevier Ltd. All rights reserved.

Biliary and pancreatic ductal dilation in patients on methadone maintenance therapy.

PubMed

Bates, David D B; Tamayo-Murillo, Dorathy; Kussman, Steven; Luce, Adam; LeBedis, Christina A; Soto, Jorge A; Anderson, Stephan W

2017-03-01

To determine whether the diameter of intrahepatic and extrahepatic bile ducts and pancreatic ducts in patients on methadone maintenance therapy is increased when compared with control subjects. Between January 1, 2000 and March 15, 2013, a total of 97 patients (mean age 49.9, range 22-79, 65 male, 32 female) were identified who were receiving chronic methadone maintenance therapy (MMT) when they underwent imaging with abdominal MRI or a contrast-enhanced abdominopelvic CT. A group of 97 consecutive non-MMT control patients (mean age 51.4, range 21-86, 45 male, 52 female) who underwent imaging with abdominal MRI or contrast-enhanced abdominopelvic CT were identified. Patients with known pancreaticobiliary pathology that may confound biliary ductal measurements were excluded. Blinded interpretation was performed, documenting the diameters of the intrahepatic and extrahepatic bile ducts and pancreatic ducts. Descriptive statistics were performed. Patients on MMT demonstrated increased bile duct diameter, with an average increase in duct diameter of 2.39 mm for the common bile duct (p < 0.001; 95% CI 1.88-2.90 mm), 1.43 mm for the intrahepatic bile ducts (p < 0.001; 95% CI 1.12-1.74 mm), and 0.90 mm for the pancreatic duct (p < 0.001; 95% CI 0.64-1.16 mm). No statistically significant correlation was found between ductal diameters and the daily dose of methadone. Patients on methadone maintenance therapy demonstrate significantly increased intra- and extrahepatic bile duct and pancreatic duct diameter when compared with controls. There was no correlation between the dose of methadone and ductal diameter.

Outcome and toxicity associated with a dose-intensified, maintenance-free CHOP-based chemotherapy protocol in canine lymphoma: 130 cases.

PubMed

Sorenmo, Karin; Overley, B; Krick, E; Ferrara, T; LaBlanc, A; Shofer, F

2010-09-01

A dose-intensified/dose-dense chemotherapy protocol for canine lymphoma was designed and implemented at the Veterinary Hospital of the University of Pennsylvania. In this study, we describe the clinical characteristics, prognostic factors, efficacy and toxicity in 130 dogs treated with this protocol. The majority of the dogs had advanced stage disease (63.1% stage V) and sub-stage b (58.5%). The median time to progression (TTP) and lymphoma-specific survival were 219 and 323 days, respectively. These results are similar to previous less dose-intense protocols. Sub-stage was a significant negative prognostic factor for survival. The incidence of toxicity was high; 53.9 and 45% of the dogs needed dose reductions and treatment delays, respectively. Dogs that required dose reductions and treatment delays had significantly longer TTP and lymphoma-specific survival times. These results suggest that dose density is important, but likely relative, and needs to be adjusted according to the individual patient's toxicity for optimal outcome.

EVALUATION OF EYE LENS DOSE TO WORKERS IN THE STEAM GENERATOR AT THE KOREAN OPTIMIZED POWER REACTOR 1000.

PubMed

Maeng, Sung Jun; Kim, Jinhwan; Cho, Gyuseong

2018-03-15

ICRP (2011) revised the dose limit to the eye lens to 20 mSv/y based on a recent epidemiological study of radiation-induced cataracts. Maintenance of steam generators at nuclear power plants is one of the highest radiation-associated tasks within a non-uniform radiation field. This study aims to evaluate eye lens doses in the steam generators of the Korean OPR1000 design. The source term was characterized based on the CRUD-specific activity, and both the eye lens dose and organ dose were simulated using MCNP6 combined with an ICRP voxel phantom and a mesh phantom, respectively. The eye lens dose was determined to be 5.39E-02-9.43E-02 Sv/h, with a negligible effect by beta particles. As the effective dose was found to be 0.81-1.21 times the lens equivalent dose depending on the phantom angles, the former can be used to estimate the lens dose in the SG of the OPR1000 for radiation monitoring purposes.

A phase I study of gefitinib with concurrent dose-escalated weekly docetaxel and conformal three-dimensional thoracic radiation followed by consolidative docetaxel and maintenance gefitinib for patients with stage III non-small cell lung cancer.

PubMed

Center, Brian; Petty, William Jeffrey; Ayala, Diandra; Hinson, William H; Lovato, James; Capellari, James; Oaks, Timothy; Miller, Antonius A; Blackstock, Arthur William

2010-01-01

Concurrent radiation and chemotherapy is the standard of care for good performance status patients with stage III non-small cell lung cancer. Locoregional control remains a significant factor relating to poor outcome. Preclinical and early clinical data suggest that docetaxel and gefitinib have radiosensitizing activity. This study sought to define the maximum tolerated dose of weekly docetaxel that could be given with daily gefitinib and concurrent thoracic radiation therapy. Patients with histologically confirmed, inoperable stage III non-small cell lung cancer and good performance status (Eastern Cooperative Oncology Group 0-1) were eligible for this study. Patients received three-dimensional conformal thoracic radiation to a dose of 70 Gy concurrently with oral gefitinib at a dose of 250 mg daily and intravenous, weekly docetaxel at escalating doses from 15 to 30 mg/m2 in cohorts of patients. Patients were given a 2-week rest period after the concurrent therapy, during which they received only gefitinib. After the 2-week rest period, patients received consolidation chemotherapy with docetaxel 75 mg/m2 given every 21 days for two cycles. Maintenance gefitinib was continued until disease progression or study completion. Sixteen patients were enrolled on the study between December 2003 and April 2007 with the following characteristics: median age, 64 years (range 43-79 years); M/F: 9/7; and performance status 0/1, 1/15. Dose-limiting pulmonary toxicity and esophagitis were encountered at a weekly docetaxel dose of 25 mg/m2, resulting in a maximum tolerated dose of 20 mg/m2/wk. Overall, grade 3/4 hematologic toxicity was observed in 27% of patients. Grade 3/4 esophageal and pulmonary toxicities were reported in 27% and 20% of patients, respectively. The overall response rate was 46%, and the median survival for all patients was 21 months. Concurrent thoracic radiation with weekly docetaxel and daily gefitinib is feasible but results in moderate toxicity. For further studies, the recommended weekly docetaxel dose for this chemoradiation regimen is 20 mg/m2.

EFFECTIVENESS OF THE ANESTHETIC AQUI-S® 20E IN MARINE FINFISH AND ELASMOBRANCHS.

PubMed

Silbernagel, Constance; Yochem, Pamela

2016-04-01

Immersion anesthetics are used in hatchery settings by veterinarians, field biologists, and laboratory researchers to aid in handling finfish for medical procedures, research purposes, and moderating perceived stress responses. The only Food and Drug Administration- (FDA) approved anesthetic for food fish, tricaine methanesulfonate, requires a 21-d withdrawal period prior to harvest. Ten percent eugenol (AQUI-S® 20E) has been gaining momentum for FDA approval because of its 0-d withdrawal time if fish are not of harvestable size within 72 h of exposure. We performed two trials to determine appropriate anesthetic doses for two cultured marine finfish: Atractoscion nobilis (white seabass, WSB) and Seriola lalandi (California yellowtail, YT). Fish were held in a treated water bath for 10 min or until opercular beat rate slowed to a rate of <2 beats/min. Based on these results, we conducted a field trial with wild Paralabrax maculatofasciatus (spotted bay bass), Paralabrax nebulifer (barred sand bass), Paralichthys californicus (California halibut), Triakis semifasciata (leopard shark), and Mustelus californicus (grey smooth-hound) at a single dosing regime, with animals held 5-10 min in anesthetic baths. Anesthetic dosing of 35-55 mg L(-1) provided relatively fast induction and good anesthetic maintenance in cultured and wild finfish. Anesthetic induction times were comparable among S. lalandi and A. nobilis at 35-mg L(-1) to 75-mg L(-1) doses, but recovery times were variable. Mortality rates of 20-90% were observed at higher doses (75 mg L(-1) and 100 mg L(-1), A. nobilis; 55 mg L(-1) and 75 mg L(-1), S. lalandi). The apparent increase in sensitivity of S. lalandi may have been associated with nutritional stress in the fish tested. There were no differences in time to anesthesia or recovery among wild finfish species tested at a single dose. Anesthetic induction, maintenance, and recovery were less predictable in the elasmobranch species tested and additional trials are needed to determine optimal dosing.

Protocol for a multicentred randomised controlled trial investigating the use of personalised golimumab dosing tailored to inflammatory load in ulcerative colitis: the GOAL-ARC study (GLM dose Optimisation to Adequate Levels to Achieve Response in Colitis) led by the INITIAtive group (NCT 0268772)

PubMed Central

Sheridan, Juliette; Coe, Carol Ann; Doran, Peter; Egan, Laurence; Cullen, Garret; Kevans, David; Leyden, Jan; Galligan, Marie; O’Toole, Aoibhlinn; McCarthy, Jane; Doherty, Glen

2018-01-01

Introduction Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD), often leading to an impaired quality of life in affected patients. Current treatment modalities include antitumour necrosis factor (anti-TNF) monoclonal antibodies (mABs) including infliximab, adalimumab and golimumab (GLM). Several recent retrospective and prospective studies have demonstrated that fixed dosing schedules of anti-TNF agents often fails to consistently achieve adequate circulating therapeutic drug levels (DL) with consequent risk of immunogenicity treatment failure and potential risk of hospitalisation and colectomy in patients with UC. The design of GLM dose Optimisation to Adequate Levels to Achieve Response in Colitis aims to address the impact of dose escalation of GLM immediately following induction and during the subsequent maintenance phase in response to suboptimal DL or persisting inflammatory burden as represented by raised faecal calprotectin (FCP). Aim The primary aim of the study is to ascertain if monitoring of FCP and DL of GLM to guide dose optimisation (during maintenance) improves rates of patient continuous clinical response and reduces disease activity in UC. Methods and analysis A randomised, multicentred two-arm trial studying the effect of dose optimisation of GLM based on FCP and DL versus treatment as per SMPC. Eligible patients will be randomised in a 1:1 ratio to 1 of 2 treatment groups and shall be treated over a period of 46 weeks. Ethics and dissemination The study protocol was approved by the Research Ethics committee of St. Vincent’s University Hospital. The results will be published in a peer-reviewed journal and shared with the worldwide medical community. Trial registration numbers EudraCT number: 2015-004724-62; Clinicaltrials.gov Identifier: NCT0268772; Pre-results. PMID:29379609

Long-Term Effects of Radiation Exposure and Metabolic Status on Telomere Length of Peripheral Blood T Cells in Atomic Bomb Survivors.

PubMed

Yoshida, Kengo; Misumi, Munechika; Kubo, Yoshiko; Yamaoka, Mika; Kyoizumi, Seishi; Ohishi, Waka; Hayashi, Tomonori; Kusunoki, Yoichiro

2016-10-01

In a series of studies of atomic bomb survivors, radiation-dose-dependent alterations in peripheral T-cell populations have been reported. For example, reduced size in naïve T-cell pools and impaired proliferation ability of T cells were observed. Because these alterations are also generally observed with human aging, we hypothesized that radiation exposure may accelerate the aging process of the T-cell immune system. To further test this hypothesis, we conducted cross-sectional analyses of telomere length, a hallmark of cellular aging, of naïve and memory CD4 T cells and total CD8 T cells in the peripheral blood of 620 atomic bomb survivors as it relates to age and radiation dose, using fluorescence in situ hybridization with flow cytometry. Since telomere shortening has been recently demonstrated in obesity-related metabolic abnormalities and diseases, the modifying effects of metabolic status were also examined. Our results indicated nonlinear relationships between T-cell telomere length and prior radiation exposure, i.e., longer telomeres with lower dose exposure and a decreasing trend of telomere length with individuals exposed to doses higher than 0.5 Gy. There were associations between shorter T-cell telomeres and higher hemoglobin Alc levels or fatty liver development. In naïve and memory CD4 T cells, radiation dose and high-density lipoprotein (HDL) cholesterol were found to positively interact with telomere length, suggesting that the decreasing trend of telomere length from a higher radiation dose was less conspicuous in individuals with a higher HDL cholesterol. It is therefore likely that radiation exposure perturbs T-cell homeostasis involving telomere length maintenance by multiple biological mechanisms, depending on dose, and that long-term-radiation-induced effects on the maintenance of T-cell telomeres may be modified by the subsequent metabolic conditions of individuals.

A randomized study of rotigotine dose response on 'off' time in advanced Parkinson's disease.

PubMed

Nicholas, Anthony P; Borgohain, Rupam; Chaná, Pedro; Surmann, Erwin; Thompson, Emily L; Bauer, Lars; Whitesides, John; Elmer, Lawrence W

2014-01-01

Previous phase III studies in patients with advanced Parkinson's disease (PD) not adequately controlled on levodopa demonstrated significant reduction of 'off' time with rotigotine transdermal system up to 16 mg/24 h. However, the minimal effective dose has not been established. This international, randomized, double-blind, placebo-controlled study (SP921; NCT00522379) investigated rotigotine dose response up to 8 mg/24 h. Patients with advanced idiopathic PD (≥2.5 h of daily 'off' time on stable doses of levodopa) were randomized 1:1:1:1:1 to receive rotigotine 2, 4, 6, or 8 mg/24 h or placebo, titrated over 4 weeks and maintained for 12 weeks. The primary efficacy variable was change from baseline to end of maintenance in absolute time spent 'off'. 409/514 (80%) randomized patients completed maintenance. Mean (±SD) baseline daily 'off' times (h/day) were placebo: 6.4 (±2.5), rotigotine 2-8 mg/24 h: 6.4 (±2.6). Rotigotine 8 mg/24 h was the minimal dose to significantly reduce 'off' time versus placebo. LS mean (±SE) absolute change in daily 'off' time (h/day) from baseline was -2.4 (±0.28) with rotigotine 8 mg/24 h, and -1.5 (±0.26) with placebo; absolute change in 'off' time in the 8 mg/24 h group compared with placebo was -0.85 h/day (95% CI -1.59, -0.11; p = 0.024). There was an apparent dose-dependent trend. Adverse events (AEs) reported at a higher incidence in the rotigotine 8 mg/24 h group versus placebo included application site reactions, nausea, dry mouth, and dyskinesia; there was no worsening of insomnia, somnolence, orthostatic hypotension, confusional state or hallucinations, even in patients ≥75 years of age. The minimal statistically significant effective dose of rotigotine to reduce absolute 'off' time was 8 mg/24 h. The AE profile was similar to previous studies.

Cost-effectiveness comparison of current proton-pump inhibitors to treat gastro-oesophageal reflux disease in the UK.

PubMed

Remák, E; Brown, R E; Yuen, C; Robinson, A

2005-10-01

Gastro-oesophageal reflux disease (GORD) is a recurring condition with many patients requiring long-term maintenance therapy. Therefore initial choice of treatment has long-term cost implications. The aim was to compare the costs and effectiveness of treatment of GORD the (unconfirmed by endoscopy) with seven proton pump inhibitors (PPIs: esomeprazole, lansoprazole (capsules and oro-dispersible tablets), omeprazole (generic and branded), pantoprazole and rabeprazole), over one year. A treatment model was developed of 13 interconnected Markov models incorporating acute treatment of symptoms, long-term therapy and subsequent decisions to undertake endoscopy to confirm diagnosis. Patients were allowed to stop treatment or to receive maintenance treatment either continuously or on-demand depending on response to therapy. Long-term dosing schedule (high dose or step-down dose) was based on current market data. Efficacy of treatments was based on clinical trials and follow-up studies, while resource use patterns were determined by a panel of physicians. The model predicts total expected annual costs, number of symptom-free days and quality-adjusted life-years (QALY). Generic omeprazole and rabeprazole dominated (i.e. cost less and resulted in more symptom-free days and higher QALY gains) the other PPIs. Rabeprazole had a favourable cost-effectiveness ratio of 3.42 pounds per symptom-free day and 8308 pounds/quality-adjusted life-year gained when compared with generic omeprazole. Rabeprazole remained cost-effective independent of choice of maintenance treatment (i.e. proportion of patients remaining on continuous treatment versus on-demand treatment). Economic models provide a useful framework to evaluate PPIs in realistic clinical scenarios. Our findings show that rabeprazole is cost-effective for the treatment of GORD.

P2X7-regulated protection from exacerbations and loss of control is independent of asthma maintenance therapy.

PubMed

Denlinger, Loren C; Manthei, David M; Seibold, Max A; Ahn, Kwangmi; Bleecker, Eugene; Boushey, Homer A; Calhoun, William J; Castro, Mario; Chinchili, Vernon M; Fahy, John V; Hawkins, Greg A; Icitovic, Nicolina; Israel, Elliot; Jarjour, Nizar N; King, Tonya; Kraft, Monica; Lazarus, Stephen C; Lehman, Erik; Martin, Richard J; Meyers, Deborah A; Peters, Stephen P; Sheerar, Dagna; Shi, Lei; Sutherland, E Rand; Szefler, Stanley J; Wechsler, Michael E; Sorkness, Christine A; Lemanske, Robert F

2013-01-01

The function of the P2X(7) nucleotide receptor protects against exacerbation in people with mild-intermittent asthma during viral illnesses, but the impact of disease severity and maintenance therapy has not been studied. To evaluate the association between P2X(7), asthma exacerbations, and incomplete symptom control in a more diverse population. A matched P2RX7 genetic case-control was performed with samples from Asthma Clinical Research Network trial participants enrolled before July 2006, and P2X(7) pore activity was determined in whole blood samples as an ancillary study to two trials completed subsequently. A total of 187 exacerbations were studied in 742 subjects, and the change in asthma symptom burden was studied in an additional 110 subjects during a trial of inhaled corticosteroids (ICS) dose optimization. African American carriers of the minor G allele of the rs2230911 loss-of-function single nucleotide polymorphism were more likely to have a history of prednisone use in the previous 12 months, with adjustment for ICS and long-acting β(2)-agonists use (odds ratio, 2.7; 95% confidence interval, 1.2-6.2; P = 0.018). Despite medium-dose ICS, attenuated pore function predicted earlier exacerbations in incompletely controlled patients with moderate asthma (hazard ratio, 3.2; confidence interval, 1.1-9.3; P = 0.033). After establishing control with low-dose ICS in patients with mild asthma, those with attenuated pore function had more asthma symptoms, rescue albuterol use, and FEV(1) reversal (P < 0.001, 0.03, and 0.03, respectively) during the ICS adjustment phase. P2X(7) pore function protects against exacerbations of asthma and loss of control, independent of baseline severity and the maintenance therapy.

Extended nicotine self-administration increases sensitivity to nicotine, motivation to seek nicotine and the reinforcing properties of nicotine-paired cues.

PubMed

Clemens, Kelly J; Lay, Belinda P P; Holmes, Nathan M

2017-03-01

An array of pharmacological and environmental factors influence the development and maintenance of tobacco addiction. The nature of these influences likely changes across the course of an extended smoking history, during which time drug seeking can become involuntary and uncontrolled. The present study used an animal model to examine the factors that drive nicotine-seeking behavior after either brief (10 days) or extended (40 days) self-administration training. In Experiment 1, extended training increased rats' sensitivity to nicotine, indicated by a leftward shift in the dose-response curve, and their motivation to work for nicotine, indicated by an increase in the break point achieved under a progressive ratio schedule. In Experiment 2, extended training imbued the nicotine-paired cue with the capacity to maintain responding to the same high level as nicotine itself. However, Experiment 3 showed that the mechanisms involved in responding for nicotine or a nicotine-paired cue are dissociable, as treatment with the partial nicotine receptor agonist, varenicline, suppressed responding for nicotine but potentiated responding for the nicotine-paired cue. Hence, across extended nicotine self-administration, pharmacological and environmental influences over nicotine seeking increase such that nicotine seeking is controlled by multiple sources, and therefore highly resistant to change. © 2015 Society for the Study of Addiction.

A 5-year evaluation of a methadone medical maintenance program.

PubMed

Harris, Kenneth A; Arnsten, Julia H; Joseph, Herman; Hecht, Joe; Marion, Ira; Juliana, Patti; Gourevitch, Marc N

2006-12-01

Methadone medical maintenance (MMM) is a model for the treatment of opioid dependence in which a monthly supply of methadone is distributed in an office setting, in contrast to more highly regulated settings where daily observed dosing is the norm. We assessed patient characteristics and treatment outcomes of an MMM program initiated in the Bronx, New York, in 1999 by conducting a retrospective chart review. Participant characteristics were compared with those of patients enrolled in affiliated conventional methadone maintenance treatment programs. Patients had diverse ethnicities, occupations, educational backgrounds, and income levels. Urine toxicology testing detected illicit opiate and cocaine use in 0.8% and 0.4% of aggregate samples, respectively. The retention rate was 98%, which compares favorably with the four other MMM programs that have been reported in the medical literature. This study demonstrates that selected patients from a socioeconomically disadvantaged population remained clinically stable and engaged in treatment in a far less intensive setting than traditional methadone maintenance.

A 5-year evaluation of a methadone medical maintenance program

PubMed Central

Harris, Kenneth A.; Arnsten, Julia H.; Joseph, Herman; Hecht, Joe; Marion, Ira; Juliana, Patti; Gourevitch, Marc N.

2009-01-01

Methadone medical maintenance (MMM) is a model for the treatment of opioid dependence in which a monthly supply of methadone is distributed in an office setting, in contrast to more highly regulated settings where daily observed dosing is the norm. We assessed patient characteristics and treatment outcomes of an MMM program initiated in the Bronx, New York, in 1999 by conducting a retrospective chart review. Participant characteristics were compared with those of patients enrolled in affiliated conventional methadone maintenance treatment programs. Patients had diverse ethnicities, occupations, educational backgrounds, and income levels. Urine toxicology testing detected illicit opiate and cocaine use in 0.8% and 0.4% of aggregate samples, respectively. The retention rate was 98%, which compares favorably with the four other MMM programs that have been reported in the medical literature. This study demonstrates that selected patients from a socioeconomically disadvantaged population remained clinically stable and engaged in treatment in a far less intensive setting than traditional methadone maintenance. PMID:17084798

Fit and Strong!: bolstering maintenance of physical activity among older adults with lower-extremity osteoarthritis.

PubMed

Hughes, Susan L; Seymour, Rachel B; Campbell, Richard T; Desai, Pankaja; Huber, Gail; Chang, H Justina

2010-01-01

To compare the impact of negotiated vs. mainstreamed follow-up with telephone reinforcement (TR) on maintenance of physical activity (PA) after Fit and Strong! ended. A multisite comparative effectiveness trial with repeated measures. Single group random effects analyses showed significant improvements at 2, 6, 12, and 18 months on PA maintenance, lower-extremity (LE) pain and stiffness, LE function, sit-stand, 6-minute distance walk, and anxiety/depression. Analyses by follow-up condition showed persons in the negotiated with TR group maintained a 21% increase in caloric expenditures over baseline at 18 months, with lesser benefits seen in the negotiated-only, mainstreamed-with-TR, and mainstreamed-only groups. Significant benefits of telephone dose were also seen on LE joint stiffness, pain, and function as well as anxiety and anxiety/depression. The negotiated follow-up contract that Fit and Strong! uses, bolstered by TR, is associated with enhanced long-term PA maintenance and health outcomes.

Antiepileptic Drug Titration and Related Health Care Resource Use and Costs.

PubMed

Fishman, Jesse; Kalilani, Linda; Song, Yan; Swallow, Elyse; Wild, Imane

2018-02-27

Unexpected breakthrough seizures resulting from suboptimal antiepileptic drug (AED) dosing during the titration period, as well as adverse events resulting from rapid AED titration, may influence the titration schedule and significantly increase health care resource use (HRU) and health care costs. To assess the relationship between AEDs, HRU, and costs during AED titration and maintenance. Practicing neurologists were recruited from a nationwide panel to provide up to 3 patient records each for this retrospective medical chart review. Patients with epilepsy who were aged ≥ 18 years and had initiated an AED between January 1, 2014, and January 1, 2016, were followed for 6 months from AED initiation. Titration duration was the time from AED initiation to the beginning of treatment maintenance as determined by the physician. Outcomes were epilepsy-specific HRU (hospitalizations, emergency department visits, outpatient visits, physician referral, laboratory testing/diagnostic imaging, and phone calls) and related costs that occurred during the titration or maintenance treatment periods. Of 811 patients, 156, 128, 125, 120, 114, 107, and 61 initiated the following AEDs: levetiracetam, lamotrigine, lacosamide, valproate, topiramate, carbamazepine, and phenytoin, respectively. Most patients (619/803 [77.1%] with complete AED data) received monotherapy. Baseline characteristics were similar across AEDs (mean [SD] age, 36.6 [14.4] years; 59.0% male). Kaplan-Meier estimates of titration duration ranged from 3.3 weeks (phenytoin) to 8.1 weeks (lamotrigine). From titration to maintenance, the overall incidence of HRU per person-month decreased 54.5%-89.3% for each HRU measure except outpatient visits (24.6% decrease). Total epilepsy-related costs decreased from $80.48 to $42.77 per person-month, or 46.9% from titration to maintenance. AED titration periods had higher HRU rates and costs than AED maintenance, suggesting that use of AEDs with shorter titration requirements reduces health care costs, although disease severity may also factor into overall cost. UCB Pharma sponsored this study and reviewed the manuscript. Fishman and Kalilani are employees of UCB Pharma. Wild was an employee of UCB Pharma at the time this analysis was conducted. Song and Swallow are employees of Analysis Group, which received funding from UCB Pharma. Study concept and design were contributed by Fishman, Kalilani, and Wild, along with other authors. Data collection was performed by Song and Swallow. All authors contributed to data interpretation. Writing of the manuscript was led by Fishman, Song, and Swallow, with revisions by all authors.

Oral hyposensitization to poison ivy and poison oak.

PubMed

Marks, J G; Trautlein, J J; Epstein, W L; Laws, D M; Sicard, G R

1987-04-01

We evaluated the safety and efficacy of a 1:1 mixture of pentadecylcatechol (PDC) and heptadecylcatechol (HDC) diacetate in reducing hypersensitivity to poison ivy and poison oak. The study was double-blind, parallel, randomized, and placebo controlled. The 44 subjects receiving the active drug ingested a cumulative dose of 306.5 mg over a five-week period. Subsequently, 14 patients were continued on a maintenance phase, ingesting an additional 960 mg of drug. The PDC-HDC diacetate was well tolerated, with no significant side effects. Evaluation of efficacy compared poststudy and prestudy reactions to patch tests using urushiol in doses of 0.025, 0.05, 0.125, 0.25, and 0.5 micrograms applied to the forearm. The results indicated that the induction phase as well as the maintenance phase did not induce a statistically significant hyposensitivity to urushiol, and we were thus unable to decrease sensitivity to poison ivy and poison oak in humans using orally ingested PDC-HDC diacetate.

Impact of Cannabis Use During Stabilization on Methadone Maintenance Treatment

PubMed Central

Scavone, Jillian L.; Sterling, Robert C.; Weinstein, Stephen P.; Van Bockstaele, Elisabeth J.

2016-01-01

Background and Objectives Illicit drug use, particularly of cannabis, is common among opiate-dependent individuals, and has the potential to impact treatment in a negative manner. Methods To examine this, patterns of cannabis use prior to and during methadone maintenance treatment (MMT) were examined to assess possible cannabis-related effects on MMT, particularly during methadone stabilization. Retrospective chart analysis was used to examine outpatient records of patients undergoing MMT (n=91), focusing specifically on past and present cannabis use and its association with opiate abstinence, methadone dose stabilization, and treatment compliance. Results Objective rates of cannabis use were high during methadone induction, dropping significantly following dose stabilization. History of cannabis use correlated with cannabis use during MMT, but did not negatively impact the methadone induction process. Pilot data also suggested that objective ratings of opiate withdrawal decrease in MMT patients using cannabis during stabilization. Conclusions and Scientific Significance The present findings may point to novel interventions to be employed during treatment for opiate dependence that specifically target cannabinoid-opioid system interactions. PMID:23795873

Excess thyroid hormone inhibits embryonic neural stem/progenitor cells proliferation and maintenance through STAT3 signalling pathway.

PubMed

Chen, Chunhai; Zhou, Zhou; Zhong, Min; Li, Maoquan; Yang, Xuesen; Zhang, Yanwen; Wang, Yuan; Wei, Aimin; Qu, Mingyue; Zhang, Lei; Xu, Shangcheng; Chen, Shude; Yu, Zhengping

2011-07-01

Hyperthyroidism is prevalent during pregnancy, but little is known about the effects of excess thyroid hormone on the development of embryonic neural stem/progenitor cells (NSCs), and the mechanisms underlying these effects. Previous studies indicate that STAT3 plays a crucial role in determining NSC fate during neurodevelopment. In this study, we investigated the effects of a supraphysiological dose of 3,5,3'-L-triiodothyronine (T3) on the proliferation and maintenance of NSCs derived from embryonic day 13.5 mouse neocortex, and the involvement of STAT3 in this process. Our results suggest that excess T3 treatment inhibits NSC proliferation and maintenance. T3 decreased tyrosine phosphorylation of JAK1, JAK2 and STAT3, and subsequently inhibited STAT3-DNA binding activity. Furthermore, proliferation and maintenance of NSCs were decreased by inhibitors of JAKs and STAT3, indicating that the STAT3 signalling pathway is involved in the process of NSC proliferation and maintenance. Taken together, these results suggest that the STAT3 signalling pathway is involved in the process of T3-induced inhibition of embryonic NSC proliferation and maintenance. These findings provide data for understanding the effects of hyperthyroidism during pregnancy on fetal brain development, and the mechanisms underlying these effects.

Plasma prolactin and homovanillic acid as markers for psychopathology and abnormal movements after neuroleptic dose decrease.

PubMed

Newcomer, J W; Riney, S J; Vinogradov, S; Csernansky, J G

1992-01-01

Plasma prolactin concentration (pPRL), plasma homovanillic acid concentration (pHVA), and symptomatology were measured in 24 male subjects with schizophrenia during maintenance haloperidol treatment. Fourteen subjects subsequently underwent 50 percent dose decreases under placebo-controlled, double-blind conditions. At baseline, a significant inverse correlation was found between pPRL and both tardive dyskinesia (TD) and "thinking disorder"; pPRL was directly correlated with negative symptoms. No such relationship was found with pHVA. In the patients who underwent a dose decrease, no relationship was found between baseline pPRL or pHVA and any clinical variable after the decrease. These data do not support the use of baseline pPRL or pHVA as markers of central dopamine function subsequent to a neuroleptic dose decrease.

Maintenance immunosuppression with intermittent intravenous IL-2 receptor antibody therapy in renal transplant recipients.

PubMed

Gabardi, Steven; Catella, Jennifer; Martin, Spencer T; Perrone, Ronald; Chandraker, Anil; Magee, Colm C; McDevitt-Potter, Lisa M

2011-09-01

To report what we believe to be the first 2 cases of long-term (>24 months) intermittent intravenous interleukin-2 receptor antibody (IL-2RA) therapy for maintenance immunosuppression following renal transplantation. The first patient is a 52-year-old female with a history of intolerance to calcineurin inhibitors (CNIs) and sirolimus. Following her second transplant, the patient received mycophenolate mofetil 100 mg twice daily, a tapering corticosteroid regimen (initial dose of methylprednisolone 500 mg tapered over 1 week to prednisone 30 mg/day), and biweekly intravenous daclizumab 1-1.2 mg/kg/dose; 33 months after transplant the IL-2RA was changed to intravenous basiliximab 40 mg once a month. At 40 months after transplant, the patient continued to have stable renal function (estimated glomerular filtration rate 48 mL/min/1.73 m²) with excellent tolerability. The second patient is a 59-year-old female also intolerant to CNIs and sirolimus who required intermittent maintenance therapy with intravenous basiliximab 20 mg/dose. Despite an initial rejection episode, the patient tolerated more than 2 years of basiliximab therapy with good renal function (estimated glomerular filtration rate 103 months after transplant 69 mL/min/1.73 m²) and no adverse events. The IL-2RAs basiliximab and daclizumab possess several characteristics of ideal maintenance immunosuppressive agents (ie, nondepleting, long half-lives, limited adverse events). Based on a MEDLINE search (through December 31, 2010) using the search terms basiliximab, daclizumab, organ transplant, immunosuppression, and/or maintenance immunosuppression, and an advanced search in the published abstracts from the American Transplant Congress and World Transplant Congress (2000-2010), it appears that IL-2RAs have been used successfully as short-term therapy in both renal and extrarenal transplant recipients to allow for renal recovery following CNI-induced nephrotoxicity. In heart transplant recipients, the IL-2RAs have been used for <24 months as maintenance immunosuppression in patients intolerant of CNIs or sirolimus. To the best of our knowledge, these 2 cases are the first to demonstrate that IL-2RAs can be used as an alternative to a CNI in a de novo immunosuppressive regimen. Also, this is the first report to illustrate successful long-term use of IL-2RAs in renal transplant recipients. This alternative approach was well tolerated by our patients, with no apparent adverse events. Although the efficacy of such regimens cannot be determined with 2 case reports, the fact that intermittent intravenous IL-2RA administration was successfully accomplished in these patients provides impetus to evaluate this treatment modality in prospective studies.

Safety and Efficacy of a Progressively Prolonged Maintenance Interval of Venom Immunotherapy.

PubMed

Kontou-Fili, Kalliopi; Pitsios, Constantinos; Kompoti, Evangelia; Giannakopoulos, Dionysios; Kouridakis, Spyros

2018-01-01

The long-term protection provided by venom immunotherapy (VIT) is related to the dose administered and to its long duration; the latter, however, becomes inconvenient for patients in countries like Greece, with many islanders or inhabitants of distant mountainous areas. Maintenance interval prolongation reduces the number of office visits - saving time and money - and as a consequence contributes to the patients' compliance. The aim of this prospective study was to evaluate the safety and efficacy of VIT on a progressively prolonged maintenance interval (PPMI). 450 venom-allergic patients were reviewed for participation in our study; all of them were initially treated with a modified rush or an ultrarush protocol using freshly reconstituted, pure venoms. Upon reaching the maintenance dose, the VIT interval was scheduled to be gradually prolonged - by 1 week each time - aiming at a maximal interval of 26 weeks. 267/450 patients consented to participate in our VIT PPMI protocol: 98 were treated with vespid(s) venom, 142 with honeybee venom, and 27 with both. The mean duration of patient follow-up was 9.1 ± 4.2 years. The majority of systemic reactions due to VIT injections occurred up to the 8-weeks PPMI; few additional reactions were documented in a small fraction (2.9%) of our patient population beyond 9 weeks and up to 16 weeks; all were caused by honeybee VIT. No reactions were observed during VIT administration at the 26-week interval. Ninety-six patients reported 204 field sting occurrences by the culprit insect. Ten systemic reactions (8 mild and 2 moderate in severity) were registered between the 9- and 18-week PPMI; the honeybee was the culprit insect in all cases. 108 field stings by the offending insect were sustained beyond the 20- and up to the 26-week PPMI; there were no reactions at all. Progressively prolonging the VIT maintenance interval up to 26 weeks appears to be safe and efficacious. © 2018 S. Karger AG, Basel.

Implementing methadone maintenance treatment in prisons in Malaysia.

PubMed

Wickersham, Jeffrey A; Marcus, Ruthanne; Kamarulzaman, Adeeba; Zahari, Muhammad Muhsin; Altice, Frederick L

2013-02-01

In Malaysia, human immunodeficiency virus (HIV) infection is highly concentrated among people who inject opioids. For this reason, the country undertook a three-phase roll-out of a methadone maintenance treatment (MMT) programme. In Phase 3, described in this paper, MMT was implemented within prisons and retention in care was assessed. After developing standard operating procedures and agreement between its Prisons Department and Ministry of Health, Malaysia established pilot MMT programmes in two prisons in the states of Kelantan (2008) and Selangor (2009) - those with the highest proportions of HIV-infected prisoners. Community-based MMT programmes were also established in Malaysia to integrate treatment activities after prisoners' release. Having failed to reduce the incidence of HIV infection, in 2005 Malaysia embarked on a harm reduction strategy. STANDARD OPERATING PROCEDURES WERE MODIFIED TO: (i) escalate the dose of methadone more slowly; (ii) provide ongoing education and training for medical and correctional staff and inmates; (iii) increase the duration of methadone treatment before releasing prisoners; (iv) reinforce linkages with community MMT programmes after prisoners' release; (v) screen for and treat tuberculosis; (vi) escalate the dose of methadone during treatment for HIV infection and tuberculosis; and (vii) optimize the daily oral dose of methadone (> 80 mg) before releasing prisoners. Prison-based MMT programmes can be effectively implemented but require adequate dosing and measures are needed to improve communication between prison and police authorities, prevent police harassment of MMT clients after their release, and improve systems for tracking release dates.

[Effectiveness of various dopamine doses in acute myocardial ischemia complicated by cardiogenic shock (an experimental study)].

PubMed

Kipshidze, N N; Korotkov, A A; Marsagishvili, L A; Prigolashvili, T Sh; Bokhua, M R

1981-06-01

The effect of various doses of dopamine on the values of cardiac contractile and hemodynamic function under conditions of acute two-hour ischemia complicated by cardiogenic shock was studied in 27 experiments on dogs. In a dose of 5 microgram/kg/min dopamine caused an optimum increase in cardiac productive capacity, reduction of peripheral resistance, adequate increase in coronary circulation and decrease in ST segment depression on the ECG. Infusion of 10 microgram/kg/min dopamine usually caused myocardial hyperfunction with an increase in total peripheral resistance and cardiac performance. Maximum dopamine doses (10 microgram/kg/min and more) were effective in the areactive form of cardiogenic shock. In longterm dopamine infusion it is necessary to establish continuous control over the hemodynamic parameters and the ECG to prevent aggravation of ischemia and for stage-by-stage reduction of the drug concentration and determination of the minimum maintenance dose.

Nicotine Interactions with Low-Dose Alcohol: Pharmacological Influences on Smoking and Drinking Motivation

PubMed Central

Oliver, Jason A.; Blank, Melissa D.; Rensburg, Kate Janse Van; MacQueen, David A.; Brandon, Thomas H.; Drobes, David J.

2014-01-01

An extensive literature documents a close association between cigarette and alcohol use. The joint pharmacological effects of alcohol and nicotine on smoking and drinking motivation may help explain this relationship. This experiment was designed to test the separate and combined pharmacological effects of nicotine and a low dose of alcohol (equivalent to 1–2 standard drinks) on substance use motivation using a double-blind and fully-crossed within-subjects design. Participants (N = 87) with a wide range of smoking and drinking patterns completed four counter-balanced experimental sessions during which they consumed an alcohol (Male: 0.3 g/kg; Female: 0.27 g/kg) or placebo beverage and smoked a nicotine (.6 mg) or placebo cigarette. Outcome measures assessed the impact of drug administration (alcohol or nicotine) on craving to smoke, craving to drink, affect, and liking of the beverage and cigarette. Results indicated that combined administration produced higher cravings to smoke for the entire sample, as well as higher cravings to drink among women and lighter drinkers. Heavier users of either alcohol or cigarettes also exhibited enhanced sensitivity to the effects of either drug in isolation. Separate, but not interactive, effects of alcohol and nicotine on mood were observed, as well as both same-drug and cross-drug effects on beverage and cigarette liking. Together, these findings support the notion that the interactive pharmacological effects of nicotine and low-doses of alcohol play an important role in motivating contemporaneous use and suggest roles for cross-reinforcement and cross-tolerance in the development and maintenance of alcohol and nicotine use and dependence. PMID:24364618

Cigarette smoke exposure during adolescence enhances sensitivity to the rewarding effects of nicotine in adulthood, even after a long period of abstinence.

PubMed

de la Peña, June Bryan; Ahsan, Hafiz Muhammad; Tampus, Reinholdgher; Botanas, Chrislean Jun; dela Peña, Irene Joy; Kim, Hee Jin; Sohn, Aeree; dela Peña, Ike; Shin, Chan Young; Ryu, Jong Hoon; Cheong, Jae Hoon

2015-12-01

Adolescence is a period of enhanced vulnerability to the motivational properties of tobacco/cigarette smoking. Several studies have suggested that smoking initiation during this period will more likely lead to long-lasting cigarette or nicotine addiction. In the present study, we investigated the influences of adolescent cigarette smoke or nicotine exposure on the rewarding effects of nicotine, particularly whether these influences persist even after a long period of abstinence. Towards this, adolescent and adult Sprague-Dawley rats were repeatedly exposed to cigarette smoke or nicotine, for 14 days, and then were subjected to a 1-month abstinence period. Thereafter, the rewarding effects of nicotine were evaluated through the conditioned place preference (CPP) and self-administration (SA) tests. Even after a 1-month abstinence period, rats pre-exposed to either nicotine or cigarette smoke demonstrated enhanced CPP for the higher dose (0.6 mg/kg) of nicotine. Notably, cigarette smoke-preexposed adolescent rats, now adults, showed CPP for both 0.2 and 0.6 mg/kg dose of nicotine. Moreover, only these rats (pre-exposed to cigarette smoke during adolescence) showed significant acquisition and maintenance of nicotine (0.03 mg/kg/infusion) SA. These results suggest that cigarette smoke exposure during adolescence enhances sensitivity to the rewarding effects of nicotine in adulthood, even after a long period of abstinence. This may be a factor in the high rates of nicotine addiction and dependence observed in smokers who started during adolescence. More importantly, our findings highlight the enduring consequences of adolescent-onset cigarette smoking and the need to protect this vulnerable population. Copyright © 2015 Elsevier Ltd. All rights reserved.

Gene variants in responsiveness to clopidogrel have no impact on clinical outcomes in Chinese patients undergoing percutaneous coronary intervention - A multicenter study.

PubMed

Li, Chenze; Zhang, Lina; Wang, Haoran; Li, Sha; Zhang, Yan; You, Ling; Sun, Yang; Wang, Dong; Yang, Jun; Cui, Yinghua; Cao, Yanyan; Shen, Xiaoqing; Wang, Yan; Cui, Wei; Yan, Jiangtao; Zeng, Hesong; Guo, Xiaomei; Li, Jianjun; Wang, Dao Wen

2017-08-01

Gene variants contribute to variability in individual responsiveness to clopidogrel and influence cardiovascular outcomes in Caucasian patients with acute coronary syndrome (ACS). However, limited data is available in Asian populations. We resequenced 14 genes in metabolizing and activity pathway of clopidogrel in 138 patients with ACS and prospectively assessed the modulating effects of 13 variants possibly related to clopidogrel efficacy on one-year cardiovascular event occurrence in 5820 ACS patients after percutaneous coronary intervention (PCI). In addition, platelet aggregation rate was measured in 1084 participants and plasma levels of active metabolite were determined in 15 patients to test whether increasing clopidogrel maintenance doses increases active metabolite exposure. No significant associations were found between any of the tested variants and risk of cardiovascular events (P>0.05), although CYP2C19*2 carriers had slightly higher on-treatment platelet aggregation rate and lower active metabolite exposure compared with that of non-carriers (Median [IQR] 51.49 [35.43-66.75] vs. 49.05 [32.36-63.38], P=0.012) (means±SD AUC, 22.84±5.00 vs. 35.05±12.34, P=0.008). Switching from 75mg daily clopidogrel to 150mg daily fully overcomes low exposure to clopidogrel active metabolite in CYP2C19*2 carriers (means±SD AUC, 32.35±8.65 vs. 35.05±12.34, P=0.314). Different from Caucasian populations, genetic variants have no significant influence on clinical outcomes and have much milder effects on inhibition of platelet and active clopidogrel metabolite levels in Chinese patients with ACS after PCI, an effect which could be overcome with a dose escalation to 150mg daily. Copyright © 2017. Published by Elsevier B.V.

Clinical trial: efficacy and safety of dexlansoprazole MR 60 and 90 mg in healed erosive oesophagitis - maintenance of healing and symptom relief.

PubMed

Howden, C W; Larsen, L M; Perez, M C; Palmer, R; Atkinson, S N

2009-11-01

Dexlansoprazole MR, a modified-release formulation of dexlansoprazole, an enantiomer of lansoprazole, effectively heals erosive oesophagitis. To assess dexlansoprazole MR in maintaining healed erosive oesophagitis. Patients (n = 451) with erosive oesophagitis healed in either of two dexlansoprazole MR healing trials randomly received dexlansoprazole MR 60 or 90 mg or placebo once daily in this double-blind trial. The percentage of patients who maintained healing at month 6 was analysed using life table and crude rate methods. Secondary endpoints were percentages of nights and of 24-h days without heartburn based on daily diaries. Dexlansoprazole MR 60 and 90 mg were superior to placebo for maintaining healing (P < 0.0025). Maintenance rates were 87% and 82% for the 60 and 90 mg doses, respectively, vs. 26% for placebo (life table), and 66% and 65% vs. 14%, respectively (crude rate). Both doses were superior to placebo for the percentage of 24-h heartburn-free days (60 mg, 96%; 90 mg, 94%; placebo, 19%) and nights (98%, 97%, and 50%, respectively). Diarrhoea, flatulence, gastritis (symptoms) and abdominal pain occurred more frequently with dexlansoprazole MR than placebo, but were not dose-related. Dexlansoprazole MR effectively maintained healed erosive oesophagitis and symptom relief compared with placebo, and was well tolerated.

Causal evidence for frontal involvement in memory target maintenance by posterior brain areas during distracter interference of visual working memory

PubMed Central

Feredoes, Eva; Heinen, Klaartje; Weiskopf, Nikolaus; Ruff, Christian; Driver, Jon

2011-01-01

Dorsolateral prefrontal cortex (DLPFC) is recruited during visual working memory (WM) when relevant information must be maintained in the presence of distracting information. The mechanism by which DLPFC might ensure successful maintenance of the contents of WM is, however, unclear; it might enhance neural maintenance of memory targets or suppress processing of distracters. To adjudicate between these possibilities, we applied time-locked transcranial magnetic stimulation (TMS) during functional MRI, an approach that permits causal assessment of a stimulated brain region's influence on connected brain regions, and evaluated how this influence may change under different task conditions. Participants performed a visual WM task requiring retention of visual stimuli (faces or houses) across a delay during which visual distracters could be present or absent. When distracters were present, they were always from the opposite stimulus category, so that targets and distracters were represented in distinct posterior cortical areas. We then measured whether DLPFC-TMS, administered in the delay at the time point when distracters could appear, would modulate posterior regions representing memory targets or distracters. We found that DLPFC-TMS influenced posterior areas only when distracters were present and, critically, that this influence consisted of increased activity in regions representing the current memory targets. DLPFC-TMS did not affect regions representing current distracters. These results provide a new line of causal evidence for a top-down DLPFC-based control mechanism that promotes successful maintenance of relevant information in WM in the presence of distraction. PMID:21987824

Effect of chronic kidney disease on warfarin management in a pharmacist-managed anticoagulation clinic.

PubMed

Kleinow, Megan E; Garwood, Candice L; Clemente, Jennifer L; Whittaker, Peter

2011-09-01

There is growing evidence that kidney disease affects hepatically cleared drugs. Accordingly, we hypothesized that chronic kidney disease (CKD) would disrupt anticoagulation of warfarin-treated patients and thereby increase the amount of management required to maintain appropriate anticoagulation. Specifically, we anticipated that more dose manipulations (both dose changes and transient dose adjustments) and shorter times between scheduled clinic visits would be required for anticoagulation patients with CKD. To determine how CKD affected warfarin maintenance dose, anticoagulation stability, the proportion of clinic visits that necessitated a dose manipulation (either a change in the prescribed weekly dose or a transient dose adjustment), and the length of time between scheduled visits in 2 pharmacist-managed anticoagulation clinics. Our retrospective, cohort chart review investigated warfarin response in anticoagulation clinic patients. From the clinic database of patients with an international normalized ratio (INR) target range of 2.0-3.0, we matched 20 of 24 patients with CKD (estimated creatinine clearance less than 60 mL per minute) to 20 comparison group patients (estimated creatinine clearance greater than 60 mL per minute) based on parameters demonstrated to affect warfarin dose: ethnicity, gender, age, body surface area, and simvastatin use. We calculated the average weekly dose used to maintain target INR (assessment period range=116-1,408 days). To evaluate anticoagulation stability and patient management, we quantified several parameters, including the percentage of total time in therapeutic range, the proportion of clinic visits that required a dose change, and the time between scheduled visits. We compared group means using t-tests, and categorical data were compared using Fisher's exact test. Our population was predominantly female (75%) and of African ancestry (95%); average age 60 years. Patients with CKD required a 24% lower dose than the comparison group (mean [SD]=35.9 [10.7] vs. 47.0 [11.2] mg per week, P=0.003) and spent less time in therapeutic range required increased clinic management versus the comparison group, as indicated by a significantly higher proportion of clinic visits at which dose changes occurred (22% vs. 12%, P<0.001) and a decreased time between scheduled visits (mean [SD] of 16.0 [3.2] days vs. 19.7 [3.4] days, respectively, P=0.001). CKD was associated with both decreased warfarin maintenance dose and decreased anticoagulation stability which, in turn, required more frequent and intensive anticoagulation clinic management.

Dosing of Milrinone in Preterm Neonates to Prevent Postligation Cardiac Syndrome: Simulation Study Suggests Need for Bolus Infusion.

PubMed

Hallik, Maarja; Tasa, Tõnis; Starkopf, Joel; Metsvaht, Tuuli

2017-01-01

Milrinone has been suggested as a possible first-line therapy for preterm neonates to prevent postligation cardiac syndrome (PLCS) through decreasing systemic vascular resistance and increasing cardiac contractility. The optimal dosing regimen, however, is not known. To model the dosing of milrinone in preterm infants for prevention of PLCS after surgical closure of patent ductus arteriosus (PDA). Milrinone time-concentration profiles were simulated for 1,000 subjects using the volume of distribution and clearance estimates based on one compartmental population pharmacokinetic model by Paradisis et al. [Arch Dis Child Fetal Neonatal Ed 2007;92:F204-F209]. Dose optimization was based on retrospectively collected demographic data from neonates undergoing PDA ligation in Estonian PICUs between 2012 and 2014 and existing pharmacodynamic data. The target plasma concentration was set at 150-200 ng/ml. The simulation study used demographic data from 31 neonates who underwent PDA ligation. The median postnatal age was 13 days (range: 3-29) and weight was 760 g (range: 500-2,351). With continuous infusion of milrinone 0.33 μg/kg/min, the proportion of subjects within the desired concentration range was 0% by 3 h, 36% by 6 h, and 61% by 8 h; 99% of subjects exceeded the range by 18 h. The maximum proportion of total simulated concentrations in the target range was attained with a bolus infusion of 0.73 μg/kg/min for 3 h followed by a 0.16-μg/kg/min maintenance infusion. Mathematical simulations suggest that in preterm neonates the plasma time-concentration profile of milrinone can be optimized with a slow loading dose followed by maintenance infusion. © 2016 S. Karger AG, Basel.

Comparison of buprenorphine and methadone effects on opiate self-administration in primates.

PubMed

Mello, N K; Bree, M P; Mendelson, J H

1983-05-01

The effects of ascending and descending doses of buprenorphine (0.014-0.789 mg/kg/day) and methadone (0.179-11.86 mg/kg/day) on opiate and food intake were studied in Macaque monkeys over 195 to 245 days. Food (1-g banana pellets) and i.v. drug self-administration (heroin 0.01 or 0.02 mg/kg/injection or Dilaudid 0.02 mg/kg/injection) were maintained on a second-order schedule of reinforcement [FR 4 (VR 16:S)]. Buprenorphine (0.282-0.789 mg/kg/day) produced a significant suppression of opiate self-administration at 2.5 to 7 times the dose shown to be effective in human opiate abusers (P less than .05-.001). Methadone (1.43-11.86 mg/kg/day) did not suppress opiate self-administration in four of five monkeys across a dose range equivalent to 100 to 800 mg/day in man. The distribution of opiate self-administration across drug sessions did not account for the absence of methadone suppression as monkeys took 43% of the total daily opiate injections during the first daily drug session, 2.5 hr after methadone administration. During buprenorphine maintenance, food intake remained stable or increased significantly above base-line levels. Methadone maintenance was associated with significant decrements in food intake in four of five monkeys. Buprenorphine appeared to be significantly more effective in suppressing opiate self-administration than methadone across the dose range studied. Buprenorphine had none of the toxic side effects (seizures, respiratory depression, profound psychomotor retardation) associated with high doses of methadone over 6 to 8 months of daily drug treatment. These data are consistent with clinical studies of buprenorphine effects on heroin self-administration in human opiate addicts.

Status of Tamil Language in Singapore: An Analysis of Family Domain

ERIC Educational Resources Information Center

Kadakara, Shanmugam

2015-01-01

This paper addresses the phenomenon of Language Maintenance and Language Shift through a qualitative study of Tamil language in the family domain in Singapore. The influence of Singapore's bilingual policy and the institutional support offered for maintenance of Tamil language provide the context in which the central research problem of the status…

The Generation and Maintenance of Visual Mental Images: Evidence from Image Type and Aging

ERIC Educational Resources Information Center

De Beni, Rossana; Pazzaglia, Francesca; Gardini, Simona

2007-01-01

Imagery is a multi-componential process involving different mental operations. This paper addresses whether separate processes underlie the generation, maintenance and transformation of mental images or whether these cognitive processes rely on the same mental functions. We also examine the influence of age on these mental operations for…

Psychological Conditions of Engagement among Community College Maintenance Employees: A Cross-Sectional Study

ERIC Educational Resources Information Center

Franks, Tammy T.

2017-01-01

This dissertation examined the relationship between employee engagement and the factors that may influence the three psychological conditions of engagement: meaningfulness, safety, and availability for the sector of employees classified as maintenance, grounds, and custodial employees in a community college setting. The factors for each of the…

Subcutaneous narcotic infusions for cancer pain: treatment outcome and guidelines for use.

PubMed

Moulin, D E; Johnson, N G; Murray-Parsons, N; Geoghegan, M F; Goodwin, V A; Chester, M A

1992-03-15

To provide guidelines for the institution and maintenance of a continuous subcutaneous narcotic infusion program for cancer patients with chronic pain through an analysis of the narcotic requirements and treatment outcomes of patients who underwent such therapy and a comparison of the costs of two commonly used infusion systems. Retrospective study. Tertiary care facilities and patients' homes. Of 481 patients seen in consultation for cancer pain between July 1987 and April 1990, 60 (12%) met the eligibility criteria (i.e., standard medical management had failed, and they had adequate supervision at home). Continuous subcutaneous infusion with hydromorphone hydrochloride or morphine started on an inpatient basis and continued at home whenever possible. Patient selectivity, narcotic dosing requirements, discharge rate, patient preference for analgesic regimen, side effects, complications and cost-effectiveness. The mean initial maintenance infusion dose after dose titration was almost three times higher than the dose required before infusion (hydromorphone or equivalent 6.2 v. 2.1 mg/h). Eighteen patients died, and the remaining 42 were discharged home for a mean of 94.4 (standard deviation 128.3) days (extremes 12 and 741 days). The mean maximum infusion rate was 24.1 mg/h (extremes 0.5 and 180 mg/h). All but one of the patients preferred the infusion system to their previous oral analgesic regimen. Despite major dose escalations nausea and vomiting were well controlled in all cases. Twelve patients (20%) experienced serious systemic toxic effects or complications; six became encephalopathic, which necessitated dose reduction, five had a subcutaneous infection necessitating antibiotic treatment, and one had respiratory depression. The programmable computerized infusion pump was found to be more cost-effective than the disposable infusion device after a break-even point of 8 months. Continuous subcutaneous infusion of opioid drugs with the use of a portable programmable pump is safe and effective in selected patients who have failed to respond to standard medical treatment of their cancer pain. Dose titration may require rapid dose escalation, but this is usually well tolerated. For most communities embarking on such a program a programmable infusion system will be more cost-effective than a disposable system.

A phase 1 trial of ABT-510 concurrent with standard chemoradiation for patients with newly diagnosed glioblastoma.

PubMed

Nabors, Louis B; Fiveash, John B; Markert, James M; Kekan, Manasi S; Gillespie, George Y; Huang, Zhi; Johnson, Martin J; Meleth, Sreelatha; Kuo, Huichien; Gladson, Candece L; Fathallah-Shaykh, Hassan M

2010-03-01

To determine the maximum tolerated dose of ABT-510, a thrombospondin-1 mimetic drug with antiangiogenic properties, when used concurrently with temozolomide and radiotherapy in patients with newly diagnosed glioblastoma. Phase 1 dose-escalation clinical trial. Comprehensive Cancer Center, University of Alabama at Birmingham. Patients A total of 23 patients with newly diagnosed, histologically verified glioblastoma enrolled between April 2005 and January 2007. Four cohorts of 3 patients each received subcutaneous ABT-510 injection at doses of 20, 50, 100, or 200 mg/d. The maximum cohort was expanded to 14 patients to obtain additional safety and gene expression data. The treatment plan included 10 weeks of induction phase (temozolomide and radiotherapy with ABT-510 for 6 weeks plus ABT-510 monotherapy for 4 weeks) followed by a maintenance phase of ABT-510 and monthly temozolomide. Patients were monitored with brain magnetic resonance imaging and laboratory testing for dose-limiting toxicities, defined as grades 3 or 4 nonhematological toxicities and grade 4 hematological toxicities. Therapy was discontinued if 14 maintenance cycles were completed, disease progression occurred, or if the patient requested withdrawal. Disease progression, survival statistics, and gene expression arrays were analyzed. There were no grade 3 or 4 dose-limiting toxicity events that appeared related to ABT-510 for the dose range of 20 to 200 mg/d. A maximum tolerated dose was not defined. Most adverse events were mild, and injection-site reactions. The median time to tumor progression was 45.9 weeks, and the median overall survival time was 64.4 weeks. Gene expression analysis using TaqMan low-density arrays identified angiogenic genes that were differentially expressed in the brains of controls compared with patients with newly diagnosed glioblastoma, and identified FGF-1 and TIE-1 as being downregulated in patients who had better clinical outcomes. ABT-510, at subcutaneous doses up to 200 mg/d, is tolerated well with concurrent temozolomide and radiotherapy in patients with newly diagnosed glioblastoma, and low-density arrays provide a useful method of exploring gene expression profiles.

Effect of NQO1 and CYP4F2 genotypes on warfarin dose requirements in Hispanic-Americans and African-Americans.

PubMed

Bress, Adam; Patel, Shitalben R; Perera, Minoli A; Campbell, Richard T; Kittles, Rick A; Cavallari, Larisa H

2012-12-01

The objective of this study was to determine the additional contribution of NQO1 and CYP4F2 genotypes to warfarin dose requirements across two racial groups after accounting for known clinical and genetic predictors. The following were assessed in a cohort of 260 African-Americans and 53 Hispanic-Americans: clinical data; NQO1 p.P187S (*1/*2); CYP2C9*2, *3, *5, *6, *8 and *11; CYP4F2 p.V433M; and VKORC1 c.-1639G>A genotypes. Both the CYP4F2 433M (0.23 vs 0.06; p < 0.05) and NQO1*2 (0.27 vs 0.18; p < 0.05) allele frequencies were higher in Hispanic-Americans compared with African-Americans. Multiple regression analysis in the Hispanic-American cohort revealed that each CYP4F2 433M allele was associated with a 22% increase in warfarin maintenance dose (p = 0.019). Possession of the NQO1*2 allele was associated with a 34% increase in warfarin maintenance dose (p = 0.004), while adjusting for associated genetic (CYP2C9, CYP4F2 and VKORC1) and clinical factors. In this population, the inclusion of CYP4F2 and NQO1*2 genotypes improved the dose variability explained by the model from 0.58 to 0.68 (p = 0.001), a 17% relative improvement. By contrast, there was no association between CYP4F2 or NQO1*2 genotype and therapeutic warfarin dose in African-Americans after adjusting for known genetic and clinical predictors. In our cohort of inner-city Hispanic-Americans, the CYP4F2 and NQO1*2 genotypes significantly contributed to warfarin dose requirements. If our findings are confirmed, they would suggest that inclusion of the CYP4F2 and NQO1*2 genotypes in warfarin dose prediction algorithms may improve the predictive ability of such algorithms in Hispanic-Americans.

Effect of NQO1 and CYP4F2 genotypes on warfarin dose requirements in Hispanic–Americans and African–Americans

PubMed Central

Bress, Adam; Patel, Shitalben R; Perera, Minoli A; Campbell, Richard T; Kittles, Rick A; Cavallari, Larisa H

2013-01-01

Aim The objective of this study was to determine the additional contribution of NQO1 and CYP4F2 genotypes to warfarin dose requirements across two racial groups after accounting for known clinical and genetic predictors. Patients & methods The following were assessed in a cohort of 260 African–Americans and 53 Hispanic–Americans: clinical data; NQO1 p.P187S (*1/*2); CYP2C9*2, *3, *5, *6, *8 and *11; CYP4F2 p.V433M; and VKORC1 c.-1639G>A genotypes. Results Both the CYP4F2 433M (0.23 vs 0.06; p < 0.05) and NQO1*2 (0.27 vs. 0.18; p < 0.05) allele frequencies were higher in Hispanic–Americans compared with African–Americans. Multiple regression analysis in the Hispanic–American cohort revealed that each CYP4F2 433M allele was associated with a 22% increase in warfarin maintenance dose (p = 0.019). Possession of the NQO1*2 allele was associated with a 34% increase in warfarin maintenance dose (p = 0.004), while adjusting for associated genetic (CYP2C9, CYP4F2 and VKORC1) and clinical factors. In this population, the inclusion of CYP4F2 and NQO1*2 genotypes improved the dose variability explained by the model from 0.58 to 0.68 (p = 0.001), a 17% relative improvement. By contrast, there was no association between CYP4F2 or NQO1*2 genotype and therapeutic warfarin dose in African–Americans after adjusting for known genetic and clinical predictors. Conclusion In our cohort of inner-city Hispanic–Americans, the CYP4F2 and NQO1*2 genotypes significantly contributed to warfarin dose requirements. If our findings are confirmed, they would suggest that inclusion of the CYP4F2 and NQO1*2 genotypes in warfarin dose prediction algorithms may improve the predictive ability of such algorithms in Hispanic–Americans. PMID:23215885

[Maintenance Treatment With Antipsychotics for Adult Patients Diagnosed With Schizophrenia].

PubMed

Gómez-Restrepo, Carlos; Bohórquez Peñaranda, Adriana Patricia; de la Hoz Bradford, Ana María; Tamayo Martínez, Nathalie; García Valencia, Jenny; Jaramillo González, Luis Eduardo

2014-01-01

To determine the effectiveness and security of the antipsychotics available for the management of adult patients with schizophrenia in the maintenance phase. To develop recommendations of treatment for the maintenance phase of the disease. A clinical practice guideline was elaborated under the parameters of the Methodological Guide of the Ministerio de Salud y Protección Social to identify, synthesize and evaluate the evidence and make recommendations about the treatment and follow-up of adult patients with schizophrenia. The evidence of NICE guide 82 was adopted and updated. The evidence was presented to the Guideline Developing Group and recommendations, employing the GRADE system, were produced. 18 studies were included to evaluate the effectiveness and / or safety of different antipsychotic drugs first and second generation. Overall, antipsychotics (AP) showed superiority over placebo in relapse rate over 12 months (RR 0.59 95% CI 0.42, 0.82) and hospitalization rate over 24 months of follow-up (RR 0.38 95% 0.27, 0.55); its use is associated with increased risk of treatment dropout (RR 0.53 95% CI 0.46, 0.61) and adverse events such as weight gain, dystonia, extrapyramidal symptoms and sedation. There was no difference in the outcome of re hospitalizations, comparisons on quality of life, negative symptoms or weight gain between AP first and second generation. Continuous or standard dose regimens appear to be superior to intermittent or low doses in reducing the risk of abandonment of treatment regimes. Adult patients diagnosed with schizophrenia should receive maintenance treatment with antipsychotics. The medication of choice will depend on the management of the acute phase, the patient's tolerance to it and the presentation of adverse events. Copyright © 2014 Asociación Colombiana de Psiquiatría. Publicado por Elsevier España. All rights reserved.

Hydrocortisone accelerates the decay of iconic memory traces: on the modulation of executive and stimulus-driven constituents of sensory information maintenance.

PubMed

Miller, Robert; Weckesser, Lisa J; Smolka, Michael N; Kirschbaum, Clemens; Plessow, Franziska

2015-03-01

A substantial amount of research documents the impact of glucocorticoids on higher-order cognitive functioning. By contrast, surprisingly little is known about the susceptibility of basic sensory processes to glucocorticoid exposure given that the glucocorticoid receptor density in the human visual cortex exceeds those observed in prefrontal and most hippocampal brain regions. As executive tasks also rely on these sensory processes, the present study investigates the impact of glucocorticoid exposure on different performance parameters characterizing the maintenance and transfer of sensory information from iconic memory (IM; the sensory buffer of the visual system) to working memory (WM). Using a crossover factorial design, we administered one out of three doses of hydrocortisone (0.06, 0.12, or 0.24mg/kg bodyweight) and a placebo to 18 healthy young men. Thereafter participants performed a partial report task, which was used to assess their individual ability to process sensory information. Blood samples were concurrently drawn to determine free and total cortisol concentrations. The compiled pharmacokinetic and psychophysical data demonstrates that free cortisol specifically accelerated the decay of sensory information (r=0.46) without significantly affecting the selective information transfer from IM to WM or the capacity limit of WM. Specifically, nonparametric regression revealed a sigmoid dose-response relationship between free cortisol levels during the testing period and the IM decay rates. Our findings highlight that glucocorticoid exposure may not only impact on the recruitment of top-down control for an active maintenance of sensory information, but alter their passive (stimulus-driven) maintenance thereby changing the availability of information prior to subsequent executive processing. Copyright © 2014 Elsevier Ltd. All rights reserved.

Theoretical explanations for maintenance of behaviour change: a systematic review of behaviour theories.

PubMed

Kwasnicka, Dominika; Dombrowski, Stephan U; White, Martin; Sniehotta, Falko

2016-09-01

Behaviour change interventions are effective in supporting individuals in achieving temporary behaviour change. Behaviour change maintenance, however, is rarely attained. The aim of this review was to identify and synthesise current theoretical explanations for behaviour change maintenance to inform future research and practice. Potentially relevant theories were identified through systematic searches of electronic databases (Ovid MEDLINE, Embase, PsycINFO). In addition, an existing database of 80 theories was searched, and 25 theory experts were consulted. Theories were included if they formulated hypotheses about behaviour change maintenance. Included theories were synthesised thematically to ascertain overarching explanations for behaviour change maintenance. Initial theoretical themes were cross-validated. One hundred and seventeen behaviour theories were identified, of which 100 met the inclusion criteria. Five overarching, interconnected themes representing theoretical explanations for behaviour change maintenance emerged. Theoretical explanations of behaviour change maintenance focus on the differential nature and role of motives, self-regulation, resources (psychological and physical), habits, and environmental and social influences from initiation to maintenance. There are distinct patterns of theoretical explanations for behaviour change and for behaviour change maintenance. The findings from this review can guide the development and evaluation of interventions promoting maintenance of health behaviours and help in the development of an integrated theory of behaviour change maintenance.

Theoretical explanations for maintenance of behaviour change: a systematic review of behaviour theories

PubMed Central

Kwasnicka, Dominika; Dombrowski, Stephan U; White, Martin; Sniehotta, Falko

2016-01-01

ABSTRACT Background: Behaviour change interventions are effective in supporting individuals in achieving temporary behaviour change. Behaviour change maintenance, however, is rarely attained. The aim of this review was to identify and synthesise current theoretical explanations for behaviour change maintenance to inform future research and practice. Methods: Potentially relevant theories were identified through systematic searches of electronic databases (Ovid MEDLINE, Embase, PsycINFO). In addition, an existing database of 80 theories was searched, and 25 theory experts were consulted. Theories were included if they formulated hypotheses about behaviour change maintenance. Included theories were synthesised thematically to ascertain overarching explanations for behaviour change maintenance. Initial theoretical themes were cross-validated. Findings: One hundred and seventeen behaviour theories were identified, of which 100 met the inclusion criteria. Five overarching, interconnected themes representing theoretical explanations for behaviour change maintenance emerged. Theoretical explanations of behaviour change maintenance focus on the differential nature and role of motives, self-regulation, resources (psychological and physical), habits, and environmental and social influences from initiation to maintenance. Discussion: There are distinct patterns of theoretical explanations for behaviour change and for behaviour change maintenance. The findings from this review can guide the development and evaluation of interventions promoting maintenance of health behaviours and help in the development of an integrated theory of behaviour change maintenance. PMID:26854092

Research on Application of FMECA in Missile Equipment Maintenance Decision

NASA Astrophysics Data System (ADS)

Kun, Wang

2018-03-01

Fault mode effects and criticality analysis (FMECA) is a method widely used in engineering. Studying the application of FMEA technology in military equipment maintenance decision-making, can help us build a better equipment maintenance support system, and increase the using efficiency of weapons and equipment. Through Failure Modes, Effects and Criticality Analysis (FMECA) of equipment, known and potential failure modes and their causes are found out, and the influence on the equipment performance, operation success, personnel security are determined. Furthermore, according to the synthetical effects of the severity of effects and the failure probability, possible measures for prevention and correction are put forward. Through replacing or adjusting the corresponding parts, corresponding maintenance strategy is decided for preventive maintenance of equipment, which helps improve the equipment reliability.

Paclitaxel-induced hypothermia and hypoperfusion increase breast cancer metastasis and angiogenesis in mice

PubMed Central

Ami, Nozomi; Sato, Hideki; Hayakawa, Yoshihiro

2018-01-01

Housing temperature has been shown to influence thermoregulation and behavior of preclinical cancer models; and anti-cancer drugs typically reduce peripheral blood flow and body temperature. In the present study, the effects of paclitaxel (PTX)-induced reduction of body temperature and peripheral blood flow on metastatic 4T1 breast cancer was investigated in a mouse model and the modification of these effects by thermoneutral temperature was also assessed. A single dose of PTX decreased the body temperature and peripheral blood flow in mice housed at a standard temperature (23°C). Furthermore, although lung metastasis and angiogenesis of inoculated 4T1 cells increased in mice pretreated with PTX, mice housed at a thermoneutral temperature (30°C) could compensate their body temperature and peripheral blood flow compared with control mice, and also suppressed 4T1 angiogenesis and metastasis to lung. The present results imply that maintenance of body temperature or efficient energy supply for thermogenesis may prevent tumor relapse or metastasis after chemotherapy. PMID:29434941

Building a maintenance policy through a multi-criterion decision-making model

NASA Astrophysics Data System (ADS)

Faghihinia, Elahe; Mollaverdi, Naser

2012-08-01

A major competitive advantage of production and service systems is establishing a proper maintenance policy. Therefore, maintenance managers should make maintenance decisions that best fit their systems. Multi-criterion decision-making methods can take into account a number of aspects associated with the competitiveness factors of a system. This paper presents a multi-criterion decision-aided maintenance model with three criteria that have more influence on decision making: reliability, maintenance cost, and maintenance downtime. The Bayesian approach has been applied to confront maintenance failure data shortage. Therefore, the model seeks to make the best compromise between these three criteria and establish replacement intervals using Preference Ranking Organization Method for Enrichment Evaluation (PROMETHEE II), integrating the Bayesian approach with regard to the preference of the decision maker to the problem. Finally, using a numerical application, the model has been illustrated, and for a visual realization and an illustrative sensitivity analysis, PROMETHEE GAIA (the visual interactive module) has been used. Use of PROMETHEE II and PROMETHEE GAIA has been made with Decision Lab software. A sensitivity analysis has been made to verify the robustness of certain parameters of the model.

Benchmark Dose Software Development and Maintenance Ten Berge Cxt Models

EPA Science Inventory

This report is intended to provide an overview of beta version 1.0 of the implementation of a concentration-time (CxT) model originally programmed and provided by Wil ten Berge (referred to hereafter as the ten Berge model). The recoding and development described here represent ...

Recovery in remitted first-episode psychosis at 7 years of follow-up of an early dose reduction/discontinuation or maintenance treatment strategy: long-term follow-up of a 2-year randomized clinical trial.

PubMed

Wunderink, Lex; Nieboer, Roeline M; Wiersma, Durk; Sytema, Sjoerd; Nienhuis, Fokko J

2013-09-01

Short-term outcome studies of antipsychotic dose-reduction/discontinuation strategies in patients with remitted first-episode psychosis (FEP) showed higher relapse rates but no other disadvantages compared with maintenance treatment; however, long-term effects on recovery have not been studied before. To compare rates of recovery in patients with remitted FEP after 7 years of follow-up of a dose reduction/discontinuation (DR) vs maintenance treatment (MT) trial. Seven-year follow-up of a 2-year open randomized clinical trial comparing MT and DR. One hundred twenty-eight patients participating in the original trial were recruited from 257 patients with FEP referred from October 2001 to December 2002 to 7 mental health care services in a 3.2 million-population catchment area. Of these, 111 patients refused to participate and 18 patients did not experience remission. PARTICIPANTS After 7 years, 103 patients (80.5%) of 128 patients who were included in the original trial were located and consented to follow-up assessment. After 6 months of remission, patients were randomly assigned to DR strategy or MT for 18 months. After the trial, treatment was at the discretion of the clinician. Primary outcome was rate of recovery, defined as meeting the criteria of symptomatic and functional remission. Determinants of recovery were examined using logistic regression analysis; the treatment strategy (MT or DR) was controlled for baseline parameters. The DR patients experienced twice the recovery rate of the MT patients (40.4% vs 17.6%). Logistic regression showed an odds ratio of 3.49 (P = .01). Better DR recovery rates were related to higher functional remission rates in the DR group but were not related to symptomatic remission rates. Dose reduction/discontinuation of antipsychotics during the early stages of remitted FEP shows superior long-term recovery rates compared with the rates achieved with MT. To our knowledge, this is the first study showing long-term gains of an early-course DR strategy in patients with remitted FEP. Additional studies are necessary before these results are incorporated into general practice. isrctn.org Identifier: ISRCTN16228411.

Vitamin D in corticosteroid-naïve and corticosteroid-treated Duchenne muscular dystrophy: what dose achieves optimal 25(OH) vitamin D levels?

PubMed

Alshaikh, Nahla; Brunklaus, Andreas; Davis, Tracey; Robb, Stephanie A; Quinlivan, Ros; Munot, Pinki; Sarkozy, Anna; Muntoni, Francesco; Manzur, Adnan Y

2016-10-01

Assessment of the efficacy of vitamin D replenishment and maintenance doses required to attain optimal levels in boys with Duchenne muscular dystrophy (DMD). 25(OH)-vitamin D levels and concurrent vitamin D dosage were collected from retrospective case-note review of boys with DMD at the Dubowitz Neuromuscular Centre. Vitamin D levels were stratified as deficient at <25 nmol/L, insufficient at 25-49 nmol/L, adequate at 50-75 nmol/L and optimal at >75 nmol/L. 617 vitamin D samples were available from 197 boys (range 2-18 years)-69% from individuals on corticosteroids. Vitamin D-naïve boys (154 samples) showed deficiency in 28%, insufficiency in 42%, adequate levels in 24% and optimal levels in 6%. The vitamin D-supplemented group (463 samples) was tested while on different maintenance/replenishment doses. Three-month replenishment of daily 3000 IU (23 samples) or 6000 IU (37 samples) achieved optimal levels in 52% and 84%, respectively. 182 samples taken on 400 IU revealed deficiency in 19 (10%), insufficiency in 84 (47%), adequate levels in 67 (37%) and optimal levels in 11 (6%). 97 samples taken on 800 IU showed deficiency in 2 (2%), insufficiency in 17 (17%), adequate levels in 56 (58%) and optimal levels in 22 (23%). 81 samples were on 1000 IU and 14 samples on 1500 IU, with optimal levels in 35 (43%) and 9 (64%), respectively. No toxic level was seen (highest level 230 nmol/L). The prevalence of vitamin D deficiency and insufficiency in DMD is high. A 2-month replenishment regimen of 6000 IU and maintenance regimen of 1000-1500 IU/day was associated with optimal vitamin D levels. These data have important implications for optimising vitamin D dosing in DMD. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

A pharmacodynamic comparison of prasugrel vs. high-dose clopidogrel in patients with type 2 diabetes mellitus and coronary artery disease: results of the Optimizing anti-Platelet Therapy In diabetes MellitUS (OPTIMUS)-3 Trial

PubMed Central

Angiolillo, Dominick J.; Badimon, Juan Jose; Saucedo, Jorge F.; Frelinger, Andrew L.; Michelson, Alan D.; Jakubowski, Joseph A.; Zhu, Baojin; Ojeh, Clement K.; Baker, Brian A.; Effron, Mark B.

2011-01-01

Aims Patients with diabetes mellitus (DM) have increased platelet reactivity and reduced platelet response to clopidogrel compared with patients without DM. Prasugrel, a more potent antiplatelet agent, is associated with greater reductions in ischaemic events compared with clopidogrel, particularly in patients with DM. The aim of this study was to perform serial pharmacodynamic assessments of prasugrel with high-dose clopidogrel in patients with DM. Methods and results Optimizing anti-Platelet Therapy In diabetes MellitUS (OPTIMUS)-3 was a prospective, randomized, double-blind, crossover study in patients with type 2 DM and coronary artery disease (CAD). Patients (n= 35) were randomly assigned to either prasugrel 60 mg loading dose (LD)/10 mg maintenance dose (MD) or clopidogrel 600 mg LD/150 mg MD over two 1-week treatment periods separated by a 2-week washout period. Platelet function was assessed by VerifyNow® P2Y12 assay, light transmission aggregometry, and vasodilator-stimulated phosphoprotein phosphorylation at 0, 1, 4, and 24 h and 7 days. Greater platelet inhibition by VerifyNow® P2Y12 was achieved by prasugrel compared with clopidogrel at 4 h post-LD (least squares mean, 89.3 vs. 27.7%, P< 0.0001; primary endpoint). The difference in platelet inhibition between prasugrel and clopidogrel was significant from 1 h through 7 days (P < 0.0001). Similar results were obtained using all other platelet function measures. Prasugrel resulted in fewer poor responders at all time points irrespective of definition used. Conclusion In patients with type 2 DM and CAD, standard-dose prasugrel is associated with greater platelet inhibition and better response profiles during both the loading and maintenance periods when compared with double-dose clopidogrel. Clinical trial identifier: www.clinicaltrials.gov—NCT00642174 PMID:21252171

Pharmacogenetic testing for clopidogrel using the rapid INFINITI analyzer: a dose-escalation study.

PubMed

Gladding, Patrick; White, Harvey; Voss, Jamie; Ormiston, John; Stewart, Jim; Ruygrok, Peter; Bvaldivia, Badi; Baak, Ruth; White, Catherine; Webster, Mark

2009-11-01

Our aim was to assess whether a higher clopidogrel maintenance dose has a greater antiplatelet effect in CYP2C19*2 allele carriers compared with noncarriers. Clopidogrel is a prodrug that is biotransformed by the cytochrome P450 enzymes CYP2C19, 2C9, and 3A4, 2B6, 1A2. The CYPC219*2 loss of function variant has been associated with a reduced antiplatelet response to clopidogrel and a 3-fold risk of stent thrombosis. Forty patients on standard maintenance dosage clopidogrel (75 mg), for 9.4 +/- 9.2 weeks, were enrolled into a dose escalation study. Platelet function was assessed at baseline and after 1 week of 150 mg once daily using the VerifyNow platelet function analyzer (Accumetrics Ltd., San Diego, California). Genomic DNA was hybridized to a BioFilmChip microarray on the INFINITI analyzer (AutoGenomics Inc., Carlsbad, California) and analyzed for the CYP19*2, *4, *17, and CYP2C9*2, *3 polymorphisms. Platelet inhibition increased over 1 week, mean +8.6 +/- 13.5% (p = 0.0003). Carriers of the CYP2C19*2 allele had significantly reduced platelet inhibition at baseline (median 18%, range 0% to 72%) compared with wildtype (wt) (median 59%, range 11% to 95%, p = 0.01) and at 1 week (p = 0.03). CYP2C19*2 allele carriers had an increase in platelet inhibition of (mean +9 +/- 11%, p = 0.03) and reduction in platelet reactivity (mean -26 +/- 38 platelet response unit, p = 0.04) with a higher dose. Together CYP2C19*2 and CYP2C9*3 loss of function carriers had a greater change in platelet inhibition with 150 mg daily than wt/wt (+10.9% vs. +0.7%, p = 0.04). Increasing the dose of clopidogrel in patients with nonresponder polymorphisms can increase antiplatelet response. Personalizing clopidogrel dosing using pharmacogenomics may be an effective method of optimizing treatment.

Effects of Age and Acute Moderate Alcohol Administration on Electrophysiological Correlates of Working Memory Maintenance

PubMed Central

Boissoneault, Jeff; Frazier, Ian; Lewis, Ben; Nixon, Sara Jo

2016-01-01

Background Previous studies suggest older adults may be differentially susceptible to the acute neurobehavioral effects of moderate alcohol intake. To our knowledge, no studies have addressed acute moderate alcohol effects on the electrophysiological correlates of working memory in younger and older social drinkers. This study characterized alcohol-related effects on frontal theta (FTP) and posterior alpha power (PAP) associated with maintenance of visual information during a working memory task. Methods Older (55–70 years of age; n = 51, 29 women) and younger (25–35 years of age; n = 70, 39 women) community-dwelling moderate drinkers were recruited for this study. Participants were given either placebo or an active dose targeting breath alcohol concentrations (BrACs) of 0.04 or 0.065 g/dL. Following absorption, participants completed a visual working memory task assessing cue recognition following a 9s delay. FTP and PAP were determined via Fourier transformation and subjected to 2 (age group) X 3 (dose) X 2 (repeated: working memory task condition) mixed models analysis. Results In addition to expected age-related reductions in PAP, a significant age group X dose interaction was detected for PAP such that 0.04 g/dL dose level was associated with greater PAP in younger adults but lower PAP in their older counterparts. PAP was lower in older vs younger adults at both active doses. Further mixed models revealed a significant negative association between PAP and working memory efficiency for older adults. No effects of age, dose, or their interaction were noted for FTP. Conclusions Results bolster the small but growing body of evidence that older adults exhibit differential sensitivity to the neurobehavioral effects of moderate alcohol use. Given the theoretical role of PAP in attentional and working memory function, these findings shed light on the attentional mechanisms underlying effects of acute moderate alcohol on working memory efficiency in older adults. PMID:27419803

Traditional Chinese medicine versus western medicine as used in China in the management of rheumatoid arthritis: a randomized, single-blind, 24-week study.

PubMed

He, Yi-Ting; Ou, Ai-Hua; Yang, Xiao-Bo; Chen, Wei; Fu, Li-Yuan; Lu, Ai-Ping; Yan, Xiao-Ping; Feng, Xing-Hua; Su, Li; Song, Yue-Jin; Zeng, Sheng-Ping; Liu, Wei; Qian, Xian; Zhu, Wan-Hua; Lao, Ying-Rong; Xu, Wei-Hua; Wen, Ze-Huai; He, Xiao-Hong; Wang, Bao-Juan; Chen, Geng-Xin; Xue, Su-Qin

2014-12-01

This study is designed to compare the efficacy and safety of traditional Chinese medicine (TCM) with western medicine (WM) in the management of rheumatoid arthritis (RA). This is a 24-week, randomized, multicenter, single-blind study comparing TCM with WM (as used in China) carried out between June 2002 and December 2004 in nine research centers in China, involving 489 patients. Patients were randomized to receive TCM (n = 247), MTX and SSZ (n = 242). MTX was started at a dose of 5 mg to a final dose of 7.5-15 mg weekly. The maintenance dose was 2.5-7.5 mg weekly. The starting dose of SSZ was 0.25 g bid, increasing by 0.25 g a day once a week to a final dose of 0.5-1 g qid. The maintenance dose was 0.5 g tid to qid. Primary end point was the proportion of patients with response according to the American College of Rheumatology 20 % improvement criteria (ACR20) at weeks 24. At 24 weeks, ACR20 responses were 53.0 % in TCM group and 66.5 % in WM group, (P < 0.001) at 24 weeks. ACR 50 responses were 31.6 % of TCM group and 42.6 % in WM group, (P = 0.01). ACR70 responses were 12.6 % in TCM group and 17.4 % in WM group, (P = 0.14). Side effects were observed more frequently in WM group. In this study, ACR20, ACR50 responses at 24 weeks were significantly better in the WM treated group, by intention to treat (ITT) and per protocol analysis. The ACR 70 response showed no significant difference between the two groups. TCM, while effective in treating RA, appears to be less effective than WM in controlling symptoms, but TCM is associated with fewer side effects.

Analysis of activation and shutdown contact dose rate for EAST neutral beam port

NASA Astrophysics Data System (ADS)

Chen, Yuqing; Wang, Ji; Zhong, Guoqiang; Li, Jun; Wang, Jinfang; Xie, Yahong; Wu, Bin; Hu, Chundong

2017-12-01

For the safe operation and maintenance of neutral beam injector (NBI), specific activity and shutdown contact dose rate of the sample material SS316 are estimated around the experimental advanced superconducting tokamak (EAST) neutral beam port. Firstly, the neutron emission intensity is calculated by TRANSP code while the neutral beam is co-injected to EAST. Secondly, the neutron activation and shutdown contact dose rates for the neutral beam sample materials SS316 are derived by the Monte Carlo code MCNP and the inventory code FISPACT-2007. The simulations indicate that the primary radioactive nuclides of SS316 are 58Co and 54Mn. The peak contact dose rate is 8.52 × 10-6 Sv/h after EAST shutdown one second. That is under the International Thermonuclear Experimental Reactor (ITER) design values 1 × 10-5 Sv/h.

Update on risk stratification and treatment of newly diagnosed multiple myeloma.

PubMed

Kapoor, Prashant; Rajkumar, S Vincent

2011-10-01

Multiple myeloma is the second most common hematologic malignancy. Chromosomal aberrations are important prognostic determinants that influence the clinical decision-making in newly-diagnosed multiple myeloma (NDMM). Patients are considered high-risk if any of the following features are detected: hypodiploidy, deletion 13 by cytogenetics, t(4;14), t(14;16), t(14;20) and/or 17 p deletion. In the absence of these features patients are considered standard risk. Outside of trials, risk-adapted therapy in the transplant-eligible high-risk patients advocates use of bortezomib-based induction therapy followed by autologous stem cell transplantation (ASCT) and bortezomib-based maintenance therapy. High-risk, transplant-ineligible patients should also utilize bortezomib as initial therapy since it is known to overcome the poor prognosis associated with some high-risk features. The goal of therapy in high-risk patients is to attain and maintain a state of complete remission as much as possible. In contrast, the standard-risk, transplant-eligible patients may be treated with either lenalidomide-dexamethasone or bortezomib-based therapy followed by ASCT. In such patients, ASCT can also be deferred until first relapse if the patients are tolerating initial therapy well. Lenalidomide maintenance therapy in the post-transplant setting in standard-risk patients is controversial and not recommended routinely. For transplant-ineligible standard-risk patients, multiple options exist, although in the absence direct comparisons, we prefer lenalidomide plus low-dose dexamethasone over melphalan-based combinations. This review outlines evidence-based management approaches in NDMM, with a focus on risk-adapted therapy.

Maintenance of Smoking Cessation: Effect of Follow-Up Letters, Smoking Motivation, Muscle Tension, and Health Locus of Control.

ERIC Educational Resources Information Center

Shipley, Robert H.

1981-01-01

Following smoking-cessation treatment, half of 44 subjects were sent supportive maintenance letters. Letters produced no main effect but reduced smoking in subjects who smoked from habit or received little pleasure from smoking. Letters increased smoking among opposite subject groups and those believing powerful others could not influence their…

Using Focus Groups to Identify Factors Affecting Healthful Weight Maintenance in Latino Immigrants

ERIC Educational Resources Information Center

Greaney, Mary L.; Lees, Faith D.; Lynch, Breanna; Sebelia, Linda; Greene, Geoffrey W.

2012-01-01

Objective: To explore (1) how migration influenced physical activity and dietary behaviors among Latino immigrants and (2) participants' perception of concepts related to a Health at Every Size (HAES) approach to weight maintenance (mindful eating, taking care of oneself). Methods: Four focus groups (n = 35), homogenous by sex, were conducted in…

EFFECTS OF WEST NILE VIRUS DOSE AND EXTRINSIC INCUBATION TEMPERATURE ON TEMPORAL PROGRESSION OF VECTOR COMPETENCE IN CULEX PIPIENS QUINQUEFASCIATUS

PubMed Central

ANDERSON, SHERI L.; RICHARDS, STEPHANIE L.; TABACHNICK, WALTER J.; SMARTT, CHELSEA T.

2010-01-01

Culex pipiens quinquefasciatus were fed blood containing either 7.0 ± 0.1 logs plaque-forming units (pfu)/ml (high dose) or 5.9 ± 0.1 logs pfu/ml (low dose) of West Nile virus and held at extrinsic incubation temperatures (EIT) of 28°C or 25°C. Approximately 20 mosquitoes per dose were collected after incubation periods (IP) of 4, 6, 8, and 12 days postinfection (dpi). Infection rates were influenced by EIT and virus dose but not by IP. Body titer was significantly higher for mosquitoes fed the high dose and held at 28°C at the later IPs (6, 8, and 12 dpi). However, leg titer was significantly higher for mosquitoes at the later IPs but did not differ between EITs or doses. Because infection rates varied with EIT and dose, there is likely a midgut infection barrier influenced by these factors that is not influenced by IP. Dissemination rates were influenced by all 3 factors consistent with the presence of a midgut escape barrier. Dissemination rate, body titer, and leg titer were dependent on IP, indicating the need to investigate multiple time points in vector competence studies to elucidate critical events in infection and dissemination. PMID:20402358

Effects of West Nile virus dose and extrinsic incubation temperature on temporal progression of vector competence in Culex pipiens quinquefasciatus.

PubMed

Anderson, Sheri L; Richards, Stephanie L; Tabachnick, Walter J; Smartt, Chelsea T

2010-03-01

Culex pipiens quinquefasciatus were fed blood containing either 7.0 +/- 0.1 logs plaque-forming units (pfu)/ml (high dose) or 5.9 +/- 0.1 logs pfu/ml (low dose) of West Nile virus and held at extrinsic incubation temperatures (EIT) of 28 degrees C or 25 degrees C. Approximately 20 mosquitoes per dose were collected after incubation periods (IP) of 4, 6, 8, and 12 days postinfection (dpi). Infection rates were influenced by EIT and virus dose but not by IP. Body titer was significantly higher for mosquitoes fed the high dose and held at 28 degrees C at the later IPs (6, 8, and 12 dpi). However, leg titer was significantly higher for mosquitoes at the later IPs but did not differ between EITs or doses. Because infection rates varied with EIT and dose, there is likely a midgut infection barrier influenced by these factors that is not influenced by IP. Dissemination rates were influenced by all 3 factors consistent with the presence of a midgut escape barrier. Dissemination rate, body titer, and leg titer were dependent on IP, indicating the need to investigate multiple time points in vector competence studies to elucidate critical events in infection and dissemination.

The effects of interferon-alpha/beta in a model of rat heart transplantation

NASA Technical Reports Server (NTRS)

Slater, A. D.; Klein, J. B.; Sonnenfeld, G.; Ogden, L. L. 2nd; Gray, L. A. Jr

1992-01-01

Interferons have multiple immunologic effects. One such effect is the activation of expression of cell surface antigens. Interferon alpha/beta enhance expression of class I but not class II histocompatibility antigens. Contradictory information has been published regarding the effect of interferon-alpha/beta administration in patients with kidney transplantation. In a model of rat heart transplantation we demonstrated that administration of interferon-alpha/beta accelerated rejection in a dose-dependent fashion in the absence of maintenance cyclosporine. Animals treated with maintenance cyclosporine had evidence of increased rejection at 20 days that was resolved completely at 45 days with cyclosporine alone.

A TAD better for myeloma therapy?

PubMed

Giralt, Sergio

2010-02-11

In this issue of Blood, Lokhorst and colleagues report on the results of HOVON-50, a phase 3 randomized trial designed to evaluate the effects of thalidomide during induction treatment and as maintenance in patients with multiple myeloma. There were 556 patients randomly assigned either to 3 cycles of VAD or to TAD. All patients were to receive high-dose melphalan with autologous stem cell support followed by maintenance with interferon for the VAD arm or thalidomide for the TAD arm.(1) This study together with other randomized and nonrandomized trials establish a definitive role for thalidomide as induction therapy in conjunction with dexamethasone, anthracyclines, and alkylating agents.

Rechallenging With Intrathecal Methotrexate After Developing Subacute Neurotoxicity in Children With Hematologic Malignancies.

PubMed

Badke, Colleen; Fleming, Amy; Iqbal, Asneha; Khilji, Ohmed; Parhas, Sophia; Weinstein, Joanna; Morgan, Elaine; Hijiya, Nobuko

2016-04-01

Methotrexate is associated with neurologic side effects. It is recommended that patients who developed neurotoxicity be rechallenged with methotrexate, but little is known about the safety of this approach. We performed a chart review to identify patients who received high-dose or intrathecal (IT) methotrexate. Twenty-one of 298 patients (7%) experienced neurologic symptoms attributed to methotrexate treatment in the premaintenance phase. Seventeen of these patients were rechallenged with IT methotrexate and 13 (76%) had no further neurotoxic events. No patients rechallenged during maintenance (n = 9) experienced recurrence of neurotoxic events. It is safe to rechallenge with IT methotrexate in maintenance. © 2015 Wiley Periodicals, Inc.

Role of the vestibular nuclei in endothelin-1-induced barrel rotation in rats.

PubMed

Kozako, Tomohiro; Kawachi, Akio; Cheng, Shi-Bin; Kuchiiwa, Satoshi; Motoya, Toshiro; Nakagawa, Shiro; Yamada, Katsushi

2002-11-15

The fourth or lateral ventricular injection of endothelin-1 resulted in a dose-dependent increase in the barrel rotation and produced marked induction of c-Fos-positive cells in the vestibular nuclei. The doses of the former injection were lower and had shorter mean latent periods compared with the later injection. c-Fos expression after endothelin-1 injection was prevented by the pretreatment with the endothelin ET(A) receptor antagonist, cyclo(D-alpha-aspartyl-L-propyl-D-valyl-L-leucyl-D-tryptophyl) (BQ-123), the glutamate NMDA receptor antagonist, dizocilpine maleate (MK-801), or the L-type Ca(2+) channel antagonist, verapamil, in addition to the incidence of the rotational behavior. There was a significant difference in c-Fos expression between the right and left medial vestibular nuclei, and the number of c-Fos-labeled neurons in the medial vestibular nucleus was markedly increased on the opposite side of the rotational direction. These results suggest that the elicitation of the barrel rotation may be mediated by endothelin ET(A) receptors, glutamate NMDA receptors, and L-type Ca(2+) channels. The changes in the receptor and channel systems induced by endothelin-1 injections appeared to exert crucial influences on the vestibular nuclei and then on the maintenance of equilibrium. The direction of the barrel rotation has a deep connection with the imbalance of neuronal activity in the left and right medial vestibular nuclei.

Bevacizumab-induced chronic interstitial pneumonia during maintenance therapy in non-small cell lung cancer.

PubMed

Sekimoto, Yasuhito; Kato, Motoyasu; Shukuya, Takehiko; Koyama, Ryo; Nagaoka, Tetsutaro; Takahashi, Kazuhisa

2016-04-01

Bevacizumab is a monoclonal antibody targeting the vascular endothelial growth factor receptor and a key drug for advanced non-small cell lung cancer. There are few reports describing bevacizumab-induced chronic interstitial pneumonia. A 62-year-old man with advanced non-small cell lung cancer was admitted to our hospital with dyspnea. He previously received four courses of carboplatin plus paclitaxel with bevacizumab combination therapy and thereafter received four courses of maintenance bevacizumab monotherapy. A chest-computed tomography scan on admission revealed diffuse ground glass opacity. He had not received any other drugs and did not have pneumonia. Thus, he was diagnosed with bevacizumab-induced chronic interstitial pneumonia and was treated with a high dose of corticosteroids. After steroid treatment, his dyspnea and radiological findings improved. This case report is the first description of bevacizumab-induced chronic interstitial pneumonia during maintenance therapy in a patient with non-small cell lung cancer.

Comparison of Adrenal Suppression between Etomidate and Dexmedetomidine in Children with Congenital Heart Disease.

PubMed

Gu, Hongbin; Zhang, Mazhong; Cai, Meihua; Liu, Jinfen

2015-05-29

The aim of this study was to compare plasma cortisol concentration during anesthesia of children with congenital heart disease who received dexmedetomidine (DEX) with those who received etomidate (ETO). We recruited 99 ASA physical status II-III pediatric patients scheduled for congenital heart disease (CHD) corrective surgery and divided into them into 3 groups. Group DEX received an infusion of DEX intravenously with a bolus dose of 0.5 µg·kg-1 within 10 min during anesthesia induction, followed by a maintenance dose of DEX 0.5 µg·kg-1·h-1. Group ETO received ETO intravenously with a bolus dose of 0.3 mg·kg-1 without a maintenance dose. Group CON received routine anesthetics as controls. The preset timepoints were: before anesthesia induction (T0), at the end of induction (T1), 30 min after anesthesia induction (T2), at the time of aortic and inferior vena catheterization (T3), and at 180 min (T4) and 24 h (T5) after anesthesia induction. The cortisol concentration decreased gradually after anesthesia induction in all groups, and returned to baseline values after 24 h. The cortisol concentration was significantly lower in Group ETO children than in Group DEX or group CON at T4. The plasma concentrations of cortisol decreased in CHD children after the operation, but returned to baseline after 24 h of anesthesia induction. The adrenal cortex function inhibition induced by ETO in CHD children is longer and more serious than that induced by DEX (if any) during the preoperative period.

Implementing methadone maintenance treatment in prisons in Malaysia

PubMed Central

Wickersham, Jeffrey A; Marcus, Ruthanne; Kamarulzaman, Adeeba; Zahari, Muhammad Muhsin

2013-01-01

Abstract Problem In Malaysia, human immunodeficiency virus (HIV) infection is highly concentrated among people who inject opioids. For this reason, the country undertook a three-phase roll-out of a methadone maintenance treatment (MMT) programme. In Phase 3, described in this paper, MMT was implemented within prisons and retention in care was assessed. Approach After developing standard operating procedures and agreement between its Prisons Department and Ministry of Health, Malaysia established pilot MMT programmes in two prisons in the states of Kelantan (2008) and Selangor (2009) – those with the highest proportions of HIV-infected prisoners. Community-based MMT programmes were also established in Malaysia to integrate treatment activities after prisoners’ release. Local setting Having failed to reduce the incidence of HIV infection, in 2005 Malaysia embarked on a harm reduction strategy. Relevant changes Standard operating procedures were modified to: (i) escalate the dose of methadone more slowly; (ii) provide ongoing education and training for medical and correctional staff and inmates; (iii) increase the duration of methadone treatment before releasing prisoners; (iv) reinforce linkages with community MMT programmes after prisoners’ release; (v) screen for and treat tuberculosis; (vi) escalate the dose of methadone during treatment for HIV infection and tuberculosis; and (vii) optimize the daily oral dose of methadone (> 80 mg) before releasing prisoners. Lessons learnt Prison-based MMT programmes can be effectively implemented but require adequate dosing and measures are needed to improve communication between prison and police authorities, prevent police harassment of MMT clients after their release, and improve systems for tracking release dates. PMID:23554524

Maintenance fluid therapy in a tertiary hospital: A prevalence study.

PubMed

Uña Orejón, R; Gisbert de la Cuadra, L; Garríguez Pérez, D; Díez Sebastián, J; Ureta Tolsada, M P

To assess the types of maintenance fluids used in our hospital, comparing their volume and composition to the standards recommended by the guidelines. Observational, cross-sectional study. Volume and type of fluid therapy administered during 24h to patients admitted to various hospital departments were recorded. Patients receiving fluid therapy because of water-electrolyte imbalance were excluded. Out of 198 patients registered, 74 (37.4%) were excluded because they did not meet the criteria for inclusion. Mean administered volume was 2,500cc/day. Mean daily glucose dose was 36g per 24h (SD: 31.4). The most frequent combination included normal saline solution (NSS) and glucose 5% (64.4%). Mean daily dose of sodium and chlorine was, respectively, 173mEq (SD: 74.8) and 168mEq (SD: 75), representing a surplus daily dose of +87.4mEq and +85mEq. Potassium, magnesium and calcium daily deficit was, respectively, -50mEq, -22mEq and -21mEq per day. Buffer administration was exceptional, bicarbonate (2.29%), acetate (1.29%), lactate (1.15%) and gluconate (1.10%) being the buffering agents most frequently used. NNS is the most frequently used solution. In contrast to excess doses of sodium and chlorine, there is a great deficit of other ions, buffering agents and caloric intake in the fluid therapy regimens that are usually prescribed. Copyright © 2017 Sociedad Española de Anestesiología, Reanimación y Terapéutica del Dolor. Publicado por Elsevier España, S.L.U. All rights reserved.

[Neuromuscular blocking effects of Org 9426 (rocuronium bromide); a comparative study with vecuronium bromide in Japanese patients].

PubMed

Shingu, Koh; Masuzawa, Munehiro; Omote, Keiichi; Namiki, Akiyoshi; Kikuchi, Hirosato; Kawamada, Miwako; Sato, Shigehito; Kimura, Tomomasa; Hatano, Norio; Nakatsuka, Hideki; Morita, Kiyoshi; Hara, Tetsuya; Kanmura, Yuichi; Takeda, Junzo

2006-09-01

Efficacy and safety of Org 9426 were compared with those of vecuronium bromide in Japanese patients. We studied 88 Japanese patients undergoing surgery requiring general anesthesia. Patients were allocated randomly to receive intubation dose of 0.6 mg x kg(-1), 0.9 mg x kg(-1) of Org 9426 or 0.1mg x kg(-1) of vecuronium. Following an intubation dose, patients received maintenance doses of 0.1, 0.15 or 0.2 mg x kg(-1) of Org 9426 or 0.025 mg x kg(-1) of vecuronium. The neuromuscular block was monitored with acceleromyography using TOF stimuli. Sevoflurane was administered to all treatment groups after intubation. The onset times of the 0.6 and 0.9 mg x kg(-1) of Org 9426 groups were 84.6 and 77.1 sec respectively, which showed statistical difference between the onset time of 0.1 mg x kg(-1) of vecuronium, 125.7 sec. The intubation condition was similar among three treatment groups. The clinical durations of 0.6 and 0.9 mg x kg(-1) of Org 9426 and 0.1 mg x kg(-1) of vecuronium were 53.4, 73.4 and 59.9 min, respectively. Clinical duration and spontaneous recovery time of maintenance dose of 0.15 mg x kg(-1) of Org 9426 were similar to those of 0.025 mg x kg(-1) of vecuronium. Org 9426 showed more rapid onset time than that of vecuronium and similar clinical duration and recovery times to those of vecuronium in Japanese patients.

Experimental evidence for frequency dependent self-fertilization in the gynodioecious plant, Silene vulgaris.

PubMed

Miyake, Keiko; Olson, Matthew S

2009-06-01

After over a half century of empirical and theoretical research regarding the evolution and maintenance of gynodioecy in plants, unexplored factors influencing the relative fitnesses of females and hermaphrodites remain. Theoretical studies suggest that hermaphrodite self-fertilization (selfing) rate influences the maintenance of gynodioecy and we hypothesized that population sex ratio may influence hermaphrodite selfing rate. An experimental test for frequency-dependent self-fertilization was conducted using replicated populations constructed with different sex ratios of the gynodioecious plant Silene vulgaris. We found that hermaphrodite selfing increased with decreased hermaphrodite frequency, whereas evidence for increased inbreeding depression was equivocal. We argue that incorporation of context dependent inbreeding into future models of the evolution of gynodioecy is likely to yield novel insights into sex ratio evolution.

Long-term safety and efficacy of rotigotine transdermal patch for moderate-to-severe idiopathic restless legs syndrome: a 5-year open-label extension study.

PubMed

Oertel, Wolfgang; Trenkwalder, Claudia; Beneš, Heike; Ferini-Strambi, Luigi; Högl, Birgit; Poewe, Werner; Stiasny-Kolster, Karin; Fichtner, Andreas; Schollmayer, Erwin; Kohnen, Ralf; García-Borreguero, Diego

2011-08-01

Safety and efficacy of non-ergot dopamine agonists for the treatment of idiopathic restless legs syndrome have been shown in short-term trials. We did a prospective open-label extension of a 6-week, double-blind randomised trial to assess the safety, tolerability, and efficacy of rotigotine transdermal patch for up to 5 years in patients with restless legs syndrome. Patients (aged 18-75 years) with moderate-to-severe idiopathic restless legs syndrome were treated with once-daily rotigotine transdermal patch in 33 centres in Austria, Germany, and Spain between July 31, 2003, and April 15, 2009. The dose was titrated in weekly increments (up to 4 weeks) from 0·5 mg/24 h to a maximum of 4 mg/24 h, and was followed by up to 5 years of maintenance at the optimum dose. Primary safety outcomes included occurrence of adverse events and dropouts. Efficacy assessments were secondary and included the International Restless Legs Syndrome study group severity rating scale (IRLS). Augmentation of symptoms was assessed by means of standard diagnostic criteria and was confirmed by an international expert panel. All patients who received at least one dose of study drug were included in assessments. This study is registered with ClinicalTrials.gov, number NCT00498186. 295 patients entered the open-label study, of whom 126 (43%) completed 5 years of follow-up. 169 (57%) patients discontinued treatment, 89 (30%) because of adverse events and 31 (11%) because of lack of efficacy. 70 patients (24%) discontinued during year 1 of maintenance. The most common adverse events were application site reactions, which occurred in 37% (106/290) of patients in year 1, 17% (38/220) of patients in year 2, 14% (27/191) of patients in year 3, and in less than 6% of patients during year 4 (8/159) and year 5 (8/147). 56 patients (19%) discontinued because of application site reactions. Mean rotigotine dose was 2·43 mg/24 h (SD 1·21) after initial titration and 3·09 mg/24 h (1·07) at the end of maintenance. Of 89 patients who discontinued because of adverse events, 28 (31%) were on 4 mg/24 h rotigotine. Mean IRLS score of patients entering the open-label study was 27·8 (SD 5·9) at baseline of the double-blind trial. In patients who completed the maintenance period, mean IRLS score was reduced from a baseline score of 27·7 (SD 6·0) by a mean of 18·7 points (SD 9·5) to a score of 9·0 (SD 9·2) at the end of maintenance. 39% (48/123) of patients who completed the trial were classified as symptom free according to the IRLS. Clinically significant augmentation was recorded in 39 patients (13%), of whom 15 (5%) were receiving a dose of rotigotine within the range approved by the European Medicines Agency (EMA; 1-3 mg/24 h) and 24 (8%) were receiving 4 mg/24 h rotigotine. Rotigotine transdermal patch is generally well tolerated after 1 year and provides sustained efficacy for patients with moderate-to-severe restless legs syndrome at a stable dose for up to 5 years. Thus, rotigotine transdermal patch is an appropriate long-term treatment option for moderate-to-severe restless legs syndrome, a disorder that often requires lifelong treatment. UCB BioSciences, on behalf of Schwarz Pharma, Ireland. Copyright © 2011 Elsevier Ltd. All rights reserved.

Caffeine's Influence on Nicotine's Effects in Nonsmokers

PubMed Central

Blank, Melissa D.; Kleykamp, Bethea A.; Jennings, Janine M.; Eissenberg, Thomas

2011-01-01

Objective To determine if nicotine's effects are influenced by caffeine in nonsmoking, moderate-caffeine consuming individuals (N=20). Methods The first 3 sessions included one of 3 randomly ordered, double-blind caffeine doses (0, 75, or 150 mg, oral [po]) and 2 single-blind nicotine gum doses (2 and 4 mg) in ascending order. The fourth session (single blind) repeated the 0 mg caffeine condition. Results Nicotine increased heart rate and subjective ratings indicative of aversive effects, and decreased reaction times. These effects were independent of caffeine dose and reliable across sessions. Conclusions In nonsmokers, nicotine effects are not influenced by moderate caffeine doses. PMID:17555378

Degarelix: a gonadotropin-releasing hormone antagonist for the management of prostate cancer.

PubMed

Steinberg, Michael

2009-01-01

Prostate cancer is the most commonly diagnosed cancer among men. Treatment can include surgery, radiation, chemotherapy, or hormonal manipulation. Gonadotropin-releasing hormone (GnRH) analogues are used to manage prostate cancer by desensitizing the stimulus to synthesize and release gonadotropins, such as luteinizing hormone (LH), which stimulate the synthesis and release of androgens, in turn stimulating the growth of prostate cancer cells. Although effective, these agents have limitations, such as a flare-up of cancer symptoms within the first 2 weeks of starting the drug. This article reviews the pharmacology, pharmacokinetic and pharmacodynamic characteristics, and clinical data available on the newly approved drug degarelix for use in treating prostate cancer. A search of the medical literature was performed in January 2009 with the databases MEDLINE and EMBASE (1950-present) and International Pharmaceutical Abstracts (1970-November 2008) using the terms degarelix and FE200486; follow-up searches using the same strategy were conducted in May 2009 and August 2009. Additional sources were identified by scanning available references and online journals and textbooks. GnRH antagonists, such as degarelix, offer clinicians another means to reduce the level of circulating androgens and limit this growth stimulus directed at malignant prostate tissue. Degarelix has been shown in animal studies to antagonize GnRH receptors in the pituitary gland, resulting in a significant reduction in circulating LH and a subsequent decrease in the synthesis of testosterone. Pharmacokinetic analysis suggests that upon subcutaneous administration, degarelix forms a gel depot, from which the drug then distributes to the rest of the body in a first-order manner. A Phase II study of the effect of degarelix in 187 men with prostate cancer found a loading dose of 240 mg to be not significantly better than 200 mg in reducing serum testosterone concentrations to < or =0.5 ng/mL within 3 days of dosing (200 mg, 88%; 240 mg, 92%). This difference in percentage of patients with testosterone suppression became statistically significant when measured again 1 month into the study (200 mg, 86%; 240 mg, 95%; P = 0.048). Evaluation of 80-, 120-, and 160-mg maintenance doses found all doses effective in maintaining suppression of testosterone, LH, and prostate-specific antigen (PSA); only minor differences were observed during the study period. In a Phase III study of 610 patients with prostate cancer, a loading dose of degarelix 240 mg SC followed by monthly maintenance doses of either 80 or 160 mg was compared with monthly doses of leuprolide 7.5 mg IM. Degarelix was found to be at least as effective as leuprolide in the ability to suppress serum testosterone to < or =0.5 ng/mL for up to 1 year (degarelix response rate, 80 mg, 97.2%; 95% CI, 93.5%-98.8%; degarelix 160 mg, 98.3%; 95% CI, 94.8%-99.4%; leuprolide response rate, 96.4%; 95% CI, 92.5%-98.2%). Other studies investigating various doses and schedules of degarelix have also been conducted. Adverse effects of degarelix in clinical trials were mild and relatively uncommon and included flushing reactions, injection-site pain, weight gain, and increases in serum transaminase levels. Degarelix offers another option for chemical castration to reduce the androgenic growth stimulus on prostate cancer cells. The manufacturer of degarelix recommends a loading dose of 240 mg SC followed by the first monthly maintenance dose of 80 mg 28 days later. Serum testosterone and PSA concentrations must be obtained to monitor the response during treatment with degarelix. Copyright 2009 Excerpta Medica Inc. All rights reserved.

A randomized controlled trial of interim methadone maintenance.

PubMed

Schwartz, Robert P; Highfield, David A; Jaffe, Jerome H; Brady, Joseph V; Butler, Carol B; Rouse, Charles O; Callaman, Jason M; O'Grady, Kevin E; Battjes, Robert J

2006-01-01

Effective alternatives to long waiting lists for entry into methadone hydrochloride maintenance treatment are needed to reduce the complications of continuing heroin dependence and to increase methadone treatment entry. To compare the effectiveness of interim methadone maintenance with that of the usual waiting list condition in facilitating methadone treatment entry and reducing heroin and cocaine use and criminal behavior. Randomized, controlled, clinical trial using 2 conditions, with treatment assignment on a 3:2 basis to interim maintenance-waiting list control. A methadone treatment program in Baltimore. A total of 319 individuals meeting the criteria for current heroin dependence and methadone maintenance treatment. Participants were randomly assigned to either interim methadone maintenance, consisting of an individually determined methadone dose and emergency counseling only for up to 120 days, or referral to community-based methadone treatment programs. Entry into comprehensive methadone maintenance therapy at 4 months from baseline; self-reported days of heroin use, cocaine use, and criminal behavior; and number of urine drug test results positive for heroin and cocaine at the follow-up interview conducted at time of entry into comprehensive methadone treatment (or at 4 months from baseline for participants who did not enter regular treatment). Significantly more participants assigned to the interim methadone maintenance condition entered comprehensive methadone maintenance treatment by the 120th day from baseline (75.9%) than those assigned to the waiting list control condition (20.8%) (P<.001). Overall, in the past 30 days at follow-up, interim participants reported significantly fewer days of heroin use (P<.001), had a significant reduction in heroin-positive drug test results (P<.001), reported spending less money on drugs (P<.001), and received less illegal income (P<.02) than the waiting list participants. Interim methadone maintenance results in a substantial increase in the likelihood of entry into comprehensive treatment, and is an effective means of reducing heroin use and criminal behavior among opioid-dependent individuals awaiting entry into a comprehensive methadone treatment program.

Using Acceptance and Commitment Therapy during Methadone Dose Reduction: Rationale, Treatment Description, and a Case Report

ERIC Educational Resources Information Center

Stotts, Angela L.; Masuda, Akihiko; Wilson, Kelly

2009-01-01

Many clients who undergo methadone maintenance (MM) treatment for heroin and other opiate dependence prefer abstinence from methadone. Attempts at methadone detoxification are often unsuccessful, however, due to distressing physical as well as psychological symptoms. Outcomes from an MM client who voluntarily participated in an Acceptance and…

Influence of handpiece maintenance sprays on resin bonding to dentin.

PubMed

Sugawara, Toyotarou; Kameyama, Atsushi; Haruyama, Akiko; Oishi, Takumi; Kukidome, Nobuyuki; Takase, Yasuaki; Tsunoda, Masatake

2010-01-01

To investigate the influence of maintenance spray on resin bonding to dentin. The crown of extracted, caries-free human molars was transversally sectioned with a model trimmer to prepare the dentin surfaces from mid-coronal sound dentin, and then uniformly abraded with #600 silicon carbide paper. The dentin surfaces were randomly divided into three groups: oil-free spray group where maintenance cleaner for air bearing handpieces was sprayed onto the dentin surface for 1 s and rinsed with water spray for 30 s; oil-containing spray group where maintenance cleaner for micro motor handpieces was sprayed onto the dentin surface for 1 s and rinsed with water spray for 30 s; and control group where the surface was rinsed with water spray for 30 s and then air-dried. These surfaces were then bonded with Clearfil SE Bond (Kuraray Medical), and resin composite (Clearfil AP-X, Kuraray Medical) build-up crowns were incrementally constructed on the bonded surfaces. After storage for 24 h in 37°C water, the bonded teeth were sectioned into hour-glass shaped slices (0.7-mm thick) perpendicular to the bonded surfaces. The specimens were then subjected to microtensile bond strength (μTBS) testing at a crosshead speed of 1.0 mm/min. Data were analyzed with one-way ANOVA and the Tukey-Kramer test. Maintenance spray-contaminated specimens (oil-free and oil-containing spray groups) showed significantly lower μTBS than control specimens (P < 0.05). However, there was no significant difference between the spray-contaminated groups (P > 0.05). Maintenance spray significantly reduces the bond strength of Clearfil SE Bond to dentin.

The effect of a jail methadone maintenance therapy (MMT) program on inmate recidivism.

PubMed

McMillan, Garnett P; Lapham, Sandra; Lackey, Michael

2008-12-01

To evaluate the effects of a jail-based continuation of methadone maintenance therapy (MMT) on subsequent inmate recidivism risks. Prospective, longitudinal, observational study. A large, Southwestern United States jail that continues MMT for heroin-addicted inmates on MMT at the time of booking. A total of 589 inmates booked between 22 November 2005 (the start date for the MMT program) and 31 October 2006. The outcome measure was time from release to subsequent re-booking in the jail. Predictors included binary dosing with methadone in the jail, final dose received (mg), age, gender, race/ethnicity, previous bookings and days in jail. Random effects Weibull proportional hazards models were fit to the recidivism times to estimate the impact of treatment with MMT in the jail on re-booking risks. There was no statistically significant effect of receiving methadone in the jail or dosage on subsequent recidivism risks (hazard ratio = 1.16; 95% confidence interval = 0.8-1.68). Offering jail-based MMT does not increase recidivism risks by eliminating the deterrent effect of imposed withdrawal, nor does it reduce recidivism in this high-risk population.

IgPro20, the Polyneuropathy and Treatment with Hizentra® study (PATH), and the treatment of chronic inflammatory demyelinating polyradiculoneuropathy with subcutaneous IgG.

PubMed

Berger, Melvin; Harbo, Thomas; Cornblath, David R; Mielke, Orell

2018-05-16

Subcutaneous IgG (SCIG) administration may be preferred over the intravenous route (IVIG) in chronic inflammatory demyelinating polyneuropathy (CIDP) because it minimizes 'end of cycle' treatment-related fluctuations, reduces systemic adverse effects, improves convenience/quality of life and potentially lowers overall costs. Early reports of the use of highly concentrated SCIG preparations suggested they were effective and well-tolerated in chronic inflammatory demyelinating polyneuropathy. This was confirmed in the Polyneuropathy and Treatment with Hizentra ® study of 172 subjects randomized to receive maintenance therapy with placebo or one of two doses of IgPro20 (20% IgG stabilized with L-Proline) for 6 months. Risk of relapse was reduced by SCIG in a dose-related manner as compared with placebo. A total of 88% of polyneuropathy and treatment with hizentra subjects felt the subcutaneous method was 'easy to learn'. Local adverse events were mostly mild or moderate, and systemic adverse events were infrequent. Some patients may prefer maintenance therapy with SCIG over IVIG.

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

Lenie, Koen; Mulier, Guido; Vandorpe, Marc

Safe decontamination is a regular requirement in the lifecycle of a nuclear plant and is integral to the careful maintenance of any nuclear installation for 4 key reasons: - To decrease the risk of radioactive contamination spreading; - To limit the radioactive doses contracted by maintenance personnel; - To limit the radioactive doses incurred during decommissioning; - To downgrade the class of radioactive waste The primary goal of decommissioning is to remove aged and/or contaminated and/or activated components of an installation, safely and securely, in as short a time as possible. There are several reasons why this may be necessary:more » - To eliminate the risk of radioactive contamination spreading; - To eliminate the risk of radiation; - To downgrade a site or a circuit to a point where it no longer is submitted to regular inspection; - To remove installations or parts that are no longer in service or have aged There are many different D and D techniques, tools and materials available today. What is important is knowing how best to use them. This paper describes the experiences and the future projects of Tecnubel in D and D projects in Belgium and abroad. (authors)« less

A Decision Tool to Evaluate Budgeting Methodologies for Estimating Facility Recapitalization Requirements

DTIC Science & Technology

2008-03-01

1 . Maintenance Practices Influence Service Life .......................................................... 11 2 . Expectations or Standards May...BRB, 1991, p. 1 - 2 ) Additionally, public sector organizations typically have a larger inventory of facilities to maintain, making asset management...questions were answered. 1 . What are the long term causes and effects of under-funding the maintenance of facilities? 2 . What methods currently

Folate deficiency in north Indian children undergoing maintenance chemotherapy for acute lymphoblastic leukemia-Implications and outcome.

PubMed

Roy Moulik, Nirmalya; Kumar, Archana; Agrawal, Suraksha; Mahdi, Abbas Ali

2018-01-01

Treatment-related toxicity and mortality are not uncommon during maintenance chemotherapy for childhood acute lymphoblastic leukemia (ALL), especially in the low- and middle-income countries (LMIC). Undernutrition and micronutrient deficiencies are commonly seen in children from LMICs undergoing treatment for ALL. The present study examines the prevalence and clinical implications of folate deficiency in north Indian children with ALL during the maintenance phase of treatment in view of prolonged antifolate treatment and high population prevalence of folate deficiency. Pre-cycle folate levels/deficiency as well as weight for age z-score and serum albumin level were determined and correlated with complications of treatment and mortality encountered during the maintenance phase of treatment. Twenty-nine of 52 children enrolled in the study had folate deficiency at some point during maintenance chemotherapy. Neutropenia (18 of 29 vs. 4 of 23; P = 0.002), thrombocytopenia (17 of 29 vs. 4 of 23; P = 0.005), febrile neutropenia (17 of 29 vs. 4 of 23; P = 0.005), and need for chemotherapy dose reduction (20 of 29 vs. 7 of 21; P = 0.01) were more common in folate-deficient children. Maintenance deaths were higher (8 of 29 vs. 1 of 23; P = 0.03) and survival lower (P = 0.02) in deficient children. In multivariate analysis, hypoalbuminemia (P = 0.02) and folate deficiency (P = 0.01) were associated with febrile neutropenia, and folate deficiency with maintenance deaths (P = 0.03). Folate deficiency was associated with treatment-related complications and adverse outcome in our patients. The risks and benefits of folate supplementation in deficient children during maintenance chemotherapy need to be explored with properly designed randomized studies in similar settings. © 2017 Wiley Periodicals, Inc.

Recent advances in post autologous transplantation maintenance therapies in B-cell non-Hodgkin lymphomas

PubMed Central

Epperla, Narendranath; Fenske, Timothy S; Hari, Parameswaran N; Hamadani, Mehdi

2015-01-01

Lymphomas constitute the second most common indication for high dose therapy (HDT) followed by autologous hematopoietic cell transplantation (auto-HCT). The intent of administering HDT in these heterogeneous disorders varies from cure (e.g., in relapsed aggressive lymphomas) to disease control (e.g., most indolent lymphomas). Regardless of the underlying histology or remission status at transplantation, disease relapse remains the number one cause of post auto-HCT therapy failure and mortality. The last decade has seen a proliferation of clinical studies looking at prevention of post auto-HCT therapy failure with various maintenance strategies. The benefit of such therapies is in turn dependent on disease histology and timing of transplantation. In relapsed, chemosensitive diffuse large B-cell lymphoma (DLBCL), although post auto-HCT maintenance rituximab seems to be safe and feasible, it does not provide improved survival outcomes and is not recommended. The preliminary results with anti- programmed death -1 (PD-1) antibody therapy as post auto-HCT maintenance in DLBCL is promising but requires randomized validation. Similarly in follicular lymphoma, maintenance therapies including rituximab following auto-HCT should be considered investigational and offered only on a clinical trial. Rituximab maintenance results in improved progression-free survival but has not yet shown to improve overall survival in mantle cell lymphoma (MCL), but given the poor prognosis with post auto-HCT failure in MCL, maintenance rituximab can be considered on a case-by-case basis. Ongoing trials evaluating the efficacy of post auto-HCT maintenance with novel compounds (e.g., immunomodulators, PD-1 inhibitors, proteasome inhibitors and bruton’s tyrosine kinase inhibitors) will likely change the practice landscape in the near future for B cell non-Hodgkin lymphomas patients following HDT and auto-HCT. PMID:26421260

Post-autologous transplant maintenance therapies in lymphoid malignancies: are we there yet?

PubMed

Epperla, N; Fenske, T S; Lazarus, H M; Hamadani, M

2015-11-01

Disease relapse after autologous hematopoietic transplant (auto-HCT) remains the number one cause of post-transplant therapy failure and mortality. The last decade has seen a proliferation of clinical studies looking at the prevention of post-auto-HCT therapy failure with various maintenance strategies. The benefit of such therapies is in turn dependent on disease histology and timing of transplantation. Although high dose therapy (HDT) provides durable responses in chemosensitive relapsed diffuse large B-cell lymphoma (DLBCL), a sizable subset experiences disease relapse. Unfortunately, the addition of rituximab as a post-auto-HCT maintenance strategy did not improve survival outcomes. The preliminary results with programmed death -1 (PD-1) Ab as post-auto maintenance in DLBCL is promising but requires randomized validation. In follicular lymphoma, the 5- and 10-year PFS rates are ~60% and 31%, respectively. Although the addition of rituximab improved PFS, there is no survival benefit, to date. Disease relapse after auto-HCT in mantle cell lymphoma (MCL) is not uncommon. Rituximab maintenance in this setting provides a PFS benefit. Given the poor prognosis of post-auto-HCT failures in MCL, maintenance can be considered on a case-by-case basis. In chemosensitive relapsed Hodgkin lymphoma, addition of brentuximab vedotin after auto-HCT improved 2-year PFS (65 vs 45%) and can be considered as an option for maintenance therapy post auto-HCT, in select higher risk patients. Ongoing trials evaluating the efficacy of post-auto-HCT maintenance with novel agents (for example, immunomodulators, proteasome inhibitors, PD-1 inhibitors, Bruton's tyrosine kinase inhibitors and so on) will likely change the practice landscape for lymphoma patients following HDT and auto-HCT.

A Phase IIIb, Multicentre, Randomised, Parallel-Group, Placebo-Controlled, Double-Blind Study to Investigate the Efficacy and Safety of OROS Hydromorphone in Subjects with Moderate-to-Severe Chronic Pain Induced by Osteoarthritis of the Hip or the Knee

PubMed Central

Vojtaššák, Jozef; Vojtaššák, Jozef; Jacobs, Adam; Rynn, Leonie; Waechter, Sandra; Richarz, Ute

2011-01-01

Background. Opioid analgesics are included in treatment guidelines for the symptomatic management of osteoarthritis (OA). Starting with a low dose of opioid and slowly titrating to a higher dose may help avoid intolerable side effects. Methods. Subjects aged ≥40 years, with moderate to severe pain induced by OA of the hip or knee not adequately controlled by previous non-steroidal anti-inflammatory drugs (NSAIDs) or paracetamol treatment, were enrolled. Subjects received OROS hydromorphone 4 mg or placebo once-daily. The dose was titrated every 3-4 days in case of unsatisfactory pain control during the 4-week titration phase. A 12 week maintenance phase followed. The primary efficacy endpoint was the change in “pain on average” measured on the Brief Pain Inventory (BPI) scale from baseline to the end of the maintenance phase. Results. 139 subjects received OROS hydromorphone and 149 subjects received placebo. All efficacy endpoints showed similar improvements from baseline to end of study in the 2 groups. The safety results were consistent with the safety profile of OROS hydromorphone. Conclusion.The study did not meet the primary endpoint; although many subjects' pain was not adequately controlled at inclusion, their pain may have improved with continued paracetamol or NSAID treatment. PMID:22110921

Nitrous oxide-induced slow and delta oscillations.

PubMed

Pavone, Kara J; Akeju, Oluwaseun; Sampson, Aaron L; Ling, Kelly; Purdon, Patrick L; Brown, Emery N

2016-01-01

Switching from maintenance of general anesthesia with an ether anesthetic to maintenance with high-dose (concentration >50% and total gas flow rate >4 liters per minute) nitrous oxide is a common practice used to facilitate emergence from general anesthesia. The transition from the ether anesthetic to nitrous oxide is associated with a switch in the putative mechanisms and sites of anesthetic action. We investigated whether there is an electroencephalogram (EEG) marker of this transition. We retrospectively studied the ether anesthetic to nitrous oxide transition in 19 patients with EEG monitoring receiving general anesthesia using the ether anesthetic sevoflurane combined with oxygen and air. Following the transition to nitrous oxide, the alpha (8-12 Hz) oscillations associated with sevoflurane dissipated within 3-12 min (median 6 min) and were replaced by highly coherent large-amplitude slow-delta (0.1-4 Hz) oscillations that persisted for 2-12 min (median 3 min). Administration of high-dose nitrous oxide is associated with transient, large amplitude slow-delta oscillations. We postulate that these slow-delta oscillations may result from nitrous oxide-induced blockade of major excitatory inputs (NMDA glutamate projections) from the brainstem (parabrachial nucleus and medial pontine reticular formation) to the thalamus and cortex. This EEG signature of high-dose nitrous oxide may offer new insights into brain states during general anesthesia. Copyright © 2015 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

The pharmacokinetics of high dose metoclopramide in patients with neoplastic disease.

PubMed Central

Bryson, S M; McGovern, E M; Kelman, A W; White, K; Addis, G J; Whiting, B

1985-01-01

High dose metoclopramide infusions (10 mg/kg) were administered to nineteen patients with bronchial carcinoma who were receiving intravenous cyclophosphamide as single agent chemotherapy. Considerable interindividual variability in metoclopramide disposition was observed. Mean clearance was 0.33 +/- 0.13 (s.d.) l h-1 kg-1, mean volume of distribution at steady state was 3.8 +/- 1.2 (s.d.) l/kg and mean elimination half-life was 8.3 +/- 4.4 (s.d.) h. These results were significantly different from mean values previously reported for young healthy volunteers given conventional doses (0.70 l h-1 kg-1, 2.2 l/kg and 2.6 h respectively). Significant correlations were found between serum urea, serum creatinine and metoclopramide clearance. The metoclopramide regimens were well tolerated and, with the exception of two patients, were completely effective in the prevention of nausea and vomiting. To achieve and maintain target serum metoclopramide concentrations of 1 microgram/ml, we now administer a loading infusion of 3.61 mg/kg over 30 min followed by a maintenance infusion of 0.36 mg kg-1 h-1 for 10 h. Cyclophosphamide is normally administered concurrently with the second infusion. For patients with evidence of mild renal impairment, the maintenance infusion rate of metoclopramide hydrochloride should be adjusted according to the predicted individual clearance value; CL (l h-1 kg-1) = 0.57 - [0.036 X urea (mmol/l)]. PMID:4027119

Evaluation of the Environmental Gamma-ray Dose Rate by Skyshine Analysis During the Maintenance of an Activated TFC in ITER

NASA Astrophysics Data System (ADS)

Sato, S.; Takatsu, H.; Maki, K.; Yamada, K.; Mori, S.; Iida, H.; Santoro, R. T.

1997-09-01

Gamma-ray exposure dose rates at the ITER site boundary were estimated for the cases of removal of a failed activated Toroidal Field (TF) coil from the torus and removal of a failed activated TF coil together with a sector of the activated Vacuum Vessel (VV). Skyshine analyses were performed using the two-dimensional SN radiation transport code, DOT3.5. The exposure gamma-ray dose rates on the ground at the site boundary (presently assumed to be 1 km from the ITER building), were calculated to be 1.1 and 84 μSv/year for removal of the TF coil without and with a VV sector, respectively. The dose rate level for the latter case is close to the tentative radiation limit of 100 μSv/year so an additional ˜14 cm of concrete is required in the ITER building roof to satisfy the criterion for a safety factor often for the site boundary dose rate.

Role of genetic background in induced instability

NASA Technical Reports Server (NTRS)

Kadhim, Munira A.; Nelson, G. A. (Principal Investigator)

2003-01-01

Genomic instability is effectively induced by ionizing radiation. Recently, evidence has accumulated supporting a relationship between genetic background and the radiation-induced genomic instability phenotype. This is possibly due to alterations in proteins responsible for maintenance of genomic integrity or altered oxidative metabolism. Studies in human cell lines, human primary cells, and mouse models have been performed predominantly using high linear energy transfer (LET) radiation, or high doses of low LET radiation. The interplay between genetics, radiation response, and genomic instability has not been fully determined at low doses of low LET radiation. However, recent studies using low doses of low LET radiation suggest that the relationship between genetic background and radiation-induced genomic instability may be more complicated than these same relationships at high LET or high doses of low LET radiation. The complexity of this relationship at low doses of low LET radiation suggests that more of the population may be at risk than previously recognized and may have implications for radiation risk assessment.

Tools to support maintenance strategies under soft soil conditions

NASA Astrophysics Data System (ADS)

Lambert, J. W. M.; van Meerten, J. J.; Woning, M. P.; Eijbersen, M. J.; Huber, M.

2015-11-01

Costs for maintenance of infrastructure in municipalities with soft soil underground conditions, are estimated to be almost 40 % higher than in others. As a result, these municipalities meet financial problems that cause overdue maintenance. In some cases municipalities are even afraid to be unable to offer a minimum service level in future. In common, traditional practice, roads and sewerage systems have been constructed in trenches that consist of sandy material that replaces the upper meters of the soft soil. Under influence of its weight, this causes accelerated settlements of the construction. A number of alternative constructions have been developed, e.g. using light-weight materials to limit settlement velocity. In order to limit future maintenance costs, improvement of maintenance strategies is desired. Tools have been and will be developed to support municipalities in improving their maintenance strategies and save money by doing that. A model (BALANS) that weighs the attractiveness of alternative solutions under different soil, environmental and economic circumstances, will be presented.

Systemic and bronchodilator effects of inhaled rac-formoterol in subjects with chronic obstructive pulmonary disease: a dose–response study

PubMed Central

Whale, Christopher I; Sovani, Milind P; Mortimer, Kevin J; Harrison, Timothy W; Tattersfield, Anne E

2008-01-01

AIMS Rac-formoterol is effective as maintenance treatment for both asthma and chronic obstructive pulmonary disease (COPD) and is now used as relief therapy in asthma. Using rac-formoterol for relief and maintenance treatment could involve inhalation of high doses, and whether this is of benefit in COPD is uncertain. Our aim was to determine whether higher doses of inhaled rac-formoterol produce systemic adverse effects that outweigh the limited bronchodilator benefit seen in subjects with COPD. METHODS We examined airway and systemic effects of 6, 12, 24 and 48 μg rac-formoterol and placebo on separate days in 20 subjects with symptomatic COPD [forced expiratory volume in 1 s (FEV1) 47% predicted]. FEV1, oxygen saturation, dyspnoea, 6-min walk distance, patient satisfaction and systemic effects were measured and treatment was assessed against placebo and for dose–response effects. RESULTS FEV1[area under the time–response curve (AUC)] and satisfaction scores increased with all formoterol doses compared with placebo, as did AUC tremor with the 24- and 48-μg doses and AUC heart rate with the 48-μg dose. A dose–response relationship was seen with FEV1 and tremor, but not with satisfaction scores. There was no difference between placebo and rac-formoterol for other variables. CONCLUSIONS Our results show that in patients with COPD rac-formoterol improves FEV1 and patient satisfaction without a corresponding reduction in dyspnoea. Since the systemic effects from a relatively high dose were minimal, its use as relief medication in COPD merits further evaluation. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT The long-acting inhaled β2-agonist formoterol has systemic effects when taken in high doses. It can be used as relief medication in asthma and there is interest in this approach in chronic obstructive pulmonary disease (COPD). Relief medication can involve high doses, and in subjects with COPD who have limited ability to bronchodilate the adverse effects can outweigh the benefits. There are concerns with the overall safety of high-dose β2-agonists in subjects with COPD, and this study looks at the balance of beneficial and adverse effects of a range of doses of inhaled formoterol. WHAT THIS STUDY ADDS Among subjects with COPD, high-dose inhaled formoterol produced a dose-related increase in forced expiratory volume in 1 s without a corresponding reduction in dyspnoea or increase in walk distance.Systemic effects were modest, however, and high doses did not appear to reduce patient satisfaction.Although further safety data are needed, inhaled formoterol may have a role as relief medication in COPD. PMID:18394012

Pulmonary Bovine-Type Tuberculosis in Rabbits: Bacillary Virulence, Inhaled Dose Effects, Tuberculin Sensitivity, and Mycobacterium vaccae Immunotherapy

PubMed Central

Converse, P. J.; Dannenberg, A. M.; Shigenaga, T.; McMurray, D. N.; Phalen, S. W.; Stanford, J. L.; Rook, G. A. W.; Koru-Sengul, T.; Abbey, Helen; Estep, J. E.; Pitt, M. L. M.

1998-01-01

This report elucidates four aspects of the immunology of pulmonary tuberculosis produced in rabbits: (i) the virulence of bovine-type tubercle bacilli, strain Ravenel S, (ii) systemic factors influencing the generation of visible primary pulmonary tubercles, (iii) differences in tuberculin sensitivity of rabbits and humans, and (iv) the effect of Mycobacterium vaccae immunotherapy on cavitary tuberculosis. Laboratory strain Ravenel S (ATCC 35720) was not fully virulent. Fully virulent strains produce one visible primary pulmonary tubercle for each three bacillary units inhaled. Strain ATCC 35720 produced one such tubercle for each 18 to 107 bacillary units inhaled, indicating that its virulence was reduced by 6- to 36-fold. When a low dose of this Ravenel S strain was inhaled, the host resistance (measured by the number of inhaled bacilli needed to generate one visible primary pulmonary tubercle) was increased at least 3.5-fold compared to the host resistance when a high dose was inhaled. Rabbits and humans differ in the degree and in the maintenance of their dermal sensitivities to tuberculin. Compared to rabbits, humans are 100 times more sensitive to tuberculin. Also, at 33 weeks rabbits with well-controlled cavitary tuberculosis usually showed a decrease in their tuberculin reactions of about 50% from peak values, whereas humans with such well-controlled tuberculosis are thought to maintain strong reactions for many years. These species differences may be due to desensitization to group II mycobacterial antigens in the rabbits because they have a different diet and a different type of digestive tract. M. vaccae immunotherapy of rabbits with cavitary tuberculosis produced no statistically significant effects. Experiments with many more rabbits would be required to prove whether or not such immunotherapy is beneficial. PMID:9801350

Synergistic Effect of High Charge and Energy Particle Radiation and Chronological Age on Biomarkers of Oxidative Stress and Tissue Degeneration: A Ground-Based Study Using the Vertebrate Laboratory Model Organism Oryzias latipes

PubMed Central

Zheng, Xuan; Zhang, Xinyan; Ding, Lingling; Lee, Jeffrey R.; Weinberger, Paul M.; Dynan, William S.

2014-01-01

High charge and energy (HZE) particles are a main hazard of the space radiation environment. Uncertainty regarding their health effects is a limiting factor in the design of human exploration-class space missions, that is, missions beyond low earth orbit. Previous work has shown that HZE exposure increases cancer risk and elicits other aging-like phenomena in animal models. Here, we investigate how a single exposure to HZE particle radiation, early in life, influences the subsequent age-dependent evolution of oxidative stress and appearance of degenerative tissue changes. Embryos of the laboratory model organism, Oryzias latipes (Japanese medaka fish), were exposed to HZE particle radiation at doses overlapping the range of anticipated human exposure. A separate cohort was exposed to reference γ-radiation. Survival was monitored for 750 days, well beyond the median lifespan. The population was also sampled at intervals and liver tissue was subjected to histological and molecular analysis. HZE particle radiation dose and aging contributed synergistically to accumulation of lipid peroxidation products, which are a marker of chronic oxidative stress. This was mirrored by a decline in PPARGC1A mRNA, which encodes a transcriptional co-activator required for expression of oxidative stress defense genes and for mitochondrial maintenance. Consistent with chronic oxidative stress, mitochondria had an elongated and enlarged ultrastructure. Livers also had distinctive, cystic lesions. Depending on the endpoint, effects of γ-rays in the same dose range were either lesser or not detected. Results provide a quantitative and qualitative framework for understanding relative contributions of HZE particle radiation exposure and aging to chronic oxidative stress and tissue degeneration. PMID:25375139

Nicotine interactions with low-dose alcohol: pharmacological influences on smoking and drinking motivation.

PubMed

Oliver, Jason A; Blank, Melissa D; Van Rensburg, Kate Janse; MacQueen, David A; Brandon, Thomas H; Drobes, David J

2013-11-01

An extensive literature documents a close association between cigarette and alcohol use. The joint pharmacological effects of alcohol and nicotine on smoking and drinking motivation may help explain this relationship. This experiment was designed to test the separate and combined pharmacological effects of nicotine and a low dose of alcohol (equivalent to 1-2 standard drinks) on substance use motivation using a double-blind and fully crossed within-subjects design. Participants (N = 87) with a wide range of smoking and drinking patterns completed 4 counterbalanced experimental sessions during which they consumed an alcohol (male: 0.3g/kg; female: 0.27g/kg) or placebo beverage and smoked a nicotine (.6 mg) or placebo cigarette. Outcome measures assessed the impact of drug administration (alcohol or nicotine) on craving to smoke, craving to drink, affect, and liking of the beverage and cigarette. Results indicated that combined administration produced higher cravings to smoke for the entire sample, as well as higher cravings to drink among women and lighter drinkers. Heavier users of either alcohol or cigarettes also exhibited enhanced sensitivity to the effects of either drug in isolation. Separate, but not interactive, effects of alcohol and nicotine on mood were observed as well as both same-drug and cross-drug effects on beverage and cigarette liking. Together, these findings support the notion that the interactive pharmacological effects of nicotine and low doses of alcohol play an important role in motivating contemporaneous use and suggest roles for cross-reinforcement and cross-tolerance in the development and maintenance of alcohol and nicotine use and dependence. PsycINFO Database Record (c) 2013 APA, all rights reserved.

Beneficial effect of soy isoflavones on bone mineral content was modified by years since menopause, body weight, and calcium intake: a double-blind, randomized, controlled trial.

PubMed

Chen, Yu-Ming; Ho, Suzanne C; Lam, Silvia S H; Ho, Susan S S; Woo, Jean L F

2004-01-01

Many studies have shown that soy isoflavones have an effect in preventing estrogen-related bone loss, but no data reported whether such an effect could be influenced by other important factors affecting bone loss. This study examines whether the associations between isoflavone supplementation and rates of change in bone mineral content (BMC) could be modified by years since menopause (YSM), body weight (BW), and dietary calcium intake in postmenopausal Chinese women aged 48 to 62 years. A group of 203 eligible women were randomly assigned to three treatment groups: placebo (daily dose of 0 mg isoflavones + 500 mg calcium, n = 67), mid-dose (40 mg isoflavones + 500 mg calcium, n = 68); and high-dose (80 mg isoflavones + 500 mg calcium, n = 68). Bone mineral density (BMD) and BMC at the whole body, spine, and hip were measured by dual-energy x-ray absorptiometry at baseline and posttreatment after 1 year. YSM, BW, and dietary calcium intake stratified analyses were performed to evaluate whether the associations between isoflavones supplementation and BMC change rates were varied with these factors. Both univariate and multivariate analyses observed significant favorable effect of isoflavone supplementation on rates of change in BMC at the total hip and trochanter among later postmenopausal women (> 4 y), in women with lower BW (< or =median, 55.5 kg), or among women with lower level of calcium intake (< or =median, 1095 mg/d). The independent effect of soy on the maintenance of hip BMC is more marked in women in later menopause or those with lower BW or calcium intake.

Synergistic Effect of High Charge and Energy Particle Radiation and Chronological Age on Biomarkers of Oxidative Stress and Tissue Degeneration: A Ground-Based Study Using the Vertebrate Laboratory Model Organism Oryzias latipes

DOE PAGES

Zheng, Xuan; Zhang, Xinyan; Ding, Lingling; ...

2014-11-06

High charge and energy (HZE) particles are a main hazard of the space radiation environment. Uncertainty regarding their health effects is a limiting factor in the design of human exploration-class space missions, that is, missions beyond low earth orbit. Previous work has shown that HZE exposure increases cancer risk and elicits other aging-like phenomena in animal models. Here, we investigate how a single exposure to HZE particle radiation, early in life, influences the subsequent age-dependent evolution of oxidative stress and appearance of degenerative tissue changes. Embryos of the laboratory model organism, Oryzias latipes (Japanese medaka fish), were exposed to HZEmore » particle radiation at doses overlapping the range of anticipated human exposure. A separate cohort was exposed to reference γ-radiation. Survival was monitored for 750 days, well beyond the median lifespan. The population was also sampled at intervals and liver tissue was subjected to histological and molecular analysis. HZE particle radiation dose and aging contributed synergistically to accumulation of lipid peroxidation products, which are a marker of chronic oxidative stress. This was mirrored by a decline in PPARGC1A mRNA, which encodes a transcriptional co-activator required for expression of oxidative stress defense genes and for mitochondrial maintenance. Consistent with chronic oxidative stress, mitochondria had an elongated and enlarged ultrastructure. Livers also had distinctive, cystic lesions. Depending on the endpoint, effects of γ-rays in the same dose range were either lesser or not detected. Results provide a quantitative and qualitative framework for understanding relative contributions of HZE particle radiation exposure and aging to chronic oxidative stress and tissue degeneration.« less

Prevalence of depression in maintenance hemodialysis patients and its correlation with adherence to medications.

PubMed

Ossareh, Shahrzad; Tabrizian, Shiva; Zebarjadi, Marjan; Joodat, Rashin S

2014-11-01

This study was designed to evaluate the adherence of maintenance hemodialysis patients to medications and its correlation with quality of life and depressive symptoms. A total of 150 maintenance hemodialysis patients with a mean age of 56.4 ± 16.4 years (52.7% women) were included. Medication adherence was evaluated via the Simplified Medication Adherence Questionnaire, based on which nonadherent patients were identified. Specifically, the Drug-Intake Percentage Questionnaire was used for evaluation of adherence to phosphate binders, quality of life was assessed with short Form-36 and depression by the Beck Depression Inventory (BDI). A BDI score of 15 and greater was documented in 40.7%, and nonadherence in 24.7% of the patients. Adherent patients were significantly older than nonadherent ones, had a lower mean parathyroid hormone level, and had lower BDI scores. The quality of life scores were not significantly different between adherent and nonadherent patients. Multivariable analysis demonstrated that BDI score was a significant predictor of nonadherence (odds ratio for each unit increase, 1.11; 95% confidence interval, 1.04 to 1.18; P = .001). Overall, 55.5% of patients were taking more than 66% of their prescribed dose of calcium carbonate, while 10.3% and 53.8% of patients were taking more than 66% of their prescribed dose of aluminum hydroxide and sevelamer, respectively. Adherence to medication was mainly associated with hemodialysis patients' depressive symptom scores. Control of depression may significantly improve adherence to medications and patient management.

Administration of the glial cell modulator, minocycline, in the nucleus accumbens attenuated the maintenance and reinstatement of morphine-seeking behavior.

PubMed

Arezoomandan, Reza; Haghparast, Abbas

2016-03-01

Relapse to drug use is one of the most difficult clinical problems in treating addiction. Glial activation has been linked with the drug abuse, and the glia modulators such as minocycline can modulate the drug abuse effects. The aim of the present study was to determine whether minocycline could attenuate the maintenance and reinstatement of morphine. Conditioned place preference (CPP) was induced by subcutaneous injection of morphine (5 mg/kg) for 3 days. Following the acquisition of the CPP, the rats were given daily bilateral intra-NAc injections of either minocycline (1, 5, and 10 μg/0.5 μL) or saline (0.5 μL). The animals were tested for conditioning score 60 min after each injection. To induce the reinstatement, a priming dose of morphine (1 mg/kg) was injected 1 day after the final extinction day. The morphine-induced CPP lasted for 7 days after cessation of morphine treatment. Our data revealed that a priming dose of morphine could reinstate the extinguished morphine-induced CPP. Daily intra-accumbal injection of minocycline during the extinction period blocked the maintenance of morphine CPP and also attenuated the priming-induced reinstatement. Our findings indicated that minocycline could facilitate the extinction and attenuate the reinstatement of morphine. These results provided new evidence that minocycline might be considered as a promising therapeutic agent for the treatment of several symptoms associated with morphine abuse.

The potential beneficial effect of nicardipine in a rat model of transient forebrain ischemia.

PubMed

Alps, B J; Hass, W K

1987-05-01

In a rat 3-day survival model of 10-minute four-vessel occlusion, halothane anesthesia was used to attenuate the ictal blood pressure elevation of the cerebral ischemic response and thereby maintain an isoelectric EEG. Selectively vulnerable regions of the brain were protected by preischemia plus postischemia maintenance treatment with the calcium entry blocker nicardipine. Compared with untreated animals, repeated doses at 500 micrograms/kg IP were markedly more effective than doses of 50 micrograms/kg. Ongoing studies demonstrate a neurocytoprotective action of nicardipine when deferred treatment is given postischemia.

Single maintenance and reliever therapy (SMART) of asthma: a critical appraisal.

PubMed

Chapman, Kenneth R; Barnes, Neil C; Greening, Andrew P; Jones, Paul W; Pedersen, S

2010-08-01

The use of a combination inhaler containing budesonide and formoterol as both maintenance and quick relief therapy (SMART) has been recommended as an improved method of using inhaled corticosteroid/long-acting beta agonist (ICS/LABA) therapy. Published double-blind trials show that budesonide/formoterol therapy delivered in SMART fashion achieves better asthma outcomes than budesonide monotherapy or lower doses of budesonide/formoterol therapy delivered in constant dosage. Attempts to compare budesonide/formoterol SMART therapy with regular combination ICS/LABA dosing using other compounds have been confounded by a lack of blinding and unspecified dose adjustment strategies. The asthma control outcomes in SMART-treated patients are poor; it has been reported that only 17.1% of SMART-treated patients are controlled. In seven trials of 6-12 months duration, patients using SMART have used quick reliever daily (weighted average 0.92 inhalations/day), have awakened with asthma symptoms once every 7-10 days (weighted average 11.5% of nights), have suffered asthma symptoms more than half of days (weighted average 54.0% of days) and have had a severe exacerbation rate of one in five patients per year (weighted average 0.22 severe exacerbations/patient/year). These poor outcomes may reflect the recruitment of a skewed patient population. Although improvement from baseline has been attributed to these patients receiving additional ICS therapy at pivotal times, electronic monitoring has not been used to test this hypothesis nor the equally plausible hypothesis that patients who are non-compliant with maintenance medication have used budesonide/formoterol as needed for self-treatment of exacerbations. Although the long-term consequences of SMART therapy have not been studied, its use over 1 year has been associated with significant increases in sputum and biopsy eosinophilia. At present, there is no evidence that better asthma treatment outcomes can be obtained by moment-to-moment symptom-driven use of ICS/LABA therapy than conventional physician-monitored and adjusted ICS/LABA therapy.

P2X7-Regulated Protection from Exacerbations and Loss of Control Is Independent of Asthma Maintenance Therapy

PubMed Central

Manthei, David M.; Seibold, Max A.; Ahn, Kwangmi; Bleecker, Eugene; Boushey, Homer A.; Calhoun, William J.; Castro, Mario; Chinchili, Vernon M.; Fahy, John V.; Hawkins, Greg A.; Icitovic, Nicolina; Israel, Elliot; Jarjour, Nizar N.; King, Tonya; Kraft, Monica; Lazarus, Stephen C.; Lehman, Erik; Martin, Richard J.; Meyers, Deborah A.; Peters, Stephen P.; Sheerar, Dagna; Shi, Lei; Sutherland, E. Rand; Szefler, Stanley J.; Wechsler, Michael E.; Sorkness, Christine A.; Lemanske, Robert F.

2013-01-01

Rationale: The function of the P2X7 nucleotide receptor protects against exacerbation in people with mild-intermittent asthma during viral illnesses, but the impact of disease severity and maintenance therapy has not been studied. Objectives: To evaluate the association between P2X7, asthma exacerbations, and incomplete symptom control in a more diverse population. Methods: A matched P2RX7 genetic case-control was performed with samples from Asthma Clinical Research Network trial participants enrolled before July 2006, and P2X7 pore activity was determined in whole blood samples as an ancillary study to two trials completed subsequently. Measurements and Main Results: A total of 187 exacerbations were studied in 742 subjects, and the change in asthma symptom burden was studied in an additional 110 subjects during a trial of inhaled corticosteroids (ICS) dose optimization. African American carriers of the minor G allele of the rs2230911 loss-of-function single nucleotide polymorphism were more likely to have a history of prednisone use in the previous 12 months, with adjustment for ICS and long-acting β2-agonists use (odds ratio, 2.7; 95% confidence interval, 1.2–6.2; P = 0.018). Despite medium-dose ICS, attenuated pore function predicted earlier exacerbations in incompletely controlled patients with moderate asthma (hazard ratio, 3.2; confidence interval, 1.1–9.3; P = 0.033). After establishing control with low-dose ICS in patients with mild asthma, those with attenuated pore function had more asthma symptoms, rescue albuterol use, and FEV1 reversal (P < 0.001, 0.03, and 0.03, respectively) during the ICS adjustment phase. Conclusions: P2X7 pore function protects against exacerbations of asthma and loss of control, independent of baseline severity and the maintenance therapy. PMID:23144325

Specific signals involved in the long-term maintenance of radiation-induced fibrogenic differentiation: a role for CCN2 and low concentration of TGF-beta1.

PubMed

Haydont, Valérie; Riser, Bruce L; Aigueperse, Jocelyne; Vozenin-Brotons, Marie-Catherine

2008-06-01

The fibrogenic differentiation of resident mesenchymal cells is a key parameter in the pathogenesis of radiation fibrosis and is triggered by the profibrotic growth factors transforming growth factor (TGF)-beta1 and CCN2. TGF-beta1 is considered the primary inducer of fibrogenic differentiation and is thought to control its long-term maintenance, whereas CCN2 is considered secondary effector of TGF-beta1. Yet, in long-term established fibrosis like that associated with delayed radiation enteropathy, in situ TGF-beta1 deposition is low, whereas CCN2 expression is high. To explore this apparent paradox, cell response to increasing doses of TGF-beta1 was investigated in cells modeling initiation and maintenance of fibrosis, i.e., normal and fibrosis-derived smooth muscle cells, respectively. Activation of cell-specific signaling pathways by low TGF-beta1 doses was demonstrated with a main activation of the Rho/ROCK pathway in fibrosis-derived cells, whereas the Smad pathway was mainly activated in normal cells. This leads to subsequent and cell-specific regulation of the CCN2 gene. These results suggested a specific profibrotic role of CCN2 in fibrosis-initiated cells. Furthermore, the modulation of CCN2 expression by itself and the combination of TGF-beta1 and CCN2 was investigated in fibrosis-derived cells. In fibrosis-initiated cells CCN2 triggered its autoinduction; furthermore, low concentration of TGF-beta1-potentiated CCN2 autoinduction. Our findings showed a differential requirement and action of TGF-beta1 in the fibrogenic response of normal vs. fibrosis-derived cells. This study defines a novel Rho/ROCK but Smad3-independent mode of TGF-beta signaling that may operate during the chronic stages of fibrosis and provides evidence of both specific and combinatorial roles of low TGF-beta1 dose and CCN2.

Within- and between- subject variability in methadone pharmacokinetics and pharmacodynamics in methadone maintenance subjects

PubMed Central

Hanna, Julia; Foster, David JR; Salter, Amy; Somogyi, Andrew A; White, Jason M; Bochner, Felix

2005-01-01

Aims To investigate within- and between-subject variability of the pharmacodynamics and pharmacokinetics of (R)- and (S)-methadone in methadone maintenance subjects at steady-state. Methods Six non-holder subjects were studied on three occasions at 7–16 day intervals; doses (20–170 mg/day) remained unchanged. Blood samples and pharmacodynamic data were collected 10–12 times over a 24-h inter-dosing interval. All pharmacodynamic data were expressed as the area under the end-point versus time curve. Using analyses of variance with mixed effects, best estimates were made of the ratio of between- to within-subject variation, with corresponding 95% confidence intervals (CI) for within-subject variation at the average value. Results Subjects were relatively consistent between occasions, whereas there was much greater between-subject variability (P < 0.02) for all measures. Estimates of the ratio of between- to within-subject variation ranged from 2.2–12.8 for pharmacodynamic measures, and 1.3–7.9 for pharmacokinetic parameters. For pain, total mood disturbance, withdrawal, pupil size and respiration rate, 95% CI for within-subject measures ranged ≤2-fold, while this was greater for subjective direct opioid effects (4.2-fold). For CL/F of the active (R)-methadone, the variance ratio was 4.9 (P < 0.0003), with 95% CI for within-subject measures ranging ≤2-fold. (S)-methadone CL/F demonstrated greater within-subject variability (3.4-fold), possibly contributing to a smaller (2.7; P < 0.0003) ratio of between- to within-subject variance. Conclusions Non-holder methadone maintenance treatment participants appear to respond consistently with respect to pharmacokinetics and pharmacodynamics over a 1–2 month period. Such knowledge may help prescribers to determine whether alternative dosing regimens or treatments might be more appropriate in this population. PMID:16187972

Roxadustat (FG-4592) Versus Epoetin Alfa for Anemia in Patients Receiving Maintenance Hemodialysis: A Phase 2, Randomized, 6- to 19-Week, Open-Label, Active-Comparator, Dose-Ranging, Safety and Exploratory Efficacy Study.

PubMed

Provenzano, Robert; Besarab, Anatole; Wright, Steven; Dua, Sohan; Zeig, Steven; Nguyen, Peter; Poole, Lona; Saikali, Khalil G; Saha, Gopal; Hemmerich, Stefan; Szczech, Lynda; Yu, K H Peony; Neff, Thomas B

2016-06-01

Roxadustat (FG-4592) is an oral hypoxia-inducible factor prolyl-hydroxylase inhibitor that promotes erythropoiesis through increasing endogenous erythropoietin, improving iron regulation, and reducing hepcidin. Phase 2, randomized (3:1), open-label, active-comparator, safety and efficacy study. Patients with stable end-stage renal disease treated with hemodialysis who previously had hemoglobin (Hb) levels maintained with epoetin alfa. Part 1: 6-week dose-ranging study in 54 individuals of thrice-weekly oral roxadustat doses versus continuation of intravenous epoetin alfa. Part 2: 19-week treatment in 90 individuals in 6 cohorts with various starting doses and adjustment rules (1.0-2.0mg/kg or tiered weight based) in individuals with a range of epoetin alfa responsiveness. Intravenous iron was prohibited. Primary end point was Hb level response, defined as end-of-treatment Hb level change (ΔHb) of -0.5g/dL or greater from baseline (part 1) and as mean Hb level ≥ 11.0g/dL during the last 4 treatment weeks (part 2). Hepcidin, iron parameters, cholesterol, and plasma erythropoietin (the latter in a subset). Baseline epoetin alfa doses were 138.3±51.3 (SD) and 136.3±47.7U/kg/wk in part 1 and 152.8±80.6 and 173.4±83.7U/kg/wk in part 2, in individuals randomly assigned to roxadustat and epoetin alfa, respectively. Hb level responder rates in part 1 were 79% in pooled roxadustat 1.5 to 2.0mg/kg compared to 33% in the epoetin alfa control arm (P=0.03). Hepcidin level reduction was greater at roxadustat 2.0mg/kg versus epoetin alfa (P<0.05). In part 2, the average roxadustat dose requirement for Hb level maintenance was ∼1.7mg/kg. The least-squares-mean ΔHb in roxadustat-treated individuals was comparable to that in epoetin alfa-treated individuals (about -0.5g/dL) and the least-squares-mean difference in ΔHb between both treatment arms was -0.03 (95% CI, -0.39 to 0.33) g/dL (mixed effect model-repeated measure). Roxadustat significantly reduced mean total cholesterol levels, not observed with epoetin alfa. No safety concerns were raised. Short treatment duration and small sample size. In this phase 2 study of anemia therapy in patients with end-stage renal disease on maintenance hemodialysis therapy, roxadustat was well tolerated and effectively maintained Hb levels. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Vitamin D, bones and muscle: myth versus reality.

PubMed

Duque, Gustavo; Daly, Robin M; Sanders, Kerrie; Kiel, Douglas P

2017-03-01

Evidence regarding the efficacy and dosing of vitamin D on fall and fracture prevention, with or without calcium, is characterised by uncertainty. A panel of experts was organised at the First Australasian Conference on Sarcopenia and Frailty in Melbourne, Australia, in November 2016 to provide an interpretation of the current evidence and to give their opinions regarding the supplementation of vitamin D in three hypothetical cases. The authors conclude that (i) target serum 25(OH)D concentration should be 50 to 60 nmol/L year round, with a conservative upper limit <100 nmol/L; (ii) change in serum concentrations at any given dose is highly variable among individuals; (iii) dosing interval may need to be <2 months to have a continuous benefit; (iv) a loading dose can raise levels to target quickly, but there is no evidence yet that this has any positive effect on falls or fracture outcomes; and (v) a maintenance dose of 1000 IU/day, or given as an equivalent dose weekly or monthly, is sufficient for most individuals. © 2017 AJA Inc.

Improving the performance of membrane bioreactors by powdered activated carbon dosing with cost considerations.

PubMed

Yang, W; Paetkau, M; Cicek, N

2010-01-01

Effects of powdered activated carbon (PAC) dosing on the overall performance of membrane bioreactors (MBR) were investigated in two bench-scale submerged MBRs. Positive impacts of PAC dosing on membrane fouling and the removal of 17beta-estradiol (E2) and 17alpha-ethyinylestradiol (EE2) were demonstrated over a six-month stable operational period. PAC dosing in the MBR increased the removal rates of E2 and EE2 by 3.4% and 15.8%, respectively. The average soluble extracellular polymeric substances (EPS) and colloidal total organic carbon (TOC) concentrations in the PAC-MBR sludge was 60.1% and 61.8% lower than the control MBR sludge, respectively. Lower soluble EPS and colloidal TOC concentrations in the PAC-MBR sludge resulted in a slower rate of trans-membrane pressure (TMP) increase during MBRs operation, which could prolong the lifespan of membranes. Cost assessment showed that PAC dosing could reduce the operating cost for membrane cleaning and/or membrane replacement by about 25%. The operating cost for PAC dosing could be offset by the benefit from its reducing the cost for membrane maintenance.

Long term maintenance of weight loss with non-surgical interventions in obese adults: systematic review and meta-analyses of randomised controlled trials

PubMed Central

Dombrowski, S U; Knittle, K; Avenell, A; Araújo-Soares, V

2014-01-01

Objective To systematically review and describe currently available approaches to supporting maintenance of weight loss in obese adults and to assess the evidence for the effectiveness of these interventions. Design Systematic review with meta-analysis. Data sources Medline, PsycINFO, Embase, and the Cochrane Central Register of Controlled Trials. Study selection Studies were identified through to January 2014. Randomised trials of interventions to maintain weight loss provided to initially obese adults (aged ≥18) after weight loss of ≥5% body weight with long term (≥12 months) follow-up of weight change (main outcome) were included. Study appraisal and synthesis Potential studies were screened independently and in duplicate; study characteristics and outcomes were extracted. Meta-analyses were conducted to estimate the effects of interventions on weight loss maintenance with the inverse variance method and a random effects model. Results are presented as mean differences in weight change, with 95% confidence intervals. Results 45 trials involving 7788 individuals were included. Behavioural interventions focusing on both food intake and physical activity resulted in an average difference of −1.56 kg (95% confidence interval −2.27 to −0.86 kg; 25 comparisons, 2949 participants) in weight regain compared with controls at 12 months. Orlistat combined with behavioural interventions resulted in a −1.80 kg (−2.54 to −1.06; eight comparisons, 1738 participants) difference compared with placebo at 12 months. All orlistat studies reported higher frequencies of adverse gastrointestinal events in the experimental compared with placebo control groups. A dose-response relation for orlistat treatment was found, with 120 mg doses three times a day leading to greater weight loss maintenance (−2.34 kg, −3.03 to −1.65) compared with 60 mg and 30 mg three times a day (−0.70 kg, 95% confidence interval −1.92 to 0.52), P=0.02. Conclusions Behavioural interventions that deal with both diet and physical activity show small but significant benefits on weight loss maintenance. PMID:25134100

Examining maintenance responsibilities.

PubMed

Lam, K C

2001-06-01

This paper has examined the important responsibilities of the two organisations involved in the provision of maintenance service for the vital building services in many of our highly serviced buildings. The issues raised could be put to beneficial use in both clients and maintenance providers. All in all, the clients should work closely with their maintenance providers. Engineering services in buildings will not perform satisfactorily and efficiently if both parties do not work together and understand the maintenance tasks based on a business partnering mode. Put forward is the view that the management of the activities involved in the operation and maintenance process is a "shared commitment/involvement" between the client and the maintenance provider. It is obvious that many factors can influence the continued effectiveness of a quality maintenance scheme set up by client and provider. Some of these factors are: Change in key personnel Updates in technology Amendments to engineering practice Implementation of legislative requirements Changes in operation by client or provider Change of use of building Passage of time These factors must be fully reviewed by both parties from time to time, and necessary actions taken. A cooperative team working relationship and improved communication should be fostered by the client and his provider for the best management of services maintenance. This arrangement will contribute to better building services systems with continuous improvement; improved value for clients and higher return for the maintenance provider.

Pharmacodynamic Comparison of Prasugrel Versus Ticagrelor in Patients With Type 2 Diabetes Mellitus and Coronary Artery Disease: The OPTIMUS (Optimizing Antiplatelet Therapy in Diabetes Mellitus)-4 Study.

PubMed

Franchi, Francesco; Rollini, Fabiana; Aggarwal, Niti; Hu, Jenny; Kureti, Megha; Durairaj, Ashwin; Duarte, Valeria E; Cho, Jung Rae; Been, Latonya; Zenni, Martin M; Bass, Theodore A; Angiolillo, Dominick J

2016-09-13

Patients with diabetes mellitus (DM) are at increased risk of atherothrombotic events, underscoring the importance of effective platelet inhibiting therapies. Prasugrel and ticagrelor reduce thrombotic complications to a greater extent than clopidogrel. Subgroup analyses of pivotal clinical trials testing prasugrel and ticagrelor versus clopidogrel showed DM patients to have benefits that were consistent with the overall trial populations, although the magnitude of the ischemic risk reduction appeared to be enhanced with prasugrel. Whether these findings may be attributed to differences in the pharmacodynamic profiles of these drugs in DM patients remains poorly explored and represented the aim of this study. In this prospective, randomized, double-blind, double-dummy, crossover pharmacodynamic study, aspirin-treated DM patients (n=50) with coronary artery disease were randomly assigned to receive prasugrel (60 mg loading dose [LD]/10 mg maintenance dose once daily) or ticagrelor (180 mg LD/90 mg maintenance dose twice daily) for 1 week. Pharmacodynamic assessments were conducted using 4 different assays, including VerifyNow P2Y12, vasodilator-stimulated phosphoprotein, light transmittance aggregometry, and Multiplate, which allowed us to explore ADP- and non-ADP-induced (arachidonic acid-, collagen-, thrombin receptor-activating, peptide-induced) platelet signaling pathways. The acute (baseline, 30 minutes, and 2 hours post-LD) and maintenance (1 week) effects of therapy were assessed. The primary end point of the study was the comparison of P2Y12 reaction units determined by VerifyNow P2Y12 at 1 week between prasugrel and ticagrelor. ADP- and non-ADP-induced measures of platelet reactivity reduced significantly with both prasugrel and ticagrelor LD and maintenance dose. P2Y12 reaction units defined by VerifyNow were similar between prasugrel and ticagrelor at 30 minutes and 2 hours post-LD. At 1 week, P2Y12 reaction units were significantly lower with ticagrelor than with prasugrel (52 [32-72] versus 83 [63-103]; least-square means difference: -31; 95% confidence interval, -57 to -4; P=0.022; primary end point). Pharmacodynamic assessments measured by vasodilator-stimulated phosphoprotein, light transmittance aggregometry, and Multiplate were similar between prasugrel and ticagrelor at each time point, including at 1 week. Rates of high on-treatment platelet reactivity were similar between groups with all assays at all time points. In DM patients with coronary artery disease, ticagrelor exerts similar or greater inhibition of ADP-induced platelet reactivity in comparison with prasugrel in the acute and chronic phases of treatment, whereas the inhibition of measures of non-ADP-induced platelet reactivity was not significantly different between the 2 agents. URL: http://www.clinicaltrials.gov. Unique identifier: NCT01852214. © 2016 American Heart Association, Inc.

Do Asian renal transplant patients need another mycophenolate mofetil dose compared with Caucasian or African American patients?

PubMed

Li, Pengmei; Shuker, Nauras; Hesselink, Dennis A; van Schaik, Ron H N; Zhang, Xianglin; van Gelder, Teun

2014-10-01

Mycophenolate mofetil (MMF) is used to prevent acute rejection following solid organ transplantation in transplant centers all over the world. Patients from different ethnic backgrounds are treated with this drug, for which therapeutic drug monitoring (TDM) has not become the standard of practice in most centers. Whether or not some ethnic groups require a different MMF dose has been a topic of debate in recent years. In this review, it is shown that Asian patients, compared with Caucasian patients, with a comparable MMF dose reach higher mycophenolic acid (MPA) exposure. Also clinical experience points toward more adverse events in case of treatment with 1 g MMF bid in Asian patients, and therefore, for this ethnic group, a lower maintenance dose seems justified. In contrast, African American patients reach similar drug concentrations as Caucasians patients receiving the same MMF dose, but due to immunological reasons, they require a higher MMF dose to reach comparable acute rejection incidences. When TDM is performed, clinicians can correct the dose and compensate for interethnic differences in drug exposure. Otherwise, it is important to choose the right dose. This optimal dose is 20-46% lower in Asian transplant recipients than in Caucasian or African American patients. © 2014 Steunstichting ESOT.

Three different up-titration regimens of ponesimod, an S1P1 receptor modulator, in healthy subjects.

PubMed

Scherz, Michael W; Brossard, Patrick; D'Ambrosio, Daniele; Ipek, Murat; Dingemanse, Jasper

2015-06-01

Ponesimod is a selective S1P1 receptor modulator, and induces dose-dependent reduction of circulating lymphocytes upon oral dosing. Previous studies showed that single doses up to 75 mg or multiple doses up to 40 mg once daily are well tolerated, and heart rate (HR) reduction and atrio-ventricular conduction delays upon treatment initiation are reduced by gradual up-titration to the maintenance dose. This single-center, open-label, randomized, multiple-dose, 3-treatment, 3-way crossover study compared the tolerability, safety, pharmacokinetics, cardiodynamics, and effects on lymphocytes of 3 different up-titration regimens of ponesimod in healthy male and female subjects. Up-titration regimens comprised escalating periods of b.i.d. dosing (2.5 or 5 mg) and q.d. dosing (10 or 20 mg or both). After the third up-titration period a variable-duration washout period of 1-3 days was followed by re-challenge with a single 20-mg dose of ponesimod. Adverse events were transient and mild to moderate in intensity, not different between regimens. HR decrease after the first dose was greater than after all subsequent doses, including up-titration doses. Little or no HR change was observed with morning doses of b.i.d. regimens, suggesting that 2.5 and 5 mg b.i.d. are sufficient to sustain cardiac desensitization for the 12-hours dosing interval. © 2015, The American College of Clinical Pharmacology.

Efficacy and Safety of Escalation of Adalimumab Therapy to Weekly Dosing in Pediatric Patients with Crohn's Disease.

PubMed

Dubinsky, Marla C; Rosh, Joel; Faubion, William A; Kierkus, Jaroslaw; Ruemmele, Frank; Hyams, Jeffrey S; Eichner, Samantha; Li, Yao; Huang, Bidan; Mostafa, Nael M; Lazar, Andreas; Thakkar, Roopal B

2016-04-01

The efficacy of adalimumab in inducing and maintaining remission in children with moderately to severely active Crohn's disease was shown in the IMAgINE 1 trial (NCT00409682). As per protocol, nonresponders or patients experiencing flare(s) on every other week (EOW) maintenance dosing could escalate to weekly dosing; we aimed to determine the therapeutic benefits of weekly dose escalation in this subpopulation. Week 52 remission and response rates were assessed in patients who escalated to weekly dosing from their previous EOW schedule, which was according to randomized treatment dose (higher dose [HD] adalimumab [≥40 kg, 40 mg EOW; <40 kg, 20 mg EOW] or lower dose [LD; ≥40 kg, 20 mg EOW; <40 kg, 10 mg EOW]). Adverse events were reported for patients remaining on EOW dosing and patients receiving weekly dosing. Escalation to weekly dosing occurred in 48/95 (50.5%) patients randomized to LD and 35/93 (37.6%) patients randomized to HD adalimumab (P = 0.076). Week 52 remission and response rates were 18.8% and 47.9% for patients receiving LD adalimumab weekly and 31.4% and 57.1% for patients receiving HD adalimumab weekly, respectively (LD versus HD, P = 0.19 for remission; P = 0.41 for response). Adverse event rates were similar for patients receiving EOW and weekly adalimumab. Weekly adalimumab dosing was clinically beneficial for children with Crohn's disease who experienced nonresponse or flare on EOW dosing. No increased safety risks were observed with weekly dosing.

Activity of Oral ALS-008176 in a Respiratory Syncytial Virus Challenge Study.

PubMed

DeVincenzo, John P; McClure, Matthew W; Symons, Julian A; Fathi, Hosnieh; Westland, Christopher; Chanda, Sushmita; Lambkin-Williams, Rob; Smith, Patrick; Zhang, Qingling; Beigelman, Leo; Blatt, Lawrence M; Fry, John

2015-11-19

BACKGROUND Respiratory syncytial virus (RSV) infection is a cause of substantial morbidity and mortality. There is no known effective therapy. METHODS We conducted a randomized, double-blind, clinical trial in healthy adults inoculated with RSV. Participants received the oral nucleoside analogue ALS-008176 or placebo 12 hours after confirmation of RSV infection or 6 days after inoculation. Treatment was administered every 12 hours for 5 days. Viral load, disease severity, resistance, and safety were measured throughout the 28-day study period, with measurement beginning before inoculation. The primary end point was the area under the curve (AUC) for viral load, which was assessed immediately before administration of the first dose through the 12th day after inoculation in participants infected with RSV. RESULTS A total of 62 participants received placebo or one of three ALS-008176 dosing regimens: 1 loading dose of 750 mg followed by 9 maintenance doses of 500 mg (group 1), 1 loading dose of 750 mg followed by 9 maintenance doses of 150 mg (group 2), or 10 doses of 375 mg (group 3). In the 35 infected participants (23 of whom were treated with ALS-008176), the AUCs for viral load for groups 1, 2, and 3 and the placebo group were 59.9, 73.7, 133.4, and 500.9 log10 plaque-forming-unit equivalents × hours per milliliter, respectively (P≤0.001). The time to nondetectability on polymerase-chain-reaction assay (P<0.001), the peak viral load (P≤0.001), the AUC for symptom score (P<0.05), and the AUC for mucus weight were lower in all groups receiving ALS-008176 than in the placebo group. Antiviral activity was greatest in the two groups that received a loading dose--viral clearance was accelerated (P≤0.05), and the AUC for viral load decreased by 85 to 88% as compared with the placebo group. Within this small trial, no viral rebound or resistance was identified. There were no serious adverse events, and there was no need for premature discontinuation of the study drug. CONCLUSIONS In this RSV challenge study, more rapid RSV clearance and a greater reduction of viral load, with accompanying improvements in the severity of clinical disease, were observed in the groups treated with ALS-008176 than in the placebo group. (Funded by Alios BioPharma; ClinicalTrials.gov number, NCT02094365.).

Charging for hospital pharmaceutical services: flat free based on the medication record.

PubMed

Wyatt, B K

1979-03-01

A 200-bed hospital's change in pricing drug products from a cost-plus-fee system to a flat fee per dose based on the medication administration record (MAR) is described. With the flat-fee system, drug charges are not recorded when the drug is dispensed by the pharmacy; data for charging doses are obtained directly from the MAR forms generated by the nursing staff. Charges are 55 cents per oral or suppository dose and $3.00 per injection dose. Drugs administered intravenously, topical drugs, injections costing more than $10.00 per dose, and miscellaneous nondrug items are still charged on a cost-plus-fee basis. Man-hours are saved in the pharmacy department because of the elimination of the pricing function and maintenance of price lists. The need for nursing staff to charge for any doses administered from emergency or Schedule II floor-stock supplies is eliminated. The workload for business office personnel is reduced because the number of individual charges is less than with the cost-plus charging system. The system is accepted by patients and third-party payers and has made a complete unit dose drug distribution system possible at lower cost.

Dyshidrotic eczema associated with the use of IVIg

PubMed Central

Kotan, Dilcan; Erdem, Teoman; Acar, Bilgehan Atilgan; Boluk, Ayhan

2013-01-01

Intravenous immunoglobulin (IVIg) treatment is highly effective for autoimmune diseases including myasthenia gravis. Recovery is observed at approximately. 75% of myasthenia gravis patients through IVIg treatment. As a result of many clinical studies, the recommended dose is determined as 0.4 g/kg for 5 days (maximum total dose at 2 g/kg body weight). If an additional immunomodulatory treatment is not administered, IVIg maintenance treatment is needed mostly. However, some side effects may inhibit long-term treatment. For this reason, it is important to know the effect profile well and when the treatment should be discontinued. A female myasthenia gravis patient case is presented here, where dyshidrotic eczema has occurred after the second dose of  intravenous Ig medication and whose treatment is despite further IVIg therapy. PMID:23417935

[Examination of patient dose reduction in cardiovasucular X-ray systems with a metal filter].

PubMed

Yasuda, Mitsuyoshi; Kato, Kyouichi; Tanabe, Nobuaki; Sakiyama, Koushi; Uchiyama, Yushi; Suzuki, Yoshiaki; Suzuki, Hiroshi; Nakazawa, Yasuo

2012-01-01

In interventional X-ray for cardiology of flat panel digital detector (FPD), the phenomenon that exposure dose was suddenly increased when a subject thickness was thickened was recognized. At that time, variable metal built-in filters in FPD were all off. Therefore, we examined whether dose reduction was possible without affecting a clinical image using metal filter (filter) which we have been conventionally using for dose reduction. About 45% dose reduction was achieved when we measured an exposure dose at 30 cm of acrylic thickness in the presence of a filter. In addition, we measured signal to noise ratio/contrast to noise ratio/a resolution limit by the visual evaluation, and there was no influence by filter usage. In the clinical examination, visual evaluation of image quality of coronary angiography (40 cases) using a 5-point evaluation scale by a physician was performed. As a result, filter usage did not influence the image quality (p=NS). Therefore, reduction of sudden increase of exposure dose was achieved without influencing an image quality by adding filter to FPD.

Profiles of For-Profit Educational Management Organizations: Eleventh Annual Report

ERIC Educational Resources Information Center

Molnar, Alex; Miron, Gary; Urschel, Jessica

2009-01-01

Education management organizations, or EMOs, emerged in the early 1990s in the context of widespread interest in so-called market-based school reform proposals. Wall Street analysts coined the term EMO as an analogue to health maintenance organizations (HMOs). Proponents of EMOs claim that they bring a much needed dose of entrepreneurial spirit…

Erotic Imagery and Self-Castration in Transvestism/Transsexualism: A Case Report

ERIC Educational Resources Information Center

van Kammen, Daniel P.; Money, John

1977-01-01

After nearly 30 years of marriage, a 51-year-old man castrated himself to fulfill a long-standing fantasy of being a girl. It led the patient to elect low-dose maintenance on androgen to permit some degree of continued marital sex. The rehabilitative program as a transvestite man has continued for three years. (Author)

Methadone maintenance treatment (MMT): a review of historical and clinical issues.

PubMed

Joseph, H; Stancliff, S; Langrod, J

2000-01-01

Methadone maintenance has been evaluated since its development in 1964 as a medical response to the post-World War II heroin epidemic in New York City. The findings of major early studies have been consistent. Methadone maintenance reduces and/or eliminates the use of heroin, reduces the death rates and criminality associated with heroin use, and allows patients to improve their health and social productivity. In addition, enrollment in methadone maintenance has the potential toreduce the transmission of infectious diseases associated with heroin injection, such as hepatitis and HIV. The principal effects of methadone maintenance are to relieve narcotic craving, suppress the abstinence syndrome, and block the euphoric effects associated with heroin. A majority of patients require 80-120 mg/d of methadone, or more, to achieve these effects and require treatment for an indefinite period of time, since methadone maintenance is a corrective but not a curative treatment for heroin addiction. Lower doses may not be as effective or provide the blockade effect. Methadone maintenance has been found to be medically safe and nonsedating. It is also indicated for pregnant women addicted to heroin. Reviews issued by the Institute of Medicine and the National Institutes of Health have defined narcotic addiction as a chronic medical disorder and have claimed that methadone maintenance coupled with social services is the most effective treatment for this condition. These agencies recommend reducing governmental regulation to facilitate patients access to treatment. In addition, they recommend that the number of programs be expanded, and that new models of treatment be implemented,if the nationwide problem of addiction is to be brought under control. The National Institutes of Health also recommend that methadone maintenance be available to persons under legal supervision, such as probationers, parolees and the incarcerated. However, stigma and bias directed at the programs and the patients have hindered expansion and the effective delivery of services. Professional community leadership is necessary to educate the general public if these impediments are to be overcome.

Social network influences on initiation and maintenance of reduced drinking among college students.

PubMed

Reid, Allecia E; Carey, Kate B; Merrill, Jennifer E; Carey, Michael P

2015-02-01

To determine whether (a) social networks influence the extent to which college students initiate and/or maintain reductions in drinking following an alcohol intervention and (b) students with riskier networks respond better to a counselor-delivered, vs. a computer-delivered, intervention. Mandated students (N = 316; 63% male) provided their perceptions of peer network members' drinking statuses (e.g., heavy drinker) and how accepting each friend would be if the participant reduced his or her drinking. Next, they were randomized to receive a brief motivational intervention (BMI) or Alcohol Edu for Sanctions (EDU). In latent growth models controlling for baseline levels on outcomes, influences of social networks on 2 phases of intervention response were examined: initiation of reductions in drinks per heaviest week, peak blood alcohol content (BAC), and consequences at 1 month (model intercepts) and maintenance of reductions between 1 and 12 months (model slopes). Peer drinking status predicted initiation of reductions in drinks per heaviest week and peak BAC; peer acceptability predicted initial reductions in consequences. Peer Acceptability × Condition interactions were significant or marginal for all outcomes in the maintenance phase. In networks with higher perceived acceptability of decreasing use, BMI and EDU exhibited similar growth rates. In less accepting networks, growth rates were significantly steeper among EDU than BMI participants. For consumption outcomes, lower perceived peer acceptability predicted steeper rates of growth in drinking among EDU but not BMI participants. Understanding how social networks influence behavior change and how interventions mitigate their influence is important for optimizing efficacy of alcohol interventions. (PsycINFO Database Record (c) 2015 APA, all rights reserved).

Using Animal Models to Determine the Role of Gustatory Neural Input in the Control of Ingestive Behavior and the Maintenance of Body Weight

PubMed Central

Ciullo, Dana L.

2015-01-01

Introduction Decades of research have suggested that nutritional intake contributes to the development of human disease, mainly by influencing the development of obesity and obesity-related conditions. A relatively large body of research indicates that functional variation in human taste perception can influence nutritional intake as well as body mass accumulation. However, there are a considerable number of studies that suggest that no link between these variables actually exists. These discrepancies in the literature likely result from the confounding influence of a variety of other, uncontrolled, factors that can influence ingestive behavior. Strategy In this review, the use of controlled animal experimentation to alleviate at least some of these issues related to the lack of control of experimental variables is discussed. Specific examples of the use of some of these techniques are examined. Discussion and conclusions The review will close with some specific suggestions aimed at strengthening the link between gustatory neural input and its putative influence on ingestive behaviors and the maintenance of body weight. PMID:26557212

Rapid Syllable Transitions (ReST) treatment for Childhood Apraxia of Speech: the effect of lower dose-frequency.

PubMed

Thomas, Donna C; McCabe, Patricia; Ballard, Kirrie J

2014-01-01

This study investigated the effectiveness of twice-weekly Rapid Syllable Transitions (ReST) treatment for Childhood Apraxia of Speech (CAS). ReST is an effective treatment at a frequency of four sessions a week for three consecutive weeks. In this study we used a multiple-baselines across participants design to examine treatment efficacy for four children with CAS, aged four to eight years, who received ReST treatment twice a week for six weeks. The children's ability to acquire new skills, generalize these skills to untreated items and maintain the skills after treatment was examined. All four children improved their production of the target items. Two of the four children generalized the treatment effects to similar untreated pseudo words and all children generalized to untreated real words. During the maintenance phase, all four participants maintained their skills to four months post-treatment, with a stable rather than rising profile. This study shows that ReST treatment delivered twice-weekly results in significant retention of treatment effects to four months post-treatment and generalization to untrained but related speech behaviors. Compared to ReST therapy four times per week, the twice-weekly frequency produces similar treatment gains but no ongoing improvement after the cessation of treatment. This implies that there may be a small but significant benefit of four times weekly therapy compared with twice-weekly ReST therapy. Readers will be able to define dose-frequency, and describe how this relates to overall intervention intensity. Readers will be able to explain the acquisition, generalization and maintenance effects in the study and describe how these compare to higher dose frequency treatments. Readers will recognize that the current findings give preliminary support for high dose-frequency CAS treatment. Copyright © 2014 Elsevier Inc. All rights reserved.

Gamma irradiation of sun-dried apricots ( Prunus armeniaca L.) for quality maintenance and quarantine purposes

NASA Astrophysics Data System (ADS)

Hussain, Peerzada R.; Meena, Raghuveer S.; Dar, Mohd A.; Wani, Ali M.

2011-07-01

The study is aimed at the optimization of gamma irradiation treatment of sun-dried apricots for quality maintenance and quarantine purposes. Sun-dried apricots pre-treated with potassium meta-bisulphite (KMS) at 2.5% w/v were procured from progressive apricot grower of district Kargil, Ladakh region of Jammu and Kashmir state. The sun-dried apricots were packed in 250 gauge polyethylene packs and gamma irradiated in the dose range 1.0-3.0 kGy. The gamma irradiated fruit including control was stored under ambient (15±2-25±2 °C, RH 70-80%) conditions and periodically evaluated for physico-chemical, sensory and microbial quality parameters. Radiation treatment at dose levels of 2.5 and 3.0 kGy proved significantly ( p≤0.05) beneficial in retention of higher levels of β-carotene, ascorbic acid, total sugars and color values without impairing the taste as perceived by the sensory panel analysists. The above optimized doses retained the β-carotene content of sun-dried apricots to the extent of 71.2% and 72.6% compared to 63.9% in control samples after 18 months of storage. Irradiation treatment facilitated the release of residual sulfur dioxide in KMS pre-treated sun-dried apricots significantly ( p≤0.05) below the prescribed limit for dried products. During storage, two-fold decrease in sulfur dioxide content was recorded in irradiated samples (3.0 kGy) as compared to 16.9% in control. The above optimized doses besides maintaining the higher overall acceptability of sun-dried apricots resulted in 5 log reductions in microbial load just after irradiation and 1.0 and 1.3 log reductions in yeast and mold and bacterial count after 18 months of ambient storage.

Cebranopadol, a novel first-in-class analgesic drug candidate: first experience in patients with chronic low back pain in a randomized clinical trial.

PubMed

Christoph, Annette; Eerdekens, Marie-Henriette; Kok, Maurits; Volkers, Gisela; Freynhagen, Rainer

2017-09-01

Chronic low back pain (LBP) is a common condition, usually with the involvement of nociceptive and neuropathic pain components, high economic burden and impact on quality of life. Cebranopadol is a potent, first-in-class drug candidate with a novel mechanistic approach, combining nociceptin/orphanin FQ peptide and opioid peptide receptor agonism. We conducted the first phase II, randomized, double-blind, placebo- and active-controlled trial, evaluating the analgesic efficacy, safety, and tolerability of cebranopadol in patients with moderate-to-severe chronic LBP with and without neuropathic pain component. Patients were treated for 14 weeks with cebranopadol 200, 400, or 600 μg once daily, tapentadol 200 mg twice daily, or placebo. The primary efficacy endpoints were the change from baseline pain to the weekly average 24-hour pain during the entire 12 weeks and during week 12 of the maintenance phase. Cebranopadol demonstrated analgesic efficacy, with statistically significant and clinically relevant improvements over placebo for all doses as did tapentadol. The responder analysis (≥30% or ≥50% pain reduction) confirmed these results. Cebranopadol and tapentadol displayed beneficial effects on sleep and functionality. Cebranopadol treatment was safe, with higher doses leading to higher treatment discontinuations because of treatment-emergent adverse events occurring mostly during titration. Those patients reaching the target doses had an acceptable tolerability profile. The incidence rate of most frequently reported treatment-emergent adverse events during maintenance phase was ≤10%. Although further optimizing the titration scheme to the optimal dose for individual patients is essential, cebranopadol is a new drug candidate with a novel mechanistic approach for potential chronic LBP treatment.

Different effects of propofol and isoflurane on cochlear blood flow and hearing function in Guinea pigs.

PubMed

Xiao, Ying; Wen, Jian; Bai, Yanxia; Duan, Na; Jing, G X

2014-01-01

To investigate the effects of isoflurane and propofol on mean arterial pressure (MAP), cochlear blood flow (CoBF), distortion-product otoacoustic emission (DPOAE), and the ultrastructure of outer hair cells (OHCs) in guinea pig cochleae. Forty-eight male guinea pigs were randomly assigned to one of six treatment groups. Groups 1 to 3 were infused (i.v.) with a loading dose of propofol (5 mg/kg) for 5 min and three maintenance doses (10, 20, or 40 mg kg-1·h-1, respectively) for 115 min. Groups 4 to 6 were inhaled with isoflurane at concentrations of 1.15 vol%, 2.30 vol% or 3.45 vol% respectively for 120 min. CoBF and MAP were recorded prior to and at 5 min intervals during drug administration. DPOAE was measured before, immediately after, and 1 h after administration. Following the final DPOAE test, cochleae were examined using scanning electron microscopy. Propofol treatment reduced MAP in a dose-dependent manner. CoBF and DPOAE showed increases at propofol maintenance doses of 10 and 20 mg kg-1·h-1. Inhalation of isoflurane at concentrations of 2.30 vol% and 3.45 vol% reduced MAP and CoBF. DPOAE amplitude increased following inhalation of 1.15 vol% isoflurane, but decreased following inhalations of 2.30 vol% and 3.45 vol%. Cochlear structure was changed following inhalation of either 2.30 vol% or 3.45 vol% isoflurane. Propofol could decrease MAP and increase both CoBF and DPOAE without affecting OHC structure. Inhalation of isoflurane at concentrations >2.30 vol% decreased CoBF and DPOAE, and produced injury to OHCs.

Insect sting allergy in adults: key messages for clinicians.

PubMed

Nittner-Marszalska, Marita; Cichocka-Jarosz, Ewa

2015-01-01

During their lifetime, 94.5% of people are stung by wasps, honeybees, hornets, or bumblebees (order Hymenoptera). After a sting, most people show typical local symptoms, 5% to 15% develop local allergic reactions, and 3% to 8.9%--systemic allergic reactions (SARs), which may be potentially life-threatening in about 10% of them. In mild forms of Hymenoptera-venom allergy (HVA), the leading symptoms are urticaria and edema (grades I and II, respectively, according to the Mueller classification). Severe SARs are classified as grade III (respiratory symptoms) and IV (cardiovascular symptoms). Rare manifestations of HVA are Kounis syndrome and takotsubo cardiomyopathy. All patients after an SAR require standard (skin test, IgE, tryptase) or comprehensive (component diagnosis, basophil activation test) allergy testing. All patients with severe systemic symptoms (hypertension, disturbances in consciousness) should be tested for mastocytosis. Additionally, a relationship was found between the severity of HVA symptoms and intake of angiotensin-converting enzyme inhibitors (ACEIs). There is a similar concern, although less well-documented, about the use of β-blockers. Patients with HVA who have experienced a SAR are potential candidates for venom immunotherapy (VIT), which is effective in 80% to 100% of individuals treated for 3 to 5 years. An increased risk of a VIT failure has been reported in patients with systemic mastocytosis and those treated with ACEIs. In certain groups (beekeepers, patients who develop a SAR to stings during a VIT with a standard dose, as well as those with a SAR to maintenance doses of VIT), a twice higher maintenance dose is recommended. Indications, contraindications, treatment protocols, and vaccine doses are regulated by the international guidelines of allergy societies.

Prasugrel Results in Higher Decrease in High-Sensitivity C-Reactive Protein Level in Patients Undergoing Percutaneous Coronary Intervention Comparing to Clopidogrel.

PubMed

Hajsadeghi, Shokoufeh; Chitsazan, Mandana; Chitsazan, Mitra; Salehi, Negar; Amin, Ahmad; Bidokhti, Arash Amin; Babaali, Nima; Bordbar, Armin; Hejrati, Maral; Moghadami, Samar

2016-01-01

A growing body of clinical and laboratory evidence indicates that inflammation plays a crucial role in atherosclerosis. In the present study, we compared the effects of clopidogrel and prasugrel on high-sensitivity C-reactive protein (hs-CRP) in patients undergoing percutaneous coronary intervention (PCI). The present randomized, double-blind clinical trial included 120 patients who underwent PCI. Eligible patients were randomly assigned 2:1 to one of the two groups: 80 patients in the first group received clopidogrel (Plavix(®); loading dose and maintenance dose of 300 and 75 mg daily, respectively) and 40 patients in the second group received prasugrel (Effient(®); loading dose and maintenance dose of 60 and 10 mg, respectively) for 12 weeks. The hs-CRP levels between baseline and 12th week were compared. Of the 120 patients, 69 patients (57.5%) were male. Pretreatment hs-CRP level was statistically comparable in clopidogrel (median, 15.10 mg/dL; interquartile range [IQR], 9.62-23.75 mg/dL) and prasugrel groups (median, 18 mg/dL; IQR, 14.25-22 mg/dL; P = 0.06). Patients taking clopidogrel showed a significant reduction in hs-CRP level compared with the baseline values (P < 0.001). Prasugrel administration also resulted in a significant reduction in hs-CRP level (P < 0.001). A significant 73% overall reduction in the hs-CRP level was seen with prasugrel compared with 39% overall reduction in hs-CRP level with clopidogrel (P = 0.002). Prasugrel seems to be superior to clopidogrel in the reduction of hs-CRP in patients undergoing PCI.

Once-daily versus multiple-daily mesalamine for patients with ulcerative colitis: a meta-analysis.

PubMed

Tong, Jin Lu; Huang, Mei Lan; Xu, Xi Tao; Qiao, Yu Qi; Ran, Zhi Hua

2012-04-01

To systematically review the efficacy and safety of once-daily (OD) mesalamine for the treatment of ulcerative colitis (UC) compared with multiple-daily (MD) mesalamine. Electronic databases up to July 2011 were searched for related studies evaluating the efficacy of OD vs MD for treatment of UC. Only randomized controlled trials (RCTs) were considered eligible. Remission rates or relapse rates were analyzed using intention-to-treat (ITT) and per-protocol (PP) analysis. Pooled relative risk (RR) and 95% confidence interval (CI) were calculated. Publication bias was assessed with a funnel plot. Overall 10 RCTs including 9 full-text manuscripts and one abstract met the inclusion criteria. OD dosing of mesalamine was shown to be as effective as MD dosing for the maintenance of clinical remission in patients with quiescent UC (RR = 1.00, 95% CI 0.89-1.12) by ITT analysis. For active UC, a mild but significant benefit was achieved by OD dosing compared with MD dosing (RR = 0.80, 95% CI 0.64-0.99). Total adverse events were similar using OD and MD mesalamine in quiescent UC (RR = 1.06, 95% CI 0.93-1.20). Compliance with OD was slightly better than with MD (RR = 0.92, 95% CI 0.82-1.03). OD mesalamine is as effective and has a comparable safety profile as MD regimens for the maintenance treatment of UC, and is even more effective for inducing remission in active UC. © 2012 The Authors. Journal of Digestive Diseases © 2012 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and Blackwell Publishing Asia Pty Ltd.

Refuting the ticagrelor-aspirin black box warning: and proposing a ticagrelor early-PCI black box warning.

PubMed

DiNicolantonio, James J; Serebruany, Victor L; Tomek, Ales

2013-10-03

Ticagrelor, a novel reversible antiplatelet agent, has a black box warning to avoid maintenance doses of aspirin>100mg. However, a significant ticagrelor-early percutaneous coronary intervention (PCI) interaction exists. To discuss the inappropriateness of the black box warning for aspirin doses>100mg with ticagrelor and the appropriateness (and need) for a black box warning for ticagrelor patients needing early (within 24 hours of randomization) PCI. The FDA Complete Response Review for ticagrelor indicates that aspirin doses ≥ 300 mg/daily was not a significant interaction. In the ticagrelor-aspirin ≥ 300 mg cohort, all-cause mortality (through study end) and cardiovascular (CV) mortality (through study end) were not significantly increased (HR=1.27; 95% CI, 0.84-1.93, p=0.262 and HR=1.39; 95% CI:0.87-2.2, p=0.170), respectively. However, in patients treated with early (within 24 hours) PCI, ticagrelor significantly increased all-cause mortality (30 day: HR=1.89; 95% CI: 1.26-2.81, p=0.002, and through study end, HR=1.41; 95% CI,1.08-1.84, p=0.012) and increased CV mortality (30 day: HR=1.31; 95% CI: 0.97-1.77, p=0.075, and through study end, HR=1.35; 95% CI, 0.995-1.82, p=0.054) compared to clopidogrel. Early-PCI was more prevalent in the US versus outside-US regions (61% versus 49%). The black box warning for the use of maintenance aspirin doses over 100mg/daily with ticagrelor is inappropriate and ignores the more important, credible, and highly significant ticagrelor-early PCI adverse interaction in PLATO. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Morphine, Nortriptyline and their Combination vs. Placebo in Patients with Chronic Lumbar Root Pain

PubMed Central

Khoromi, Suzan; Cui, Lihong; Nackers, Lisa; Max, Mitchell B.

2007-01-01

Although lumbar radicular pain is the most common chronic neuropathic pain syndrome, there have been few randomized studies of drug treatments. We compared the efficacy of morphine (15–90 mg), nortriptyline (25 –100 mg), their combination, and a benztropine “active placebo” (0.25-1 mg) in patients with chronic sciatica. Each period consisted of 5 weeks of dose escalation, 2 weeks of maintenance at the highest tolerated doses, and 2 weeks of dose tapering. The primary outcome was the mean daily leg pain score on a 0–10 scale during the maintenance period. Secondary outcomes included a 6-point ordinal global pain relief scale, the Beck Depression Inventory (BDI), the Oswestry Back Pain Disability Index (ODI) and the SF-36. In the 28 out of 61 patients who completed the study, none of the treatments produced significant reductions in average leg pain or other leg or back pain scores. Pain reduction, relative to placebo treatment was 14% for nortriptyline (95% CI= [−2%, 30%]), 7% for morphine (95% CI= [−8%, 22%]), and 7% for the combination treatment (95% CI= [−4%, 18%]). Mean doses were: nortriptyline alone, 84 +/− 24.44 (SD)mg/day; morphine alone, 62 +/−29mg/day; and combination, morphine, 49 +/−27 mg/day plus nortriptyline, 55 mg+/− 33.18 mg/day. Over half of the study completers reported some adverse effect with morphine, nortriptyline or their combination. Within the limitations of the modest sample size and high dropout rate, these results suggest that nortriptyline, morphine and their combination may have limited effectiveness in the treatment of chronic sciatica. PMID:17182183

Pharmacological Modulation of the Mitochondrial Electron Transport Chain in Paclitaxel-Induced Painful Peripheral Neuropathy.

PubMed

Griffiths, Lisa A; Flatters, Sarah J L

2015-10-01

Paclitaxel is an effective first-line chemotherapeutic with the major dose-limiting side effect of painful neuropathy. Mitochondrial dysfunction and oxidative stress have been implicated in paclitaxel-induced painful neuropathy. Here we show the effects of pharmacological modulation of mitochondrial sites that produce reactive oxygen species using systemic rotenone (complex I inhibitor) or antimycin A (complex III inhibitor) on the maintenance and development of paclitaxel-induced mechanical hypersensitivity in adult male Sprague Dawley rats. The maximally tolerated dose (5 mg/kg) of rotenone inhibited established paclitaxel-induced mechanical hypersensitivity. However, some of these inhibitory effects coincided with decreased motor coordination; 3 mg/kg rotenone also significantly attenuated established paclitaxel-induced mechanical hypersensitivity without any motor impairment. The maximally tolerated dose (.6 mg/kg) of antimycin A reversed established paclitaxel-induced mechanical hypersensitivity without any motor impairment. Seven daily doses of systemic rotenone or antimycin A were given either after paclitaxel administration or before and during paclitaxel administration. Rotenone had no significant effect on the development of paclitaxel-induced mechanical hypersensitivity. However, antimycin A significantly inhibited the development of paclitaxel-induced mechanical hypersensitivity when given before and during paclitaxel administration but had no effect when given after paclitaxel administration. These studies provide further evidence of paclitaxel-evoked mitochondrial dysfunction in vivo, suggesting that complex III activity is instrumental in paclitaxel-induced pain. This study provides further in vivo evidence that mitochondrial dysfunction is a key contributor to the development and maintenance of chemotherapy-induced painful neuropathy. This work also indicates that selective modulation of the electron transport chain can induce antinociceptive effects in a preclinical model of paclitaxel-induced pain. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Peritubular Myoid Cells Participate in Male Mouse Spermatogonial Stem Cell Maintenance

PubMed Central

Chen, Liang-Yu; Brown, Paula R.; Willis, William B.

2014-01-01

Peritubular myoid (PM) cells surround the seminiferous tubule and together with Sertoli cells form the cellular boundary of the spermatogonial stem cell (SSC) niche. However, it remains unclear what role PM cells have in determining the microenvironment in the niche required for maintenance of the ability of SSCs to undergo self-renewal and differentiation into spermatogonia. Mice with a targeted disruption of the androgen receptor gene (Ar) in PM cells experienced a progressive loss of spermatogonia, suggesting that PM cells require testosterone (T) action to produce factors influencing SSC maintenance in the niche. Other studies showed that glial cell line-derived neurotrophic factor (GDNF) is required for SSC self-renewal and differentiation of SSCs in vitro and in vivo. This led us to hypothesize that T-regulated GDNF expression by PM cells contributes to the maintenance of SSCs. This hypothesis was tested using an adult mouse PM cell primary culture system and germ cell transplantation. We found that T induced GDNF expression at the mRNA and protein levels in PM cells. Furthermore, when thymus cell antigen 1-positive spermatogonia isolated from neonatal mice were cocultured with PM cells with or without T and transplanted to the testes of germ cell-depleted mice, the number and length of transplant-derived colonies was increased considerably by in vitro T treatment. These results support the novel hypothesis that T-dependent regulation of GDNF expression in PM cells has a significant influence on the microenvironment of the niche and SSC maintenance. PMID:25181385

A high polymerized grass pollen extract is efficacious and safe in a randomized double-blind, placebo-controlled study using a novel up-dosing cluster-protocol

PubMed Central

Klimek, L; Uhlig, J; Mösges, R; Rettig, K; Pfaar, O

2014-01-01

Background Cluster immunotherapy represents an interesting alternative to conventional up-dosing schedules because it allows achieving the maintenance dose within a shorter time interval. In this study, the efficacy and safety of cluster immunotherapy with a high polymerized allergen extract of a grass/rye pollen mixture have been evaluated in a randomized, double-blind, placebo-controlled, multicenter study. Methods In total, 121 patients with allergic rhinoconjunctivitis due to grass pollen were randomized 1 : 1 to verum or placebo group. A short cluster up-dosing schedule of only 1 week was applied to achieve the maintenance dose which was administered monthly during the study period of 1 year. Total combined symptom and medication score (TCS) was defined as primary outcome parameter. Secondary outcome parameters were individual symptom and medication scores, ‘well days,’ global improvement as well as immunological effects and nasal allergen challenge. The safety profile was evaluated based on the European academy of allergy and clinical immunology grading system. Results Significant reduction in the verum compared to the placebo group (intention-to-treat, population, verum: n = 55; placebo: n = 47) was found regarding TCS (P = 0.005), rhinoconjunctivitis total symptom score (RTSS, P = 0.006), and total rescue medication score (TRMS, P = 0.002). Additionally, secondary outcomes such as ‘well days,’ nasal challenge results, and increase of specific IgG4 were in favor of the active treatment. All systemic adverse reactions (0.8% of all injections in the verum group) were of mild intensity. No severe reactions related to the study medication were observed. Conclusion Cluster immunotherapy with high polymerized grass pollen extracts resulted in significant clinical efficacy and has been shown to be a safe treatment for grass pollen-allergic patients. PMID:25130503

Treatment patterns of adjuvant interferon-α2b for high-risk melanoma: a retrospective study of the Grupo Español Multidisciplinar de Melanoma – Prima study

PubMed Central

Soriano, Virtudes; Malvehy, Josep; Berrocal, Alfonso; Martínez de Prado, Purificación; Quindós, María; Soria, Ainara; Márquez-Rodas, Iván; Palacio, Isabel; Cerezuela, Pablo; López-Vivanco, Guillermo; Alonso, Lorenzo; Samaniego, Elia; Ballesteros, Ana; Puértolas, Teresa; Díaz-Beveridge, Rodrigo; de la Cruz-Merino, Luis; López Castro, Rafael; López López, Rafael; Stevinson, Kendall; del Barrio, Patricia; Tornamira, Maria V.; Guillém, Vicente; Martín-Algarra, Salvador

2016-01-01

Adjuvant interferon-α2b (IFN-α2b) has been studied extensively in clinical trials, but there have been few studies of real-world use. The aim of this study is to describe the IFN-α2b real-world patterns in patients with high-risk melanoma in Spain. This was a retrospective and multicentre chart review study of an unselected cohort of patients with melanoma at high risk for relapse (stage IIB/IIC/III) treated with IFN-α2b. Patterns were assessed in terms of dose and compliance to planned treatment. A survival analysis was carried out for the full population and according to Kirkwood scheme compliance and the presence of ulceration. Of 327 patients treated with IFN-α2b, 318 received a high-dose regimen following the standard Kirkwood scheme; thus, patterns are described for this regimen. A total of 121 (38%) and 88 (28%) patients had at least one dose reduction during the induction and maintenance phases, respectively. Dose delay was required in fewer than 10% of patients. A total of 78, 40 and 38% of the patients completed the induction phase, maintenance phase and completed treatment, respectively. The median progression-free and overall survival for the full population were 3.2 and 10.5 years, respectively. There were no differences in progression-free survival and overall survival according to Kirkwood scheme compliance and the presence of ulceration. The most frequent adverse events were neutropenia (31%) and fatigue (30%). High-dose IFN-α2b is the most frequently used regimen in Spain as an adjuvant systemic treatment for high-risk melanoma. Despite poor compliance, in this retrospective study, IFN-α2b treatment provided a benefit consistent with that described previously. PMID:26958991

Treatment patterns of adjuvant interferon-α2b for high-risk melanoma: a retrospective study of the Grupo Español Multidisciplinar de Melanoma - Prima study.

PubMed

Espinosa, Enrique; Soriano, Virtudes; Malvehy, Josep; Berrocal, Alfonso; Martínez de Prado, Purificación; Quindós, María; Soria, Ainara; Márquez-Rodas, Iván; Palacio, Isabel; Cerezuela, Pablo; López-Vivanco, Guillermo; Alonso, Lorenzo; Samaniego, Elia; Ballesteros, Ana; Puértolas, Teresa; Díaz-Beveridge, Rodrigo; de la Cruz-Merino, Luis; López Castro, Rafael; López López, Rafael; Stevinson, Kendall; Del Barrio, Patricia; Tornamira, Maria V; Guillém, Vicente; Martín-Algarra, Salvador

2016-06-01

Adjuvant interferon-α2b (IFN-α2b) has been studied extensively in clinical trials, but there have been few studies of real-world use. The aim of this study is to describe the IFN-α2b real-world patterns in patients with high-risk melanoma in Spain. This was a retrospective and multicentre chart review study of an unselected cohort of patients with melanoma at high risk for relapse (stage IIB/IIC/III) treated with IFN-α2b. Patterns were assessed in terms of dose and compliance to planned treatment. A survival analysis was carried out for the full population and according to Kirkwood scheme compliance and the presence of ulceration. Of 327 patients treated with IFN-α2b, 318 received a high-dose regimen following the standard Kirkwood scheme; thus, patterns are described for this regimen. A total of 121 (38%) and 88 (28%) patients had at least one dose reduction during the induction and maintenance phases, respectively. Dose delay was required in fewer than 10% of patients. A total of 78, 40 and 38% of the patients completed the induction phase, maintenance phase and completed treatment, respectively. The median progression-free and overall survival for the full population were 3.2 and 10.5 years, respectively. There were no differences in progression-free survival and overall survival according to Kirkwood scheme compliance and the presence of ulceration. The most frequent adverse events were neutropenia (31%) and fatigue (30%). High-dose IFN-α2b is the most frequently used regimen in Spain as an adjuvant systemic treatment for high-risk melanoma. Despite poor compliance, in this retrospective study, IFN-α2b treatment provided a benefit consistent with that described previously.

A Comparison of Fospropofol to Midazolam for Moderate Sedation During Outpatient Dental Procedures

PubMed Central

Yen, Philip; Prior, Simon; Riley, Cara; Johnston, William; Smiley, Megann; Thikkurissy, Sarat

2013-01-01

Moderate intravenous (IV) sedation combined with local anesthesia is common for outpatient oral surgery procedures. An ideal sedative agent must be safe and well tolerated by patients and practitioners. This study evaluated fospropofol, a relatively new sedative/hypnotic, in comparison to midazolam, a commonly used benzodiazepine, for IV moderate sedation during oral and maxillofacial surgery. Sixty patients were randomly assigned to either the fospropofol or the midazolam group. Each participant received 1 μg/kg of fentanyl prior to administration of the selected sedative. Those in the fospropofol group received an initial dose of 6.5 mg/kg, with 1.6 mg/kg supplemental doses as needed. Those in the midazolam group received initial doses of 0.05 mg/kg, followed by 0.02 mg/kg supplemental doses. The quality of sedation in each patient was evaluated with regard to (a) onset of sedation, maintenance, and recovery profile; (b) patient and surgeon satisfaction; and (c) hemodynamic stability and adverse effects. The fospropofol group demonstrated shorter physical recovery times than midazolam patients, taking a mean of 11.6 minutes versus 18.4 minutes for physical recovery (P = .007). Cognitive recovery comparison did not find any difference with a mean of 7.5 minutes versus 8.8 minutes between the 2 drug groups (P = .123). The fospropofol group had a higher rate of local anesthetic injection recall (90.5 vs 44.4%, P = .004). Other parameters of recall were comparable. Two adverse effects demonstrated significance, with more patients in the midazolam group experiencing tachycardia (48.2 vs 9.4%, P = .001), and more patients in the fospropofol group experiencing perineal discomfort (40.6 vs 0, P < .001). No significant difference was found in any other measures of sedation safety, maintenance, or satisfaction. Fospropofol, when administered intravenously by a dentist anesthesiologist at the indicated dose in this study, appears to be a safe, well-tolerated alternative to midazolam for intravenous moderate sedation during minor oral surgery procedures. PMID:24423419

Immunogenicity and safety of a high-dose hepatitis B vaccine among patients receiving methadone maintenance treatment: A randomized, double-blinded, parallel-controlled trial.

PubMed

Shi, Jing; Feng, Yongliang; Gao, Linying; Feng, Dan; Yao, Tian; Shi, Shan; Zhang, Yawei; Liang, Xiaofeng; Wang, Suping

2017-04-25

To explore whether the immunization with high-dose (60μg) hepatitis B vaccines in patients receiving methadone maintenance treatment (MMT) could yield a superior protection against hepatitis B infection than did the standard dose (20μg). We conducted a randomized, double-blinded, parallel-controlled trial in MMT patients. Patients with serologically negative hepatitis B surface antigen (HBsAg) and hepatitis B surface antibody (anti-HBs) were randomized in a ratio of 1:1 to receive three intramuscular injections of 20μg or 60μg recombinant hepatitis B vaccine at months 0, 1, and 6. Serum HBsAg and anti-HBs were measured at months 7 and 12 post-vaccination to assess the immunogenicity. A total of 196 MMT patients were randomized and 195 received at least one injection (98 and 97 in 20 and 60μg vaccine groups, respectively). The 60μg vaccine group showed a seroconversion of anti-HBs of 87.3%, high-level response rate of 56.3%, and GMC of 742.9mIU/mL at month 7. While these results were numerically higher than the 20μg group, a statistical difference was not found. HIV infection and concomitant drug abuse were negatively associated with the robust immune responses. 7.7% of MMT patients receiving at least one dose of vaccine reported solicited adverse reactions within 7days after vaccination, 2.6% reported unsolicited adverse reactions within 28days after vaccination. None of the MMT patients reported serious adverse events or became HBsAg positive during the follow-up. The three-dose regimen of 60μg recombinant hepatitis B vaccine at months 0, 1, and 6 can yield a similar immunogenicity among MMT patients as compared to the 20μg vaccine. ClinicalTrials.gov identifier: NCT02991599. Copyright © 2017. Published by Elsevier Ltd.

Dynamics of Implementation and Maintenance of Organizational Health Interventions.

PubMed

Jalali, Mohammad S; Rahmandad, Hazhir; Bullock, Sally Lawrence; Ammerman, Alice

2017-08-15

In this study, we present case studies to explore the dynamics of implementation and maintenance of health interventions. We analyze how specific interventions are built and eroded, how the building and erosion mechanisms are interconnected, and why we can see significantly different erosion rates across otherwise similar organizations. We use multiple comparative obesity prevention case studies to provide empirical information on the mechanisms of interest, and use qualitative systems modeling to integrate our evolving understanding into an internally consistent and transparent theory of the phenomenon. Our preliminary results identify reinforcing feedback mechanisms, including design of organizational processes, motivation of stakeholders, and communication among stakeholders, which influence implementation and maintenance of intervention components. Over time, these feedback mechanisms may drive a wedge between otherwise similar organizations, leading to distinct configurations of implementation and maintenance processes.

Anchoring of development workings in a zone of influence of mining in case of the level anchoring system

NASA Astrophysics Data System (ADS)

Demin, V. F.; Fofanov, O. B.; Demina, T. V.; Yavorskiy, V. V.

2017-02-01

Regularities of the change of the stress-strain state of coal containing rock masses, depending on mining-geological factors, were revealed. These factors allow establishing rational parameters of anchoring of wall rocks to enhance the stability of development workings. Specific conditions of the deflected mode, displays of rock pressure, terms of maintenance depending on technological parameters are investigated. Researches allowed determining the degree of their development influence on the efficiency of application of the anchoring of the hollow making and will allow a reasonable application of anchoring certificates, provide stability of the rocks mining and reduce expenses on its realization and maintenance.

Radiation effects on type I fiber Bragg gratings: influence of recoating

NASA Astrophysics Data System (ADS)

Blanchet, T.; Laffont, G.; Cotillard, R.; Marin, E.; Morana, A.; Boukenter, A.; Ouerdane, Y.; Girard, S.

2017-04-01

We investigated the Bragg Wavelength Shift (BWS) induced by X-rays in a large set of conventional FBGs up to 100kGy dose. Obtained results give some insights on the influence of irradiation parameters such as dose, dose rate as well as the impact of some writing process parameters such as thermal treatment or acrylate recoating on the FBG radiation tolerance.

The most common problem facing by the maintenance department: A case Study between Universiti Tun Hussein Onn Malaysia (UTHM) and Universiti Teknologi Malaysia (UTM)

NASA Astrophysics Data System (ADS)

Norazam Yasin, Mohd; Mohamad Zin, Rosli; Halid Abdullah, Abd; Shafiq Mahmad, Muhammad; Fikri Hasmori, Muhammad

2017-11-01

From time to time, the maintenance works become more challenging due to construction of new building and also aging of the existing buildings. University buildings without any exception require proper maintenance services to support their function requirements and this can be considered as major responsibilities to be fulfilled by the maintenance department in the universities. Maintenance department specifically will face various kinds of problems in their operation works and thus this might influence the maintenance work operations itself. This study purposely to identify the common problem facing by the maintenance department and also to examine the current status of the maintenance department. In addition, this study would also propose any suitable approach that could be implemented to overcome the problem facing by the maintenance department. To achieve the objectives of this study, a combination of deep literature study and carrying out a survey is necessary. Literature study aimed to obtain deeper information about this study, meanwhile a survey aimed at identifying the common problem facing by the maintenance department and also to provide the information of the maintenance department’s organization. Several methods will be used in analyzing the data obtained through the survey, including Microsoft Office Excel and also using mean index formula. This study has identified three categories of problem in the maintenance department, which are management problems, human resource problem, and technical problems. Following the findings, several solutions being proposed which can be implemented as the solution to the problem facing. These suggestions have the potential to improve the maintenance department work efficiency, thus could help to increase the department productivity.

Genome-health nutrigenomics and nutrigenetics: nutritional requirements or 'nutriomes' for chromosomal stability and telomere maintenance at the individual level.

PubMed

Bull, Caroline; Fenech, Michael

2008-05-01

It is becoming increasingly evident that (a) risk for developmental and degenerative disease increases with more DNA damage, which in turn is dependent on nutritional status, and (b) the optimal concentration of micronutrients for prevention of genome damage is also dependent on genetic polymorphisms that alter the function of genes involved directly or indirectly in the uptake and metabolism of micronutrients required for DNA repair and DNA replication. The development of dietary patterns, functional foods and supplements that are designed to improve genome-health maintenance in individuals with specific genetic backgrounds may provide an important contribution to an optimum health strategy based on the diagnosis and individualised nutritional prevention of genome damage, i.e. genome health clinics. The present review summarises some of the recent knowledge relating to micronutrients that are associated with chromosomal stability and provides some initial insights into the likely nutritional factors that may be expected to have an impact on the maintenance of telomeres. It is evident that developing effective strategies for defining nutrient doses and combinations or 'nutriomes' for genome-health maintenance at the individual level is essential for further progress in this research field.

Assessment of human exposure doses received by activation of medical linear accelerator components

NASA Astrophysics Data System (ADS)

Lee, D.-Y.; Kim, J.-H.; Park, E.-T.

2017-08-01

This study analyzes the radiation exposure dose that an operator can receive from radioactive components during maintenance or repair of a linear accelerator. This study further aims to evaluate radiological safety. Simulations are performed on 10 MV and 15 MV photon beams, which are the most frequently used high-energy beams in clinics. The simulation analyzes components in order of activity and the human exposure dose based on the amount of neutrons received. As a result, the neutron dose, radiation dose, and human exposure dose are ranked in order of target, primary collimator, flattening filter, multi-leaf collimator, and secondary collimator, where the minimum dose is 9.34E-07 mSv/h and the maximum is 1.71E-02 mSv/h. When applying the general dose limit (radiation worker 20 mSv/year, pubic 1 mSv/year) in accordance with the Nuclear Safety Act, all components of a linear accelerator are evaluated as below the threshold value. Therefore, the results suggest that there is no serious safety issue for operators in maintaining and repairing a linear accelerator. Nevertheless, if an operator recognizes an exposure from the components of a linear accelerator during operation and considers the operating time and shielding against external exposure, exposure of the operator is expected to be minimized.

A bounding estimate of neutron dose based on measured photon dose around single pass reactors at the Hanford site.

PubMed

Taulbee, Timothy D; Glover, Samuel E; Macievic, Gregory V; Hunacek, Mickey; Smith, Cheryl; DeBord, Gary W; Morris, Donald; Fix, Jack

2010-07-01

Neutron and photon radiation survey records have been used to evaluate and develop a neutron to photon (NP) ratio to reconstruct neutron doses to workers around Hanford's single pass reactors that operated from 1945 to 1972. A total of 5,773 paired neutron and photon measurements extracted from 57 boxes of survey records were used in the development of the NP ratio. The development of the NP ratio enables the use of the recorded dose from an individual's photon dosimeter badge to be used to estimate the unmonitored neutron dose. The Pearson rank correlation between the neutron and photon measurements was 0.71. The NP ratio best fit a lognormal distribution with a geometric mean (GM) of 0.8, a geometric standard deviation (GSD) of 2.95, and the upper 95 th % of this distribution was 4.75. An estimate of the neutron dose based on this NP ratio is considered bounding due to evidence that up to 70% of the total photon exposure received by workers around the single pass reactors occurs during shutdown maintenance and refueling activities when there is no significant neutron exposure. Thus when this NP ratio is applied to the total measured photon dose from an individual film badge dosimeter, the resulting neutron dose is considered bounded.

Evaluation of genotype-guided acenocoumarol dosing algorithms in Russian patients.

PubMed

Sychev, Dmitriy Alexeyevich; Rozhkov, Aleksandr Vladimirovich; Ananichuk, Anna Viktorovna; Kazakov, Ruslan Evgenyevich

2017-05-24

Acenocoumarol dose is normally determined via step-by-step adjustment process based on International Normalized Ratio (INR) measurements. During this time, the risk of adverse reactions is especially high. Several genotype-based acenocoumarol dosing algorithms have been created to predict ideal doses at the start of anticoagulant therapy. Nine dosing algorithms were selected through a literature search. These were evaluated using a cohort of 63 patients with atrial fibrillation receiving acenocoumarol therapy. None of the existing algorithms could predict the ideal acenocoumarol dose in 50% of Russian patients. The Wolkanin-Bartnik algorithtm based on European population was the best-performing one with the highest correlation values (r=0.397), mean absolute error (MAE) 0.82 (±0.61). EU-PACT also managed to give an estimate within the ideal range in 43% of the cases. The two least accurate results were yielded by the Indian population-based algorithms. Among patients receiving amiodarone, algorithms by Schie and Tong proved to be the most effective with the MAE of 0.48±0.42 mg/day and 0.56±0.31 mg/day, respectively. Patient ethnicity and amiodarone intake are factors that must be considered when building future algorithms. Further research is required to find the perfect dosing formula of acenocoumarol maintenance doses in Russian patients.

Acquired hemophilia in the patient suffering from rheumatoid arthritis: case report.

PubMed

Drobiecki, Arkadiusz; Pasiarski, Marcin; Hus, Iwona; Sokołowska, Bożena; Wątek, Marzena

2013-12-01

Acquired hemophilia is a severe bleeding diathesis caused by autoantibodies against a coagulation factor VIII (FVIII inhibitor). Massive bleeding diathesis, often life threatening are observed in almost 90% of patients. In 50-60% of cases, inhibitor emerges spontaneously. However, there are some conditions like pregnancy, puerperium, autoimmune disorders or cancers that seem to induce acquired hemophilia. We report a case of a 49-year-old woman suffering from rheumatoid arthritis (RA) for several years, who was diagnosed with acquired hemophilia in September 2011. The patient had been treated by steroids and leflunomide during the last few months. At the time of diagnosis, diffuse bruising of the forearms and the trunk was observed. The patient was treated with recombinant activated factor VII, and the first-line immunosuppressive therapy was introduced (cyclophosphamide and prednisone). We observed the elimination of symptoms and the disappearance of diathesis. Significant reduction of the titer of inhibitor was achieved, but only partial remission was obtained. It lasted until the beginning of December 2011, when the titer of the inhibitor increased again and massive bleeding to the left lower limb occurred. It was necessary to administer recombinant factor VIIa together with the second-line immunosuppressive therapy based on the Budapest protocol. The rapid reduction of the diathesis and improvement of the patient's general condition was achieved as previously. However, still there was no complete remission. After 2 weeks of treatment, the titer of inhibitor diminished, and factor VIII activity increased slightly. Because of RA, the patient was treated with methylprednisolone in maintenance doses during the next few weeks. Unfortunately, after over a month, the increase of inhibitor titer and the decrease of FVIII level were observed again. Some bruises appeared. It was necessary to increase doses of corticosteroids to therapeutic levels and add cyclophosphamide in low doses to prevent the appearance of more hemorrhagic diathesis. Partial remission was achieved a second time at the end of April 2012. The patient was given methylprednisolone with chloroquine as a maintenance treatment and the control of RA. The titer of the inhibitor increased again in June 2012, but there were no signs of diathesis. In August 2012, some bruises were detected, and we decided to add cyclophosphamide again instead of escalating the doses of methylprednisolone to prevent the occurrence of side-effects of corticosteroids. Cyclophosphamide was given with intervals only depending on activated partial thromboplastin time. No further diathesis was observed in spite of the lack of remission. We were forced to withdrawn cyclophosphamide completely in October 2012 because of signs of hematuria. Fortunately, right nephrolithiasis and urinary tract infection were the cause of that condition. These symptoms vanished after standard supportive treatment. Maintenance doses of corticosteroids and chloroquine were continued as the main treatment. The patient's condition was good, but the titer of inhibitor increased over the value that had been detected at the time of diagnosis, and some bruises appeared again at the end of January 2013. The decision to use rituximab as the next-line therapy was made. This anti-CD20 monoclonal antibody is primarily used in the management of lymphomas. However, it has been successfully applied in the management of various autoimmune conditions. The usual treatment regime involves four separate intravenous infusions of 375 mg/m each, administered at weekly intervals. At the time of admission to the hospital in the second half of February 2013, the titer of inhibitor was dangerously high, almost three times more than the initial level. Fortunately, only a few bruises were observed, and no bypassing agents were needed. The patient was given the whole-planned therapy. Concomitant continuation of maintenance doses of corticosteroids was necessary to enforce the effect of eradication of inhibitor because of high levels of its titer during rituximab administration. It prevented the patient from massive diathesis that might occur. The laboratory tests were improving during the next subsequent weeks after the last dose of rituximab. Over a month later, a significant decrease of the titer of inhibitor and an increase of factor VIII activity was observed. Probably, the laboratory tests will be improving during the next few weeks. The patient is in outpatient care now. She is treated with maintenance doses of corticosteroids and chloroquine as the main treatment of RA. We will try to withdraw corticosteroids unless it is not feasible to achieve complete remission. We will have to introduce another kind of immunosuppressive agent in case of recurrence.

Policy for equipment’s leasing period extension with minimum cost of maintenance

NASA Astrophysics Data System (ADS)

Lestari, C.; Kurniati, N.

2018-04-01

The cost structure for equipment investment including purchase cost and maintenance cost is getting more expensive. The company considers to lease the equipment instead of purchase it under a contractual agreement. Offering to extend the lease period, following to the base lease period, will provide more benefits for both the lessor (owner) and the lessee (user). Whenever the lease period extension offered at the beginning of the contract, there are some risks in finance e.g. uncertainty of the equipment performance and lessor responsibility. Therefore, this research attempts to model the optimal maintenance policy for lease period extension offered at the end of the contract. Minimal repair is performed to rectify a failed equipment, while imperfect preventive maintenance is conducted to improve the operational state of the equipment when reaches a certain control limit to avoid failures. The mathematical model is constructed to determine the optimal control limit, the number and degree of preventive maintenance, and the multiplication number of the lease period extension. Finally, numerical examples are given to illustrate the influences of the optimal length of the extended lease and the maintenance policy to minimize the maintenance cost.

Adolescent Romantic Couples Influence on Substance Use in Young Adulthood

ERIC Educational Resources Information Center

Gudonis-Miller, Lauren C.; Lewis, Lisa; Tong, Yan; Tu, Wanzhu; Aalsma, Matthew C.

2012-01-01

Research has demonstrated that adolescent peer group affiliations are consistent predictors of substance use initiation and maintenance; it is less clear how adolescent "romantic" relationships influence substance use behavior. Data were drawn from the National Longitudinal Study of Adolescent Health. Participants in the final dataset…

Effects of naltrexone and LY255582 on ethanol maintenance, seeking, and relapse responding by alcohol-preferring (P) rats.

PubMed

Dhaher, Ronnie; Toalston, Jamie E; Hauser, Sheketha R; Bell, Richard L; McKinzie, David L; McBride, William J; Rodd, Zachary A

2012-02-01

Research indicates opioid antagonists can reduce alcohol drinking in rodents. However, tests examining the effects of opioid antagonists on ethanol seeking and relapse behavior have been limited. The present study examined the effects of two opioid antagonists on ethanol maintenance, seeking, and relapse responding by alcohol-preferring (P) rats. Adult P rats were self-trained in two-lever operant chambers to self-administer 15% (vol/vol) ethanol on a fixed-ratio 5 (FR5) versus water on a FR1 concurrent schedule of reinforcement in daily 1-h sessions. After 10 weeks, rats underwent extinction training, followed by 2 weeks in their home cages. Rats were then returned to the operant chambers without ethanol or water to measure responses on the ethanol and water levers for four sessions. After a subsequent 2 weeks in the home cage, without access to ethanol, rats were returned to the operant chambers with ethanol and water available. Effects of antagonists on maintenance responding were tested after several weeks of daily 1-h sessions. Naltrexone (NAL; 1-10mg/kg, subcutaneously [s.c.]; n=8/dose), LY255582 (LY; 0.03-1mg/kg, s.c.; n=8/dose), or vehicle were injected 30min before the first session (in the absence of ethanol), following 2 weeks in their home cages, and for four consecutive sessions of ethanol self-administration under maintenance and relapse conditions. Both NAL and LY reduced responses on the ethanol lever without any fluids present, and ethanol self-administration under relapse and on-going drinking conditions, with LY being more potent than NAL. Both NAL and LY were less effective in reducing responding in the absence of ethanol than in reducing ethanol self-administration. Overall, the results indicate that the opioid system is involved in mediating ethanol seeking, and ethanol self-administration under relapse and on-going alcohol drinking, but that different neurocircuits may underlie these behaviors. Published by Elsevier Inc.

Belatacept: a novel biologic for maintenance immunosuppression after renal transplantation.

PubMed

Martin, Spencer T; Tichy, Eric M; Gabardi, Steven

2011-04-01

In the past decade, the availability of new immunosuppressive maintenance therapies for use in solid organ transplantation has remained limited. Patients and clinicians have relied on immunosuppressive drugs that require a significant amount of therapeutic monitoring and are associated with a variety of adverse effects that affect both quality of life and allograft function. Belatacept is an investigational intravenous biologic agent for long-term use in renal transplant recipients. The costimulatory pathway (signal 2) of T-cell activation and proliferation is produced by stimulation of the T-cell surface marker, CD28, and is essential to the immune system's cellular response and ability to recognize an allograft as foreign. Belatacept is a potent antagonist of B7-1 (CD80) and B7-2 (CD86) ligands present on antigen-presenting cells that are responsible for activation of CD28. Recent phase III trials describe various dosing strategies of belatacept versus a standard cyclosporine protocol in recipients of both living- and deceased-donor renal transplants, as well as in patients receiving kidneys transplanted from extended-criteria donors. Compared with cyclosporine, belatacept has been shown to be noninferior in both patient and allograft survival rates. However, the rate of biopsy-proven acute cellular rejection occurred more frequently in the belatacept groups. Also, compared with standard calcineurin-based regimens, the risk of posttransplant lymphoproliferative disorder is increased in patients receiving belatacept, with the greatest risk in transplant recipients who are Epstein-Barr virus seronegative before transplantation. However, this investigational immunosuppressive agent may avert common adverse effects experienced with standard immunosuppressive protocols including renal dysfunction, metabolic disorders, neurotoxicities, glucose abnormalities, and cosmetic effects. More data on the long-term risks of belatacept are needed to better define its role as immunosuppressive maintenance therapy. Aside from an increased risk of malignancy, belatacept's limited adverse-effect profile and convenient dosing strategy may make it an attractive option for immuno-suppressive maintenance for both the patient and clinician.

A systematic review of cost-effectiveness studies comparing conventional, biological and surgical interventions for inflammatory bowel disease

PubMed Central

Dusheiko, Mark; Burnand, Bernard; Pittet, Valérie

2017-01-01

Background Inflammatory bowel disease (IBD) is a chronic disease placing a large health and economic burden on health systems worldwide. The treatment landscape is complex with multiple strategies to induce and maintain remission while avoiding long-term complications. The extent to which rising treatment costs, due to expensive biologic agents, are offset by improved outcomes and fewer hospitalisations and surgeries needs to be evaluated. This systematic review aimed to assess the cost-effectiveness of treatment strategies for IBD. Materials and methods A systematic literature search was performed in March 2017 to identify economic evaluations of pharmacological and surgical interventions, for adults diagnosed with Crohn’s disease (CD) or ulcerative colitis (UC). Costs and incremental cost-effectiveness ratios (ICERs) were adjusted to reflect 2015 purchasing power parity (PPP). Risk of bias assessments and a narrative synthesis of individual study findings are presented. Results Forty-nine articles were included; 24 on CD and 25 on UC. Infliximab and adalimumab induction and maintenance treatments were cost-effective compared to standard care in patients with moderate or severe CD; however, in patients with conventional-drug refractory CD, fistulising CD and for maintenance of surgically-induced remission ICERs were above acceptable cost-effectiveness thresholds. In mild UC, induction of remission using high dose mesalazine was dominant compared to standard dose. In UC refractory to conventional treatments, infliximab and adalimumab induction and maintenance treatment were not cost-effective compared to standard care; however, ICERs for treatment with vedolizumab and surgery were favourable. Conclusions We found that, in general, while biologic agents helped improve outcomes, they incurred high costs and therefore were not cost-effective, particularly for use as maintenance therapy. The cost-effectiveness of biologic agents may improve as market prices fall and with the introduction of biosimilars. Future research should identify optimal treatment strategies reflecting routine clinical practice, incorporate indirect costs and evaluate lifetime costs and benefits. PMID:28973005

A systematic review of cost-effectiveness studies comparing conventional, biological and surgical interventions for inflammatory bowel disease.

PubMed

Pillai, Nadia; Dusheiko, Mark; Burnand, Bernard; Pittet, Valérie

2017-01-01

Inflammatory bowel disease (IBD) is a chronic disease placing a large health and economic burden on health systems worldwide. The treatment landscape is complex with multiple strategies to induce and maintain remission while avoiding long-term complications. The extent to which rising treatment costs, due to expensive biologic agents, are offset by improved outcomes and fewer hospitalisations and surgeries needs to be evaluated. This systematic review aimed to assess the cost-effectiveness of treatment strategies for IBD. A systematic literature search was performed in March 2017 to identify economic evaluations of pharmacological and surgical interventions, for adults diagnosed with Crohn's disease (CD) or ulcerative colitis (UC). Costs and incremental cost-effectiveness ratios (ICERs) were adjusted to reflect 2015 purchasing power parity (PPP). Risk of bias assessments and a narrative synthesis of individual study findings are presented. Forty-nine articles were included; 24 on CD and 25 on UC. Infliximab and adalimumab induction and maintenance treatments were cost-effective compared to standard care in patients with moderate or severe CD; however, in patients with conventional-drug refractory CD, fistulising CD and for maintenance of surgically-induced remission ICERs were above acceptable cost-effectiveness thresholds. In mild UC, induction of remission using high dose mesalazine was dominant compared to standard dose. In UC refractory to conventional treatments, infliximab and adalimumab induction and maintenance treatment were not cost-effective compared to standard care; however, ICERs for treatment with vedolizumab and surgery were favourable. We found that, in general, while biologic agents helped improve outcomes, they incurred high costs and therefore were not cost-effective, particularly for use as maintenance therapy. The cost-effectiveness of biologic agents may improve as market prices fall and with the introduction of biosimilars. Future research should identify optimal treatment strategies reflecting routine clinical practice, incorporate indirect costs and evaluate lifetime costs and benefits.

Intravenous immunoglobulin for maintenance treatment of multifocal motor neuropathy: A multi-center, open-label, 52-week phase 3 trial.

PubMed

Kuwabara, Satoshi; Misawa, Sonoko; Mori, Masahiro; Iwai, Yuta; Ochi, Kazuhide; Suzuki, Hidekazu; Nodera, Hiroyuki; Tamaoka, Akira; Iijima, Masahiro; Toda, Tatsushi; Yoshikawa, Hiroo; Kanda, Takashi; Sakamoto, Ko; Kusunoki, Susumu; Sobue, Gen; Kaji, Ryuji

2018-06-01

Intravenous immunoglobulin (IVIg) therapy is currently the only established treatment in patients with multifocal motor neuropathy (MMN), and many patients have an IVIg-dependent fluctuation. We aimed to investigate the efficacy and safety of every 3 week IVIg (1.0 g/kg) for 52 weeks. This study was an open-label phase 3 clinical trial, enrolling 13 MMN patients. After an induction IVIg therapy (0.4 g/kg/d for 5 consecutive days), maintenance dose (1.0 g/kg) was given every 3 weeks for 52 weeks. The major outcome measures were the Medical Research Council (MRC) sum score and hand-grip strength at week 52. This trial is registered with ClinicalTrials.gov, number NCT01827072. At week 52, 11 of the 13 patients completed the study, and all 11 had a sustained improvement. The mean (SD) MRC sum score was 85.6 (8.7) at the baseline, and 90.6 (12.8) at week 52. The mean grip strength was 39.2 (30.0) kPa at the baseline and 45.2 (32.8) kPa at week 52. Two patients dropped out because of adverse event (dysphagia) and decision of an investigator, respectively. Three patients developed coronary spasm, dysphagia, or inguinal herniation, reported as the serious adverse events, but considered not related with the study drug. The other adverse effects were mild and resolved by the end of the study period. Our results show that maintenance treatment with 1.0 g/kg IVIg every 3 week is safe and efficacious for MMN patients up to 52 weeks. Further studies are required to investigate optimal dose and duration of maintenance IVIg for MMN. © 2018 The Authors. Journal of the Peripheral Nervous System published by Wiley Periodicals, Inc. on behalf of Peripheral Nerve Society.

Short-term retention of visual information: Evidence in support of feature-based attention as an underlying mechanism.

PubMed

Sneve, Markus H; Sreenivasan, Kartik K; Alnæs, Dag; Endestad, Tor; Magnussen, Svein

2015-01-01

Retention of features in visual short-term memory (VSTM) involves maintenance of sensory traces in early visual cortex. However, the mechanism through which this is accomplished is not known. Here, we formulate specific hypotheses derived from studies on feature-based attention to test the prediction that visual cortex is recruited by attentional mechanisms during VSTM of low-level features. Functional magnetic resonance imaging (fMRI) of human visual areas revealed that neural populations coding for task-irrelevant feature information are suppressed during maintenance of detailed spatial frequency memory representations. The narrow spectral extent of this suppression agrees well with known effects of feature-based attention. Additionally, analyses of effective connectivity during maintenance between retinotopic areas in visual cortex show that the observed highlighting of task-relevant parts of the feature spectrum originates in V4, a visual area strongly connected with higher-level control regions and known to convey top-down influence to earlier visual areas during attentional tasks. In line with this property of V4 during attentional operations, we demonstrate that modulations of earlier visual areas during memory maintenance have behavioral consequences, and that these modulations are a result of influences from V4. Copyright © 2014 Elsevier Ltd. All rights reserved.

Effects of Age and Acute Moderate Alcohol Administration on Electrophysiological Correlates of Working Memory Maintenance.

PubMed

Boissoneault, Jeff; Frazier, Ian; Lewis, Ben; Nixon, Sara Jo

2016-09-01

Previous studies suggest older adults may be differentially susceptible to the acute neurobehavioral effects of moderate alcohol intake. To our knowledge, no studies have addressed acute moderate alcohol effects on the electrophysiological correlates of working memory in younger and older social drinkers. This study characterized alcohol-related effects on frontal theta (FTP) and posterior alpha power (PAP) associated with maintenance of visual information during a working memory task. Older (55 to 70 years of age; n = 51, 29 women) and younger (25 to 35 years of age; n = 70, 39 women) community-dwelling moderate drinkers were recruited for this study. Participants were given either placebo or an active dose targeting breath alcohol concentrations (BrACs) of 0.04 or 0.065 g/dl. Following absorption, participants completed a visual working memory task assessing cue recognition following a 9-s delay. FTP and PAP were determined via Fourier transformation and subjected to 2 (age group) × 3 (dose) × 2 (repeated: working memory task condition) mixed models analysis. In addition to expected age-related reductions in PAP, a significant age group × dose interaction was detected for PAP such that 0.04 g/dl dose level was associated with greater PAP in younger adults but lower PAP in their older counterparts. PAP was lower in older versus younger adults at both active doses. Further mixed models revealed a significant negative association between PAP and working memory efficiency for older adults. No effects of age, dose, or their interaction were noted for FTP. Results bolster the small but growing body of evidence that older adults exhibit differential sensitivity to the neurobehavioral effects of moderate alcohol use. Given the theoretical role of PAP in attentional and working memory function, these findings shed light on the attentional mechanisms underlying effects of acute moderate alcohol on working memory efficiency in older adults. Copyright © 2016 by the Research Society on Alcoholism.

Impact of mycophenolate mofetil dose posttransplantation on 12-month renal function: analysis of the MOST database.

PubMed

Salvadori, M; Bock, A; Chapman, J; Dussol, B; Fritsche, L; Kliem, V; Lebranchu, Y; Oppenheimer, F; Pohanka, E; Tufveson, G; Rosati, A; Puig, X; Corbetta, G

2005-01-01

Mycophenolate mofetil (MMF) has greatly reduced the risk of acute rejection episodes (ARE) after renal transplantation, but dose reductions/withdrawals could jeopardize long-term results. The MOST database of "de novo" patients treated with MMF at month 1 and functioning grafts at month 12 were divided into 2 groups: groups 1, 2 g MMF at month 1 and month 12; and group 2, 2 g MMF at month 1 but MMF <2 g at month 12 to evaluate renal function glonerular filtration rate (GFR). In this study, 1136 patients were receiving 2 g MMF at month 1. On month 12, 645 were on 2 g (56.8%, group 1) and 431 were on <2 g (43.2%, group 2). Group 1 included younger recipients of younger donors with fewer patients with delayed graft function (DGF). Group 1 showed more ARE during month 1 and more patients who received induction. Mean Neoral daily doses at month 1/month 12 were 5.3/3.0 and 5.3/3.1 mg/kg in group 1 and group 2, respectively (P = .05 at month 12). GFR in group 1 and group 2 were 59.06 (CI 57.10-60.60) and 53.81 (CI 52-55.7) at month 1 (P < .001); 63.7 (CI 62.1-65.30) and 55.9 (CI 54.1-57.7) mL/min*1.73 m(2) at month 12 (P < .001). The mean increases in GFR between month 1 and month 12 were 4.64 and 1.94 mL/min*1.73 m(2), respectively (P < .05). A multivariate analysis also included 795 patients from the "maintenance" patient database with retrospective detailed information. The following parameters were highly predictive for good renal function at month 12: donor age younger than 60 years, recipient age younger than 60 years, immediate graft function, 12-month MMF dose = 2 g, absence of CMV infection, and 12-month Neoral dose <3 mg/kg/d. Maintenance of MMF dose at 2 g/d during the first year appears to facilitate the attainment of optimal renal function at 12-months after kidney transplantation.

Research on Operation Assessment Method for Energy Meter

NASA Astrophysics Data System (ADS)

Chen, Xiangqun; Huang, Rui; Shen, Liman; chen, Hao; Xiong, Dezhi; Xiao, Xiangqi; Liu, Mouhai; Xu, Renheng

2018-03-01

The existing electric energy meter rotation maintenance strategy regularly checks the electric energy meter and evaluates the state. It only considers the influence of time factors, neglects the influence of other factors, leads to the inaccuracy of the evaluation, and causes the waste of resources. In order to evaluate the running state of the electric energy meter in time, a method of the operation evaluation of the electric energy meter is proposed. The method is based on extracting the existing data acquisition system, marketing business system and metrology production scheduling platform that affect the state of energy meters, and classified into error stability, operational reliability, potential risks and other factors according to the influencing factors, based on the above basic test score, inspecting score, monitoring score, score of family defect detection. Then, according to the evaluation model according to the scoring, we evaluate electric energy meter operating state, and finally put forward the corresponding maintenance strategy of rotation.

A Method of Evaluating Operation of Electric Energy Meter

NASA Astrophysics Data System (ADS)

Chen, Xiangqun; Li, Tianyang; Cao, Fei; Chu, Pengfei; Zhao, Xinwang; Huang, Rui; Liu, Liping; Zhang, Chenglin

2018-05-01

The existing electric energy meter rotation maintenance strategy regularly checks the electric energy meter and evaluates the state. It only considers the influence of time factors, neglects the influence of other factors, leads to the inaccuracy of the evaluation, and causes the waste of resources. In order to evaluate the running state of the electric energy meter in time, a method of the operation evaluation of the electric energy meter is proposed. The method is based on extracting the existing data acquisition system, marketing business system and metrology production scheduling platform that affect the state of energy meters, and classified into error stability, operational reliability, potential risks and other factors according to the influencing factors, based on the above basic test score, inspecting score, monitoring score, score of family defect detection. Then, according to the evaluation model according to the scoring, we evaluate electric energy meter operating state, and finally put forward the corresponding maintenance strategy of rotation.

The Influence of Hydroxylation on Maintaining CpG Methylation Patterns: A Hidden Markov Model Approach.

PubMed

Giehr, Pascal; Kyriakopoulos, Charalampos; Ficz, Gabriella; Wolf, Verena; Walter, Jörn

2016-05-01

DNA methylation and demethylation are opposing processes that when in balance create stable patterns of epigenetic memory. The control of DNA methylation pattern formation by replication dependent and independent demethylation processes has been suggested to be influenced by Tet mediated oxidation of 5mC. Several alternative mechanisms have been proposed suggesting that 5hmC influences either replication dependent maintenance of DNA methylation or replication independent processes of active demethylation. Using high resolution hairpin oxidative bisulfite sequencing data, we precisely determine the amount of 5mC and 5hmC and model the contribution of 5hmC to processes of demethylation in mouse ESCs. We develop an extended hidden Markov model capable of accurately describing the regional contribution of 5hmC to demethylation dynamics. Our analysis shows that 5hmC has a strong impact on replication dependent demethylation, mainly by impairing methylation maintenance.

The influence of protection system failures and preventive maintenance on protection systems in distribution systems

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

Meeuwsen, J.J.; Kling, W.L.; Ploem, W.A.G.A.

1997-01-01

Protection systems in power systems can fail either by not responding when they should (failure to operate) or by operating when they should not (false tripping). The former type of failure is particularly serious since it may result in the isolation of large sections of the network. However, the probability of a failure to operate can be reduced by carrying out preventive maintenance on protection systems. This paper describes an approach to determine the impact of preventive maintenance on protection systems on the reliability of the power supply to customers. The proposed approach is based on Markov models.

Service contract of Renault Kerax 440 truck with deductible and policy limit coverage modification

NASA Astrophysics Data System (ADS)

Bustami, Pasaribu, Udjianna. S.; Husniah, Hennie

2016-02-01

In this paper we discuss a service contracts with coverage modification that only offer preventive maintenance and corrective maintenance for Renault Kerax 440 Truck by service contract provider. Corrective maintenance costs is modified with deductible and policy limit during the period of the service contract. Demand for a service contract is only influenced by the price of the service contract, deductible, and policy limit offered by producer to consumer. The main problem in this thesis is determining the price of a service contract, deductible, and policy limit to get maximum profit for producer for each of service contract.

Plane of nutrition during the preweaned period and Mannheimia haemolytica dose influence metabolic responses in post-weaned Holstein calves challenged with bovine herpesvirus-1 and Mannheimia haemolytica

USDA-ARS?s Scientific Manuscript database

To determine whether previous plane of milk replacer nutrition (PON) and M. haemolytica (MH) dose influences metabolic responses to a combined viral-bacterial respiratory challenge, Holstein calves (1 day of age; n=30) were assigned to treatments in a 2 x 3 factorial with preweaned PON and dose of M...

Plane of nutrition during the preweaned period and Mannheimia haemolytica dose influences inflammatory responses to a combined bovine herpesvirus-1 and Mannheimia haemolytica challenge in post-weaned Holstein calves

USDA-ARS?s Scientific Manuscript database

To determine whether previous plane of milk replacer nutrition (PON) and M. haemolytica (MH) dose influences inflammatory responses to a combined viral-bacterial respiratory challenge, Holstein calves (1 day of age; n=30) were assigned to treatments in a 2 x 3 factorial with preweaned PON and dose o...

Identification of the human factors contributing to maintenance failures in a petroleum operation.

PubMed

Antonovsky, Ari; Pollock, Clare; Straker, Leon

2014-03-01

This research aimed to identify the most frequently occurring human factors contributing to maintenance-related failures within a petroleum industry organization. Commonality between failures will assist in understanding reliability in maintenance processes, thereby preventing accidents in high-hazard domains. Methods exist for understanding the human factors contributing to accidents. Their application in a maintenance context mainly has been advanced in aviation and nuclear power. Maintenance in the petroleum industry provides a different context for investigating the role that human factors play in influencing outcomes. It is therefore worth investigating the contributing human factors to improve our understanding of both human factors in reliability and the factors specific to this domain. Detailed analyses were conducted of maintenance-related failures (N = 38) in a petroleum company using structured interviews with maintenance technicians. The interview structure was based on the Human Factor Investigation Tool (HFIT), which in turn was based on Rasmussen's model of human malfunction. A mean of 9.5 factors per incident was identified across the cases investigated.The three most frequent human factors contributing to the maintenance failures were found to be assumption (79% of cases), design and maintenance (71%), and communication (66%). HFIT proved to be a useful instrument for identifying the pattern of human factors that recurred most frequently in maintenance-related failures. The high frequency of failures attributed to assumptions and communication demonstrated the importance of problem-solving abilities and organizational communication in a domain where maintenance personnel have a high degree of autonomy and a wide geographical distribution.

Safety and efficacy of repaglinide in type 2 diabetic patients with and without impaired renal function.

PubMed

Hasslacher, Christoph

2003-03-01

To evaluate the influence of renal impairment on the safety and efficacy of repaglinide in type 2 diabetic patients. This multinational, open-label study comprised a 6-week run-in period, continuing prestudy antidiabetic medication, followed by a titration period (1-4 weeks) and a 3-month maintenance period. Patients with normal renal function (n = 151) and various degrees of renal impairment (n = 130) were treated with repaglinide (maximal dose of 4 mg, three times daily). Safety and efficacy assessments were performed at baseline (end of run-in) and at the end of study treatment. The type and severity of adverse events during repaglinide treatment were similar to the run-in period. The number of patients with adverse events was not significantly related to renal function during run-in or repaglinide treatment. Percentage of patients with hypoglycemic episodes increased significantly (P = 0.007) with increasing severity of renal impairment during run-in but not during repaglinide treatment (P = 0.074). Metabolic control (HbA(1c) and fasting blood glucose) with repaglinide was unchanged from that on previous antidiabetic medication. Final repaglinide dose tended to be lower for patients with severe and extreme renal impairment than for patients with less severe renal impairment or normal renal function (P = 0.032). Repaglinide has a good safety and efficacy profile in type 2 diabetic patients complicated by renal impairment and is an appropriate treatment choice, even for individuals with more severe degrees of renal impairment.

Suvorexant: a promising, novel treatment for insomnia

PubMed Central

Lee-Iannotti, Joyce K; Parish, James M

2016-01-01

Suvorexant a novel, orexin receptor antagonist was recently approved by the US Food and Drug Administration for the treatment of sleep onset and sleep maintenance insomnia in August 2014. Multiple animal and human studies support the efficacy, safety, and tolerability of suvorexant for patients of various profiles. Current recommendations advocate for a starting dose of 10 mg and a maximum dose of 20 mg, with cautious use in women, obese patients, and patients taking other CYP3A4 inhibitors. More head-to-head studies comparing suvorexant to other sedative-hypnotic therapies are needed to further delineate which patients will benefit the most from this medication over others. PMID:26955275

Correlation between measles vaccine doses: implications for the maintenance of elimination.

PubMed

McKee, A; Ferrari, M J; Shea, K

2018-03-01

Measles eradication efforts have been successful at achieving elimination in many countries worldwide. Such countries actively work to maintain this elimination by continuing to improve coverage of two routine doses of measles vaccine following measles elimination. While improving measles vaccine coverage is always beneficial, we show, using a steady-state analysis of a dynamical model, that the correlation between populations receiving the first and second routine dose also has a significant impact on the population immunity achieved by a specified combination of first and second dose coverage. If the second dose is administered to people independently of whether they had the first dose, high second-dose coverage improves the proportion of the population receiving at least one dose, and will have a large effect on population immunity. If the second dose is administered only to people who have had the first dose, high second-dose coverage reduces the rate of primary vaccine failure, but does not reach people who missed the first dose; this will therefore have a relatively small effect on population immunity. When doses are administered dependently, and assuming the first dose has higher coverage, increasing the coverage of the first dose has a larger impact on population immunity than does increasing the coverage of the second. Correlation between vaccine doses has a significant impact on the level of population immunity maintained by current vaccination coverage, potentially outweighing the effects of age structure and, in some cases, recent improvements in vaccine coverage. It is therefore important to understand the correlation between vaccine doses as such correlation may have a large impact on the effectiveness of measles vaccination strategies.

Perceptions That Influence the Maintenance of Scientific Integrity in Community-Based Participatory Research

ERIC Educational Resources Information Center

Kraemer Diaz, Anne E.; Spears Johnson, Chaya R.; Arcury, Thomas A.

2015-01-01

Scientific integrity is necessary for strong science; yet many variables can influence scientific integrity. In traditional research, some common threats are the pressure to publish, competition for funds, and career advancement. Community-based participatory research (CBPR) provides a different context for scientific integrity with additional and…

Influence of the Social Context on Pragmatic Skills of Adults with Mental Retardation.

ERIC Educational Resources Information Center

Oetting, Janna B.; Rice, Mabel L.

1991-01-01

The influence of social context on pragmatic skills of 16 adults with mild to moderate mental retardation was examined using videotaped conversations. Data analysis revealed that the subjects were proficient in judging topic maintenance presentations in a simplified but not a complex context. (DB)

Preference for brand-name buprenorphine is related to severity of addiction among outpatients in opioid maintenance treatment.

PubMed

Binder, Philippe; Messaadi, Nassir; Perault-Pochat, Marie-Christine; Gagey, Stéphanie; Brabant, Yann; Ingrand, Pierre

2016-01-01

As a form of opioid maintenance treatment, high-dose buprenorphine is increasingly being used in the United States. On the French market since 1996, it is the most commonly prescribed and frequently employed opioid maintenance treatment. For unknown reasons, the brand-name form is used far more often than the generic form (76-24%). The objective was to show that the patients' levels of addiction were differentiated according to the form of buprenorphine currently being used and to their previous experience of a different form. An observational study in 9 sites throughout France used self-assessment questionnaires filled out in retail pharmacies by all patients to whom their prescribed buprenorphine treatment was being delivered. The 151 canvassed pharmacies solicited 879 patients, of whom 724 completed the questionnaires. Participants were statistically similar to non-participants. The patients using the brand-name form subsequent to experience with the generic form exhibited a more elevated addiction severity index and a higher dosage than brand-name form users with no experience of a different form. Compared to generic users, their doses were higher, their was addiction more severe, and their alcohol consumption was more excessive; they were also more likely to make daily use of psychotropic substances. However, the level of misuse or illicit consumption was similar between these groups. Preferring the brand-name buprenorphine form to the generic form is associated with a higher level of severe addiction, a more frequent need for daily psychotropics, and excessive drinking; but the study was unable to show a causal link.

Postoperative weight gain during the first year after kidney, liver, heart, and lung transplant: a prospective study.

PubMed

Kugler, Christiane; Einhorn, Ina; Gottlieb, Jens; Warnecke, Gregor; Schwarz, Anke; Barg-Hock, Hannelore; Bara, Christoph; Haller, Hermann; Haverich, Axel

2015-03-01

Studies of all types of organ transplant recipients have suggested that weight gain, expressed as an increase in body mass index (BMI), after transplant is common. To describe weight gain during the first year after transplant and to determine risk factors associated with weight gain with particular attention to type of transplant. A prospective study of 502 consecutive organ transplant recipients (261 kidney, 73 liver, 29 heart, 139 lung) to identify patterns of BMI change. Measurements were made during regular outpatient clinical visits at 2, 6, and 12 months after transplant. Data were retrieved from patients' charts and correlated with maintenance corticosteroid doses. Overall, mean BMI (SD; range) was 23.9 (4.5; 13.6-44.1) at 2 months and increased to 25.4 (4.0; 13.0-42.2) by the end of the first postoperative year. BMI levels organized by World Health Organization categories showed a trend toward overweight/obesity in kidney (53.4%), liver (51.5%), heart (51.7%), and lung (33.1%) patients by 12 months after transplant. BMI changed significantly (P= .05) for all organ types and between all assessment points, except in kidney recipients. Maintenance corticosteroid doses were not a predictor of BMI at 12 months after transplant for most patients. Weight gain was common among patients undergoing kidney, liver, heart, and lung transplant; however, many showed BMI values close to normality at the end of the first year after transplant. In most cases, increased BMI levels were related to obesity before transplant and not to maintenance corticosteroid therapy.

Smooth muscle in the maintenance of increased airway resistance elicited by methacholine in humans.

PubMed

Chapman, David G; Pascoe, Chris D; Lee-Gosselin, Audrey; Couture, Christian; Seow, Chun Y; Paré, Peter D; Salome, Cheryl M; King, Gregory G; Bossé, Ynuk

2014-10-15

Airway narrowing is maintained for a prolonged period after acute bronchoconstriction in humans in the absence of deep inspirations (DIs). To determine whether maintenance of airway smooth muscle (ASM) shortening is responsible for the persistence of airway narrowing in healthy subjects following transient methacholine (MCh)-induced bronchoconstriction. On two separate visits, five healthy subjects underwent MCh challenges until respiratory system resistance (Rrs) had increased by approximately 1.5 cm H2O/L/s. Subjects took a DI either immediately after or 30 minutes after the last dose. The extent of renarrowing following the bronchodilator effect of DI was used to assess the continued action of MCh (calculated as percent change in Rrs from the pre-DI Rrs). We then used human bronchial rings to determine whether ASM can maintain shortening during a progressive decrease of carbachol concentration. The increased Rrs induced by MCh was maintained for 30 minutes despite waning of MCh concentration over that period, measured as attenuated renarrowing when the DI was taken 30 minutes after compared with immediately after the last dose (7 min post-DI, -36.2 ± 11.8 vs. 14.4 ± 13.2%; 12 min post-DI, -39.5 ± 9.8 vs. 15.2 ± 17.8%). Ex vivo, ASM shortening was largely maintained during a progressive decrease of carbachol concentration, even down to concentrations that would not be expected to induce shortening. The maintenance of airway narrowing despite MCh clearance in humans is attributed to an intrinsic ability of ASM to maintain shortening during a progressive decrease of contractile stimulation.

Wildlife and electric power transmission

USGS Publications Warehouse

Ellis, D.H.; Goodwin, J.G.; Hunt, J.R.; Fletcher, John L.; Busnel, R.G.

1978-01-01

Hundreds of thousands of miles of transmission lines have been introduced into our natural environment. These lines and their corridors can be damaging or beneficial to wildlife communities depending on how they are designed, where they are placed, and when they are constructed and maintained. With the current trend toward UHV systems, new problems (associated with additional increments in audible noise, electric and magnetic force fields, etc.) must be addressed. We recommend the following areas for careful study: (1) the response of wilderness species to transmission lines and line construction and maintenance activities (2) the magnitude of bird collision and electrocution mortality, (3) the response of power corridor and power tower in habiting wildlife to laboratory and field doses of electro-chemical oxidants, corona noise, electric and magnetic fields, etc., (4) the productivity of tower inhabiting birds compared with nearby non-tower nesters, and (5) the influence of powerline corridors on mammalian and avian migration patterns. It is our hope that the questions identified in this study will help stimulate further research so that we can maximize wildlife benefits and minimize wildlife detriments.

Inactivation of Lactobacillus rhamnosus GG by fixation modifies its probiotic properties.

PubMed

Markowicz, C; Kubiak, P; Grajek, W; Schmidt, M T

2016-01-01

Probiotics are microorganisms that have beneficial effects on the host and are safe for oral intake in a suitable dose. However, there are situations in which the administration of living microorganisms poses a risk for immunocompromised host. The objective of this study was to evaluate the influence of several fixation methods on selected biological properties of Lactobacillus rhamnosus GG that are relevant to its probiotic action. Fixation of the bacterial cells with ethanol, 2-propanol, glutaraldehyde, paraformaldehyde, and heat treatment resulted in a significant decrease of alkaline phosphatase, peroxidase, and β-galactosidase activities. Most of the fixation procedures reduced bacterial cell hydrophobicity and increased adhesion capacity. The fixation procedures resulted in a different perception of the bacterial cells by enterocytes, which was shown as changes in gene expression in enterocytes. The results show that some procedures of inactivation allow a fraction of the enzymatic activity to be maintained. The adhesion properties of the bacterial cells were enhanced, but the response of enterocytes to fixed cells was different than to live bacteria. Inactivation allows maintenance and modification of some of the properties of the bacterial cells.

Evaluation of 16 genotype-guided Warfarin Dosing Algorithms in 310 Korean Patients Receiving Warfarin Treatment: Poor Prediction Performance in VKORC1 1173C Carriers.

PubMed

Yang, Mina; Choi, Rihwa; Kim, June Soo; On, Young Keun; Bang, Oh Young; Cho, Hyun-Jung; Lee, Soo-Youn

2016-12-01

The purpose of this study was to evaluate the performance of 16 previously published warfarin dosing algorithms in Korean patients. The 16 algorithms were selected through a literature search and evaluated using a cohort of 310 Korean patients with atrial fibrillation or cerebral infarction who were receiving warfarin therapy. A large interindividual variation (up to 11-fold) in warfarin dose was observed (median, 25 mg/wk; range, 7-77 mg/wk). Estimated dose and actual maintenance dose correlated well overall (r range, 0.52-0.73). Mean absolute error (MAE) of the 16 algorithms ranged from -1.2 to -20.1 mg/wk. The percentage of patients whose estimated dose fell within 20% of the actual dose ranged from 1.0% to 49%. All algorithms showed poor accuracy with increased MAE in a higher dose range. Performance of the dosing algorithms was worse in patients with VKORC1 1173TC or CC than in total (r range, 0.38-0.61 vs 0.52-0.73; MAE range, -2.6 to -28.0 mg/wk vs -1.2 to -20.1 mg/wk). The algorithms had comparable prediction abilities but showed limited accuracy depending on ethnicity, warfarin dose, and VKORC1 genotype. Further studies are needed to develop genotype-guided warfarin dosing algorithms with greater accuracy in the Korean population. Copyright © 2016 Elsevier HS Journals, Inc. All rights reserved.

Synergistic Cytotoxicity of Lenalidomide and Dexamethasone in Mantle Cell Lymphoma via Cereblon-dependent Targeting of the IL-6/STAT3/PI3K Axis.

PubMed

Ma, Jiexian; Wu, Kefei; Bai, Weiya; Cui, Xiaoxian; Chen, Yan; Xie, Youhua; Xie, Yanhui

2017-06-01

At our center, relapsed mantle cell lymphoma (MCL) can be treated with maintenance therapy composed of consecutive low-dose lenalidomide and short-term, high-dose dexamethasone (LD regimen), which achieves good responses (longer overall survival and progression-free survival) and low toxicity. Cereblon is probably targeted by both lenalidomide and dexamethasone, which leads to synergistic cytotoxicity in MCL by inhibiting the interleukin-6/signal transducer and activator of transcription 3 (IL-6/STAT3), phosphatidylinositol 3-kinase (PI3K)/AKT and AKT2/Forkhead box O3 (FOXO3A)/BCL2-like 11 (BIM) pathways. The two drugs synergistically inhibit the same pathways, but through different sites. Cereblon was found expressed in most of the MCL tissues (91.3% positivity). Moreover, cereblon expression is positively correlated with LD regimen sensitivity: long-term lenalidomide exposure downregulates cereblon and induces multi-drug resistance against lenalidomide, dexamethasone, cytarabine, cisplatin, and methotrexate in vitro. Removal of lenalidomide resensitizes lenalidomide-resistant MCL cells to lenalidomide and dexamethasone. Our work suggests that rotating the LD regimen with other regimens would improve MCL maintenance therapy. Copyright © 2017. Published by Elsevier B.V.

MRI evaluation of frequent complications after intra-arterial transplantation of mesenchymal stem cells in rats

NASA Astrophysics Data System (ADS)

Namestnikova, D.; Gubskiy, I.; Gabashvili, A.; Sukhinich, K.; Melnikov, P.; Vishnevskiy, D.; Soloveva, A.; Vitushev, E.; Chekhonin, V.; Gubsky, L.; Yarygin, K.

2017-08-01

Intra-arterial transplantation of mesenchymal stem cells (MSCs) is an effective delivery route for treatment of ischemic brain injury. Despite significant therapeutic effects and targeted cells delivery to the brain infraction, serious adverse events such as cerebral embolism have been reported and may restrict potential clinical applications of this method. In current study, we evaluate potential complications of intra-arterial MSCs administration and determine the optimum parameters for cell transplantation. We injected SPIO-labeled human MSCs via internal carotid artery with different infusion parameters and cell dose in intact rats and in rats with the middle cerebral occlusion stroke model. Cerebrovascular complications and labeled cells were visualized in vivo using MRI. We have shown that the incidence of cerebral embolic events depends on such parameters as cell dose, infusion rate and maintenance of blood flow in the internal carotid artery (ICA). Optimal parameters were considered to be 5×105 hMSC in 1 ml of PBS by syringe pump with velocity 100 μ/min and maintenance of blood flow in the ICA. Obtained data should be considered before planning experiments in rats and, potentially, can help in planning clinical trials in stroke patients.

Use of Belatacept as Alternative Immunosuppression in Three Renal Transplant Patients with De Novo Drug-Induced Thrombotic Microangiopathy

PubMed Central

Cicora, Federico; Paz, Marta; Mos, Fernando; Roberti, Javier

2013-01-01

Thrombotic microangiopathy (TMA), a severe complication of renal transplantation, is a pathological process involving microvascular occlusion, thrombocytopenia, and microangiopathic hemolytic anemia. It generally appears within the first weeks after transplantation, when immunosuppressive drugs are used at high doses. De novo TMA may also be drug-induced when calcineurin inhibitors or proliferation signal inhibitors are used. We report three cases of de novo drug-induced TMA in renal transplant patients who were managed by replacing calcineurin inhibitors or proliferation signal inhibitors with belatacept, a primary maintenance immunosuppressive drug, which blocks the CD28 costimulation pathway, preventing the activation of T lymphocytes. To identify the cause of TMA, we ruled out HUS, hepatitis C serology, HIV serology, parvovirus B19, cytomegalovirus, anti-HLA antibodies, and prolonged activated partial thromboplastin time. We suspect that the TMA was caused by the calcineurin inhibitors or proliferation signal inhibitors. Belatacept treatment was initiated at a dose of 10 mg/kg on days 1, 5, 14, 28, 60, and 90; maintenance treatment was 5 mg/kg once a month for 1 year. Belatacept, in combination with other agents, prevented graft rejection in three patients. PMID:24198835

Effectiveness of physical activity interventions in achieving behaviour change maintenance in young and middle aged adults: A systematic review and meta-analysis.

PubMed

Murray, Jennifer M; Brennan, Sarah F; French, David P; Patterson, Christopher C; Kee, Frank; Hunter, Ruth F

2017-11-01

Physical activity (PA) interventions are generally effective in supporting short-term behaviour change, but increases are not always maintained. This review examined the effectiveness of PA interventions for behaviour change maintenance in young and middle-aged adults, and investigated which Behaviour Change Techniques (BCTs) and other intervention features were associated with maintenance. Six databases (Medline, EMBASE, PsycINFO, Cochrane Database of Systematic Reviews, CINAHL, Web of Science) were systematically searched. Eligibility criteria were controlled trials investigating the effectiveness of PA interventions with adult (mean age 18-64 years) non-clinical populations using validated measures of PA behaviour at baseline and ≥six months' post-baseline. Results were pooled in meta-analyses using standardised mean differences (SMD) at five time intervals (6-9, 9-15, 15-21, 21-24, >24 months). Moderator analyses investigated the influence of sample and intervention characteristics on PA maintenance at 6-9 months. Sixty-two studies were included. PA interventions had a significant effect on behaviour maintenance 6-15 months post-baseline relative to controls. Interventions had a larger effect on maintenance at 6-9 months (SMD = 0.28; 95% CI: 0.20, 0.35; I 2  = 73%) compared to 9-15 months (SMD = 0.20; 95% CI: 0.13, 0.26; I 2  = 70%). Beyond 15 months, PA measurements were infrequent with little evidence supporting maintenance. Moderator analyses showed some BCTs and intervention settings moderated PA outcomes at 6-9 months. A multivariable meta-regression model showed interventions using the BCTs 'Prompt self-monitoring of behavioural outcome' (b = 1.46, p < 0.01) and 'Use of follow-up prompts' (b = 0.38, p < 0.01) demonstrated greater effectiveness at promoting PA maintenance at 6-9 months. Interventions implemented in primary care (versus community or workplace/university) settings (b = -0.13, p = 0.10) tended to demonstrate less effectiveness. This review provides evidence of some effective BCTs for maintaining behaviour to 15 months. Greater consideration must be given to how future interventions encourage and measure maintenance of changes, and investigate broader psychological, social and environmental influences of PA behaviour. PROSPERO 2015:CRD42015025462. Copyright © 2017 Elsevier Ltd. All rights reserved.

Holocene soil-geomorphic surfaces influence the role of salmon-derived nutrients in the coastal temperate rainforest of Southeast Alaska

Treesearch

David V. D' Amore; Nicholas S. Bonzey; Jacob Berkowitz; Janine Rüegg; Scott Bridgham

2011-01-01

The influence of salmon-derived nutrients (SDN) is widely accepted as a potential factor in the maintenance of aquatic and terrestrial productivity in North American Coastal rainforests. Holocene alluvial landforms are intimately connected with the return of anadromous salmon, but the influence of the soils that occupy these landforms and support this important...

Acute effects of ethanol and acetate on glucose kinetics in normal subjects

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

Yki-Jaervinen, H.; Koivisto, V.A.; Ylikahri, R.

1988-02-01

The authors compared the effects of two ethanol doses on glucose kinetics and assessed the role of acetate as a mediator of ethanol-induced insulin resistance. Ten normal males were studied on four occasions, during which either a low or moderate ethanol, acetate, or saline dose was administered. Both ethanol doses similarly inhibited basal glucose production. The decrease in R{sub a} was matched by a comparable decrease in glucose utilization (R{sub d}), resulting in maintenance of normoglycemia. During hyperinsulinemia glucose disposal was lower in the moderate than the low-dose ethanol or saline studies. During acetate infusion, the blood acetate level wasmore » comparable with those in the ethanol studies. Acetate had no effect on glucose kinetics. In conclusion, (1) in overnight fasted subjects, ethanol does not cause hypoglycemia because its inhibitory effect on R{sub a} is counterbalanced by equal inhibition of R{sub d}; (2) basal R{sub a} and R{sub d} are maximally inhibited already by small ethanol doses, whereas inhibition of insulin-stimulated glucose disposal requires a moderate ethanol dose; and (3) acetate is not the mediator of ethanol-induced insulin resistance.« less

Dynamics of Implementation and Maintenance of Organizational Health Interventions

PubMed Central

Rahmandad, Hazhir; Bullock, Sally Lawrence; Ammerman, Alice

2017-01-01

In this study, we present case studies to explore the dynamics of implementation and maintenance of health interventions. We analyze how specific interventions are built and eroded, how the building and erosion mechanisms are interconnected, and why we can see significantly different erosion rates across otherwise similar organizations. We use multiple comparative obesity prevention case studies to provide empirical information on the mechanisms of interest, and use qualitative systems modeling to integrate our evolving understanding into an internally consistent and transparent theory of the phenomenon. Our preliminary results identify reinforcing feedback mechanisms, including design of organizational processes, motivation of stakeholders, and communication among stakeholders, which influence implementation and maintenance of intervention components. Over time, these feedback mechanisms may drive a wedge between otherwise similar organizations, leading to distinct configurations of implementation and maintenance processes. PMID:28809807

The Science of Sustaining Health Behavior Change: The Health Maintenance Consortium

PubMed Central

Ory, Marcia G.; Smith, Matthew Lee; Mier, Nelda; Wernicke, Meghan M.

2013-01-01

Objective The Health Maintenance Consortium (HMC) is a multisite Grantee Consortium funded by the National Institutes of Health from 2004–2009. The goal of HMC is to enhance understanding of the long-term maintenance of behavior change, as well as effective strategies for achieving sustainable health promotion and disease prevention. Methods This introductory research synthesis prepared by the Resource Center gives context to this theme issue by providing an overview of the HMC and the articles in this journal. Results It explores the contributions to our conceptualization of behavior change processes and intervention strategies, the trajectory of effectiveness of behavioral and social interventions, and factors influencing the long-term maintenance of behavioral and social interventions. Conclusions Future directions for furthering the science of maintaining behavior change and reducing the gaps between research and practice are recommended. PMID:20604691

Dose-dense and less dose-intense Total Therapy 5 for gene expression profiling-defined high-risk multiple myeloma.

PubMed

Jethava, Y; Mitchell, A; Zangari, M; Waheed, S; Schinke, C; Thanendrarajan, S; Sawyer, J; Alapat, D; Tian, E; Stein, C; Khan, R; Heuck, C J; Petty, N; Avery, D; Steward, D; Smith, R; Bailey, C; Epstein, J; Yaccoby, S; Hoering, A; Crowley, J; Morgan, G; Barlogie, B; van Rhee, F

2016-07-29

Multiple myeloma (MM) is a heterogeneous disease with high-risk patients progressing rapidly despite treatment. Various definitions of high-risk MM are used and we reported that gene expression profile (GEP)-defined high risk was a major predictor of relapse. In spite of our best efforts, the majority of GEP70 high-risk patients relapse and we have noted higher relapse rates during drug-free intervals. This prompted us to explore the concept of less intense drug dosing with shorter intervals between courses with the aim of preventing inter-course relapse. Here we report the outcome of the Total Therapy 5 trial, where this concept was tested. This regimen effectively reduced early mortality and relapse but failed to improve progression-free survival and overall survival due to relapse early during maintenance.

Radiation hardness study of semi-insulating GaAs detectors against 5 MeV electrons

NASA Astrophysics Data System (ADS)

Šagátová, A.; Zaťko, B.; Nečas, V.; Sedlačková, K.; Boháček, P.; Fülöp, M.; Pavlovič, M.

2018-01-01

A radiation hardness study of Semi-Insulating (SI) GaAs detectors against 5 MeV electrons is described in this paper. The influence of two parameters, the accumulative absorbed dose (from 1 to 200 kGy) and the applied dose rate (20, 40 or 80 kGy/h), on detector spectrometric properties were studied. The accumulative dose has influenced all evaluated spectrometric properties and also negatively affected the detector CCE (Charge Collection Efficiency). We have observed its systematic reduction from an initial 79% before irradiation down to about 51% at maximum dose of 200 kGy. Relative energy resolution was also influenced by electron irradiation. Its degradation was obvious in the range of doses from 24 up to a maximum dose of 200 kGy, where an increase from 19% up to 31% at 200 V reverse voltage was noticed. On the other hand, a global increase of detection efficiency with accumulative absorbed dose was observed for all samples. Concerning the actual detector degradation we can assume that the tested SI GaAs detectors will be able to operate up to a dose of 300 kGy at least, when irradiated by 5 MeV electrons. The second investigated parameter of irradiation, the dose rate of chosen ranges, did not greatly alter the spectrometric properties of studied detectors.

The Role of Fathers in Language Maintenance and Language Attrition: The Case of Korean-English Late Bilinguals in New Zealand

ERIC Educational Resources Information Center

Kim, Sun Hee Ok; Starks, Donna

2010-01-01

The father's role in children's L1 maintenance and L2 learning is a relatively unexplored area. This study considers the L1 and L2 proficiency of 30 Korean-English late bilinguals who immigrated to New Zealand during their adolescence and how their L1 and L2 proficiency is influenced by the language use of family members. Data were collected…

Flight Crew Health Maintenance

NASA Technical Reports Server (NTRS)

Gullett, C. C.

1970-01-01

The health maintenance program for commercial flight crew personnel includes diet, weight control, and exercise to prevent heart disease development and disability grounding. The very high correlation between hypertension and overweight in cardiovascular diseases significantly influences the prognosis for a coronary prone individual and results in a high rejection rate of active military pilots applying for civilian jobs. In addition to physical fitness the major items stressed in pilot selection are: emotional maturity, glucose tolerance, and family health history.

Pharmacogenetics of warfarin: challenges and opportunities

PubMed Central

Ta Michael Lee, Ming; Klein, Teri E

2014-01-01

Since the introduction in the 1950s, warfarin has become the commonly used oral anticoagulant for the prevention of thromboembolism in patients with deep vein thrombosis, atrial fibrillation or prosthetic heart valve replacement. Warfarin is highly efficacious; however, achieving the desired anticoagulation is difficult because of its narrow therapeutic window and highly variable dose response among individuals. Bleeding is often associated with overdose of warfarin. There is overwhelming evidence that an individual's warfarin maintenance is associated with clinical factors and genetic variations, most notably polymorphisms in cytochrome P450 2C9 and vitamin K epoxide reductase subunit 1. Numerous dose-prediction algorithms incorporating both genetic and clinical factors have been developed and tested clinically. However, results from major clinical trials are not available yet. This review aims to provide an overview of the field of warfarin which includes information about the drug, genetics of warfarin dose requirements, dosing algorithms developed and the challenges for the clinical implementation of warfarin pharmacogenetics. PMID:23657428

A method for depth-dose distribution measurements in tissue irradiated by a proton beam

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

Gambarini, G.; Birattari, C.; Bartolo, D. de

1994-12-31

The use of protons and heavy ions for the treatment of malignant and non-malignant disease has aroused a growing interest in the last decade. The notable advantage of heavy charged particles over photons in external beam radiotherapy lies in the possibility of irradiating a small localized region within the body, keeping a low value for the entrance dose. Owing to this high disuniformity of energy deposition, an essential requirement for treatment planning is a precise evaluation of the spatial distribution of absorbed dose. The proposed method for depth-dose distribution measurements utilizes a chemical dosimeter (ferrous sulphate solution plus sulfuric acidmore » and eventually xylenol orange) incorporated in a gelatine, whose role is the maintenance of spatial information. Ionizing radiation causes a variation in some parameters of the system such as the proton relaxation rates in the solution (measurable by NMR analysis) or the optical absorption of the gel in the visible spectrum (measurable by spectrophotometry).« less

Radionuclide production and dose rate estimation during the commissioning of the W-Ta spallation target

NASA Astrophysics Data System (ADS)

Yu, Q. Z.; Liang, T. J.

2018-06-01

China Spallation Neutron Source (CSNS) is intended to begin operation in 2018. CSNS is an accelerator-base multidisciplinary user facility. The pulsed neutrons are produced by a 1.6GeV short-pulsed proton beam impinging on a W-Ta spallation target, at a beam power of100 kW and a repetition rate of 25 Hz. 20 neutron beam lines are extracted for the neutron scattering and neutron irradiation research. During the commissioning and maintenance scenarios, the gamma rays induced from the W-Ta target can cause the dose threat to the personal and the environment. In this paper, the gamma dose rate distributions for the W-Ta spallation are calculated, based on the engineering model of the target-moderator-reflector system. The shipping cask is analyzed to satisfy the dose rate limit that less than 2 mSv/h at the surface of the shipping cask. All calculations are performed by the Monte carlo code MCNPX2.5 and the activation code CINDER’90.

Clinical Pharmacology of Phenobarbital in Neonates: Effects, Metabolism and Pharmacokinetics.

PubMed

Pacifici, Gian M

2016-01-01

Phenobarbital is an effective and safe anticonvulsant drug introduced in clinical use in 1904. Its mechanism of action is the synaptic inhibition through an action on GABAA. The loading dose of phenobarbital is 20 mg/kg intravenously and the maintenance dose is 3 to 4 mg/kg by mouth. The serum concentration of phenobarbital is up to 40 µg/ml. Nonresponders should receive additional doses of 5 to 10 mg/kg until seizures stop. Infants with refractory seizures may have a serum concentration of phenobarbital of 100 µg/ml. Phenobarbital is metabolized in the liver by CYP2C9 with minor metabolism by CYP2C19 and CYP2E1. A quarter of the dose of phenobarbital is excreted unchanged in the urine. In adults, the half-life of phenobarbital is 100 hours and in term and preterm infants is 103 and 141 hours, respectively. The half-life of phenobarbital decreases 4.6 hours per day and it is 67 hours in infants 4 week old.

Long-term survival in primary CNS lymphoma treated by high-dose methotrexate monochemotherapy: role of STAT6 activation as prognostic determinant.

PubMed

Yang, Seung-Ho; Lee, Kun Soo; Kim, Il Sup; Hong, Jae Taek; Sung, Jae Hoon; Son, Byung Chul; Lee, Sang Won; Hong, Yong-Kil

2009-03-01

We report a single-center experience of 16 immunocompetent patients diagnosed with primary central nervous system lymphoma and treated with monochemotherapy with high-dose methotrexate (MTX) and deferred radiotherapy. MTX was given at a dose of 8.0 g/m2 for induction and at a dose of 3.5-8.0 g/m2 for maintenance. There were eight complete responses (CR), one partial response, one stable disease, and six patients whose tumors progressed in spite of the chemotherapy. At final follow-up, five of five CRs were alive and well without radiotherapy, with median follow-up of 26 months. Overall survival in eight non-CRs treated with the subsequent radiotherapy was 36 months. In the immunohistochemical study, STAT6 was positively expressed in 8 out of 13 cases. They included all non-CRs and two CRs. This observation suggests that STAT6 expression can be used as a prognostic determinant for MTX chemotherapy.

Cost-effectiveness of maintenance pemetrexed in patients with advanced nonsquamous-cell lung cancer from the perspective of the Swiss health care system.

PubMed

Matter-Walstra, Klazien; Joerger, Markus; Kühnel, Ursula; Szucs, Thomas; Pestalozzi, Bernhard; Schwenkglenks, Matthias

2012-01-01

A recent randomized study showed switch maintenance with pemetrexed after nonpemetrexed-containing first-line chemotherapy in patients with advanced nonsmall-cell lung cancer to prolong overall survival by 2.8 months. We examined the cost-effectiveness of pemetrexed in this indication, from the perspective of the Swiss health care system, and assessed the influence of the costs of best supportive care (BSC) on overall cost-effectiveness. A Markov model was constructed based on the pemetrexed maintenance study, and the incremental cost-effectiveness ratio (ICER) of adding pemetrexed until disease progression was calculated as cost per quality-adjusted life-year gained. Uncertainties concerning the costs of BSC on the ICER were addressed. The base case ICER for maintenance therapy with pemetrexed plus BSC compared to BSC alone was €106,202 per quality-adjusted life-year gained. Varying the costs for BSC had a marked effect. Assuming a reduction of the costs for BSC by 25% in the pemetrexed arm resulted in an ICER of €47,531 per quality-adjusted life-year, which is below predefined criteria for cost effectiveness in Switzerland. Switch maintenance with pemetrexed in patients with advanced nonsquamous-cell lung cancer after standard first-line chemotherapy is not cost-effective. Uncertainties on the resource use and costs for BSC have a large influence on the cost-effectiveness calculation and should be reported in more detail. Copyright © 2012 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.

Informed consent to opioid agonist maintenance treatment: recommended ethical guidelines.

PubMed

Carter, Adrian; Hall, Wayne

2008-02-01

Some bioethicists have questioned whether opioid addicted individuals are able to provide free and informed consent to opioid agonist maintenance treatment. Conflicting motives for providing such treatment (e.g. improving the personal health of addicts and protecting public health and order) can also influence what individuals are required to consent to, and how that consent is obtained. We discuss both issues and attempt to specify the conditions for obtaining informed consent to agonist maintenance treatment for opioid addiction. We briefly review the neuroscientific literature on the effects of addiction on the autonomy and decision-making capacity of opioid dependent individuals, and ascertain how informed consent to the treatment of opioid addiction should be obtained. We also provide an ethical analysis of the competing social and medical forces that influence the consent process and make some recommendations on how to ensure that individuals enter maintenance treatment that is provided in an effective and ethical way. Our analysis shows that whilst the autonomy of opioid dependent individuals is impaired by their addiction, they do retain the ability to consent to treatment provided they are not in acute withdrawal or intoxication. These symptoms should have abated, either by supervised withdrawal or stabilisation on agonist maintenance, before they are asked to consent to a detailed treatment contract. Once stabilised, individuals should be provided with detailed information about the risks and benefits of all treatments, and restrictions and regulations under which they are provided. Informed consent is an important part of the treatment process that should be obtained in ways that increase the autonomy and decision-making capacity in opioid addicts.

Perspectives on Smoking Initiation and Maintenance: A Qualitative Exploration among Singapore Youth.

PubMed

Subramaniam, Mythily; Shahwan, Shazana; Fauziana, Restria; Satghare, Pratika; Picco, Louisa; Vaingankar, Janhavi Ajit; Chong, Siow Ann

2015-07-31

Studies among adolescents have shown that several important interpersonal, intrapersonal and environmental factors are associated with smoking behaviour. The current qualitative research project aimed to explore the determinants of smoking initiation and maintenance, from a youth perspective, among young people who smoked, living in a multi-ethnic Asian country. Focus group discussions (FGDs) were conducted with youths in Singapore in youth-friendly and accessible locations. Young people, from a variety of social contexts-varying on age, gender, ethnicity and educational level, were included in the study. All FGDs were conducted in English and participants were recruited using a mix of network and purposive sampling. All FGDs were audio recorded and transcribed verbatim. The data were analyzed using qualitative content analysis, allowing themes to emerge from the data with the goal of answering the research question. Ninety-one youth smokers (54 males, 37 females), aged between 14 to 29 years, participated in the study. The majority were males (59%) and of Chinese ethnicity (52%). Participants identified multiple personal, social, and familial influences on young adults' smoking behaviors. Peer and family influences, as well as risk minimization, played a key role in smoking initiation and maintenance. While young people were aware of policies that restricted smoking, these did not directly affect their decision to start smoking. The theory of triadic influence provided a promising theoretical framework to understand smoking initiation and maintenance in a sample of young adult smokers from a multi-ethnic Asian country. It also provides actionable information for initiatives to prevent smoking in young people, which includes their perspectives and emphasizes an inclusive approach without stigmatizing those who smoke.

Characterization of a new transmission detector for patient individualized online plan verification and its influence on 6MV X-ray beam characteristics.

PubMed

Thoelking, Johannes; Sekar, Yuvaraj; Fleckenstein, Jens; Lohr, Frank; Wenz, Frederik; Wertz, Hansjoerg

2016-09-01

Online verification and 3D dose reconstruction on daily patient anatomy have the potential to improve treatment delivery, accuracy and safety. One possible implementation is to recalculate dose based on online fluence measurements with a transmission detector (TD) attached to the linac. This study provides a detailed analysis of the influence of a new TD on treatment beam characteristics. The influence of the new TD on surface dose was evaluated by measurements with an Advanced Markus Chamber (Adv-MC) in the build-up region. Based on Monte Carlo simulations, correction factors were determined to scale down the over-response of the Adv-MC close to the surface. To analyze the effects beyond dmax percentage depth dose (PDD), lateral profiles and transmission measurements were performed. All measurements were carried out for various field sizes and different SSDs. Additionally, 5 IMRT-plans (head & neck, prostate, thorax) and 2 manually created test cases (3×3cm(2) fields with different dose levels, sweeping gap) were measured to investigate the influence of the TD on clinical treatment plans. To investigate the performance of the TD, dose linearity as well as dose rate dependency measurements were performed. With the TD inside the beam an increase in surface dose was observed depending on SSD and field size (maximum of +11%, SSD = 80cm, field size = 30×30cm(2)). Beyond dmax the influence of the TD on PDDs was below 1%. The measurements showed that the transmission factor depends slightly on the field size (0.893-0.921 for 5×5cm(2) to 30×30cm(2)). However, the evaluation of clinical IMRT-plans measured with and without the TD showed good agreement after using a single transmission factor (γ(2%/2mm) > 97%, δ±3% >95%). Furthermore, the response of TD was found to be linear and dose rate independent (maximum difference <0.5% compared to reference measurements). When placed in the path of the beam, the TD introduced a slight, clinically acceptable increase of the skin dose even for larger field sizes and smaller SSDs and the influence of the detector on the dose beyond dmax as well as on clinical IMRT-plans was negligible. Since there was no dose rate dependency and the response was linear, the device is therefore suitable for clinical use. Only its absorption has to be compensated during treatment planning, either by the use of a single transmission factor or by including the TD in the incident beam model. Copyright © 2015. Published by Elsevier GmbH.

State-dependent physiological maintenance in a long-lived ectotherm, the painted turtle (Chrysemys picta).

PubMed

Schwanz, Lisa; Warner, Daniel A; McGaugh, Suzanne; Di Terlizzi, Roberta; Bronikowski, Anne

2011-01-01

Energy allocation among somatic maintenance, reproduction and growth varies not only among species, but among individuals according to states such as age, sex and season. Little research has been conducted on the somatic (physiological) maintenance of long-lived organisms, particularly ectotherms such as reptiles. In this study, we examined sex differences and age- and season-related variation in immune function and DNA repair efficiency in a long-lived reptile, the painted turtle (Chrysemys picta). Immune components tended to be depressed during hibernation, in winter, compared with autumn or spring. Increased heterophil count during hibernation provided the only support for winter immunoenhancement. In juvenile and adult turtles, we found little evidence for senescence in physiological maintenance, consistent with predictions for long-lived organisms. Among immune components, swelling in response to phytohemagglutinin (PHA) and control injection increased with age, whereas basophil count decreased with age. Hatchling turtles had reduced basophil counts and natural antibodies, indicative of an immature immune system, but demonstrated higher DNA repair efficiency than older turtles. Reproductively mature turtles had reduced lymphocytes compared with juvenile turtles in the spring, presumably driven by a trade-off between maintenance and reproduction. Sex had little influence on physiological maintenance. These results suggest that components of physiological maintenance are modulated differentially according to individual state and highlight the need for more research on the multiple components of physiological maintenance in animals of variable states.

Penicillin dosing for pneumococcal pneumonia.

PubMed

Bryan, C S; Talwani, R; Stinson, M S

1997-12-01

Most textbook authors still endorse penicillin G as the specific antibiotic of choice for pneumococcal pneumonia. However, problems with early precise etiologic diagnosis of pneumonia and the emergence of drug-resistant pneumococci cause penicillin to be seldom used for this purpose today. A third explanation for the infrequent use of penicillin is lack of clear consensus dosing guidelines. Emergence of pneumococci resistant to the newer cephalosporins and concerns about overuse of vancomycin, however, have prompted renewed interest in the development of precise, rapid methods for diagnosis of pneumococcal pneumonia with the implication that penicillin might be used more frequently. We review several issues concerning penicillin dosing: intermittent vs continuous therapy, high dose vs low dose, relationship of dose to resistance, and cost-effective pharmacology. An optimum "high-dose" regimen for life-threatening pneumococcal pneumonia in a 70-kg adult consists of a 3 million unit (mu) loading dose followed by continuous infusion of 10 to 12 mu of freshly prepared drug every 12 h. The maintenance dose should be reduced in elderly patients and in patients with renal failure according to the following formula: dose (mu/24 h = 4+[creatinine clearance divided by 7]). This regimen provides a penicillin serum level of 16 to 20 microg/mL, which should suffice for all but the most highly resistant strains (minimum inhibitory concentration > or = 4 microg/mL). Newer cephalosporins and vancomycin can be reserved for patients with suspected meningitis or endocarditis or for localities in which highly resistant pneumococci are known to be prevalent.

[Effect of the frequency of maintenance therapy on patients treated for gingivitis and incipient marginal periodontitis].

PubMed

Rojas, I F; Zepeda, M S; Zúñiga, H P

1990-11-01

The effectiveness of maintenance care program applied at different period of time was evaluate in patients treated for gingivitis and incipiente marginal periodontitis. Fifty six patients were divided in three groups, each one controlled three times (each 2, 4 and 6 months respectively), to evaluate periodontal health. At each control, gingival index and plaque index was registered and patients had profilaxis and reinforcement of dental care instructions. All patients knew and practiced a control plaque control during active treatment. Results demonstrated that maintenance care program applied each 2 months, could get better clinical healthy periodontal conditions, without influence of patient's control plaque. Those patients with good hygiene could provide for an acceptable level of periodontal health even in patients controlled each 4 and 6 months. Positive correlations between controls in each index are indicative for that. Age seemingly do not have influence like etiological factor of recurrence inflammation. High correlation between plaque index and gingival index was found in every control mainly in the groups controlled each 4 and 6 months.

Social anxiety in pre-adolescent children: What do we know about maintenance?

PubMed

Halldorsson, Brynjar; Creswell, Cathy

2017-12-01

The cognitive theory of social anxiety disorder (SAD) is one of the most widely accepted accounts of the maintenance of the disorder in adults, yet it remains unknown if, or to what extent, the same cognitive and behavioral maintenance mechanisms that occur in adult SAD also apply to SAD among pre-adolescent children. In contrast to the adult literature, current models of SAD in children mostly account for etiology and maintenance processes are given limited attention. Consequently, their clinical utility for the treatment of SAD in children may be limited. This narrative review, first, critically examines the different theoretical conceptualizations of the maintenance of social anxiety in the child and adult literature and illustrates how these have resulted in different treatment approaches and clinical understanding. Second, it reviews the available evidence relating to hypotheses about the maintenance of SAD in children as derived from adult cognitive and etiological models. Third, it highlights the need to attend directly to child specific maintenance mechanisms in SAD, to draw on cognitive theory, and to account for the influence of childhood-specific contextual (e.g. family and school-based interactions) and developmental factors on children's social experiences. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

The Influence of High and Low Doses of Bisphenol A (BPA) on the Enteric Nervous System of the Porcine Ileum.

PubMed

Szymanska, Kamila; Makowska, Krystyna; Gonkowski, Slawomir

2018-03-20

Bisphenol A, used in the production of plastic, is able to leach from containers into food and cause multidirectional adverse effects in living organisms, including neurodegeneration and metabolic disorders. Knowledge of the impact of BPA on enteric neurons is practically non-existent. The destination of this study was to investigate the influence of BPA at a specific dose (0.05 mg/kg body weight/day) and at a dose ten times higher (0.5 mg/kg body weight/day), given for 28 days, on the porcine ileum. The influence of BPA on enteric neuron immunoreactive to selected neuronal active substances, including substance P (SP), vasoactive intestinal polypeptide (VIP), galanin (GAL), vesicular acetylcholine transporter (VAChT-used here as a marker of cholinergic neurons), and cocaine- and amphetamine-regulated transcript peptide (CART), was studied by the double immunofluorescence method. Both doses of BPA affected the neurochemical characterization of the enteric neurons. The observed changes depended on the type of enteric plexus but were generally characterized by an increase in the number of cells immunoreactive to the particular substances. More visible fluctuations were observed after treatment with higher doses of BPA. The results confirm that even low doses of BPA may influence the neurochemical characterization of the enteric neurons and are not neutral for living organisms.

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

Brown, Thomas

The design features developed for the Spherical Tokamak (ST) in the PPPL pilot plant study was used as the starting point in developing designs to meet the mission of a Fusion Nuclear Science Facility (FNSF) considering a range of machine sizes based on the influence of tritium consumption and maintenance strategies. The compact nature of a steady state operated ST device for this mission pushes operating conditions and places challenges in the design of components, device maintenance and the integration of supports and services. This paper reviews the general arrangement, design details and maintenance strategy of the ST-FNSF device coremore » for a 1.6-m and 1.0-m device; operating points which bracket the region between purchasing and breeding tritium.« less

Parenteral cidofovir for cytomegalovirus retinitis in patients with AIDS: the HPMPC peripheral cytomegalovirus retinitis trial. A randomized, controlled trial. Studies of Ocular complications of AIDS Research Group in Collaboration with the AIDS Clinical Trials Group.

PubMed

1997-02-15

Cytomegalovirus (CMV) retinitis is a common infection and a major cause of visual loss in patients with the acquired immunodeficiency syndrome (AIDS). To evaluate intravenous cidofovir as a treatment for CMV retinitis. Two-stage, multicenter, phase II/III, randomized, controlled clinical trial. Ophthalmology and AIDS services at tertiary care medical centers. 64 patients with AIDS and previously untreated, small, peripheral CMV retinitis lesions (that is, patients at low risk for loss of visual acuity). Patients were randomly assigned to one of three groups: the deferral group, in which treatment was deferred until retinitis progressed; the low-dose cidofovir group, which received cidofovir, 5 mg/kg of body weight once weekly for 2 weeks, then maintenance therapy with cidofovir, 3 mg/kg once every 2 weeks; or the high-dose cidofovir group, which received cidofovir, 5 mg/kg once weekly for 2 weeks, then maintenance therapy with cidofovir, 5 mg/kg once every 2 weeks. To minimize nephrotoxicity, cidofovir was administered with hydration and probenecid. Progression of retinitis, evaluated in a masked manner by a fundus photograph reading center; the amount of retinal area involved by CMV; the loss of visual acuity; and morbidity. Median time to progression was 64 days in the low-dose cidofovir group and 21 days in the deferral group (P = 0.052, log-rank test). The median time to progression was not reached in the high-dose cidofovir group but was 20 days in the deferral group (P = 0.009, log-rank test). Analysis of the rates of increase in the retinal area affected by CMV confirmed the data on time to progression. The three groups had similar rates of visual loss. Proteinuria of 2+ or more occurred at rates of 2.6 per person-year in the deferral group, 2.8 per person-year in the low-dose cidofovir group (P > 0.02), and 6.8 per person-year in the high-dose cidofovir group (P = 0.135). No patient developed 4+ proteinuria, but two cidofovir recipients developed persistent elevations of serum creatinine levels at more than 177 mumol/L (2.0 mg/dL). Reactions to probenecid occurred at a rate of 0.70 per person-year. Intravenous cidofovir, high- or low-dose, effectively slowed the progression of CMV retinitis. Concomitant probenecid and hydration therapy, intermittent dosing, and monitoring for proteinuria seemed to minimize but not eliminate the risk for nephrotoxicity.

Moderate- vs high-dose methadone in the treatment of opioid dependence: a randomized trial.

PubMed

Strain, E C; Bigelow, G E; Liebson, I A; Stitzer, M L

1999-03-17

Methadone hydrochloride treatment is the most common pharmacological intervention for opioid dependence, and recent interest has focused on expanding methadone treatment availability beyond traditional specially licensed clinics. However, despite recommendations regarding effective dosing of methadone, controlled clinical trials of higher-dose methadone have not been conducted. To compare the relative clinical efficacy of moderate- vs high-dose methadone in the treatment of opioid dependence. A 40-week randomized, double-blind clinical trial starting in June 1992 and ending in October 1995. Outpatient substance abuse treatment research clinic at the Johns Hopkins University Bayview Campus, Baltimore, Md. One hundred ninety-two eligible clinic patients. Daily oral methadone hydrochloride in the dose range of 40 to 50 mg (n = 97) or 80 to 100 mg (n = 95), with concurrent substance abuse counseling. Opioid-positive urinalysis results and retention in treatment. By intent-to-treat analysis through week 30 patients in the high-dose group had significantly lower rates of opioid-positive urine samples compared with patients in the moderate-dose group (53.0% [95% confidence interval [CI], 46.9%-59.2%] vs 61.9% [95% CI, 55.9%-68.0%]; P = .047. These differences persisted during withdrawal from methadone. Through day 210 no significant difference was evident between dose groups in treatment retention (high-dose group mean retention, 159 days; moderate-dose group mean retention, 157 days). Nineteen (33%) of 57 patients in the high-dose group and 11 (20%) of 54 patients in the moderate-dose group completed detoxification. Both moderate- and high-dose methadone treatment resulted in decreased illicit opioid use during methadone maintenance and detoxification. The high-dose group had significantly greater decreases in illicit opioid use.

Propofol anesthesia.

PubMed

Short, C E; Bufalari, A

1999-05-01

Although questions may still remain regarding the use of this unique sedative-hypnotic drug with anesthetic properties in high-risk patients, our studies have provided cardiopulmonary and neurological evidence of the efficacy and safety of propofol when used as an anesthetic under normal and selected impaired conditions in the dog. 1. Propofol can be safely and effectively used for the induction and maintenance of anesthesia in normal healthy dogs. Propofol is also a reliable and safe anesthetic agent when used during induced cardiovascular and pulmonary-impaired conditions without surgery. The propofol requirements to induce the safe and prompt induction of anesthesia prior to inhalant anesthesia with and without surgery have been determined. 2. The favorable recovery profile associated with propofol offers advantages over traditional anesthetics in clinical situations in which rapid recovery is important. Also, propofol compatibility with a large variety of preanesthetics may increase its use as a safe and reliable i.v. anesthetic for the induction and maintenance of general anesthesia and sedation in small animal veterinary practice. Although propofol has proven to be a valuable adjuvant during short ambulatory procedures, its use for the maintenance of general anesthesia has been questioned for surgery lasting more than 1 hour because of increased cost and marginal differences in recovery times compared with those of standard inhalant or balanced anesthetic techniques. When propofol is used for the maintenance of anesthesia in combination with a sedative/analgesic, the quality of anesthesia is improved as well as the ease with which the practitioner can titrate propofol; therefore, practitioners are able to use i.v. anesthetic techniques more effectively in their clinical practices. 3. Propofol can induce significant depression of respiratory function, characterized by a reduction in the rate of respiration. Potent alpha 2 sedative/analgesics (e.g., xylazine, medetomidine) or opioids (e.g., oxymorphone, butorphanol) increase the probability of respiratory depression during anesthesia. Appropriate consideration of dose reduction and speed of administration of propofol reduces the degree of depression. Cardiovascular changes induced by propofol administration consist of a slight decrease in arterial blood pressures (systolic, mean, diastolic) without a compensatory increase in heart rate. Selective premedicants markedly modify this characteristic response. 4. When coupled with subjective responses to painful stimuli, EEG responses during propofol anesthesia provide clear evidence that satisfactory anesthesia has been achieved in experimental dogs. When propofol is used as the only anesthetic agent, a higher dose is required to induce an equipotent level of CNS depression compared with the situation when dogs are premedicated. 5. The propofol induction dose requirement should be appropriately decreased by 20% to 80% when propofol is administered in combination with sedative or analgesic agents as part of a balanced technique as well as in elderly and debilitated patients. As a general recommendation, the dose of propofol should always be carefully titrated against the needs and responses of the individual patient, as there is considerable variability in anesthetic requirements among patients. Because propofol does not have marked analgesic effects and its metabolism is rapid, the use of local anesthetics, nonsteroidal anti-inflammatory agents, and opioids to provide postoperative analgesia improves the quality of recovery after propofol anesthesia. 6. The cardiovascular depressant effects of propofol are well tolerated in healthy animals, but these effects may be more problematic in high-risk patients with intrinsic cardiac disease as well as in those with systemic disease. In hypovolemic patients and those with limited cardiac reserve, even small induction doses of propofol (0.75-1.5 mg/kg i.v.) can produce profound hypotens

The importance of applicator design for intraluminal brachytherapy of rectal cancer.

PubMed

Hansen, Johnny Witterseh; Jakobsen, Anders

2006-09-01

An important aspect of designing an applicator for radiation treatment of rectal cancer is the ability to minimize dose to the mucosa and noninvolved parts of the rectum wall. For this reason we investigated a construction of a flexible multichannel applicator with several channels placed along the periphery of a cylinder and a construction of a rigid cylinder with a central channel and interchangeable shields. Calculations of the dose gradient, dose homogeneity in the tumor, and shielding ability were performed for the two applicators in question. Furthermore, the influence on dose distribution around a flexible multichannel applicator from an unintended off-axis positioning of the source inside a bent channel was investigated by film measurements on a single bent catheter. Calculations showed that a single-channel applicator with interchangeable shields yields a higher degree of shielding and has a better dose homogeneity in the tumor volume than that of a multi-channel applicator. A single-channel applicator with interchangeable shields was manufactured, and the influence of different size of shield angle on dose rate in front of and behind the shields was measured. While dose rate in front of the shield and shielding ability are closely independent of the size of the shield angle when measured 1 cm from the applicator surface, dose rate in more distant volumes will to some extent be influenced by shield angle due to volume scatter conditions.

The importance of applicator design for intraluminal brachytherapy of rectal cancer

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

Hansen, Johnny Witterseh; Jakobsen, Anders; Department of Oncology, Hospital of Vejle, DK-7100 Vejle

2006-09-15

An important aspect of designing an applicator for radiation treatment of rectal cancer is the ability to minimize dose to the mucosa and noninvolved parts of the rectum wall. For this reason we investigated a construction of a flexible multichannel applicator with several channels placed along the periphery of a cylinder and a construction of a rigid cylinder with a central channel and interchangeable shields. Calculations of the dose gradient, dose homogeneity in the tumor, and shielding ability were performed for the two applicators in question. Furthermore, the influence on dose distribution around a flexible multichannel applicator from an unintendedmore » off-axis positioning of the source inside a bent channel was investigated by film measurements on a single bent catheter. Calculations showed that a single-channel applicator with interchangeable shields yields a higher degree of shielding and has a better dose homogeneity in the tumor volume than that of a multichannel applicator. A single-channel applicator with interchangeable shields was manufactured, and the influence of different size of shield angle on dose rate in front of and behind the shields was measured. While dose rate in front of the shield and shielding ability are closely independent of the size of the shield angle when measured 1 cm from the applicator surface, dose rate in more distant volumes will to some extent be influenced by shield angle due to volume scatter conditions.« less

Sensitive maintenance: a cognitive process underlying individual differences in memory for threatening information.

PubMed

Peters, Jan H; Hock, Michael; Krohne, Heinz Walter

2012-01-01

Dispositional styles of coping with threat influence memory for threatening information. In particular, sensitizers excel over repressors in their memory for threatening information after long retention intervals, but not after short ones. We therefore suggested that sensitizers, but not repressors, employ active maintenance processes during the retention interval to selectively retain threatening material. Sensitive maintenance was studied in 2 experiments in which participants were briefly exposed to threatening and nonthreatening pictures (Experiment 1, N = 128) or words (Experiment 2, N = 145). Following, we administered unannounced recognition tests before and after an intervening task that generated either high or low cognitive load, assuming that high cognitive load would impede sensitizers' memory maintenance of threatening material. Supporting our hypotheses, the same pattern of results was obtained in both experiments: Under low cognitive load, sensitizers forgot less threat material than repressors did; no such differences were observed under high cognitive load.

Protein kinase M ζ and the maintenance of long-term memory.

PubMed

Zhang, Yang; Zong, Wei; Zhang, Lei; Ma, Yuanye; Wang, Jianhong

2016-10-01

Although various molecules have been found to mediate the processes of memory acquisition and consolidation, the molecular mechanism to maintain memory still remains elusive. In recent years, a molecular pathway focusing on protein kinase Mζ (PKMζ) has become of interest to researchers because of its potential role in long-term memory maintenance. PKMζ is an isoform of protein kinase C (PKC) and has a related structure that influences its function in maintaining memory. Considerable evidence has been gathered on PKMζ activity, including loss of function studies using PKMζ inhibitors, such as PKMζ inhibitory peptide (ZIP), suggesting PKMζ plays an important role in long-term memory maintenance. This review provides an overview of the role of PKMζ in long-term memory and outlines the molecular structure of PKMζ, the molecular mechanism of PKMζ in long-term memory maintenance and future directions of PKMζ research. Copyright © 2016 Elsevier Ltd. All rights reserved.

Clinical and socio-demographic determinants of self-care behaviours in patients with heart failure and diabetes mellitus: A multicentre cross-sectional study.

PubMed

Ausili, Davide; Rebora, Paola; Di Mauro, Stefania; Riegel, Barbara; Valsecchi, Maria Grazia; Paturzo, Marco; Alvaro, Rosaria; Vellone, Ercole

2016-11-01

Self-care is vital for patients with heart failure to maintain health and quality of life, and it is even more vital for those who are also affected by diabetes mellitus, since they are at higher risk of worse outcomes. The literature is unclear on the influence of diabetes on heart failure self-care as well as on the influence of socio-demographic and clinical factors on self-care. (1) To compare self-care maintenance, self-care management and self-care confidence of patients with heart failure and diabetes versus those heart failure patients without diabetes; (2) to estimate if the presence of diabetes influences self-care maintenance, self-care management and self-care confidence of heart failure patients; (3) to identify socio-demographic and clinical determinants of self-care maintenance, self-care management and self-care confidence in patients with heart failure and diabetes. Secondary analysis of data from a multicentre cross-sectional study. Outpatient clinics from 29 Italian provinces. 1192 adults with confirmed diagnosis of heart failure. Socio-demographic and clinical data were abstracted from patients' medical records. Self-care maintenance, self-care management and self-care confidence were measured with the Self-Care of Heart Failure Index Version 6.2; each scale has a standardized score from 0 to 100, where a score <70 indicates inadequate self-care. Multiple linear regression analyses were performed. Of 1192 heart failure patients, 379 (31.8%) had diabetes. In these 379, heart failure self-care behaviours were suboptimal (means range from 53.2 to 55.6). No statistically significant differences were found in any of the three self-care measures in heart failure patients with and without diabetes. The presence of diabetes did not influence self-care maintenance (p=0.12), self-care management (p=0.21) or self-care confidence (p=0.51). Age (p=0.04), number of medications (p=0.01), presence of a caregiver (p=0.04), family income (p=0.009) and self-care confidence (p<0.001) were determinants of self-care maintenance. Gender (p=0.01), number of medications (p=0.004) and self-care confidence (p<0.001) were significant determinants of self-care management. Number of medications (p=0.002) and cognitive function (p<0.001) were determinants of self-care confidence. Self-care was poor in heart failure patients with diabetes mellitus. This population needs more intensive interventions to improve self-care. Determinants of self-care in heart failure patients with diabetes mellitus should be systematically assessed by clinicians to identify patients at risk of inadequate self-care. Copyright © 2016 Elsevier Ltd. All rights reserved.

The role of physical activity in producing and maintaining weight loss.

PubMed

Catenacci, Victoria A; Wyatt, Holly R

2007-07-01

The majority of randomized, controlled trials (RCTs) show only modest weight loss with exercise intervention alone, and slight increases in weight loss when exercise intervention is added to dietary restriction. In most RCTs, the energy deficit produced by the prescribed exercise is far smaller than that usually produced by dietary restriction. In prospective studies that prescribed high levels of exercise, enrolled individuals achieved substantially greater weight loss-comparable to that obtained after similar energy deficits were produced by caloric restriction. High levels of exercise might, however, be difficult for overweight or obese adults to achieve and sustain. RCTs examining exercise and its effect on weight-loss maintenance demonstrated mixed results; however, weight maintenance interventions were usually of limited duration and long-term adherence to exercise was problematic. Epidemiologic, cross-sectional, and prospective correlation studies suggest an essential role for physical activity in weight-loss maintenance, and post hoc analysis of prospective trials shows a clear dose-response relationship between physical activity and weight maintenance. This article reviews the role of physical activity in producing and maintaining weight loss. We focus on prospective, RCTs lasting at least 4 months; however, other prospective trials, meta-analyses and large systematic reviews are included. Limitations in the current body of literature are discussed.

GxG epistasis in growth and condition and the maintenance of genetic polymorphism in Gambusia holbrooki.

PubMed

Culumber, Zachary W; Kraft, Brittany; Lemakos, Valerie; Hoffner, Erika; Travis, Joseph; Hughes, Kimberly A

2018-05-01

Theory on indirect genetic effects (IGEs) indicates that variation in the genetic composition of social groups can generate GxG epistasis that may promote the evolution of stable polymorphisms. Using a livebearing fish with a genetic polymorphism in coloration and associated behavioral differences, we tested whether genotypes of social partners interacted with focal individual genotypes to influence growth and condition over 16 weeks of development. We found that IGEs had a significant influence on patterns of feeding, regardless of focal fish genotype. There was no influence of social environment on juvenile length, but there was significant GxG epistasis for body condition. Each focal juvenile was in better condition when its own genotype was not present in adult social partners. These data are consistent with negative frequency-dependent selection in which each morph performs better when it is rare. Neither variation in feeding nor activity-related behaviors explained variation in body condition, suggesting that GxG epistasis for condition was caused by physiological differences between the two genotypes. These findings indicate that GxG epistasis in a given polymorphism can generate fitness landscapes that contribute to the maintenance of that polymorphism and to maintenance of genetic variation for additional fitness-related traits. © 2018 The Author(s). Evolution © 2018 The Society for the Study of Evolution.

Maintenance lenalidomide in combination with 5-azacitidine as post-remission therapy for acute myeloid leukaemia.

PubMed

Wei, Andrew; Tan, Peter; Perruzza, Sarah; Govindaraj, Chindu; Fleming, Shaun; McManus, Julie; Avery, Sharon; Patil, Sushrut; Stevenson, William; Plebanski, Magdalena; Spencer, Andrew

2015-04-01

In this Phase 1b study, the safety and tolerability of maintenance therapy, comprising lenalidomide (0-25 mg, days 5-25) in combination with azacitidine (50-75 mg/m(2) , days 1-5) every 28 d, was explored in 40 patients with acute myeloid leukaemia (AML) in complete remission after chemotherapy. Eligibility included AML in first complete remission (CR1) with adverse risk karyotype (n = 8), fms-related tyrosine kinase 3-internal tandem duplication (FLT3-ITD) (n = 5), age ≥60 years (n = 31) or AML in second remission (CR2) (n = 14). Dose-limiting toxicity was not reached. Common toxicities were haematological, infection, injection pain, constipation, fatigue and diarrhoea. In CR1, median relapse-free (RFS) and overall survival (OS) was 12 and 20 months, respectively. In CR2, median RFS was 11 months, with median OS not yet reached. Among 29 patients with intermediate cytogenetic risk, RFS was 50% at 24 months. There were five patients with concomitant FLT3-ITD and nucleophosmin (NPM1) mutation; none have relapsed and all are still alive after 17-39 months. Maintenance lenalidomide/azacitidine augmented the function of cytotoxic T lymphocytes, particularly in patients with NPM1 mutation. The lenalidomide/azacitidine maintenance combination was effective in suppressing residual DNA (cytosine-5-)-methyltransferase 3 alpha (DNMT3A)-positive disease, resulting in sustained remission in patients with concurrent NPM1 mutation. Azacitidine/lenalidomide as maintenance therapy for high-risk AML warrants further exploration. © 2015 John Wiley & Sons Ltd.

Oxytocin Augmentation in Spontaneously Laboring, Nulliparous Women: Multilevel Assessment of Maternal BMI and Oxytocin Dose

PubMed Central

Carlson, Nicole S.; Corwin, Elizabeth J.; Lowe, Nancy K.

2017-01-01

Background Synthetic oxytocin, the primary tool for labor augmentation, is less effective among obese women, leading to more unplanned cesarean deliveries for slow labor progress. It is not known if obese women require higher doses of oxytocin due to maternal, fetal, or labor factors related to maternal obesity. Objectives This study had two main objectives: 1) Examine the influence of maternal body mass index (BMI) on hourly doses of oxytocin from augmentation initiation until vaginal delivery in obese women; and 2) Examine the influence of other maternal, fetal, and labor factors on hourly doses of oxytocin in obese women. Study design Longitudinal study of a cohort (N = 136) of healthy, nulliparous, spontaneously laboring obese women (BMI ≥ 30 kg/m2) who received oxytocin augmentation and achieved vaginal delivery. We performed iterative multilevel analyses to examine the influence of maternal BMI and other factors on hourly oxytocin doses. Results Maternal BMI explained 16.56% (95% CI [13.7-20.04], p < 0.001) of the variance in hourly oxytocin doses received in a multilevel model controlling for influence of maternal, fetal, and labor characteristics. Maternal age, gestational age, status of amniotic membranes at hospital admission, and admission cervical dilation examination were not significant; however, neonatal birthweight and cervical dilation at oxytocin initiation were significant predictors of hourly oxytocin dose in these women (p < 0.001). Conclusions Even when parturition preparation has progressed adequately for spontaneous labor initiation, there still may be some obesity-related blunting of myometrial contractility and response to oxytocin used for augmentation. PMID:28347147

Oxytocin Augmentation in Spontaneously Laboring, Nulliparous Women: Multilevel Assessment of Maternal BMI and Oxytocin Dose.

PubMed

Carlson, Nicole S; Corwin, Elizabeth J; Lowe, Nancy K

2017-07-01

Synthetic oxytocin, the primary tool for labor augmentation, is less effective among obese women, leading to more unplanned cesarean deliveries for slow labor progress. It is not known if obese women require higher doses of oxytocin due to maternal, fetal, or labor factors related to maternal obesity. This study had two main objectives: (1) examine the influence of maternal body mass index (BMI) on hourly doses of oxytocin from augmentation initiation until vaginal delivery in obese women; and (2) examine the influence of other maternal, fetal, and labor factors on hourly doses of oxytocin in obese women. Longitudinal study of a cohort ( N = 136) of healthy, nulliparous, spontaneously laboring obese women (BMI ≥ 30 kg/m 2 ) who received oxytocin augmentation and achieved vaginal delivery. We performed iterative multilevel analyses to examine the influence of maternal BMI and other factors on hourly oxytocin doses. Maternal BMI explained 16.56% (95% confidence interval [CI] = [13.7, 20.04], p < .001) of the variance in hourly oxytocin doses received in a multilevel model controlling for influence of maternal, fetal, and labor characteristics. Maternal age, gestational age, status of amniotic membranes at hospital admission, and admission cervical dilation examination were not significant; however, neonatal birthweight and cervical dilation at oxytocin initiation were significant predictors of hourly oxytocin dose in these women ( p < .001). Even when parturition preparation has progressed adequately for spontaneous labor initiation, there still may be some obesity-related blunting of myometrial contractility and response to oxytocin used for augmentation.

Kinetics of blood lipoprotein spectrum indices in patients with angina pectoris during and after low-intensity laser therapy as a paraclinical criterion for treatment efficiency

NASA Astrophysics Data System (ADS)

Babushkina, G. V.; Kartelishev, A. V.

2001-04-01

An investigation was made of applying (lambda) equals 0.63 micrometers laser radiation in treating 403 patients affected by angina pectoris. The patients were administered a course of combined laser therapy consisting of the intravenous laser irradiation of blood combined with laser acupuncture. Apart from that, the patients took the maintenance doses of antianginal preparations and therapeutic doses of vitamins A and E. The blood lipoprotein spectrum revealed that this combined laser therapy was capable of producing an antiatherogenic effect. It was also found that the most effective exposure time of laser radiation was in the range of 10 to 15 min.

Long-term use of mizoribine in rheumatoid arthritis patients on hemodialysis.

PubMed

Saisho, K; Kurosawa, O; Fukanoki, T; Hanafusa, A; Tajima, N

2001-06-01

Abstract Small doses of mizoribine (MZR) were administered to five rheumatoid arthritis (RA) patients on hemodialysis (HD). A maintenance dose of 25 mg or less was administered either once per day or once following HD. The Lansbury activity index improved in all patients. The blood concentrations of MZR before and after HD were 0.33-1.79 μg/ml and 0-0.93 μg/ml, respectively. Hence, the rate of elimination by HD ranged from 50.3% to 83.4%. As far as side effects were concerned, alopecia was seen in two patients, and one patient developed shingles. However, the severity of these symptoms was mild and, after discontinuing or reducing the dose of MZR for a certain period of time, we were able to continue its administration. These findings suggest that the long-term administration of MZR is a useful treatment for RA patients on HD.

Shutdown Dose Rate Analysis for the long-pulse D-D Operation Phase in KSTAR

NASA Astrophysics Data System (ADS)

Park, Jin Hun; Han, Jung-Hoon; Kim, D. H.; Joo, K. S.; Hwang, Y. S.

2017-09-01

KSTAR is a medium size fully superconducting tokamak. The deuterium-deuterium (D-D) reaction in the KSTAR tokamak generates neutrons with a peak yield of 3.5x1016 per second through a pulse operation of 100 seconds. The effect of neutron generation from full D-D high power KSTAR operation mode to the machine, such as activation, shutdown dose rate, and nuclear heating, are estimated for an assurance of safety during operation, maintenance, and machine upgrade. The nuclear heating of the in-vessel components, and neutron activation of the surrounding materials have been investigated. The dose rates during operation and after shutdown of KSTAR have been calculated by a 3D CAD model of KSTAR with the Monte Carlo code MCNP5 (neutron flux and decay photon), the inventory code FISPACT (activation and decay photon) and the FENDL 2.1 nuclear data library.

Impact of Efavirenz on Intestinal Metabolism and Transport: Insights From an Interaction Study With Ezetimibe in Healthy Volunteers

PubMed Central

Oswald, S; zu Schwabedissen, HE Meyer; Nassif, A; Modess, C; Desta, Z; Ogburn, ET; Mostertz, J; Keiser, M; Jia, J; Hubeny, A; Ulrich, A; Runge, D; Marinova, M; Lütjohann, D; Kroemer, HK; Siegmund, W

2013-01-01

Hypercholesterolemia frequently occurs in patients treated with efavirenz who cannot be treated adequately with statins because of drug interactions. These patients may benefit from cholesterol-lowering therapy with ezetimibe. This study determined the influence of single-dose and multiple-dose efavirenz (400 mg/day for 9 days) on the pharmacokinetics and sterol-lowering of ezetimibe (10 mg) in 12 healthy subjects. In addition, the influence of efavirenz on genome-wide intestinal expression and in vitro function of ABCB1, ABCC2, UGT1A1, and OATP1B1 was studied. Efavirenz (multiple dose) had no influence on the pharmacokinetics and lipid-lowering functions of ezetimibe. Intestinal expression of enzymes and transporters (e.g., ABCB1, ABCC2, and UGT1A1) was not affected by chronic efavirenz. Efavirenz (single dose) slightly increased ezetimibe absorption and markedly decreased exposure to ezetimibe-glucuronide (single dose and multiple dose), which may be explained by inhibition of UGT1A1 and ABCB1 (in vitro data). Ezetimibe had no effect on the disposition of efavirenz. Consequently, ezetimibe may be a safe and efficient therapeutic option in patients with HIV infection. PMID:22297387